UN US 20180296525A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0296525 A1 ROIZMAN et al. (43 ) Pub . Date: Oct. 18 , 2018 (54 ) TREATMENT OF AGE -RELATED MACULAR A61K 38 /1709 ( 2013 .01 ) ; A61K 38 /1866 DEGENERATION AND OTHER EYE (2013 . 01 ) ; A61K 31/ 40 ( 2013 .01 ) DISEASES WITH ONE OR MORE THERAPEUTIC AGENTS (71 ) Applicant: MacRegen , Inc. , San Jose , CA (US ) (57 ) ABSTRACT ( 72 ) Inventors : Keith ROIZMAN , San Jose , CA (US ) ; The present disclosure provides therapeutic agents for the Martin RUDOLF , Luebeck (DE ) treatment of age - related macular degeneration ( AMD ) and other eye disorders. One or more therapeutic agents can be (21 ) Appl. No .: 15 /910 , 992 used to treat any stages ( including the early , intermediate (22 ) Filed : Mar. 2, 2018 and advance stages ) of AMD , and any phenotypes of AMD , including geographic atrophy ( including non -central GA and Related U . S . Application Data central GA ) and neovascularization ( including types 1 , 2 and 3 NV ) . In certain embodiments , an anti - dyslipidemic agent ( 60 ) Provisional application No . 62/ 467 ,073 , filed on Mar . (e .g ., an apolipoprotein mimetic and / or a statin ) is used 3 , 2017 . alone to treat or slow the progression of atrophic AMD Publication Classification ( including early AMD and intermediate AMD ) , and / or to (51 ) Int. CI. prevent or delay the onset of AMD , advanced AMD and /or A61K 31/ 366 ( 2006 . 01 ) neovascular AMD . In further embodiments , two or more A61P 27 /02 ( 2006 .01 ) therapeutic agents ( e . g ., any combinations of an anti - dys A61K 9 / 00 ( 2006 . 01 ) lipidemic agent, an antioxidant, an anti- inflammatory agent, A61K 31 /40 ( 2006 .01 ) a complement inhibitor, a neuroprotector and an anti- angio A61K 45 / 06 ( 2006 .01 ) genic agent) that target multiple underlying factors of AMD A61K 38 / 17 ( 2006 .01 ) ( e . g . , formation of lipid - rich deposits , oxidative stress , local A61K 38 / 18 ( 2006 . 01 ) inflammation , cell death and neovascularization ) are used to A61K 39 /395 ( 2006 .01 ) treat or slow the progression of atrophic AMD ( including ( 52 ) U . S . CI. non - central GA and central GA ) or neovascular AMD ( in CPC ...... A61K 31/ 366 ( 2013 .01 ) ; A61P 27 / 02 cluding types 1 , 2 and 3 NV ) , and / or to prevent or delay the ( 2018 .01 ) ; A61K 9 /0048 ( 2013 .01 ) ; A61K onset of AMD , advanced AMD and /or neovascular AMD . 39 /3955 ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; Specification includes a Sequence Listing . Patent Application Publication Oct. 18 , 2018 Sheet 1 of 4 US 2018 /0296525 A1

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TREATMENT OF AGE - RELATED MACULAR 0004 ] The one or more therapeutic agents that can be DEGENERATION AND OTHER EYE used to treat AMD and other eye diseases and disorders DISEASES WITH ONE OR MORE include without limitation : THERAPEUTIC AGENTS [0005 ] 1 ) anti- dyslipidemic agents ; [0006 ] 2 ) PPAR - a agonists , PPAR -d agonists and PPAR -Y RELATED APPLICATIONS agonists ; [0007 ] 3 ) anti -amyloid agents and inhibitors of other toxic [0001 ] This application claims priority to and the benefit substances ( e . g . , aldehydes ) ; of U . S . Provisional Patent Application No . 62 /467 ,073 filed [0008 ] 4 ) inhibitors of lipofuscin or components thereof; on Mar. 3 , 2017 , which is incorporated herein by reference [ 0009 ] 5 ) visual /light cycle modulators and dark adapta in its entirety for all purposes . tion agents; [0010 ] 6 ) antioxidants ; BACKGROUND OF THE DISCLOSURE [0011 ] 7 ) neuroprotectors (neuroprotectants ) ; [0002 ] Age -related macular degeneration ( AMD ) affects [0012 ] 8 ) apoptosis inhibitors and necrosis inhibitors; about 14 - 24 % of the people aged 65 to 74 and about 35 % of [0013 ] 9 ) C - reactive protein inhibitors ; the people over 75 , and about 200 million people , around the [0014 ] 10 ) inhibitors of the complement system or com world , and is the leading cause of legal blindness in devel ponents ( e. g ., proteins) thereof; oped countries . AMD results in vision impairment or loss in [0015 ] 11 ) inhibitors of inflammasomes ; the center of the visual field ( the macula ) because of damage [ 0016 ] 12 ) anti - inflammatory agents ; to the retina . The two principal forms of AMD are atrophic 0017 ] 13 ) immunosuppressants ; ( non - exudative or " dry ” ) AMD and neovascular ( exudative [0018 ] 14 ) modulators ( inhibitors and activators ) ofmatrix or " wet " ) AMD . Atrophic AMD is characterized by geo metalloproteinases and other inhibitors of cell migration ; graphic atrophy (GA ) at the center of the macula in the [0019 ] 15 ) anti -angiogenic agents ; advanced stage of AMD , and vision can slowly deteriorate [0020 ] 16 ) laser therapies , photodynamic therapies and over many years due to loss of photoreceptors and devel radiation therapies; opment ofGA . Neovascular AMD is a more severe form of [ 0021] 17 ) agents that preserve or improve the health of AMD and is characterized by neovascularization ( e . g . , chor the endothelium and / or the blood flow of the vascular oidal neovascularization in the advanced stage of AMD , system of the eye ; and which can rapidly lead to blindness . Neovascular AMD f 0022 ] 18 ) cell ( e . g ., RPE cell ) replacement therapies . affects about 30 million patients worldwide and is a leading [0023 ] In some embodiments , an anti -dyslipidemic agent cause of vision loss in people aged 60 years or older if ( e . g . , an apo mimetic such as an apoA - I mimetic and /or an untreated , patients are likely to lose central vision in the apoE mimetic , and / or a statin ) is used in conjunction with an affected eye within 24 months of disease onset. About 85 % antioxidant, an anti - inflammatory agent, a complement of AMD patients have the dry form , and about 15 % develop inhibitor , a neuroprotector or an anti -angiogenic agent, or neovascular AMD . There is no approved treatment for any combination or all thereof, to treat or slow the progres atrophic AMD in the United States , while approved treat sion of atrophic AMD ( including central and non - central ments for neovascular AMD (primarily anti- angiogenic geographic atrophy ) and /or neovascular AMD ( including agents ) show efficacy in about 50 % of neovascular AMD types 1 , 2 and 3 neovascularization ) , and / or to prevent or patients . delay the onset of atrophic AMD or neovascular AMD . [0024 . Besides AMD , other eye diseases and disorders SUMMARY OF THE DISCLOSURE that can be treated with one or more therapeutic agents [0003 ] Thepresent disclosure provides for the treatment of described herein include without limitation maculopathy AMD and other eye diseases and disorders using one or ( e . g ., age - related maculopathy and diabetic maculopathy ) , more therapeutic agents . In certain embodiments , the one or macular edema ( e . g . , diabetic macular edema [DME ) and more therapeutic agents include an anti - dyslipidemic agent, macular edema following retinal vein occlusion ( RVO ]) , such as an apolipoprotein ( apo ) mimetic ( e . g ., an apoA - I retinopathy ( e . g . , diabetic retinopathy [ including in patients mimetic such as L - 4F or D -4F , and / or an apoE mimetic such with DME ]) , RVO ( e . g . , central RVO and branch RVO ) , as AEM - 28 - 14 ) and /or a statin ( e . g . , atorvastatin and /or Coats ' disease ( exudative retinitis ) , uveitis , retinal pigment simvastatin ) . The one or more therapeutic agents can be epithelium detachment, and diseases associated with selected to target different underlying factors of AMD or the increased intra - or extracellular lipid storage or accumula other eye disorder , where a particular therapeutic agent can tion in addition to AMD . target one or more underlying factors. In some embodi ments , AMD or the other eye disorder is treated with two or BRIEF DESCRIPTION OF THE DRAWINGS more therapeutic agents that target multiple underlying 0025 ]. A better understanding of features and advantages factors of AMD or the other eye disorder , such as formation of the present disclosure will be obtained by reference to the of lipid - rich deposits , formation of toxic byproducts , oxida following detailed description , which sets forth illustrative tion , inflammation , neovascularization and cell death . The embodiments of the disclosure , and the accompanying draw one or more therapeutic agents can be administered to treat, ings. e . g ., AMD in different stages ( including the early , interme 100261 FIG . 1 illustrates tissue layers involved in AMD diate and advanced stages ) of AMD and for different phe pathology and the role of lipid accumulation in AMD notypes of AMD ( including geographic atrophy and neo pathogenesis . OS : outer segment of photoreceptors ; RPE : vascular AMD ) , to prevent or slow the progression to the retinal pigment epithelium ; RPE - BL : RPE basal lamina ; next stage of AMD , and to prevent or delay the onset of ICL : inner collagenous layer ; EL : elastic layer ; OCL : outer AMD . collagenous layer ; ChC -BL : ChC basal lamina ; ChC : cho US 2018 /0296525 A1 Oct . 18 , 2018 riocapillaris endothelium ; BLamD : basal laminar deposit ; combined with any one or more of the other embodiments BLinD : basal linear deposit ; pre - BLinD : pre -basal linear described herein which are consistentwith that embodiment . deposit ; L : lipofuscin ; M : melanosome; ML : melanolipo 10033 ] Where elements are presented in list format ( e . g . , in fuscin ; Mt: mitochondria ; circles : lipoprotein particles. The a Markush group ) , it is understood that each possible sub Bruch ' s membrane (BrM ) consists of the ICL , EL and OCL . group of the elements is also disclosed , and any one or more BlamD is a thickening of the RPE -BL . Basal mound is soft elements can be removed from the list or group . druse material within BLamD . RPE cells contain melano [0034 ] It is also understood that, unless clearly indicated some, lipofuscin and melanolipofuscin , which provide sig to the contrary , in any method described or claimed herein nals for, e . g . , color fundus photography , fundus autofluo that includes more than one act, the order of the acts of the rescence and optical coherence tomography . method is not necessarily limited to the order in which the [0027 ] FIG . 2 shows the scoring of staining of neutral acts of the method are recited , but the disclosure encom lipids in and on the Bruch ' s membrane with oil red O (ORO ) passes embodiments in which the order is so limited . in the injected eye and the fellow non - injected eye of [0035 ] It is further understood that , in general, where an macaques receiving 6 monthly intravitreal injections of L -4F embodiment in the description or the claims is referred to as or placebo ( scrambled L -4F ) . Statistical analysis : 1 ) paired comprising one or more features , the disclosure also encom t - test between injected eyes and non - injected eyes in the passes embodiments that consist of , or consist essentially of, same group ; 2 ) unpaired t- test between injected eyes in the such feature ( s ) . treatment ( L -4F ) group and the control (placebo ) group . 0036 ] It is also understood that any embodiment of the [0028 ] FIG . 3 shows the intensity of staining of esterified disclosure , e . g ., any embodiment found within the prior art , cholesterol in the Bruch 's membrane with filipin in the can be explicitly excluded from the claims, regardless of injected eye and the fellow non - injected eye of macaques whether or not the specific exclusion is recited in the receiving 6 monthly intravitreal injections of L -4F or pla specification . cebo ( scrambled L -4F ) . Statistical analysis : 1 ) paired t- test [0037 ] It is further understood that the present disclosure between injected eyes and non - injected eyes in the same encompasses analogs , derivatives , prodrugs, fragments , group ; 2 ) unpaired t -test between injected eyes in the salts , solvates, hydrates , clathrates and polymorphs of all of treatment ( L - 4F ) group and the control (placebo ) group . the compounds/ substances disclosed herein , as appropriate . [0029 ] FIG . 4 shows the intensity of staining of the The specific recitation of “ analogs” , “ derivatives” , “ prod membrane attack complex (MAC , C5b - 9) in the Bruch 's rugs” , “ fragments ” , “ salts ” , “ solvates” , “ hydrates” , “ clath membrane and the choriocapillaris in the injected eye and rates” or “ polymorphs ” with respect to a compound/ sub the fellow non - injected eye of macaques receiving 6 stance or a group of compounds/ substances in certain monthly intravitreal injections of L -4F or placebo instances of the disclosure shall not be interpreted as an ( scrambled L -4F ) . Statistical analysis : 1 ) paired t -test intended omission of any of these forms in other instances between injected eyes and non - injected eyes in the same of the disclosure where the compound / substance or the group ; 2 ) unpaired t - test between injected eyes in the group of compounds/ substances is mentioned without reci tation of any of these forms. treatment ( L -4F ) group and the control (placebo ) group . 0038 Headings are included herein for reference and to [0030 ] FIG . 5 shows the intensity of staining of comple aid in locating certain sections. Headings are not intended to ment factor D in the injected eye and the fellow non - injected limit the scope of the embodiments and concepts described eye of macaques receiving 6 monthly intravitreal injections in the sections under those headings , and those embodiments of L - 4F or placebo ( scrambled L - 4F ) . Statistical analysis : 1 ) and concepts may have applicability in other sections paired t - test between injected eyes and non -injected eyes in throughout the entire disclosure . the same group ; 2 ) unpaired t -test between injected eyes in [0039 ] All patent literature and all non -patent literature the treatment ( L - 4F ) group and the control (placebo ) group . cited herein are incorporated herein by reference in their [0031 ] FIG . 6 shows the thickness of the Bruch ' s mem entirety to the same extent as if each patent literature or brane measured at the temporal outer macula in the injected non - patent literature were specifically and individually indi eye and the fellow non - injected eye of macaques receiving cated to be incorporated herein by reference in its entirety . 6 monthly intravitreal injections of L - 4F or placebo ( scrambled L - 4F ). Statistical analysis : 1 ) paired t- test I. DEFINITIONS between injected eyes and non - injected eyes in the same group ; 2 ) unpaired t - test between injected eyes in the [0040 ] As used in the specification and the appended claims, the indefinite articles “ a ” and “ an ” and the definite treatment ( L - 4F ) group and the control (placebo ) group . article “ the” can include plural referents as well as singular DETAILED DESCRIPTION OF THE referents unless specifically stated otherwise . [0041 ] The term “ exemplary ” as used herein means “ serv DISCLOSURE ing as an example , instance , or illustration " . Any embodi [ 0032 ] While various embodiments of the present disclo ment characterized herein as “ exemplary ” is not necessarily sure are described herein , it will be obvious to those skilled to be construed as preferred or advantageous over other in the art that such embodiments are provided by way of embodiments . example only. Numerous modifications and changes to , and [0042 ] The term “ about” or “ approximately ” means an variations and substitutions of, the embodiments described acceptable error for a particular value as determined by one herein will be apparent to those skilled in the art without of ordinary skill in the art , which depends in part on how the departing from the disclosure . It is understood that various value is measured or determined . In certain embodiments , alternatives to the embodiments described herein may be the term “ about” or “ approximately ” means within one employed in practicing the disclosure . It is also understood standard deviation . In some embodiments , when no particu that every embodiment of the disclosure may optionally be lar margin of error ( e . g ., a standard deviation to a mean value US 2018 /0296525 A1 Oct . 18 , 2018

given in a chart or table of data ) is recited , the term “ about” [0066 ] In other embodiments , amino acids may be or “ approximately ” means that range which would encom grouped as set out below : pass the recited value and the range which would be [0067 ] 1 ) hydrophobic : Met ( M ) , Ala ( A ) , Val (V ) , Leu included by rounding up or down to the recited value as well, ( L ) , Ile (I ) , Phe (F ), Trp ( W ); taking into account significant figures . In certain embodi [0068 ] 2 ) aromatic : Trp ( W ) , Tyr ( Y ) , Phe ( F ), His ( H ) ; ments, the term “ about” or “ approximately ” means within [0069 ] 3 ) neutral hydrophilic : Cys ( C ) , Ser ( S ) , Thr ( T ) , Asn ( N ) , Gln ( Q ) ; 20 % , 15 % , 10 % or 5 % of the specified value. Whenever the [0070 ] 4 ) acidic : Asp ( D ), Glu (E ); term “ about ” or “ approximately ” precedes the first numeri [0071 ] 5 ) basic : His ( H ) , Lys ( K ), Arg ( R ) ; and cal value in a series of two or more numerical values or in 10072 ] 6 ) residues that influence backbone orientation : a series of two or more ranges of numerical values , the term Gly (G ), Pro (P ) . “ about ” or “ approximately ” applies to each one of the [ 0073 ] The term “ pharmaceutically acceptable ” refers to a numerical values in that series of numerical values or in that substance ( e . g ., an active ingredient or an excipient ) that is series of ranges of numerical values . suitable for use in contact with the tissues and organs of a [0043 ] Whenever the term “ at least ” or “ greater than ” subject without excessive irritation , allergic response , precedes the first numerical value in a series of two or more immunogenicity and toxicity, is commensurate with a rea numerical values , the term “ at least" or " greater than ” sonable benefit/ risk ratio , and is effective for its intended applies to each one of the numerical values in that series of use . A “ pharmaceutically acceptable ” carrier or excipient of numerical values . a pharmaceutical composition is also compatible with the [0044 ] Whenever the term “ no more than ” or “ less than ” other ingredients of the composition . precedes the first numerical value in a series of two or more [ 0074 ] The term “ therapeutically effective amount ” refers numerical values , the term “ no more than ” or “ less than ” to an amount of a substance that, when administered to a applies to each one of the numerical values in that series of subject, is sufficient to prevent , reduce the risk of develop numerical values . ing , delay the onset of, or slow the progression of the [0045 ] The term “ antioxidants” includes without limita medical condition being treated ( e . g ., age - related macular tion substances that inhibit the oxidation of other substances , degeneration ( AMD )) , or to alleviate to some extent one or substances that retard the deterioration of other substances more symptoms or complications of that condition . The term by oxidation , and scavengers of free radical species, reactive " therapeutically effective amount" also refers to an amount oxygen species, hydroxyl radical species, and oxidized of a substance that is sufficient to elicit the biological or lipids and lipid peroxidation products . medical response of a cell , tissue , organ , system , animal or human which is sought by a researcher , veterinarian , medi [0046 ] The term “ apolipoprotein mimetics " encompasses cal doctor or clinician . apolipoprotein peptide mimetics and apolipoprotein mimetic [0075 ] The terms “ treat ” , “ treating” , and “ treatment” peptides. include alleviating or abrogating a medical condition or one [0047 ] The term " conservative substitution ” refers to sub or more symptoms or complications associated with the stitution of an amino acid in a polypeptide with a function condition , and alleviating or eradicating one or more causes ally, structurally or chemically similar natural or unnatural of the condition . Reference to " treatment” of a medical amino acid . In certain embodiments , the following groups condition ( e . g ., AMD ) includes preventing ( precluding ) , each contain natural amino acids that are conservative reducing the risk of developing , delaying the onset of, and substitutions for one another : slowing the progression of, the condition or one or more [ 0048 ] 1 ) Glycine (G ), Alanine ( A ) ; symptoms or complications associated with the condition . [ 0049 ] 2 ) Isoleucine (I ), Leucine (L ), Methionine (M ), 10076 ] The term “ medical conditions ” includes diseases Valine (V ), Alanine ( A ); and disorders . The terms“ diseases ” and “ disorders ” are used [0050 ] 3 ) Phenylalanine ( F ) , Tyrosine ( Y ) , Tryptophan interchangeably herein . ( W ) ; [0077 ] The term “ subject ” refers to an animal, including a [ 0051 ] 4 ) Serine ( S ) , Threonine ( T ) , Cysteine ( C ) ; mammal, such as a primate ( e . g ., a human , a chimpanzee , or [0052 ] 5 ) Asparagine ( N ) , Glutamine ( Q ) ; a monkey ) , a rodent ( e . g . , a rat , a mouse , a guinea pig , a [ 0053 ] 6 ) Aspartic acid ( D ) , Glutamic acid ( E ) ; and gerbil, or a hamster ) , a lagomorph ( e . g . , a rabbit ) , a swine [0054 ] 7 ) Arginine ( R ) , Lysine ( K ) . ( e .g ., a pig ) , an equine ( e . g ., a horse ) , a canine ( e. g . , a dog ) [ 0055 ]. In further embodiments, the following groups each and a feline ( e . g . , a cat) . The terms “ subject” and “ patient” contain natural amino acids that are conservative substitu are used interchangeably herein in reference , e . g ., to a tions for one another : mammalian subject, such as a human subject. [0056 ] 1) non -polar : Ala , Val, Leu , Ile ,Met , Pro , Phe, Trp ; [0078 ] The symbols “ ug” and “ ug ” are used interchange [0057 ] 2 ) hydrophobic : Val, Leu , lle , Phe ; ably herein to denote microgram ( s ). 10058 ] 3 ) aliphatic : Ala , Val , Leu , Ile ; II. PATHOGENESIS AND PATHOPHYSIOLOGY [0059 ] 4 ) aromatic : Phe , Tyr, Trp , His ; OF AMD [0060 ] 5) uncharged polar : Gly , Ser, Thr, Cys, Tyr, Asn , [ 0079 ] Age - related changes to the retina and the choroid Gln ; of the eye which contribute to the development of age related macular degeneration ( AMD ) include the loss of rod [ 0061] 6 ) aliphatic hydroxyl- or sulfhydryl- containing : photoreceptors , the thinning of the choroid , and the accu Ser, Thr, Cys; mulation of lipofuscin and reportedly components thereof 10062] 7 ) amide -containing : Asn , Gln ; ( e . g ., A2E [ N - retinylidene - N - retinyl- ethanolamine ]) in the [0063 ] 8 ) acidic : Asp , Glu ; retinal pigment epithelium (RPE ) as well as lipids in the [ 0064 ] 9 ) basic : Lys, Arg , His ; and sub -RPE basal lamina ( sub - RPE - BL ) space and the Bruch ' s [ 0065 ] 10 ) small : Gly , Ala , Ser , Cys. membrane (BrM , which is the inner wall of the choroid ) . US 2018 /0296525 A1 Oct . 18 , 2018

Lipoprotein particles and reportedly beta - amyloid (AB ) UC -rich lipoproteins apically . The formation of SDD in the accumulate to form basal linear deposits (BLinD ) on the subretinal space may also lead to sequelae such as inflam BrM . The RPE secretes apolipoprotein B ( apoB ) -lipoprotein mation and neovascularization (e .g ., type 2 or 3) . particles of abnormal composition into the BrM , where they [0082 ] FIG . 1 illustrates tissue layers involved in AMD accumulate with age and eventually form a lipid wall on the pathology and the role of lipid accumulation in AMD BrM . BLinD and drusen are believed to develop from such pathogenesis . The BrM consists of three layers : the inner a lipid wall. The lipid wall , and accumulation of abnormal collagenous layer (ICL ), the elastic layer (EL ) and the outer deposits resulting in part from abnormalities in proteolytic collagenous layer ( OCL ) . In healthy eyes, the RPE basal processes in regulating the BrM , stimulate chronic inflam lamina (RPE -BL ) is attached to the ICL of the BrM , and mation . The abnormal aggregates of material, combined there is no space between the RPE -BL and the ICL ( the with the loss of normal extracellular matrix ( ECM ) main sub - RPE - BL space is a " potential” space ) . Throughout tenance function ( partially mediated by altered ratios of adulthood RPE cells secrete lipoprotein particles ( circles in matrix metalloproteinases [MMPs ] and tissue inhibitors of FIG . 1 ) basally , which are dispersed in the ICL and the OCL MMPs [ TIMPs ]) , result in alterations in the BrM , with of the BrM ( the left -most panel in FIG . 1) . As more consequent formation of BLind and drusen . lipoprotein particles are secreted and accumulate over the [0080 ] Drusen are extracellular deposits rich in lipids years , they form pre - BLinD on the tightly packed ICL of the ( e . g . , esterifed cholesterol [ EC ] and phospholipids ) and BrM ( the second - from - left panel in FIG . 1 ) . Secretion and lipoprotein components ( e . g ., apoB and /or apoE ) and form accumulation of more lipoprotein particles over the years in the sub - RPE -BL space between the RPE -BL and the inner result in aggregation of the lipoprotein particles to form collagenous layer of the BrM , possibly as a result of RPE BLinD ( a layer ) on the BrM ICL and soft drusen (lumps ) secretion of EC - rich very low -density lipoproteins ( VLDLS ) ( the two middle panels in FIG . 1 ) . The formation of pre basolaterally . “ Hard ” drusen are small , distinct and far away BLind creates a space between the RPE - BL and the BrM from one another, and may not cause vision problem for a ICL (sub -RPE -BL space) , which increases with the forma long time, if at all. In contrast , “ soft ” drusen are large , have tion of BLinD and soft drusen and with a greater amount of poorly defined edges, and cluster closer together. Soft drusen them . The accumulation of lipid deposits , BLind and soft are more fragile than hard drusen , are oily upon dissection drusen , elevates the RPE off the BrM ICL ( the second - from due to a high lipid constitution , and are a major risk factor right panel in FIG . 1 ) , and if the elevation ( the sub - RPE -BL for the development of advanced atrophic or neovascular space ) is sufficiently large , the RPE - BL can become AMD . Esterified cholesterol and phospholipids ( in the form detached from the BrM ICL . For instance, drusenoid pig of lipoprotein particles of 60 - 80 nm diameter ) accumulate in ment epithelial detachment (PED ) can occur as a result of the BrM and the sub - RPE - BL space throughout adulthood formation of soft drusen with a diameter of about 350 and eventually aggregate as BLind on the BrM or soft microns or more . As drusen grow over time, RPE cells drusen in the sub -RPE - BL space of older eyes . Soft drusen become increasingly removed from their source of nutrients and BLinD are two forms ( a lump and a thin layer, respec and oxygen in the choriocapillaris . Some RPE cells on the tively ) of the same lipid - rich extracellular lesion containing top of drusen migrate anteriorly into the neurosensory retina lipoprotein - derived debris and specific to AMD . Lipid con to seek retinal vasculature , and the RPE layer breaks up as stituents of soft drusen and BLinD interact with reactive RPE cells die , resulting in atrophy of the RPE layer. Migra oxygen species to form pro - inflammatory peroxidized lipids tion or death of RPE cells can result in collapse of drusen ( or lipid peroxides ) , which inhibit paraoxonase 1 activity , because migrated or dead RPE cells no longer secrete lipids activate the complement system and elicit choroidal neo that feed drusen . Furthermore , the lipid barrier created by vascularization . Furthermore , drusen contain immunogenic BLinD and soft drusen blocks the exchange of incoming complement components . EC - rich , apoB /apoE -containing oxygen and nutrients ( including vitamin A ) and outgoing lipoproteins ( e . g ., VLDLs ) secreted by RPE cells are waste between the choriocapillaris and the RPE cells , which retained by a BrM that progressively thickens with age , until leads to RPE cell atrophy and then death . RPE cell atrophy an oily layer forms on the BrM , with oxidation of lipids or and death also result in the atrophy and death of photore other modifications followed by fusion of individual lipo ceptors as the RPE cells can no longer shuttle nutrients to the proteins over time to form BLinD . An inflammatory photoreceptors. In addition , BLinD on the BrM and soft response to the accumulated material ensues with activation drusen in the sub -RPE - BL space are rich sources of lipids of the complement system and other components of the that can be oxidized to form highly anti - inflammatory, and immune system . Moreover , by altering the BrM with sub thus pro - angiogenic , oxidized lipids such as oxidized phos sequent calcification and fracture , the accumulation of lipid pholipids . The biomechanically fragile cleavage plane cre containing material leads to neovascularization in the sub ated by BLinD and soft drusen are vulnerable to ramification RPE - BL space and breakthrough to the subretinal space , the by new blood vessels emanating from the choroid , crossing potential space between the photoreceptors and the RPE . the BrM , and infiltrating the sub -RPE -BL space in type 1 Furthermore , the lipid - rich drusen in the sub -RPE - BL space neovascularization (NV ) and breaking through to the sub and BLinD overlying the Brm block oxygen and nutrients retinal space in type 2 NV, which are described below . ( including vitamin A ) from reaching the RPE cells and the Leakage of fluid from the neovessels into the sub - RPE -BL photoreceptors ( rods and cones ) in the retina , which results space in types 1 and 2 NV further contributes to the volume in their atrophy /degeneration and eventually death . of the sub -RPE - BL space and the elevation of the RPE off [0081 ] Other extracellular lesions associated with AMD the BrM , and thereby can cause PED . include subretinal drusenoid deposits (SDD ), which are [0083 ] Chronic inflammatory responses to the changes compositionally distinct from drusen . SDD contain unest described above include complement-mediated pathways, erified ( free ) cholesterol (UC ) and form between the RPE infiltration by circulating macrophages , and activation of and photoreceptors , possibly as a result of RPE secretion of inflammasomes and microglia . Activation of the comple US 2018 /0296525 A1 Oct . 18 , 2018 ment cascade leads to activation of the central component 3 There are three types of neovascularization (NV ). Type 1 (C3 ) and initiation of the terminal pathway with the cleavage NV occurs in the sub -RPE -BL space , and new blood vessels of component 5 ( C5 ) into C5a and C5b . The terminal emanate from the choroid under the macular region . Type 2 pathway results in the assembly of a membrane attack NV occurs in the subretinal space above the RPE , and new complex (MAC ), e. g. , in the basal RPE membrane, the BrM blood vessels emanate from the choroid and break through or the choriocapillary endothelial cell membrane, by step to the subretinal space . In types 1 and 2 NV , new blood wise binding of C5b , C6 , C7 , C8 and polymerized C9 to vessels cross the BrM and may ramify in the pro - angiogenic form a pore in the lipid bilayer of the membrane . The MAC cleavage plane created by soft drusen and BLinD . Type 3 can lead to the dysfunction and death of the RPE , the BrM NV ( retinal angiomatous proliferation ) occurs predomi and / or the choriocapillary endothelium , with outer retinal nantly within the retina ( intraretinal) , but can also occur in atrophy ensuing . In addition , C5a elicits pro -angiogenic the subretinal space , and new blood vessels emanate from effects, and combined with calcification and fracture of the the retina with possible anastomoses to the choroidal circu BrM , can contribute to NV, including choroidal NV (CNV ). lation . Type 3 NV is the most difficult subtype of NV to [0084 ] The early stage of AMD (which is atrophic AMD ) diagnose and has the most devastating consequences in is characterized by the presence of a few medium - size termsof photoreceptor damage , but type 3 NV responds well drusen and pigmentary abnormalities such as hyperpigmen to treatment with an anti - VEGF agent. A neovascular AMD tation or hypopigmentation of the RPE . The intermediate patient can also have a mixture of subtypes of NV, including stage of AMD (which is atrophic AMD ) is characterized by type 1 plus type 2 , type 1 plus type 3 , and type 2 plus type the presence of at least one large druse , numerous medium 3 . The approximate occurrence of the different subtypes of size drusen , hyperpigmentation or hypopigmentation of the NV among newly presenting neovascular AMD patients is : RPE , and geographic atrophy (GA ) that does not extend to 40 % type 1 , 9 % type 2 , 34 % type 3 , and 17 % mixed (of the the center of the macula (non - central [ or para - central] GA ) . mixed , 80 % type 1 plus type 2 , 16 % type 1 plus type 3 , and GA represents the absence of a continuous pigmented layer 4 % type 2 plus type 3 ) . Another form of NV is polypoidal and the death of at least some portion of RPE cells . Non vasculopathy, which is of choroidal origin and is the most central GA spares the fovea and thus preserves central common form of NV among Asians , whose eyes generally vision . However, patients with non -central GA can experi have few drusen butmay have BLinD . The RPE can become ence visual disturbances such as paracentral scotomas , detached from the BrM in each subtype of NV . For instance , which can impair vision in dim light, decrease contrast leakage of fluid from neovessels into the sub -RPE - BL space sensitivity and impair reading ability . Sub -RPE - BL drusen in type 1 NV can result in pigment epithelium detachment. elevate the RPE off the BrM and thereby can cause mild The new blood vessels generated by NV are fragile , leading vision loss, including metamorphopsia ( a vision defect in to leakage of fluid , blood and proteins below the macula . which objects appear to be distorted ) through disturbance of Leakage of blood into the subretinal space is particularly overlying photoreceptors and slowing of rod -mediated dark toxic to photoreceptors , and intraretinal fluid signifies a poor adaptation . prognosis for vision . Bleeding and leaking from the new 10085 ] The advanced stage of AMD that remains atrophic blood vessels , with subsequent fibrosis , can cause irrevers AMD is characterized by the presence of drusen and GA that ible damage to the retina and rapid vision loss if left extends to the center of the macula (central GA ) . Central GA untreated . includes macular atrophy . Central GAinvolves the fovea and [ 0087 ] Modified lipids, including peroxidized lipids, can thus results in significant loss of central vision and visual be strongly pro - inflammatory and thus can be pro - angio acuity . RPE below the retina atrophies, which causes vision genic . Therefore , modification ( including oxidation ) of lip loss through the death of photoreceptors . RPE atrophy can ids can be an important step leading to the development of result from a large accumulation of drusen and /or BLind NV , including type 1 NV . For example , the modified lipids that contributes to the death of the overlying RPE , when the linoleate hydroperoxide and 7 -ketocholesterol can be pres drusen become thick and the RPE is far removed from the ent in and on the BrM and can stimulate NV . NV can be choriocapillaris . Drusen may include calcification in the regarded as a wound -healing process following inflamma form of hydroxyapatite , and may progress to complete tion . calcification , at which stage RPE cells have died . The [0088 ] Both eyes of a patient with AMD , whether atrophic RPE -BL thickens in a stereotypic manner to form basal or neovascular , typically are in a diseased state . However, laminar deposits (BLamD ) ; RPE cells hence reside on a one of the eyes typically is in a more diseased condition than thick layer of BLamD . Junctions between the normally the other eye . hexagonal -shaped RPE cells may be perturbed , and indi 100891 For a description of the different stages of AMD , vidual RPE cells may round up , stack and migrate anteriorly see, e. g ., R . Jager et al. , N . Engl. J. Med . , 358 : 2606 -2617 into the neurosensory retina , where the RPE cells are farther ( 2008 ) . The Age - Related Eye Disease Study (AREDS ) from their supply of nutrients and oxygen in the choriocap Research Group has also developed a fundus photographic illaris . Once RPE cells begin the anterior migration , the severity scale for AMD . See , e . g ., M . Davis et al. , Arch . overall RPE layer begins to atrophy . Ophthalmol. , 123 : 1484 - 1498 (2005 ) . [0086 ] The advanced stage of AMD that becomes neovas [0090 ) For discussions of the pathogenesis and patho cular AMD is characterized by neovascularization and any physiology of AMD , see, e . g ., C . A . Curcio et al. , The oil of its potential sequelae , including leakage ( e . g ., of plasma ) , spill in ageing Bruch membrane , Br. J . Ophthalmol. , 95 ( 12 ) : plasma lipid and lipoprotein deposition , sub -RPE -BL , sub 1638 - 1645 ( 2011 ) ; J. W . Miller , Age- Related Macular retinal and intraretinal fluid , hemorrhage , fibrin , fibrovascu Degeneration RevisitedPiecing the Puzzle , Am . J . Oph lar scars and RPE detachment. In CNV, new blood vessels thalmol. , 155 ( 1 ) : 1 - 35 ( 2013 ) ; R . Spaide et al. , Choroidal grow up from the choriocapillaris and through the BrM , neovascularization in age -related macular degeneration which causes vision loss via the aforementioned sequelae . what is the cause ?, Retina , 23 : 595 -614 ( 2003 ) ; and S . US 2018 /0296525 A1 Oct . 18 , 2018

Bressler et al. , Age -Related Macular Degeneration : Non increase lipid ( e . g . , cholesterol) efflux and activate lipopro neovascular Early AMD , Intermediate AMD , and Geo - tein lipase -mediated lipolysis of lipoproteins. A beneficial graphic Atrophy , in Retina , S . Ryan et al. , Eds. , pp . 1150 effect of increased lipoprotein lipase -mediated lipolysis of 1182 , Elsevier (London 2013) . lipoproteins can be , e. g ., reduced tissue availability of dietary -derived lipids , which may affect the upstream III . APOLIPOPROTEIN MIMETICS sources to RPE - derived lipoproteins that are secreted into [0091 ] As described above , age - related macular degenera the BrM , the sub -RPE -BL space and the subretinal space. tion ( AMD ) is a disease or disorder that has a variety of [ 0093 ] As an illustrative example , apoA - I mimetics such underlying factors. Three of the major factors of AMD are as those described herein ( e . g ., L - 4F and D - 4F ) can dissolve , formation of lipid - rich deposits , inflammation and neovas mobilize and remove accumulated extracellular , and poten cularization in the retina , the subretinal space , the sub -RPE tially intracellular, lipid deposits in the eye . For instance , BL space and the BrM . Formation of lipid -containing depos L - 4F and D - 4F may be able to remove intracellular lipids via its is one of the initial major factors that leads to sequelae the LDL receptor by forming pre - ß HDL particles. Lipid such as chronic inflammation , non - central and / or central deposits on the BrM form a lipid wall that acts as a diffusion geographic atrophy (GA ) of the retina , neovascularization barrier between the RPE and the choriocapillaris , promotes ( including CNV ) and ultimately central vision loss or legal the formation of basal linear deposits (BLinD ) and soft blindness . Lipid - scavenging apolipoprotein mimetics, drusen , and is implicated in local inflammation and oxida which also possess other beneficial properties such as anti tive stress . ApoA - I mimetics ( e . g ., L - 4F and D -4F ) can clear inflammatory , antioxidant and anti - angiogenic properties , lipid deposits from the BrM , thereby remodeling the BrM can be used to treat AMD and complications thereof. structure to a normal or healthier state and restoring the BrM [ 0092 ] Apolipoprotein peptide mimetics can effectively function , including reduced hydraulic resistivity and reduce the accumulation of lipid - rich deposits in the eye . increased metabolite and micronutrient exchange between Apolipoprotein ( apo ) mimetics can modulate ( e . g ., inhibit ) the choriocapillaris and the RPE , which improves RPE the production of lipoproteins ( e . g . , VLDLs ), modulate ( e . g . , health . In addition , apoA - I mimetics ( e . g . , L - 4F and D - 4F ) inhibit ) cellular uptake of plasma lipids (e . g. , cholesterol) can facilitate the efflux and clearance of lipids (e . g. , cho and lipoproteins ( e . g . , VLDLs ), mediate the clearance or lesterol and phospholipids ), lipoproteins and lipoprotein scavenging of lipids ( e . g . , cholesterol and oxidized lipids , components via the BrM into the choriocapillaris and sys such as oxysterols ) and lipoproteins ( e . g . , VLDLs) and temic circulation and ultimately to the liver for their metabo remnants thereof ( e . g . , low - density lipoproteins ( LDLs) and lism and excretion into the bile .Moreover , apoA - I mimetics chylomicron remnants ) , and inhibit the formation of lipid ( e . g ., L -4F and D -4F ) possess antioxidant and anti - inflam containing lesions. For example , apoE mimetics enhance the matory properties related to and independent of their lipid secretion of pre - B HDL - like , apoA - l - containing particles , clearing ability . For example , apoA - I mimetics ( e . g . , L -4F improve HDL function , induce lipid ( e . g . , cholesterol) efflux and D -4F ) can reduce local inflammation and oxidative ( e . g . , via ATP - binding cassette transporters such as ABCA1) stress by clearing lipid deposits from the BrM , BLinD and and reverse cholesterol transport, mediate the clearance of soft drusen . Furthermore , apoA - I mimetics ( e . g ., L - 4F and lipids ( e . g ., triglycerides and cholesterol) and pro - inflam - D -4F ) inhibit the oxidation of lipids and LDLs and hence the matory, apoB - containing lipoproteins (e .g ., VLDLs, LDLs formation of pro - inflammatory oxidized lipids and LDLs , and chylomicrons ) via hepatic uptake of VLDL - triglyceride scavenge lipid hydroperoxides from LDLs, and promote the ( TG ) and LDL -cholesterol , decrease the formation of lipid destruction of existing oxidized lipids ( e . g ., by enhancing containing lesions, have antioxidant properties ( e. g ., PON - 1 activity ) . For instance , apo A - I mimetics ( e . g . , L - 4F increase the activity of paraoxonase 1 [ PON - 1 ] , which inter and D -4F ) can protect phospholipids from oxidation by , e . g ., alia prevents LDL oxidation and catalyzes the hydrolysis of binding seeding molecules required for formation of pro oxidized phospholipids and lipid hydroperoxides , and inflammatory oxidized phospholipids, such as Ox - PAPC decrease the activity of myeloperoxidase , which generates ( PAPC is L - a - 1 - palmitoyl- 2 - arachidonoyl- sn - glycero - 3 reactive oxygen species and hypochlorous acid and whose phosphocholine ) , POVPC ( 1 -palmitoyl - 2 -[ 5 -oxovaleryl ] oxidation of apoA - I reduces HDL -mediated inhibition of sn -glycero - 3 -phosphocholine ), PGPC ( 1- palmitoyl- 2 - glu inflammation and apoptosis ) , have anti - inflammatory prop taryl - sn - glycero - 3 -phosphocholine ), and PEIPC erties ( e . g . , decrease the expression of pro - inflammatory ( 1 -palmitoyl - 2 - [ 5 ,6 -epoxyisoprostane E2] - sn - glycero - 3 cytokines such as TNF - a and IL - 6 ) , and have anti -angio phosphocholine ) . ApoA - I mimetics ( e . g . , L - 4F and D - 4F ) genic properties ( e . g ., inhibit the proliferation of vascular also have high affinity for pro - inflammatory oxidized lipids smooth muscle cells ). As another example , apo A -I mimetics ( e . g ., phospholipids , sterols and fatty acids ) as well as for induce the formation of nascent pre - ß HDL particles , unmodified lipids and mediate the removal of oxidized lipids enhance the functions of HDLs, promote lipid ( e . g ., choles and unmodified lipids . Moreover, apoA - I mimetics ( e . g ., terol) efflux ( e . g . , via ABC transporters such as ABCA1) and L - 4F and D - 4F ) have potent anti - inflammatory effects by , reverse cholesterol transport , reduce the formation of lipid e .g ., decreasing the production of pro -inflammatory cytok containing lesions ( in the eye and arterial intima ), have ines such as IL - 1ß and TNF - a , and increasing the expression antioxidant properties ( e .g . , stimulate PON - 1 activity and of heme oxygenase 1 (HMOX1 ) and thereby upregulating inhibit LDL oxidation ), and have anti - inflammatory proper the expression of anti- inflammatory IL - 10 and IL - 1 receptor ties ( e . g ., inhibit the expression of pro - inflammatory cytok antagonist ( IL - 1RA ) . Furthermore , apoA - I mimetics ( e . g . , ines such as TNF - a and IL - 1B and that of cell adhesion L - 4F and D -4F ) increase the expression of the antioxidant molecules such as CD11b and VCAM - 1 ) . As a further enzyme superoxide dismutase and stimulate the activity of example , apoA - V mimetics decrease VLDL - TG production paraoxonases ( e . g ., PON - 1 ) , which have anti - dyslipidemic , and stimulate lipoprotein lipase -mediated lipolysis of antioxidant and anti- inflammatory properties. In addition , VLDL - TG . As an additional example , apoC - II mimetics apo A -I mimetics (e . g. , L -4F and D -4F ) have anti -angiogenic US 2018 /0296525 A1 Oct . 18 , 2018 properties ( e. g ., inhibit the proliferation of vascular smooth hApoE , a sequence overlapping , encompassing or within muscle cells ) and anti - apoptotic properties ( e . g . , inhibit the that range [e . g. , residues about 131 - 162 or about 141- 150 ], expression of caspases ). The majority of AMD - associated or a variant thereof) . In further embodiments , apo mimetics lipid deposits are extracellular and accessible to lipid -clear - include polypeptides (including fusion proteins and chime ing apoA - I mimetics . Therefore , apoA - I mimetics ( e .g ., ras ) that comprise such lipid -binding , amphipathic a -helical L - 4F and D - 4F ) can be used at any stage of AMD , including domains of apolipoproteins or variants thereof, optionally from early - to advanced - stage AMD , to treat an important connected to an LDL receptor- binding region . upstream factor of AMD accumulation of lipid deposits 0102 ] Non - limiting examples of apoA - I mimetics include such as BlinD on the BrM and soft drusen in the sub - RPE 2F , 3F , 3F - 1, 3F - 2 , 3F - 14 , 4F (e . g ., L - 4F and D - 4F ) , 4F - P BL space and , through the removal of such deposits , to 4F , 4F - IHS - 4F , 4F2 , 5F , 6F , 7F , 18F , 5A , 5A - C1 , 5A -CH1 , inhibit or curtail downstream factors of AMD , such as local 5A -CH2 , 5A -H1 , 18A , 37pA ( 18A - P - 18A ), ELK (name ), inflammation and oxidative stress . ELK - 1A , ELK - 1F , ELK - 1K1A1E , ELK - 1L1K , ELK -1W , [ 0094 ] In some embodiments , apolipoprotein mimetics ELK -2A , ELK - 2A2K2E ( or ELK - 2K2A2E ) , ELK - 2E2K , include amphipathic a -helical domains of apolipoproteins ELK - 2F , ELK -3E3EK , ELK -3E3K3A , ELK - 3E3LK , ELK which bind to / associate with lipids ( e . g . , cholesterol) or lipid PA , ELK - P2A , ELKA (name ) , ELKA - CH2, ATI- 5261, complexes ( e . g . , VLDL - cholesterol and LDL - cholesterol) CS -6253 , ETC - 642 , FAMP (Fukuoka University apoA - I and are capable of removing / clearing lipids or lipid com mimetic peptide ) , FREL , KRES , ApoJ( 113 - 122 ) , ApoA - I plexes . In certain embodiments , lipid -binding , amphipathic Milano ( [R173C ]hAPoA - I ) , APOA - I Paris ( [R151C ] hAPoA a -helical domains of apolipoproteins include : I) , CGVLESFKASFLSALEEWTKKLQ -NH2 (monomer , [0095 ] 1 ) sequences from about amino acid (aa ) 209 to dimers and trimers ) (SEQ . ID . NO . 1 ) , DWLKAFYDK about aa 219 , sequences from about aa 220 to about aa 241, VAEKLKE (monomer , dimers and trimers ) ( SEQ . ID . NO . and sequences from about aa 209 to about aa 241 of 2 ), DWFKAFYDKVAEKFKE (monomer , dimers and trim wild -type (wt ) human apoA - I (hAPoA -I ) , sequences over ers ) (SEQ . ID . NO . 3 ), DWFKAFYDKVAEKFKEAF (4F ) lapping , encompassing or within those ranges, and variants (monomer , dimers and trimers ) (SEQ . ID . NO . 4 ), DWLKA thereof; FYDKVAEKLKEAFPDWLKAFYDKVAEKLKEAF [0096 ] 2 ) sequences from about aa 39 or 40 to about aa 50 , (SEQ . ID . NO . 5 ), DWLKAFYDKVAEKLKEFFPD sequences from about aa 51 to about aa 71 or 77 , sequences WLKAFYDKVAEKLKEFF (SEQ . ID . NO . 6 ) , DWFKA from about aa 39 or 40 to about aa 71 , and sequences from FYDKVAEKLKEAFPDWFKAFYDKVAEKLKEAF about aa 39 or 40 to about aa 77 of wt human apoA - II (SEQ . ID . NO . 7 ) , DKLKAFYDKVFEWAKEAFPD (hAPoA - II ) , sequences overlapping, encompassing or within KLKAFYDKVFEWLKEAF (SEQ . ID . NO . 8 ) , those ranges , and variants thereof; DKWKAVYDKFAEAFKEFLPDKWKAVYDK [0097 ] 3 ) sequences from about aa 7 to about aa 32 , FAEAFKEFL (SEQ . ID . NO . 9 ), DWFKAFYDKVAEK sequences from about aa 33 to about aa 53 , and sequences FKEAFPDWFKAFYDKVAEKFKEAF (4F - P -4F ) (SEQ . from about aa 7 to about aa 53 of wt human apoC - I ID . NO . 10 ), and the corresponding apoA - I mimetics having (hApoC - I ) , sequences overlapping , encompassing or within one or more , or all, D - amino acids ( e . g . , D - 4F having all those ranges, and variants thereof; D - amino acids ) and/ or the reverse order of amino acid [0098 ] 4 ) sequences from about aa 43 to about aa 55 of wt sequence ( e . g ., Rev - L -4F and Rev - D -4F ) . human apoC -II (hApoC - II ) , sequences overlapping, encom [0103 ] Non - limiting examples of apoE mimetics include passing or within that range, and variants thereof; Ac -hE18A -NH2 (AEM -28 , which contains an LDL recep [0099 ] 5 ) sequences from about aa 40 to about aa 67 of wt tor- /heparin -binding domain [apoE mimic ] and a lipid human apoC -III (hApoC - III ) , sequences overlapping , binding domain fapoA - I mimic ]) , AC - FR ] hE18A -NH , , encompassing or within that range, and variants thereof; and AEM - 28 -14 , EpK , hEp , mR18L , COG - 112 , COG - 133 , [0100 ] 6 ) sequences from about aa 203 to about aa 266 and COG - 1410 , hApoE ( 130 - 149 ) monomer and dimers ( includ sequences from about aa 244 to about aa 272 of wt human ing N -acetylated dimers ), hApoE ( 130 -159 ) monomer and apoE (hApoE ) , sequences overlapping , encompassing or dimers ( including N -acetylated dimers ) , hApoE (141 - 155 ) within those ranges ( e . g ., residues about 234 - 254 ) , and monomer and dimers ( including N - acetylated dimers ) , variants thereof. Ac - Y -hApoE ( 141 - 155 ) 2 - C , hApoE ( 202 -223 ) , hApoE ( 239 [0101 ] In some embodiments , an apo mimetic comprises 252 ), hApoE ( 245 - 266 ) , hApoE ( 263 - 286 ) and hApoE (268 two, three or more lipid -binding , amphipathic a -helical 289 ) . Examples of apoC - II mimetics include without limi domains linearly ( or tandem -wise ) or non - linearly attached tation C - II - a . to one another directly or indirectly via a linker or spacer [0104 ] The present disclosure encompasses the following group containing one ormore amino acid residues or a group apolipoprotein mimetic peptides : having multiple ( e . g . , two, three or more ) points of attach [0105 ] 1 ) apo mimetics in which all of the amino acid ment, such as in a tristar configuration . Such an apo mimetic residues have the L stereochemistry ; may have increased lipid affinity and ability to induce f0106 ] 2 ) apo mimetics in which one or more , or all , of the cholesterol efflux , for example , compared to the correspond amino acid residues have the D stereochemistry ; ing apo mimetic having only one lipid -binding , amphipathic [0107 ] 3 ) apo mimetics which have the reverse order of a - helical domain . To promote clearance of lipids ( e . g . , via amino acid sequence and in which all of the amino acid hepatic uptake of lipid - containing lipoproteins such as residues have the L stereochemistry ; VLDLs and LDLs ), in some embodiments an apo mimetic [ 0108 ] 4 ) apo mimetics which have the reverse order of comprises one or more lipid -binding , amphipathic a - helical amino acid sequence and in which one or more, or all , of the domains directly or indirectly (e . g. , via a linker) connected amino acid residues have the D stereochemistry; to a lipoprotein receptor- binding region , such as an LDL (0109 ] 5 ) multimers ( including dimers and trimers ) of an receptor -binding region ( e . g . , residues about 130 - 169 of wt apo mimetic in which two, three or more units of an apo US 2018 /0296525 A1 Oct . 18 , 2018 mimetic are linearly or non - linearly attached to one another inserted in , one or more amino acid residues are deleted directly or indirectly , including tandem repeats and multi from , or one or more natural and /or unnatural amino acids mers in which two , three or more units of an apo mimetic are are substituted ( conservative and / or non - conservative sub linearly or non - linearly attached to one another indirectly via stitutions) for one or more amino acid residues of, any ofthe a linker or spacer group containing one or more amino acid apo mimetics described herein , or any combination or all residues or a group having multiple ( e . g ., two, three ormore ) thereof. An unnatural amino acid can have the same chemi points of attachment such as in a tristar configuration , and cal structure as the counterpart natural amino acid but have including dimers and trimers in which two or three units of the D stereochemistry , or it can have a different chemical an apo mimetic are linearly attached to one another via a structure and the D or L stereochemistry . Unnatural amino linker or spacer group containing 1 - 3 or 1 - 6 (e . g ., one ) acids can be utilized , e . g . , to promote a -helix formation proline residue( s ) ; and /or increase the stability of the peptide ( e . g . , resist [0110 ] 6 ) apo mimetics comprising two , three or more proteolytic degradation ) . For example , D - 4F is resistant to different wild - type domains/ regions or variants thereof of intestinal peptidases and thus is suitable for oral use . the same apolipoprotein ( e . g . , apoA - I or apoE ) or different Examples of unnatural amino acids include without limita apolipoproteins ( e. g ., apo A - I and apoE ), wherein the two or tion proline analogs ( e . g ., CMePro [ a -MePro ]) , alanine more different domains/ regions may mediate two or more analogs ( e. g ., Q -ethylGly [Abu ), A -n -propylGly [Nva ) , different functions of the apolipoprotein ( s ) (e . g ., apoA - I a -tert -butylGly [ Tbg ], a -vinylgly [ Vig ], a -allylGly [ Alg ), and / or apo E ) and can be attached to one another in a similar C - propargylGly [ Prg ] , and 3 - cyclopropylAla [ Cpa ] ) , phe manner as described above for multimers of an apo mimetic ; nylalanine analogs { e .g ., Bip , Bip2EtMe [ Bip ( 2 - Et- 4 ' and OMe) ] , Nal( 1 ) , Nal( 2 ) , 2FPhe [Phe ( 2 - F ) ] , 2MePhe [Phe ( 2 [0111 ] 7 ) apo mimetics comprising in one compound two , Me) ] , Tmp, Tic , CMePhe [ a -MePhe ] , CMe2FPhe [ a -MePhe three or more different apo mimetics of the same category ( 2 - F )] , and CMe2MePhe [ a -MePhe (2 -Me ) ]} , tyrosine ( e . g . , apoA - I mimetics or apoE mimetics ) or different cat analogs (e . g ., Dmt and CMeTyr [ a -MeTyr ]) , glutamine egories [e . g ., apo A -I mimetic ( s ) and apoE mimetic (s ) ], analogs ( e . g . , citrulline [Cit ] ) , lysine analogs ( e . g , homolysin wherein the two or more different apo mimetics may mimic [hLys ] , ornithine [Orn ] and CMeLys [ a -MeLys ] ) , arginine different functional and /or structural aspects of the apolipo analogs ( e . g . , homoarginine ?hArg ] ) , a , a - disubstituted protein ( s ) ( e . g ., apo A - I and / or apoE ) and can be attached to amino acids ( e . g ., Aib , Ac3c [ Acp or Acpr) , Ac4c [ Acb ] , one another in a similar manner as described above for Ac5c [Acpe ], Ac6c [ Acx or Ach ], Deg [ a , a - diethylGly ), and multimers of an apo mimetic . 2 -Cha [ a - cyclohexylAla ]) , and other unnatural amino acids [0112 ] The apolipoprotein mimetics described herein can disclosed in US 2015 /031630 , WO 2014 / 081872 and A . have a protecting group at the N -terminus and /or the C - ter Santoprete et al. , J . Pept. Sci. , 17: 270 - 280 ( 2011 ) . One or minus . In some embodiments , the apo mimetics have an more peptidomimetic moieties can also be used in additions/ N - terminal protecting group that is an unsubstituted or insertions and / or substitutions. The variants can have a substituted C2- C20 or C2 -C1o acyl group ( e . g . , acetyl, pro protecting group at the N - terminus and /or the C - terminus, pionyl, butanoyl, pentanoyl , hexanoyl, octanoyl, decanoyl, such as an acyl (e .g ., acetyl) group at the N -terminus and / or lauroyl, myristoyl, palmitoyl, stearoyl or arachidoyl) , an an amide group [e .g ., - C ( O )NH2 ] at the C -terminus . In unsubstituted or substituted benzoyl group , a carbobenzoxy some embodiments , a biological or pharmacological activity group , an N -protected (e . g. , N -methyl ) anthranilyl group , or of a variant of an apo mimetic is enhanced relative to , or one or two unsubstituted or substituted C - Cmo or C , -C10 substantially similar to ( e . g . , not diminished by more than alkyl groups ( e . g ., one or two methyl, ethyl, propyl, butyl, about 10 % , 20 % or 30 % relative to ), that of the apo mimetic pentyl, hexyl, octyl, decyl , lauryl, myristyl, palmityl , stearyl with a native amino acid sequence . As a non - limiting or arachidyl groups ). Such groups can also be attached to the example , the disclosure encompasses a variant of 4F called C -terminus and /or one or more side chains . Furthermore, the 4F2 , which has the sequence DWFKAFYDKV - Aib - EK apo mimetics can have a functional group other than FKE - Aib - F (SEQ . ID . NO . 11 ) in which All and A17 are - CO , H at the C -terminus , such as a - C ( O )NH , or - C ( O ) substituted with a - aminoisobutyric acid (Aib ) . In certain NR ' R2 amide group , wherein Rl and R2 independently are embodiments , 4F2 has the structure AC -DWFKAFYDKV hydrogen , alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl, Aib -EKFKE - Aib - F -NH , (SEQ . ID . NO . 12 ) , where all the or R1 and R2 and the nitrogen atom to which they are amino acid residues have the L - form ( L - 4F2) , or one or connected form a heterocyclic or heteroaryl ring . An amide more , or all, of the amino acid residues have the D - form group at the C - terminus can be regarded as a protecting ( e .g ., D - 4F2 having all D -amino acid residues ). group at the C - terminus. Therefore, the disclosure encom [0114 ] Variants of the apoliprotein mimetics described passes apo mimetics having , e . g ., both an acetyl group at the herein also include analogs and derivatives of the apo N - terminus and a C ( O )NH , group at the C - terminus . mimetics that have another kind of modification alternative However, apo mimetics ( e . g . , L -6F ) that do not require to or in addition to an amino acid addition /insertion , deletion protection of the N - terminus and / or the C - terminus for their and / or substitution . As an example , variants of apo mimetics stability or activity can be produced by living organisms include fusion proteins and chimeras comprising a lipid ( e . g . , transgenic tomatoes ) , which can significantly decrease binding, amphipathic helical domain of an apolipoprotein or the cost of their production in large scale . a variant thereof ( e . g . , 4F ) which is directly or indirectly [0113 ] The disclosure also encompasses variants of the ( e . g ., via a linker ) attached to a heterologous peptide . The apoliprotein mimetics described herein , wherein the variants heterologous peptide can impart a beneficial property , such of the apo mimetics can comprise one or more amino acid as increased half- life . For instance , the heterologous peptide additions/ insertions , deletions and / or substitutions . In other can be an Fc domain of an immunoglobulin ( e . g . , an IgG , words , the disclosure encompasses variants in which one or such as IgG1) , or a modified Fc domain of an immuno more natural and /or unnatural amino acids are added to or globulin which has , e . g . , one or more amino acid substitu US 2018 /0296525 A1 Oct . 18 , 2018

tions or mutations that alter ( e . g ., reduce ) the effector are the main acceptors of cholesterol from peripheral cells . functions of the Fc domain . An Fc domain can be modified Non - limiting examples of phospholipids include those to have reduced ability , e . g ., to bind to an Fc receptor, described elsewhere herein . In certain embodiments , the one activate the complement system , stimulate an attack by or more phospholipids are or include one or more phospha phagocytic cells , or interfere with the physiological metabo tidylcholines , such as DMPC [ 1 , 2 - dimyristoyl- sn - glycero lism or functioning of retinal cells , or any combination or all 3 -phosphocholine ] , PLPC ( 1 - palmitoyl- 2 - linoleoyl- sn thereof. Inclusion of an Fc domain in a fusion protein or glycero - 3 - phosphocholine ) or POPC ( 1 -palmitoyl - 2 - oleoyl chimera can permit dimerization of the fusion protein or sn - glycero - 3 - phosphocholine ), or any combination or all chimera ( e . g . , via formation of an intermolecular disulfide thereof. Examples of reconstituted HDL mimetics include bond between two Fc domains ) , which may enhance the without limitation 4F /phospholipid (s ) complexes (e . g. , biological or pharmacological activity of the fusion protein 4F /DMPC complex , 4F /PLPC complex , and 4F /POPC com or chimera . Alternatively , a longevity - enhancing heterolo plex ) , 5A / phospholipid ( s ) complexes [ e . g ., 5A /DMPC com gous peptide can be , e . g . , a carboxy - terminal peptide (CTP ) plex , 5A /PLPC complex , 5AP (5A /POPC complex ), and derived from the beta chain of human chorionic gonadotro 5A / sphingomyelin - containing phospholipid ( s ) complexes] , pin , such as CTP -001 , CTP - 002 or CTP -003 as disclosed in 5A - CH1/ POPC complex , 37pA /phospholipid (s ) complexes, WO 2014 / 159813 . As another example, an apo mimetic , ELK -2A /DMPC complex , ELK - 2A /POPC complex , ELK such as an apo A - I mimetic ( e . g ., L -4F ) or an apoE mimetic 2A2K2E /POPC complex , ELKA -CH2 / POPC complex , ( e . g . , AEM - 28 - 14 ) , can be directly or indirectly ( e . g ., via a ETC -642 ( ESP - 2418 complexed with sphingomyelin ( SM ) linker ) attached to a natural or synthetic polymer ( e .g ., and 1 ,2 - dipalmitoyl- sn - glycero -3 -phosphocholine [DPPC ]) , polyethylene glycol [PEG ]) at the N - terminus, the C - termi hApoA - l/ phospholipid (s ) complexes , hAPoA - I /POPC disc nus and / or one or more side chains . PEGylation of an apo complex , CER - 001 ( recombinant hApoA - I complexed with mimetic (with , e .g ., about 2 -20 or 2 - 10 PEG units ) may sphingomyelin and dipalmitoyl phosphatidylglycerol increase the protease resistance , stability and half - life , [DPPG ]) , CSL - 111 (hAPoA - I/ soybean phosphatidylcholine reduce the aggregation , increase the solubility and enhance complex ) , CSL - 112 (hApoA - l/ phosphatidylcholine com the activity of the apo mimetic . As a further example , an apo plex ), ApoA - I Milano/ phospholipid ( s ) complexes ( e . g ., mimetic can be glycosylated ( comprise a carbohydrate or ETC - 216 [MDCO - 216 , ApoA - I Milano / POPC complex ]) , sugar moiety ) , such as an apoC - III mimetic containing one and ApoA - I Paris / phospholipid (s ) complexes ( e . g . , ApoA - I or more sialic acid residues . As an additional example , an Paris /POPC complex ) . apo mimetic can be phosphorylated . As an additional [0116 ]. In addition to or alternative to the use of an example , an apo mimetic can be complexed to a phospho apolipoprotein mimetic , an agent that increases the level of lipid (e . g . , L -4F complexed to DMPC or POPC ) . an apolipoprotein ( e . g . , apoE , apoA - I , apoA - V or apoC - II ) , [0115 ] Anti -dyslipidemic agents also include reconstituted e . g . , by stimulating its production , can be used . For example , high - density lipoprotein (rHDL ) mimetics comprising an agent that increases the level of apoA - I (e . g ., DMPC ) can hApoA - I or a variant thereof ( e . g . , a mutant and /or shortened be administered in addition to or alternative to the use of an construct thereof) , or an apoA - I mimetic , complexed with apo A - I mimetic . one or more phospholipids. ApoA - I is the main protein [0117 ] For discussions of apolipoprotein mimetic pep component of HDL particles. Such reconstituted HDL tides, including their biological properties, functions and mimetics can mimic nascent pre - B HDL and perform the actions, see , e . g ., G . Anantharamaiah et al . , Protein Pept. biological functions of HDL , including promoting efflux of Lett. , 23 : 1024 - 1031 ( 2016 ); W . D 'Souza et al ., Circ . Res ., cholesterol from cells ( e . g . , via ATP -binding cassette trans 107 :217 -227 ( 2010 ); Y . Ikenaga et al ., J. Atheroscler. porters such as ABCA1, ABCG1 and ABCG4) , incorpora Thromb. , 23 :385 - 394 (2016 ); C . Recio et al. , Front . Phar tion of cholesterol into HDL particles, and reverse transport macol. , 7 : 526 (2017 ) ; S . Reddy et al ., Curr. Opin. Lipidol. , of cholesterol from peripheral tissues to the liver for metabo 25 : 304 -308 (2014 ) ; O . Sharifov et al ., Am . J Cardiovasc . lism and biliary excretion of cholesterol. HDL also promotes Drugs, 11 :371 - 381 ( 2011 ); R . Stoekenbroek et al. , Handb . the clearance and destruction of oxidized lipids ( e . g . , by Exp . Pharmacol. , 224 :631 -648 (2015 ) ; Y . Uehara et al. , transporting them to the liver for metabolism and excretion Circ . J ., 79 : 2523 -2528 ( 2015 ) ; and C . White et al. , J . Lipid and by enhancing PON - 1 activity ) , and possesses other Res ., 55 : 2007 -2021 (2014 ). antioxidant, anti - inflammatory and anti- apoptotic proper [0118 ] Apolipoprotein mimetic peptides can be prepared ties. Therefore , reconstituted HDL mimetics can clear and according to procedures known to those of skill in the art. As destroy oxidized lipids and inhibit , e . g . , the production of a non - limiting example , apo mimetics and salts thereof can reactive oxygen species , the oxidation of LDL , the expres be prepared by sequentially condensing protected amino sion of pro - inflammatory cytokines and cell adhesion mol acids on a suitable resin support and removing the protecting ecules, and apoptosis . Reconstituted HDL mimetics can also groups, removing the resin support, and purifying the prod comprise hAPoA - II or a variant thereof ( e . g . , a mutant ucts by methods known in the art. Solid -phase synthesis of and / or shortened construct thereof) , or an apoA - II mimetic , peptides and salts thereof can be facilitated through the use alternative to or in addition to hAPoA - I or a variant thereof, of, e . g . , microwave , and can be automated through the use or an apoA - I mimetic . APOA - II is the second most abundant of commercially available peptide synthesizers . Solid - phase protein in HDL particles . In certain embodiments , reconsti synthesis of peptides and salts thereof is described in , e . g . , tuted HDL mimetics are discoidal or disc - shaped . Mature J . M . Palomo , RSC Adv . , 4 : 32658 - 32672 ( 2014 ) ; M . HDL particles destined for the liver are spherical and Amblard et al . , Mol. Biotechnol. , 33 ( 3 ) :239 - 254 ( 2006 ) ; and develop through the formation of intermediate discoidal M . Stawikowski and G . B . Fields, Curr. Protoc. Protein Sci. , HDL particles or lipid - poor pre- ß HDL particles, which are Unit 18 . 1 : Introduction to Peptide Synthesis ( 2012 ) . Pro particularly effective in inducing cholesterol efflux via inter tecting groups suitable for the synthesis of peptides and salts action of apo A -I with ABC transporters such as ABCA1 and thereof are described in , e. g ., P. Wuts and T. Greene, US 2018 /0296525 A1 Oct . 18 , 2018

Greene' s Protective Groups in Organic Synthesis , 4th Ed ., lipids with a greater affinity than apoA - I itself and reduces John Wiley and Sons (New York 2006 ). Methods for puri lipid deposits , e . g . , in the sub -RPE - BL space and on the fying peptides and salts thereof include without limitation Bruch ' s membrane (BrM ) . L - 4F is a potent lipid acceptor crystallization , column (e . g ., silica gel ) chromatography, and scavenger that removes extracellular lipids ( and poten high -pressure liquid chromatograpy ( including reverse tially intracellular lipids) , including neutral lipids, esterified phase HPLC ), hydrophobic adsorption chromatography , cholesterol and phospholipids, from , e . g . , the BrM and the silica gel adsorption chromatography, partition chromatog sub -RPE - BL space, thereby improving , e . g. , the BrM struc raphy, supercritical fluid chromatography, counter -current ture ( e . g . , reducing the thickness and normalizing the layer distribution , ion exchange chromatography, and ion arrangement of the BrM ) and the BrM function ( e . g . , exchange using basic and acidic resins . decreasing hydraulic resistivity of the BrM and increasing metabolite and micronutrient exchange between the RPE IV . TREATMENT OF AMD USING AN and the choriocapillaris , including facilitating multimolecu APOLIPOPROTEIN MIMETIC lar complexes carrying such nutrients ) . Extracellular age [ 0119 ] Some embodiments of the disclosure relate to a related lipid deposits at , e . g ., the BrM form a hydrophobic method of treating age - related macular degeneration diffusion barrier that causes oxidative stress and inflamma ( AMD ) , comprising administering to a subject in need of tion in , e . g . , the RPE and the retina , and removal of such treatment a therapeutically effective amount of an apolipo lipid deposits by L -4F curtails such oxidative stress and protein ( apo ) mimetic or a pharmaceutically acceptable salt inflammation . thereof. In some embodiments , the apo mimetic is admin [0124 ] L -4F possesses additional beneficial properties . istered locally to , into , in or around the eye in a dose from For instance, L -4F exhibits a strong anti- inflammatory prop about 0 . 1 or 0 . 3 mg to about 1 . 5 mg per administration ( e . g . , erty , due in part to its high - affinity binding to pro - inflam per injection ), and / or in a total dose from about 0 . 5 or 1 mg matory oxidized lipids ( e . g ., oxidized phospholipids) and to about 10 mg over a period of about 6 months . fatty acid hydroperoxides and its clearance of such oxidized [0120 ] The apo mimetic or a salt thereof is used in a lipids. L -4F can also enhance the ability of HDL - cholesterol substantially pure form . In certain embodiments, the apo to protect LDL -cholesterol from oxidation , thereby curtail mimetic or a salt thereof has a purity of at least about 90 % , ing the formation of pro - inflammatory oxidized lipids. Fur 95 % , 96 % , 97 % , 98 % or 99 % ( e . g ., at least about 95 % or thermore , L - 4F inhibits complement activation and reduces 98 % ) . The apo mimetic or a salt thereof can be purified , that the levels of complement factor D and the membrane attack is , substantially free from undesired chemical or biochemi complex , which can be additional reasons for its antioxidant cal components resulting from its preparation or isolation and anti - inflammatory properties and can result from its that are unsuitable for use in a pharmaceutical formulation , inhibition of downstream effects of lipid deposition . In or having a level of such undesired chemical or biochemical addition , L - 4F has anti -angiogenic property . Extracellular components sufficiently low so as not to prevent use of the lipid - rich deposits in the sub -RPE -BL space provide a apo mimetic in a pharmaceutical formulation . biomechanically fragile , pro - inflammatory milieu into 10121] Non -limiting examples of apolipoprotein mimet which new blood vessels can enter and propagate , unim ics, including apoA - I mimetics and apoE mimetics, include peded by RPE basal lamina connections to the rest of the those described elsewhere herein . In some embodiments , the BrM . Removal of such lipid deposits by L -4F can close up apo mimetic includes , or is , an apoE mimetic . In certain or substantially reduce this pro -angiogenic cleavage plane . embodiments , the apoE mimetic includes , or is , AEM -28 - 14 10125 ]. In a study conducted on a macaque model of or a variant or a pharmaceutically acceptable salt thereof . human early AMD and described below , L - 4F demonstrated [0122 ] In further embodiments , the apo mimetic includes, an effective ability to scavenge neutral lipids and esterified or is, an apoA - I mimetic alternative to or in addition to an cholesterol, to rejuvenate / normalize the BrM , and to curtail apoE mimetic ( e .g ., AEM -28 - 14 ) . In certain embodiments , downstream effects of lipid deposition such as complement the apoA - I mimetic includes, or is , 4F or a variant or a activation and local inflammation . L -4F also appeared to pharmaceutically acceptable salt ( e . g . , acetate salt ) thereof. effectively scavenge phospholipids , a major source of pro In some embodiments , all the amino acid residues of 4F inflammatory oxidized lipids, although staining for phos have the L stereochemistry ( L - 4F ) . In other embodiments , pholipids was not done in the study . The results of the one or more , or all, of the amino acid residues of 4F have the macaque study are expected to be translatable to all stages D stereochemistry ( e . g . , D - 4F having all D - amino acids ) . In and forms of AMD in humans in which extracellular lipid yet other embodiments , the apo mimetic has the reverse deposits play a pathological role , including early AMD , order of amino acid sequence of 4F ( e . g . , Rev - L - 4F or intermediate AMD and advanced AMD , and including atro Rev - D -4F ). The apo mimetic can have a protecting group at phic AMD and neovascular AMD . In humans , oil red the N - terminus and / or the C - terminus, such as an acyl ( e . g ., O -binding neutral lipids greatly accumulate in the macular acetyl) group at the N -terminus and / or an amide group ( e . g . , BrM and the sub -RPE - BL space throughout adulthood and - C ( O )NH , ) at the C - terminus . In certain embodiments , the are components of drusen , and esterified cholesterol and apo mimetic includes, or is , L - 4F having the structure phospholipids (in the form of lipoprotein particles of 60 - 80 AC -DWFKAFYDKVAEKFKEAF -NH2 ( SEQ . ID . NO . 13 ) . nm diameter ) also greatly accumulate in the macular BrM When folded into the appropriate secondary structure , L - 4F and the sub - RPE - BL space throughout adulthood and even is an amphipathic a -helix that has opposing polar and tually aggregate as BLinD on the BrM or soft drusen in the hydrophobic faces and mimics apoA - I, the predominant sub -RPE - BL space of older eyes. Drusen are rich in esteri apolipoprotein of HDL . fied cholesterol and phospholipids , attributed to the core and [0123 ] The apo A - I mimetic 4F , including L - 4F and D -4F , the surface , respectively , of RPE - secreted lipoproteins. Fur possesses anti - dyslipidemic properties . For example , L -4F is thermore , because lipoproteins ( both native and modified ) in capable of binding both oxidized lipids and unoxidized drusen are not bound to structural collagen and elastin US 2018 /0296525 A1 Oct . 18 , 2018

fibrils, unlike lipoproteins in the BrM , the former are more reduces the amount of native lipids available for modifica loosely bound than the latter and hence are easier to remove. tions such as peroxidation . Modified lipids, including per Therefore , the great reduction of filipin -binding esterified oxidized lipids, can be strongly pro - inflammatory and thus cholesterol and oil red O -binding neutral lipids from the can stimulate NV. L -4F can also scavenge any peroxidized BrM in themacaque study demonstrates the ability of L -4F lipids and other modified lipids formed . Furthermore, by to effectively reduce soft drusen and scavenge lipids, includ reducing the bulk size of drusen , L - 4F can prevent the ing neutral lipids and esterified cholesterol, from eye tissues , migration of RPE cells away from the oxygen - and nutrient including the BrM . Although the RPE has active proteases , intravitreally injected L - 4F readily crossed the RPE and transporting choriocapillaris and hence their secretion of reached the BrM , and effectively removed lipid deposits distress - induced VEGF, a potent stimulus of NV . Moreover , from the BrM in the macaque study. Removal of lipid normalization of the BrM as a result of removal of lipid deposits from the BrM by L -4F normalizes the structure and deposits from the BrM by L - 4F suppresses choroidal NV by function of the BrM . In addition , reduction of drusen volume reinforcing the natural barrier between the choriocapillaris by L -4F can decrease elevation of the RPE layer off the BrM and the sub - RPE - BL space . Therefore, through its ability to and thereby can reduce metamorphopsia , and can prevent , scavenge native lipids and modified ( e . g ., oxidized ) lipids , delay the onset of or slow the progression of non - central or L - 4F can prevent or curtail NV, including type 1 NV, and can central geographic atrophy and thereby can improve vision . improve the treatment of neovascular AMD , and reduce the Reduction of drusen volume in humans can be readily treatment burden , with anti -angiogenic agents , including quantified using spectral domain optical coherence tomog intravitreally injected anti - VEGF agents . raphy (SDOCT ) and commercially available software . [0129 ] In some embodiments , a single apo mimetic ( e . g ., [ 0126 ] By reducing lipid deposits , L -4F can maintain or an apo A - I mimetic such as L - 4F or an apoE mimetic such as improve the health of the RPE and thereby can prevent or AEM - 28 -14 ) is used to treat dry or wet AMD . The single apo forestall RPE atrophy, including in non - central and central geographic atrophy . Soft drusen and drusenoid pigment mimetic may mediate two or more different functions , such epithelial detachments ( PED ) grow over time because RPE as reduce lipid deposits and inhibit oxidation and inflam cells continue to secrete lipoproteins. The RPE layer over mation . In other embodiments , a combination of two , three the drusen and drusenoid PED roughens over time, and RPE or more different apo mimetics of the same category ( e . g . , cells migrate out of the RPE layer and anteriorly into the apo A - I mimetics or apoE mimetics ) or different categories neurosensory retina , preferentially over the apices , where [ e . g ., apoA - I mimetic ( s ) and apoE mimetic ( s ) ] is used to the RPE cells are farther from the choriocapillaris and thus treat dry or wet AMD . The two or more different apo seek oxygen from the retinal circulation . By removing mimetics may mediate two or more different functions, such native and modified lipids from drusen , L - 4F can prevent the as reduce lipid deposits and inhibit oxidation and inflam anterior migration of RPE cells and thereby can keep RPE mation . cells sufficiently close to the choriocapillaris so that RPE 0130 ] In some embodiments , the apo mimetic ?e . g ., an cells are not energetically and metabolically decompensated apo A -I mimetic ( e. g ., L - 4F ) and /or an apoE mimetic (e . g. , and hence do not atrophy. Furthermore , removal of lipid AEM -28 - 14 ) ] is administered locally in a dose of about deposits from the BrM improves the transport of incoming 0 .1 -0 . 5 mg, 0 .5 - 1 mg or 1- 1. 5 mg per administration ( e. g ., oxygen and micronutrients ( including vitamin A ) and out per injection ) . In further embodiments , the apo mimetic going waste between the choriocapillaris and the RPE . By [ e . g . , an apoA - I mimetic ( e . g . , L -4F ) and /or an apoE reducing drusen and removing lipid deposits from the BrM , mimetic (e .g ., AEM - 28 - 14 )] is administered locally in a L -4F can maintain RPE health and forestall RPE atrophy , dose of about 0 . 1 - 0 . 3 mg, 0 . 3 - 0 . 5 mg, 0 . 5 - 0 .75 mg, 0 . 75 - 1 and thereby can preserve photoreceptors and vision . Health mg, 1 - 1. 25 mg or 1 .25 - 1 . 5 mg per administration ( e .g ., per of the RPE overlying drusen can be monitored by SDOCT injection ) . The apo mimetic can also be administered locally of the macula . in a dose greater than 1 . 5 mg per administration ( e . g . , per [0127 ] Reduction of lipid deposits had downstream ben injection ) , such as up to about 2 mg or more per adminis efits in the macaque study , including a great decrease in the tration ( e . g ., per injection ) . In certain embodiments , the apo number of membrane attack complexes (MAC ) present in mimetic [ e . g . , an apoA - I mimetic ( e . g ., L -4F ) and / or an the BrM and the choriocapillaris . The MAC (C5b - 9 ) is the apoE mimetic ( e . g ., AEM - 28 - 14 ) ] is administered locally in final product of activation of the complement system , and a dose of about 0 . 1 - 0 .5 mg or 0 .5 - 1 mg per administration builds up in the BrM -choriocapillaris complex during a ( e . g . , per injection ). person ' s lifespan , starting in childhood . By decreasing the [0131 ] In further embodiments , the apo mimetic [e .g ., an level of MAC , L -4F can improve the health of the BrM and apoA - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g . , the choriocapillaris endothelium , and thereby can improve AEM - 28 - 14 ) ] is administered locally in a total or cumulative the blood supply to the outer retina and oxygen and micro dose of about 0 .5 or 1 -5 mg or 5 - 10 mg over a period of nutrient exchange between the choriocapillaris and the RPE about 6 months. In some embodiments , the apo mimetic and can promote the clearing of lipoprotein particles [ e . g ., an apoA -I mimetic ( e . g . , L -4F ) and /or an apoE secreted by the RPE into the systemic circulation . mimetic ( e. g. , AEM - 28 -14 ) ] is administered locally in a total [0128 ] In addition , by removing lipids L - 4F can prevent or or cumulative dose of about 0 . 5 or 1 - 3 mg, 3 - 5 mg, 5 - 7 . 5 mg forestall neovascularization (NV ) . Basal linear deposits and or 7 . 5 - 10 mg over a period of about 6 months . The apo soft drusen are major sources of potentially pro - inflamma mimetic can also be administered locally in a total or tory lipids in the sub -RPE -BL space where type 1 NV, the cumulative dose greater than 10 mg over a period of about most common type of NV , occurs . Removal of native lipids, 6 months , such as up to about 15 mg or more over a period including esterified cholesterol in lipoprotein deposits, from of about 6 months . In certain embodiments , the apo mimetic eye tissues by L -4F , as demonstrated in the macaque study, [ e .g ., an apo A - I mimetic (e . g. , L -4F ) and /or an apoE US 2018 /0296525 A1 Oct . 18 , 2018 mimetic ( e . g ., AEM -28 - 14 ) ] is administered locally in a total tion or implantation in the eye of genetically engineered or cumulative dose of about 0 .5 -3 mg or 3 -5 mg over a cells (e . g. , RPE cells containing an expression vector that period of about 6 months. includes a gene encoding the apo mimetic ) or a viral ( e . g . , [0132 ] In still further embodiments , the apo mimetic [ e. g. , adenoviral or lentiviral) vector containing a gene or expres an apoA - I mimetic ( e . g . , L - 4F ) and / or an apoE mimetic sion construct ( e . g ., a plasmid ) that expresses the apo ( e . g . , AEM - 28 - 14 ) ] is administered locally in a total or mimetic . Such a delivery method would have the benefit of cumulative dose of about 1 or 2 - 20 mg or 5 - 15 mg for the requiring an injection or implant of the apo mimetic - encod whole or entire treatment regimen . In certain embodiments , ing expression construct in the eye only one or two times. If the apo mimetic [ e . g . , an apoA - I mimetic ( e . g . , L - 4F ) and /or two or more apo mimetics ( e . g . , an apoA - I mimetic ( e . g . , an apoE mimetic ( e . g ., AEM - 28 - 14 ) ] is administered locally L -4F ) and an apoE mimetic ( e . g ., AEM - 28 - 14 ) ] are utilized , in a total or cumulative dose of about 1 -5 mg , 5 - 10 mg, the same expression construct or different expression con 10 - 15 mg or 15 - 20 mg for the entire treatment regimen . In structs can express the two or more apo mimetics . some embodiments , the apo mimetic [ e . g . , an apoA - I [0134 ] In embodiments where the apo mimetic [ e . g . , an mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g ., AEM apo A -I mimetic (e . g. , L -4F ) and /or an apoE mimetic (e . g. , 28 - 14 ) ) is administered locally in a total or cumulative dose AEM -28 - 14 )] is administered locally to , into , in or around of about 1 - 3 mg, 3 - 5 mg, 5 - 7 . 5 mg, 7 . 5 - 10 mg, 10 - 12 . 5 mg, the eye , the dose per administration , the total dose over a 12 . 5 - 15 mg, 15 - 17 . 5 mg or 17 . 5 - 20 mg for the entire period of about 6 months, and the total dose for the whole treatment regimen . The apo mimetic can also be adminis treatment regimen are per administered eye in certain tered locally in a total or cumulative dose greater than 20 mg embodiments and for both eyes in other embodiments . The for the entire treatment regimen , such as up to about 25 mg, blood system may allow some amount ( e . g . , a therapeuti 30 mg, 40 mg, 50 mg or more for the entire treatment cally effective amount) of the apo mimetic locally admin regimen . In certain embodiments , the apo mimetic [ e . g . , an istered ( e . g . , injected ) into or in one eye to be distributed to apoA - I mimetic ( e . g ., L -4F ) and /or an apoE mimetic ( e .g ., the other eye, in which case the dose of the apo mimetic can AEM - 28 - 14 )] is administered locally in a total or cumulative optionally be adjusted (e .g . , increased ) to take into account dose of about 1 - 5 mg or 5 - 10 mg for the entire treatment the other eye (which may be in a less diseased condition ) , regimen . and which may allow both eyes to be treated with the apo [ 0133] In some embodiments , the apo mimetic [ e. g ., an mimetic at the same time without an additional administra apo A - I mimetic ( e . g ., L - 4F ) and /or an apoE mimetic ( e . g ., tion ( e . g ., injection ) of the apo mimetic into or in the other AEM - 28 - 14 ) ] is administered locally to , into , in or around eye . For example , an intravitreally injected apo mimetic can the eye . In some embodiments , the apo mimetic [ e . g ., an move with the natural fluid flow from the vitreous humor apo A - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g ., toward the choroid via the retina and the RPE and cross the AEM - 28 - 14 ) ] is administered by injection ( e . g . , intravitreal, blood - retinal barrier (maintained by the retinal vascular subconjunctival , subretinal or sub - Tenon ' s injection ), eye endothelium and the RPE ) to reach two of the target areas , drop or implant ( e . g . , intravitreal, intraaqueous, subretinal or the sub -RPE - BL space and the Bruch ' s membrane , from sub - Tenon ' s implant ) . In certain embodiments , the apo where the apo mimetic may enter the choriocapillaris and mimetic [ e . g ., an apoA - I mimetic ( e . g ., L -4F ) and /or an ultimately the fellow non -administered eye . Also without apoE mimetic ( e . g ., AEM - 28 - 14 ) ] is administered by injec intending to be bound by theory , some amount of the apo tion ( e . g . , intravitreal, subconjunctival, subretinal or sub mimetic may enter the fellow non -administered eye by way Tenon 's injection ) . An intravitreally injected apo mimetic of the aqueous humor, which drains via the trabecular can readily reach target sites such as the sub - RPE - BL space meshwork and Schlemm 's canal that flows into the blood and the BrM from the vitreous cavity . In doing so , the apo system . Accordingly , some embodiments relate to a method mimetic can be distributed in different tissue layers of the of treating AMD , comprising administering to a subject in eye , such as the neurosensory retina , the Brm and the need of treatment a therapeutically effective amount of an choroid . The apo mimetic can have a long duration of action apo mimetic, wherein the apo mimetic is administered ( e . g . , at least about 2 , 3 or 4 weeks or longer ) through , e . g . , locally to , into , in or around one eye and has a therapeutic a continuous and slow re - supply or “ washout ” from the effect in both eyes. various tissue layers between the inner and outer retinal [0135 ] In certain embodiments , the apo mimetic [ e . g ., an layers in which the apo mimetic can be distributed . In further apoA - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g . , embodiments , the apo mimetic [ e . g ., an apoA - I mimetic AEM - 28 - 14 ) ] is administered locally to , into , in or around ( e . g . , L - 4F ) and / or an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is the eye in the initial phase of treatment, and then the apo administered by eye drop . In additional embodiments , the mimetic is administered systemically . As a non - limiting apo mimetic [ e . g . , an apoA - I mimetic ( e . g . , L - 4F ) and /or an example , the initial administration ( s ) ( e . g . , the first one to apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is administered by five administrations ) of the apo mimetic can be local via implanting in or injecting into , e . g ., the vitreal chamber, the injection ( e . g . , intravitreal, subconjunctival, subretinal or space below the retina or the aqueous humor devices or sub - Tenon ' s injection ) , and then subsequent administration systems that deliver the apo mimetic in a controlled and /or ( s ) of the apo mimetic can be systemic , such as oral , sustained manner, such as microdevices , polymeric parenteral ( e . g ., subcutaneous , intramuscular or intrave implants , bioabsorbable polymeric materials , bioabsorbable nous ), or topical ( e . g ., intranasal or pulmonary ) . In other ( e . g ., polymeric ) microparticles or nanoparticles , micro embodiments , the apo mimetic is administered only locally spheres , micelles , lipid particles ( e . g ., liposomes) , or encap ( e . g . , via injection , eye drop or an implant ). In yet other sulated or unencapsulated cells that are bioengineered to embodiments , the apo mimetic is administered only sys produce the apo mimetic . In some embodiments , the apo temically ( e . g . , orally ) . mimetic ?e . g ., an apo A - I mimetic ( e . g ., L -4F ) and /or an [0136 ] In some embodiments, the apo mimetic ( e . g . , an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is administered by injec apoA - I mimetic (e . g. , L -4F ) and / or an apoE mimetic ( e. g ., US 2018 /0296525 A1 Oct . 18 , 2018 13

AEM - 28 - 14 ) ] is administered , whether locally ( e . g ., by AEM - 28 - 14 )] is administered locally in a total of about 15 intravitreal injection ) or systemically , in a dose concentra or less , 12 or less , 9 or less , 6 or less , or 3 or less tion from about 1 , 2 , 3 , 4 or 5 mg/mL to about 12 or 15 administrations ( e . g . , intravitreal injections ) . In certain mg/mL . If two or more apo mimetics (e . g. , an apoA - I embodiments , the apo mimetic [e . g. , an apo A - I mimetic mimetic and an apoE mimetic ) are used , they can be ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is administered in the same formulation or in different formu administered locally in a total of about 3 - 6 , 6 - 9 , 9 - 12 or lations . In certain embodiments , the apo mimetic [e .g ., an 12 - 15 administrations ( e . g . , intravitreal injections ) . The apo apoA - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g . , mimetic can also be administered locally in a total of more AEM - 28 - 14 )] is administered ( e .g ., by intravitreal injection ) than 15 administrations ( e . g ., intravitreal injections ), such as in a dose concentration of about 1 - 4 mg/mL , 4 - 8 mg/ mL , up to about 20 or more administrations ( e . g ., intravitreal 8 - 12 mg/ mL , 1 - 5 mg/ mL , 5 - 10 mg/ mL or 10 - 15 mg/mL . In injections) . In some embodiments , the apo mimetic [ e . g . , an some embodiments , the apo mimetic [ e . g ., an apoA - I apo A - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g ., mimetic ( e . g . , L -4F ) and / or an apoE mimetic ( e . g . , AEM AEM -28 - 14 ) ] is administered locally in a total of about 15 , 28 - 14 ) ] is administered ( e . g ., by intravitreal injection ) in a 14 , 13, 12 , 11 or 10 administrations ( e . g ., intravitreal injec dose concentration of about 1 - 3 mg/mL , 3 - 5 mg/ mL , 5 - 7 . 5 tions ) . In other embodiments , the apo mimetic [ e . g . , an mg/ mL , 6 - 8 mg/ mL , 7 . 5 - 10 mg/ mL , 10 - 12 . 5 mg/mL or apoA - I mimetic ( e . g . , L -4F ) and /or an apoE mimetic ( e . g . , 12 . 5 - 15 mg /mL . The apo mimetic can also be administered , AEM -28 - 14 ) ] is administered locally in a total of about 9 , 8 , whether locally ( e . g ., by intravitreal injection ) or systemi 7 , 6 , 5 , 4 or 3 administrations ( e. g ., intravitreal injections) . cally , in a dose concentration greater than 15 mg/ mL , such In certain embodiments , the apo mimetic [ e . g . , an apoA - I as up to about 20 mg/ mL or more. In certain embodiments , mimetic ( e . g ., L -4F ) and /or an apoE mimetic ( e . g . , AEM the apo mimetic [ e . g . , an apoA - I mimetic ( e . g . , L -4F ) and / or 28 - 14 ) ] is administered locally in a total of about 3 - 6 or 7 - 10 an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is administered ( e . g . , administrations ( e . g . , intravitreal injections ) . In embodi by intravitreal injection ) in a dose concentration of about 1 - 5 ments where the apo mimetic is administered locally to , into , mg/ mL , 5 - 10 mg/ mL or 6 - 8 mg/ mL . in or around the eye , the frequency of administration and the [ 0137 ] In further embodiments , the apo mimetic [ e . g ., an total number of administrations (e .g . , injections ) are per apo A - I mimetic ( e . g ., L - 4F ) and /or an apoE mimetic ( e . g ., administered eye in certain embodiments and for both eyes AEM - 28 - 14 )] is administered locally (e . g ., by intravitreal in other embodiments , as the apo mimetic may also have a injection ) in a dose volume of about 50 - 150 uL or 50 - 100 therapeutic effect in the fellow non - administered eye . ul . In certain embodiments, the apo mimetic ?e . g . , an [0140 ] As with dosage per administration , total dosage apo A - I mimetic ( e . g . , L - 4F ) and / or an apoE mimetic ( e . g . , over a period of about 6 months, total dosage for the entire AEM - 28 - 14 ) ] is administered locally ( e . g . , by intravitreal treatment regimen , dosing frequency and total number of injection ) in a dose volume of about 50 -75 uL , 75 - 100 UL , administrations , the duration / length of treatment with the 100 - 125 uL or 125 - 150 uL . In some embodiments , the apo apolipoprotein mimetic can be adjusted if desired and can be mimetic [ e . g ., an apoA - I mimetic ( e . g . , L -4F ) and / or an selected by the treating physician to minimize treatment apoE mimetic ( e . g . , AEM - 28 -14 ) ] is administered locally burden and to achieve desired outcome( s ), such as reduction ( e . g ., by intravitreal injection ) in a dose volume of about 50 of lipid deposits to a desired level ( e . g . , the presence of a few UL , 75 uL , 100 uL , 125 uL or 150 uL . The apo mimetic may medium - size drusen or the absence of any large druse ) and also be administered locally ( e . g ., by injection to , into , in or elimination or reduction of geographic atrophy ( non - central around the eye ) in a dose volume greater than 150 uL , such or central) to a desired level . In some embodiments, the as up to about 200 uL , as long as the administered volume treatment regimen with the apo mimetic [ e . g . , an apoA - I does not significantly increase intraocular pressure . In cer mimetic ( e . g . , L - 4F ) and / or an apoE mimetic ( e . g ., AEM tain embodiments, the apo mimetic [ e . g . , an apoA - I mimetic 28 - 14 ) ] lasts for about 24 months or less , 18 months or less , ( e . g . , L -4F ) and/ or an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is 12 months or less, or 6 months or less. In further embodi administered locally ( e . g . , by intravitreal injection ) in a dose ments, the treatment regimen with the apo mimetic [e . g ., an volume of about 100 UL ( 0 . 1 mL ) . apoA - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g . , [ 0138 ] In additional embodiments , the apo mimetic [ e . g ., AEM - 28 - 14 ) ] lasts for about 18 - 24 months , 12 - 18 months or an apo A -I mimetic (e . g. , L -4F ) and /or an apoE mimetic 6 - 12 months . Treatment with the apo mimetic can also last ( e . g . , AEM - 28 -14 ) ] is administered locally ( e . g . , by intrav longer than 24 months ( 2 years ) , such as up to about 3 years , itreal injection ) once every month ( 4 weeks) or 1 .5 months 4 years , 5 years or longer. In some embodiments , the ( 6 weeks ) . In other embodiments , the apo mimetic ?e . g . , an treatment regimen with the apo mimetic ?e . g . , an apoA - I apoA - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g ., mimetic ( e . g . , L - 4F ) and / or an apoE mimetic ( e . g . , AEM AEM -28 - 14 ) ] is administered locally ( e . g ., by intravitreal 28 - 14 )] lasts for about 24 , 21, 18 , 15, 12 , 9 or 6 months. In injection ) once every 2 months ( 8 weeks ) , 2 . 5 months ( 10 certain embodiments , the treatment regimen with the apo weeks ) or 3 months (12 weeks ) . In yet other embodiments , mimetic [ e . g . , an apoA - I mimetic ( e . g ., L - 4F ) and /or an the apo mimetic [ e . g . , an apoA - I mimetic ( e . g . , L -4F ) and / or apoE mimetic ( e . g . , AEM - 28 - 14 ) ] lasts for about 6 - 12 or an apoE mimetic ( e . g ., AEM - 28 - 14 ) ] is administered locally 12 - 24 months . In additional embodiments, the treatment ( e . g . , by intravitreal injection or an intravitreal implant ) once regimen with the apo mimetic ( e . g ., an apoA - I mimetic ( e . g ., every 4 , 5 or 6 months . In some embodiments , the apo L -4F ) and /or an apoE mimetic (e . g ., AEM - 28 - 14 ) ] lasts at mimetic [ e . g . , an apo A - I mimetic ( e . g . , L -4F ) and / or an least about 6 , 12 , 24 or 36 months or longer ( e. g. , at least apoE mimetic ( e . g . , AEM - 28 -14 ) ] is administered locally about 12 months ) . ( e . g . , by intravitreal injection ) more frequently and / or in a [ 0141 ] In some embodiments , the apo mimetic [ e . g ., an higher dose in the initial phase of treatment. apoA - I mimetic ( e . g . , L - 4F ) and /or an apoE mimetic ( e . g . , 10139] In further embodiments , the apo mimetic [ e . g ., an AEM - 28 - 14 ) ] is administered at least in the advanced stage apoA - I mimetic ( e . g ., L -4F ) and / or an apoE mimetic ( e . g . , of AMD . In certain embodiments , the apo mimetic [e .g ., an US 2018 /0296525 A1 Oct . 18 , 2018 14 apoA - I mimetic (e . g. , L -4F ) and /or an apoE mimetic ( e. g ., can properly work again and can clear remaining abnormal AEM - 28 - 14 ) ] is administered at least in the advanced stage lipids from the eye . Furthermore , lipids accumulate in the of AMD to treat or slow the progression of central geo eye slowly over a period of years ( although fluctuations in graphic atrophy (GA ) , and/ or to prevent or delay the onset druse volume in a shorter time frame are detectable ). There of neovascular AMD . In further embodiments , the apo fore , less frequent administration ( e . g . , an intravitreal injec mimetic [ e . g . , an apoA - I mimetic ( e . g . , L - 4F ) and /or an tion every about 3 , 4 or 6 months ) and /or a smaller total apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is administered at least in number of administrations ( e . g . , about 1 , 2 or 3 intravitreal the advanced stage of AMD to treat or slow the progression injections ) of the apo mimetic can still have a therapeutic or of neovascular AMD ( including type 1 , 2 and /or 3 neovas prophylactic effect in early AMD . cularization ) . [0144 ] In other embodiments , the apo mimetic [ e . g ., an [0142 ] In additional embodiments , the apo mimetic [ e . g . , apoA - I mimetic (e . g ., D - 4F ) and / or an apoE mimetic ( e . g . , an apo A - I mimetic ( e . g ., L - 4F ) and / or an apoE mimetic AEM -28 - 14 ) ] is administered systemically ( e . g . , orally or ( e . g . , AEM - 28 - 14 ) ] is administered at least in the interme parenterally , such as intravenously ) in the early stage of diate stage of AMD . In certain embodiments, the apo AMD . To increase the resistance of an apo mimetic peptide mimetic [ e . g . , an apoA - I mimetic ( e . g . , L - 4F ) and/ or an to peptidases / proteases , a variant of the apo mimetic con apoE mimetic ( e . g ., AEM - 28 - 14 ) ] is administered at least in taining one or more, or all , D - amino acids ( e . g . , D -4F having the intermediate stage of AMD to treat or slow the progres all D - amino acid residues ) can be administered systemically sion of non - central GA , and / or to prevent or delay the onset (or by eye drop , because the ocular surface contains pepti of central GA and /or neovascular AMD . In further embodi dases /proteases ) . The dose of the apo mimetic for systemic ments, the apo mimetic [ e . g ., an apo A - I mimetic ( e . g . , L -4F ) administration can be much higher than its dose for local and / or an apoE mimetic ( e . g ., AEM - 28 - 14 ) ] is administered administration ( e . g ., by intravitreal injection or eye drop ) to at least in the early phase of intermediate AMD to prevent take into account its systemic distribution and its potential or delay the onset of non -central GA . Intermediate AMD is systemic anti - dyslipidemic effects, such as reduction or characterized by a substantial amount of confluent soft removal of atherosclerotic plaques in the systemic vascula drusen , which can mainly comprise esterified cholesterol ture , which may be a major target (and thus a sink ) for the and phospholipids . Reduction of confluent soft drusen in apo mimetic in systemic circulation . In certain embodi intermediate AMD using the apo mimetic [ e . g . , an apoA - I ments , the dose of the apo mimetic ( e . g . , an apoA - I mimetic mimetic ( e . g . , L -4F ) and / or an apoE mimetic ( e . g . , AEM ( e . g ., D -4F ) and / or an apoE mimetic ( e . g ., AEM - 28 - 14 ) ] for 28 -14 ) ] can result in decrease in the thickness (“ thinning” ) systemic administration is at least about 50 , 100 , 200 , 300 , and normalization of the Bruch ' s membrane , as well as 400 , 500 or 1 , 000 times ( e . g ., at least about 100 or 500 renewal of the overlying RPE cell layer due to improved times ) greater than its dose for local administration . In some exchange of oxygen , micronutrients and metabolites embodiments , the dose of the apo mimetic ?e . g ., an apo A - I between the choriocapillaris and the RPE . Reduction of mimetic ( e . g . , D - 4F ) and /or an apoE mimetic ( e . g . , AEM confluent soft drusen can be observed by non - invasive 28 - 14 ) ] for systemic administration amounts to at least about techniques such as spectral domain optical coherence 50 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg per day tomography (SDOCT ) . ( e . g ., amounts to at least about 50 mg or 100 mg per day if [0143 ] In further embodiments , the apo mimetic [ e . g . , an administered intravenously or amounts to at least about 200 apoA - I mimetic (e . g ., L -4F ) and / or an apoE mimetic ( e . g . , or 300 mg per day if administered orally ) . In further embodi AEM - 28 - 14 ) ] is administered at least in the early stage of ments, the apo mimetic is administered , whether systemi AMD . The apo mimetic can be administered at an earlier cally ( e . g . , orally or parenterally , such as intravenously ) or stage ( e . g ., the early stage or the intermediate stage ) of AMD locally into the eye in a non -invasive manner (e . g ., by eye to slow or stop the progression of AMD . In some embodi drop ) , one , two or more times daily , once every two days , ments , the apo mimetic [ e . g ., an apoA - I mimetic ( e . g . , L -4F ) once every three days , twice a week , once a week , once and / or an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is administered every two weeks or once a month ( e . g . , once daily or once at least in the early stage of AMD to prevent or delay the every two days ) in the early stage of AMD for a length of onset of non -central GA . In certain embodiments , the apo time selected by the treating physician ( e .g ., at least about 3 mimetic is administered locally to , into , in or around the eye months , 6 months, 12 months , 18 months , 24 months or ( e . g . , by intravitreal, subconjunctival , subretinal or sub longer ) or until the disease has been successfully treated Tenon ' s injection or eye drop ) in the early stage of AMD . If according to selected outcomemeasure ( s ) ( e . g . , elimination the apo mimetic [ e . g . , an apoA - I mimetic ( e . g . , L -4F ) and / or of all or most soft drusen or reduction of soft drusen volume an apoE mimetic ( e . g ., AEM - 28 - 14 ) ] is administered locally to a certain level ). in an invasive manner ( e . g . , by intravitreal, subconjunctival, [0145 ] In certain embodiments , the apo mimetic [ e . g . , an subretinal or sub - Tenon ' s injection ) , the apo mimetic can be apoA - I mimetic ( e . g . , L -4F ) and / or an apoE mimetic ( e . g . , administered less frequently ( e .g ., an injection every about AEM - 28 - 14 ) ] is administered ( e . g ., by intravitreal injection ) 3 , 4 or 6 months) , in a smaller total number of administra less frequently , and / or in a lower dose , the earlier the stage tions ( e . g . , about 1 , 2 or 3 injections ) or in a higher dose per of AMD . A higher dose of the apo mimetic can also be administration ( e . g . , about 0 . 5 - 1 mg or 1 - 1 . 5 mg per injec administered the earlier the stage of AMD . Phrased another tion ) , or any combination or all thereof, to minimize the way, in certain embodiments , the apo mimetic [ e . g . , an treatment burden . The apo mimetic does not need to elimi apoA -I mimetic (e . g. , L -4F ) and / or an apoE mimetic ( e. g ., nate or remove all or most of the abnormal lipid deposits AEM -28 - 14 )] is administered (e . g ., by intravitreal injection ) from the eye to have a therapeutic or prophylactic effect in more frequently (which can result in a greater total number AMD . If a threshold amount of abnormal lipids is cleared of administrations) , and / or in a higher dose (higher dose per from the eye , natural transport mechanisms, including traffic administration and /or higher total dose for the entire treat between the choriocapillaris endothelium and the RPE layer, ment regimen ) , the later the stage of AMD or the more US 2018 /0296525 A1 Oct . 18 , 2018 15 severe the AMD condition . As a non -limiting example , in an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] comprises one or more intermediate AMD and advanced AMD ( including atrophic excipients that inhibit peptide / protein aggregation , increase AMD and neovascular AMD ) , the apo mimetic can be peptide /protein solubility , reduce solution viscosity or administered by injection ( e . g . , intravitreal, subconjunctival, increase peptide /protein stability , or any combination or all subretinal or sub - Tenon ' s injection ) more frequently ( e . g ., thereof. Examples of such excipients include without limi once every about 4 - 12 or 4 - 8 weeks in intermediate AMD , tation those described elsewhere herein . Such excipients can and once every about 4 - 8 or 4 - 6 weeks in advanced AMD ) , improve the injectability of the composition containing the in a greater total number of injections ( e . g ., about 4 - 8 apo mimetic . Therefore , such excipients enable the use of a injections or more in intermediate AMD , and about 8 - 12 needle ( e . g . , an injection needle ) having a smaller gauge injections or more in advanced AMD ) , in a higher dose per ( e . g . , smaller than 30 G ) in the administration ( e . g ., by injection ( e . g ., up to about 1 - 1 . 5 mg per injection ) , or in a intravitreal injection ) of the composition containing the apo larger total dose for the entire treatment regimen ( e . g ., up to m imetic . about 10 - 15 mg or more in intermediate AMD , and up to [0149 ] Because such excipients inhibit peptide /protein about 15 - 20 mg or more in advanced AMD ) , or any com aggregation and increase peptide /protein solubility , for bination or all thereof, to remove a greater amount of lipid example , they can be employed to increase the concentration deposits , including drusen and basal linear deposits , from of a peptide or protein in a solution or suspension . Increased the eye , including from the sub -RPE - BL space and the peptide /protein concentration decreases the volume needed Bruch ' s membrane . to administer a given amount of the peptide or protein , [0146 ] The apo mimetic [ e . g ., an apoA - I mimetic ( e . g . , which can have beneficial effects such as reduced ocular L -4F ) and /or an apoE mimetic ( e .g ., AEM -28 - 14 )] can be pressure if the peptide or protein is administered by injection administered as a composition comprising one or more into the eye . Moreover, increased peptide/ protein concen pharmaceutically acceptable excipients or carriers. If two or tration allows a greater dose of the peptide or protein to be more apo mimetics ( e . g . , an apoA - I mimetic and an apoE administered for a given volume, which can permit the mimetic ) are used , they can be administered in the same peptide or protein to be administered less frequently for a composition or in different compositions . In some embodi given total dose administered over a time period . Less ments , the composition containing the apo mimetic ?e. g ., an frequent administration ( e . g ., by intravitreal injection ) of the apo A - I mimetic ( e . g . , L - 4F ) and / or an apoE mimetic ( e . g . , peptide or protein can have benefits , such as improved AEM - 28 - 14 )] comprises about 75 - 95 % (e .g . , about 90 % ) of patient compliance and health due to fewer invasive proce the apo mimetic ( s ) and about 5 -25 % ( e . g ., about 10 % ) of the dures being performed . corresponding apolipoprotein ( s ) ( e . g ., apoA - I and/ or apoE ) [0150 ] The apo mimetic ?e . g . , an apoA - I mimetic ( e . g . , or an active portion or domain thereof by weight or molarity L -4F or D -4F ) and / or an apoE mimetic ( e . g ., AEM -28 - 14 ) ] relative to their combined amount. In certain embodiments , or a salt thereof can be used alone or in combination with the composition containing the apo mimetic [ e . g ., an apoA - I one or more other therapeutic agents to treat AMD . mimetic ( e . g ., L -4F ) and / or an apoE mimetic ( e . g . , AEM Examples of other therapeutic agents include without limi 28 - 14 )] is formulated for injection (e .g . , intravitreal, sub tation those described elsewhere herein . The apo mimetic conjunctival , subretinal or sub - Tenon ' s injection ) . Examples and the one or more other therapeutic agents can be admin of formulations for injection into the eye include without istered concurrently or sequentially ( before or after one limitation those described elsewhere herein . In other another ) , and in the same composition or in different com embodiments , the composition containing the apo mimetic positions. One or more other therapeutic agents can be [ e . g . , an apoA - I mimetic ( e . g . , L - 4F ) and/ or an apoE administered in conjunction with the apo mimetic at differ mimetic ( e . g . , AEM - 28 - 14 ) ] is formulated as an eye drop or ent stages of AMD ( e . g ., the early stage , the intermediate an implant ( e . g . , an intravitreal, subretinal or sub - Tenon ' s stage and /or the advanced stage of AMD ) and for the implant ) . Use of an eye drop , or implantation of the implant treatment of different phenotypes of AMD ( e . g . , geographic one , two or three times , can avoid potential issues associated atrophy and / or neovascular AMD ) , as described elsewhere with repeated injections . herein . [0147 ] In further embodiments , the composition contain [0151 ] In some embodiments , the apo mimetic [ e . g . , an ing the apo mimetic [ e. g ., an apoA - I mimetic ( e .g ., L -4F ) apo A - I mimetic ( e . g ., L - 4F or D - 4F ) and / or an apoE and / or an apoE mimetic ( e. g . , AEM - 28 - 14 ) ] is configured mimetic ( e . g . , AEM - 28 - 14 ) ] or a salt thereof is used in for sustained release of the apo mimetic . Non - limiting combination with a statin ( e . g . , atorvastatin or a salt thereof examples of sustained - release compositions include those and /or simvastatin ) . All of the embodiments relating to the described elsewhere herein . In certain embodiments , the apo treatment of AMD with a statin which are described in mimetic [ e . g ., an apoA - I mimetic ( e . g . , L -4F ) and / or an Section V and elsewhere herein also apply to the treatment apoE mimetic ( e . g . , AEM - 28 - 14 ) ] is administered via nano of AMD with an apo mimetic and a statin . The statin can particles or microparticles, such as polymeric nanoparticles enhance the activity of the apo mimetic and /or vice versa , or or microparticles or nanoparticles or microparticles com the use of both the apo mimetic and the statin can have prising primarily or consisting essentially of the apo synergistic effect. Therefore , the apo mimetic can be admin mimetic. Use of a sustained - release composition or such istered in a lower dose and / or less frequently than the dose nanoparticles or microparticles can decrease the number of and /or the dosing frequency of the apo mimetic in the times a potentially invasive procedure ( e . g ., intravitreal absence of the statin , and/ or the statin can be administered injection ) is performed to administer a drug, and can in a lower dose and /or less frequently than the dose and /or improve the profile of the amount of the drug delivered to the dosing frequency of the statin in the absence of the apo the target site over a period of time. mimetic . 10148 ] In some embodiments , the composition containing (0152 ] In addition to another anti -dyslipidemic agent ( e . g . , the apo mimetic [ e . g ., an apoA - I mimetic ( e . g ., L -4F ) and / or a statin ), other kinds of therapeutic agents with which the US 2018 /0296525 A1 Oct . 18 , 2018 apo mimetic [ e . g . , an apoA - I mimetic ( e . g ., L -4F or D - 4F ) distance between the detached RPE - BL and the BrM ICL by and / or an apoE mimetic ( e. g ., AEM - 28 - 14 ) ] or a salt thereof at least about 50 % , 60 % , 70 % , 80 % , 90 % , 95 % or 99 % ) ; can be used in combination include without limitation an [0157 ] 3 ) enhancement of the phagocytic function ( e . g ., antioxidant, an anti - inflammatory agent, a neuroprotector, a phagocytosis of drusen and other undesired matter ) of RPE complement inhibitor or an anti - angiogenic agent, or any cells ( e . g ., increase in the percentage of phagocytic RPE combination or all thereof. cells by at least about 33 % , 50 % , 66 % , 80 % or 100 % ); [0158 ] 4 ) prevention or curtailment of atrophy and death V . TREATMENT OF AMD USING A STATIN of RPE cells and photoreceptors ( e . g . , reduction of the area [0153 ] Like apolipoprotein mimetics , statins are anti- dys of non -central and /or central geographic atrophy by at least lipidemic agents . Statins inhibit HMG -CoA reductase , the about 30 % , 40 % , 50 % , 60 % , 70 % , 80 % or 90 % ) ; enzyme that catalyzes the rate - limiting step in cholesterol [0159 ] 5) prevention or forestalling of progression to or biosynthesis , and thereby inhibit cholesterol biosynthesis in development of intermediate atrophic AMD , advanced atro eye tissues ( e . g ., the RPE ) and other tissues ( e . g ., the liver ) phic AMD or neovascular AMD ; that are potential sources of cholesterol in the eye. In addition , statins reduce apoB synthesis and secretion , [0160 ] 6 ) prevention or curtailment of vision loss ( e . g . , decrease the production of VLDL and LDL apoB ( or the reduction of loss of visual acuity to no more than about 5 , production of apoB -containing VLDLs and LDLs) , increase 4 , 3 , 2 or 1 letter ); and the level of liver LDL receptors , and lower the plasma level [ 0161] 7 ) improvement of visual acuity ( e . g ., by at least of lipids ( e . g ., LDL - cholesterol) available for uptake into the about 3 , 6 , 9 or 12 letters ) . eye. Since drusen are extracellular deposits rich in lipids [0162 ] Examples of statins include without limitation ator ( including esterifed cholesterol [ EC ] ) and lipoprotein com vastatin , cerivastatin , fluvastatin , mevastatin , monacolins ponents ( including apoB ) and form in the sub -RPE -BL space ( e . g ., monacolin K [ lovastatin ] ) , pitavastatin , pravastatin , possibly as a result of RPE secretion of EC -rich VLDLs rosuvastatin , simvastatin , and analogs , derivatives and salts basolaterally , statins can reduce drusen (including large soft thereof . In some embodiments , the statin includes , or is , a drusen ) deposits and thereby can prevent or resolve druse substantially hydrophobic / lipophilic statin or a salt thereof. noid pigment epithelial detachments (PEDs ) . Drusen are Examples of substantially hydrophobic / lipophilic statins rich sources of lipids that are susceptible to oxidation , and include, but are not limited to , atorvastatin , lovastatin , oxidized lipids can be highly pro - inflammatory and thus mevastatin and simvastatin . In certain embodiments, the pro -angiogenic . Furthermore , confluent soft drusen form a statin includes , or is , atorvastatin or a salt ( e . g . , calcium salt ) hydrophobic diffusion barrier that impedes the exchange of thereof, and /or simvastatin . incoming oxygen and nutrients and outgoing waste between [0163 ] In some embodiments , the statin ( e . g . , atorvastatin the choriocapillaris and RPE cells , which can lead to the and /or simvastatin ) or a salt thereof is administered locally atrophy and death of RPE cells and photoreceptors . In to , into , in or around the eye . Local administration of the addition , cholesterol crystals and oxidized LDLs impair the statin to the eye permits the statin to be used at a much lower phagocytic function of RPE cells and induce the secretion of dose than systemic ( e . g ., oral) administration of the statin , pro - inflammatory IL - 6 and IL - 8 from RPE cells . Therefore , which can prevent or reduce side effects that may be by tackling an important upstream cause of AMD , lipid associated with long -term use of statins in high dosage , such accumulation , statins can prevent or curtail sequelae such as as muscle toxicity or wasting . In some embodiments , the inflammation , geographic atrophy and neovascularization , statin is administered locally by eye drop , injection (e .g ., and thereby can improve vision ( e . g . , visual acuity ) . Inde intravitreal, subconjunctival , subretinal or sub - Tenon ' s pendent of or perhaps in part due to their lipid - lowering injection ) , or implant ( e . g . , intravitreal, intraaqueous , sub properties, statins increase the phagocytic function of RPE retinal or sub - Tenon ' s implant ) . In certain embodiments , the cells ( e . g . , by increasing the cell membrane fluidity of RPE statin is administered locally by eye drop . In other embodi cells ) and possess antioxidant properties ( e . g ., reduce oxi ments , the statin is administered locally by injection (e .g ., dative stress - induced injury to RPE cells ) , anti - inflammatory intravitreal, subconjunctival, subretinal or sub - Tenon ' s properties ( e . g . , decrease the levels of pro - inflammatory injection ). In additional embodiments , the statin is admin IL -6 and IL -8 ), and anti- angiogenic properties ( e. g. , down istered by implanting in or injecting into , e. g. , the vitreal regulate VEGF expression and reduce laser - induced chor chamber, the space below the retina or the aqueous humor oidal neovascularization ) . devices or systems that deliver the statin in a controlled [0154 ] Accordingly , some embodiments of the disclosure and / or sustained manner, such as microdevices, polymeric relate to a method of treating age -related macular degenera implants, bioabsorbable polymeric materials , bioabsorbable tion (AMD ), comprising administering to a subject in need ( e . g ., polymeric ) microparticles or nanoparticles , micro of treatment a therapeutically effective amount of a statin or spheres , micelles, lipid particles ( e . g . , liposomes ) , or encap a pharmaceutically acceptable salt thereof. Like treatment sulated or unencapsulated cells that naturally produce or are with an apo mimetic ( e . g . , an apoA - I mimetic such as L -4F bioengineered to produce the statin . or D - 4F , or an apoE mimetic such as AEM - 28 - 14 ) , beneficial [ 0164 ] In some embodiments , the statin (e . g . , atorvastatin effects of treatment with a statin include , but are not limited and / or simvastatin ) or a salt thereof is administered locally to : to , into , in or around the eye in a dose from about 10 -500 ug , [ 0155 ] 1 ) reduction of drusen ( including soft drusen ) size 50 - 500 ug or 100 - 500 ug per administration ( e . g ., by eye ( e . g . , diameter or volume) , number or amount ( e . g . , by at drop or injection ) . In certain embodiments , the statin is least about 50 % , 60 % , 70 % , 80 % , 90 % , 95 % or 99 % ) ; administered locally in a dose from about 10 - 50 ug , 50 - 100 [ 0156 ] 2 ) prevention or resolution of drusenoid PEDs ug, 100 - 200 ug , 200 -300 ug , 300 -400 ug or 400 -500 ug per (e . g. , promotion of re -attachment of the RPE -BL to the BrM administration ( e . g ., by eye drop or injection ) . In other ICL , or flattening of a PED or decrease in the separation / embodiments , the statin is administered locally in a dose US 2018 /0296525 A1 Oct . 18 , 2018 17 from about 10 or 20 ug to about 200 ug , or from about 10 injection or eye drop ) more frequently and /or in a higher or 20 ug to about 100 ug , per administration ( e . g ., by eye dose in the initial phase of treatment. drop or injection ). [0170 ] In additional embodiments , the statin ( e . g . , atorv 10165 ] In further embodiments , the statin ( e . g ., atorvasta astatin and / or simvastatin ) or a salt thereof , whether or not tin and / or simvastatin ) or a salt thereof is administered in the form of a sustained -release composition , is injected locally to , into , in or around the eye ( e . g . , by eye drop , into the eye in a total of about 15 or less , 12 or less, 9 or less, injection or implant) in a total or cumulative dose of about 6 or less , or 3 or less injections ( e . g ., intravitreal, subcon 0 . 1 or 0 . 3 - 15 mg or 0 . 5 or 1 - 10 mg over a period of about junctival, subretinal or sub - Tenon ' s injections ) . In certain 1 month . In certain embodiments , the statin is administered embodiments , the statin , whether or not in the form of a locally ( e . g . , by eye drop , injection or implant ) in a total dose sustained -release composition , is injected in a total of about of about 0 . 1 or 0 . 3 - 1 mg, 1 - 5 mg, 5 - 10 mg or 10 - 15 mg over 3 - 6 , 6 - 9 , 9 - 12 or 12 - 15 injections . The statin , whether or not a period of about 1 month . In other embodiments , the statin in the form of a sustained - release composition , can also be is administered locally ( e . g . , by eye drop , injection or injected in a total of more than 15 injections , such as up to implant) in a total dose of about 0 . 5 - 10 mg or 0 . 5 - 5 mg over about 20 or more injections. In some embodiments , the a period of about 1 month . statin , whether or not in the form of a sustained -release [0166 ] In still further embodiments , the statin (e .g ., ator composition , is injected in a total of about 15 , 14 , 13 , 12 , 11 vastatin and / or simvastatin ) or a salt thereof is administered or 10 injections . In other embodiments , the statin , whether locally to , into , in or around the eye ( e . g ., by eye drop , or not in the form of a sustained - release composition , is injection or implant) in a total or cumulative dose of about injected in a total of about 9 , 8 , 7 , 6 , 5 , 4 or 3 injections . In 0 . 5 or 2 - 100 mg, 5 or 10 - 100 mg, or 5 or 10 - 50 mg over a certain embodiments , the statin , whether or not in the form period of about 6 months. In certain embodiments , the statin of a sustained -release composition , is injected in a total of is administered locally ( e . g . , by eye drop , injection or about 3 - 6 or 7 - 10 injections. In embodiments where the implant ) in a total dose of about 0 . 5 - 2 mg, 2 - 10 mg, 0 . 5 -5 statin is injected into the eye , the frequency of injection and mg, 5 - 10 mg, 10 - 50 mg or 50 - 100 mg over a period of about the total number of injections are per injected eye in certain 6 months . In other embodiments , the statin is administered embodiments and for both eyes in other embodiments , as the locally ( e . g ., by eye drop , injection or implant) in a total dose statin may also have a therapeutic effect in the fellow from about 2 or 5 mg to about 50 mg, or from about 2 or 5 non - injected eye as explained above with regard to apoli mg to about 25 mg, over a period of about 6 months. poprotein mimetics . [ 0167 ] In additional embodiments , the statin ( e . g ., atorv [0171 ] In other embodiments , the statin ( e . g . , atorvastatin astatin and /or simvastatin ) or a salt thereof is administered and /or simvastatin ) or a salt thereof is administered locally locally to , into , in or around the eye ( e . g . , by eye drop , to , into , in or around the eye via a sustained -release implant injection or implant) in a total or cumulative dose of about ( e . g ., intravitreal, intraaqueous, subretinal, sub - Tenon ' s or 1 or 4 - 200 mg, 5 or 10 - 200 mg, 5 or 10 - 150 mg, or 5 or posterior juxtascleral implant) . Non -limiting examples of 10 - 100 mg for the whole or entire treatment regimen . In implants include those described elsewhere herein . The certain embodiments , the statin is administered locally ( e . g ., implant can deliver a therapeutically effective amount of the by eye drop , injection or implant ) in a total dose of about 1- 5 statin over a period of at least about 3 months , 4 months, 6 mg, 5 - 10 mg, 1 - 10 mg, 10 - 50 mg, 50 - 100 mg, 100 - 150 mg months, 1 year , 1 . 5 years , 2 years or longer. The implant can or 150 - 200 mg for the entire treatment regimen . In other be biodegradable ( e . g ., a bioabsorbable polymeric implant) embodiments , the statin is administered locally (e . g. , by eye or non -biodegradable ( e . g ., a posterior juxtascleral depot drop , injection or implant ) in a total dose from about 5 or 10 cannula ) . In certain embodiments , the implant is implanted in or around the eye once every about 3 months , 4 months , mg to about 100 mg, or from about 5 or 10 mg to about 50 6 months, 1 year, 1 . 5 years , 2 years or longer. In further mg, for the entire treatment regimen . embodiments , the implant is implanted in or around the eye 10168 ] In some embodiments , the statin ( e . g ., atorvastatin one or more ( e . g . , two, three, four or more ) times for the and / or simvastatin ) or a salt thereof is administered locally entire treatment regimen . to the eye by eye drop . In certain embodiments , the statin is [0172 ] In certain embodiments , the statin ( e . g . , atorvasta administered by eye drop one or more (e . g. , two , three , four tin and / or simvastatin ) or a salt thereof is administered ormore ) times daily , once every two days, once every three locally to , into , in or around the eye in the initial phase of days, twice a week or once a week . In some embodiments, treatment, and then the statin is administered systemically . the statin is administered by eye drop twice or thrice daily . As a non - limiting example , the initial administration ( s ) ( e . g . , [ 0169 ] In further embodiments , the statin ( e . g ., atorvasta the first one to five administrations ) of the statin , whether or tin and / or simvastatin ) or a salt thereof is administered not in the form of a sustained -release composition and locally into the eye by injection ( e . g . , intravitreal, subcon whether in early , intermediate or advanced AMD , can be junctival, subretinal or sub - Tenon ' s injection ) . In certain local via injection ( e . g ., intravitreal, subconjunctival, sub embodiments , the statin , whether or not in the form of a retinal or sub - Tenon ' s injection ) , and then subsequent sustained - release composition , is injected once every month administration ( s ) of the statin can be systemic , such as oral, ( 4 weeks ) or 1 . 5 months (6 weeks ) . In other embodiments , parenteral ( e . g . , intravenous , subcutaneous or intramuscu the statin , whether or not in the form of a sustained - release lar ) , or topical ( e . g . , intranasal or pulmonary ) . In other composition , is injected once every 2 months ( 8 weeks ) , 2 . 5 embodiments , the statin , whether or not in the form of a months ( 10 weeks ) or 3 months ( 12 weeks) . In yet other sustained -release composition , is administered only locally embodiments , the statin is administered locally ( e . g . , via a ( e . g ., via eye drop , injection or an implant ) . In yet other sustained - release implant or by injection of a sustained embodiments , the statin is administered only systemically release composition ) once every 3 , 4 , 5 or 6 months. In some ( e . g ., orally , parenterally or topically ) . In certain embodi embodiments , the statin is administered locally (e .g . by ments , the statin is administered orally . US 2018 /0296525 A1 Oct . 18 , 2018

[0173 ] If the statin ( e. g ., atorvastatin and / or simvastatin ) statin is administered at least in the advanced stage of AMD or a salt thereof is administered systemically ( e . g ., orally , to treat or slow the progression of central geographic atro parenterally or topically ) , the dose of the statin for systemic phy (GA ) , and /or to prevent or delay the onset of neovas administration can be much higher than its dose for local cular AMD . In further embodiments , the statin is adminis administration (e .g ., by eye drop or injection ) to take into tered at least in the advanced stage of AMD to treat or slow account its systemic distribution and its potential systemic the progression of neovascular AMD ( including types 1 , 2 anti - dyslipidemic effects , such as reduction or removal of and /or 3 neovascularization ). atherosclerotic plaques in the systemic vasculature , which [0176 ] In additional embodiments , the statin ( e .g . , atorv can be a major target ( and thus a sink ) for the statin in astatin and / or simvastatin ) or a salt thereof is administered systemic circulation . In certain embodiments , the dose of the at least in the intermediate stage of AMD . In certain embodi statin ( e . g ., atorvastatin and/ or simvastatin ) or a salt thereof ments , the statin is administered at least in the intermediate for systemic administration is at least about 50 , 100 , 200 , stage of AMD to treat or slow the progression of non - central 300 , 400 , 500 or 1 ,000 times ( e . g ., at least about 100 or 500 GA , and / or to prevent or delay the onset of central GA times ) greater than its dose for local administration . In some and /or neovascular AMD . In further embodiments , the statin embodiments , the statin is administered systemically ( e . g ., is administered at least in the early phase of intermediate orally ) in a dose ( e . g ., a daily dose ) of about 5 - 100 mg, 5 - 80 AMD to prevent or delay the onset of non - central GA . mg, 10 - 80 mg, 10 -40 mg, 40 -80 mg, or 20 -60 mg. In certain Intermediate AMD is characterized by a substantial amount embodiments , the statin is administered systemically ( e. g. , of confluent soft drusen , which can mainly comprise esteri orally ) in a dose ( e . g ., a daily dose ) of about 5 mg, 10 mg, fied cholesterol and phospholipids . Reduction of confluent 20 mg, 30 mg, 40 mg , 50 mg , 60 mg, 70 mg, 80 mg 90 mg soft drusen in intermediate AMD using the statin can result or 100 mg . In some embodiments , atorvastatin or a salt ( e . g . , in decrease in the thickness and normalization of the Bruch ' s calcium salt ) thereof is administered orally in a daily dose of membrane , as well as renewal of the overlying RPE cell about 20 - 80 mg, 40 - 80 mg or 60 - 80 mg, or in a daily dose layer due to improved exchange of incoming oxygen and of about 20 mg, 40 mg, 60 mg or 80 mg ( e . g . , about 80 mg) . nutrients and outgoing waste between the choriocapillaris In further embodiments , simvastatin is administered orally and the RPE . Reduction of confluent soft drusen can be in a daily dose of about 20 -60 mg, 20 - 40 mg or 40 -60 mg, observed by SDOCT. or in a daily dose of about 20 mg, 40 mg or 60 mg ( e .g . , [0177 ] In further embodiments , the statin ( e . g ., atorvasta about 40 mg ) . In some embodiments , the statin is adminis tin and / or simvastatin ) or a salt thereof is administered at tered systemically (e . g. , orally ) one or more times ( e .g ., least in the early stage of AMD . The statin can be admin twice ) daily , once every two days , once every three days , istered at an earlier stage ( e . g ., the early stage or the twice a week or once a week ( e . g . , once daily ) . The daily intermediate stage ) of AMD to slow or stop the progression dose of a statin can be administered as a single dose or of AMD . In some embodiments , the statin is administered at divided doses. For example, if the daily dose of a statin is least in the early stage ofAMD to prevent or delay the onset about 60 mg, then the dose per administration is about 60 mg of non - central GA . In certain embodiments , the statin is if the statin is administered once daily and about 30 mg if the administered systemically ( e . g . , orally ) in the early stage of statin is administered twice daily . AMD . In other embodiments , the statin is administered [0174 ] As with dosage per administration , total dosage locally to , into , in or around the eye ( e. g ., by eye drop , over a period of about 1 month , total dosage over a period injection or an implant) in the early stage of AMD . If the of about 6 months, total dosage for the entire treatment statin is administered locally in an invasive manner (e . g ., by regimen , dosing frequency and total number of administra intravitreal, subconjunctival, subretinal or sub - Tenon ' s tions , the duration /length of treatment with the statin can be injection ), the statin , whether or not in the form of a adjusted if desired and can be selected by the treating sustained - release composition , can be administered less physician to minimize treatment burden and to achieve frequently ( e . g . , an injection every about 2 , 3 or 4 months) , desired outcome( s ), such as reduction of lipid deposits to a in a smaller total number of administrations (e . g ., about 1 , 2 , desired level ( e . g ., the presence of a few medium -size drusen 3 , 4 or 5 injections ) or in a higher dose per administration or the absence of any large druse ) and elimination or ( e . g ., about 100 - 300 ug or 300 - 500 ug per injection ) , or any reduction of geographic atrophy (non - central or central) to a combination or all thereof, to minimize the treatment bur desired level. In some embodiments , the treatment regimen den . The statin does not need to eliminate or remove all or with the statin ( e . g ., atorvastatin and / or simvastatin ) or a salt most of the abnormal lipid deposits from the eye to have a thereof lasts for about 24 months or less , 18 months or less , therapeutic or prophylactic effect in AMD . If a threshold 12 months or less, or 6 months or less. In further embodi amount of abnormal lipids is cleared from the eye , natural ments , the treatment regimen with the statin lasts for about transport mechanisms, including traffic between the chorio 18 - 24 months, 12 - 18 months or 6 - 12 months. Treatment capillaris endothelium and the RPE layer, can properly work with the statin can also last longer than 24 months ( 2 years ), again and can clear remaining abnormal lipids from the eye . such as up to about 3 years , 4 years , 5 years or longer. In Furthermore , lipids accumulate in the eye slowly over a some embodiments , the treatment regimen with the statin period of years (although fluctuations in druse volume in a lasts for about 24 , 21 , 18 , 15 , 12 , 9 or 6 months . In certain shorter time frame are detectable ) . Therefore , less frequent embodiments , the treatment regimen with the statin lasts for administration ( e . g . , an intravitreal injection every about 2 , about 6 - 12 or 12 - 24 months. In additional embodiments , the 3 or 4 months) and /or a smaller total number of adminis treatment regimen with the statin lasts at least about 6 , 12 , trations ( e . g . , about 1 , 2 , 3 , 4 or 5 intravitreal injections) of 24 or 36 months or longer ( e . g ., at least about 12 months) . the statin can still have a therapeutic or prophylactic effect [0175 ] In some embodiments , the statin ( e . g . , atorvastatin in early AMD . and / or simvastatin ) or a salt thereof is administered at least 0178 ] The statin ( e . g . , atorvastatin and / or simvastatin ) or in the advanced stage of AMD . In certain embodiments, the a salt thereof can be administered in a stage ( e . g ., the early , US 2018 /0296525 A1 Oct . 18 , 2018 intermediate or advanced stage ) of AMD for a length of time [0183 ] In some embodiments , the statin ( e .g ., atorvastatin selected by the treating physician ( e . g ., at least about 3 and /or simvastatin ) or a salt thereof is used in combination months , 6 months, 12 months, 18 months , 24 months or with an apolipoprotein mimetic ( e . g . , an apoA - I mimetic longer ) or until the disease has been successfully treated such as L - 4F or D - 4F or a salt thereof, and /or an apoE according to selected outcomemeasure (s ) (e .g . , elimination mimetic such as AEM -28 - 14 or a salt thereof) . All of the of all or most soft drusen or reduction of soft drusen volume embodiments relating to the treatment of AMD with an to a certain level ) . apolipoprotein mimetic which are described in Section IV [0179 ] In embodiments where the statin ( e .g ., atorvastatin and elsewhere herein also apply to the treatment of AMD and / or simvastatin ) or a salt thereof is administered locally with a statin and an apo mimetic . The apo mimetic can to the eye in an invasive manner ( e . g . , by intravitreal, enhance the activity of the statin and / or vice versa , or the use subconjunctival, subretinal or sub - Tenon ' s injection ), the of both the statin and the apo mimetic can have synergistic statin can be administered less frequently , and in a lower effect. Therefore , the statin can be administered in a lower dose , a higher dose or the same dose , the earlier the stage of dose and / or less frequently than the dose and / or the dosing AMD . Phrased another way , the statin can be administered frequency of the statin in the absence of the apo mimetic , locally by injection more frequently (which can result in a and / or the apo mimetic can be administered in a lower dose greater total number of administrations ) , and /or in a higher and /or less frequently than the dose and / or the dosing dose (higher dose per administration and /or higher total dose frequency of the apo mimetic in the absence of the statin . over a certain time period or for the entire treatment regi 10184 ] In addition to another anti -dyslipidemic agent ( e. g ., men ) , the later the stage of AMD or the more severe the an apo mimetic ) , other kinds of therapeutic agents with AMD condition , which can also apply to cases where the which the statin ( e . g . , atorvastatin and / or simvastatin ) or a statin is administered locally in a non - invasive manner ( e . g ., salt thereof can be used in combination include without by eye drop ) or systemically ( e . g ., orally ) . As a non - limiting limitation an antioxidant, an anti- inflammatory agent , a example , in intermediate AMD and advanced AMD ( includ neuroprotector, a complement inhibitor or an anti -angio ing atrophic AMD and neovascular AMD ) , the statin , genic agent , or any combination or all thereof. whether or not in the form of a sustained -release composi tion , can be administered by injection ( e . g . , intravitreal, VI. OTHER KINDS OF THERAPEUTIC subconjunctival, subretinal or sub - Tenon ' s injection ) more AGENTS frequently ( e . g ., once every about 4 - 12 or 4 -8 weeks in intermediate AMD , and once every about 4 - 8 or 4 - 6 weeks [0185 ] As described above, AMD has a variety of under in advanced AMD ) , in a greater total number of injections lying factors, including formation of lipid - rich deposits, ( e. g ., about 4 - 8 injections or more in intermediate AMD , and formation of toxic byproducts , oxidation , inflammation , about 8 - 12 injections or more in advanced AMD ) , in a neovascularization and cell death . One or more therapeutic higher dose per injection (e . g ., about 100 - 300 ug or 300 -500 agents targeting one or more underlying factors of AMD , or ug per injection ) , or in a larger total dose for the entire having different mechanisms of action , can be utilized for treatment regimen ( e . g ., up to about 50 - 100 mg or more in the treatment of AMD . Therapeutic agents that can be used , intermediate AMD , and up to about 100 - 150 mg or 150 - 200 optionally in combination with an apolipoprotein mimetic mg in advanced AMD ) , or any combination or all thereof, to and / or a statin , to treat AMD include without limitation : remove a greater amount of lipid deposits , including drusen [0186 ] 1 ) anti- dyslipidemic agents ; and basal linear deposits , from the eye, including from the [0187 ] 2 ) PPAR - a agonists , PPAR -d agonists and PPAR -Y sub -RPE -BL space and the Bruch ' s membrane . agonists ; 10180 ] A statin ( e . g . , atorvastatin and /or simvastatin ) or a 10188 ] 3 ) anti - amyloid agents and inhibitors of other toxic salt thereof can also be used prior to signs of AMD to substances ( e . g ., aldehydes ) ; prevent or delay the onset of AMD . In such cases , the statin [0189 ] 4 ) inhibitors of lipofuscin or components thereof; can be administered locally or systemically in a non -inva [0190 ] 5) visual/ light cycle modulators and dark adapta sive manner ( e . g . , by eye drop or orally ) . tion agents ; [0181 ] In certain embodiments , the statin is administered to a subject with the at -risk complement factor H genotype [0191 ] 6 ) antioxidants ; CC (Y402H ) at any stage (e . g. , the early , intermediate or [0192 ] 7 ) neuroprotectors (neuroprotectants ) ; advanced stage ) of AMD or prior to development of AMD . [0193 ] 8 ) apoptosis inhibitors and necrosis inhibitors ; [0182 ] The statin (e . g. , atorvastatin and /or simvastatin ) or [0194 ] 9 ) C - reactive protein ( CRP) inhibitors ; a salt thereof can be used alone or in combination with one [0195 ] 10 ) inhibitors of the complement system or com or more other therapeutic agents to treat AMD . Examples of ponents (e . g. , proteins ) thereof; other therapeutic agents include without limitation those described elsewhere herein . The statin and the one or more [0196 ] 11) inhibitors of inflammasomes; other therapeutic agents can be administered concurrently or [0197 ] 12 ) anti- inflammatory agents ; sequentially (before or after one another ), and in the same [0198 ] 13 ) immunosuppressants ; composition or in different compositions . One or more other therapeutic agents can be administered in conjunction with [0199 ] 14 ) modulators (inhibitors and activators ) ofmatrix the statin at different stages of AMD ( e . g . , the early stage , metalloproteinases (MMPs ) and other inhibitors of cell the intermediate stage and / or the advanced stage of AMD ) migration ; and for the treatment of different phenotypes of AMD ( e. g ., [0200 ] 15 ) anti- angiogenic agents ; geographic atrophy and / or neovascular AMD ) , as described [0201 ] 16 ) laser therapies , photodynamic therapies and elsewhere herein . radiation therapies; US 2018 /0296525 A1 Oct . 18 , 2018

[0202 ] 17 ) agents that preserve or improve the health of [ ALA ], and fish oil [which contains , e .g ., DHA and EPA ]) the endothelium and / or the blood flow of the vascular and esters (e . g ., glyceryl and ethyl esters ) thereof. Omega -3 system of the eye; and fatty acids and esters thereof are also anti- inflammatory [ 0203] 18 ) cell ( e . g ., RPE cell ) replacement therapies . ( e .g ., they inhibit cyclooxygenase and 5 - lipoxygenase and [0204 ] A particular therapeutic agentmay exert more than hence the synthesis of prostanglandins and leukotrienes, one biological or pharmacological effect and may be clas respectively, and they inhibit the activation of NF -kB and sified in more than one category . hence the expression of pro - inflammatory cytokines such as [0205 ] A therapeutic agent is used in a therapeutically IL -6 and TNF - a ). effective amount. When used in combination with another [0208 ) Lipid - lowering agents further include pro - protein therapeutic agent (e . g ., an apolipoprotein mimetic or a convertase subtilisin /kexin type 9 ( PCSK9) inhibitors . statin ) , a therapeutic agent can be administered substantially PCSK9 inhibitors increase expression of the LDL receptor concurrently with the other therapeutic agent (such as during on hepatocytes by enhancing LDL receptor recycling to the the same doctor ' s visit , or within about 30 or 60 minutes of cell membrane surface of hepatocytes , where the LDL each other ) , or prior to or subsequent to administration of the receptor binds to and initiates ingestion of LDL particles other therapeutic agent . When administered concurrently transporting lipids such as cholesterol, Examples of PCSK9 with another therapeutic agent, a therapeutic agent can be inhibitors include without limitation berberine (which administered in the same formulation or in separate formu decreases PCSK9 annexin A2 ( which inhibits PCSK9 activ lations as the other therapeutic agent. ity ) , anti- PCSK9 monoclonal antibodies ( e . g . , alirocumab , [ 0206 ] Formation of lipid -rich deposits is an important bococizumab , evolocumab , LGT- 209 , LY3015014 and upstream cause of AMD that leads to complications such as RG7652 ) , peptides that mimic the epidermal growth fac non - central and central geographic atrophy and neovascu tor - A ( EGF - A ) domain of the LDL receptor which binds to larization . One multi -pronged approach to preventing or PCSK9, PCSK9- binding adnectins ( e . g ., BMS- 962476 ) , minimizing the accumulation of lipid -rich material is to anti - sense polynucleotides and anti -sense peptide - nucleic inhibit the production of lipids ( e. g ., cholesterol and fatty acids (PNAs ) that target mRNA for PCSK9, and PCSK9 acids ) and lipoproteins ( e. g ., VLDLs) by RPE cells , to targeting siRNAs ( e . g . , inclisiran [ ALN -PCS ] and ALN inhibit the uptake of plasma lipids ( e . g ., cholesterol and fatty PCS02) . acids ) and lipoproteins ( e . g ., VLDLs) by RPE cells , to [0209 ] Anti- sense polynucleotides and anti -sense PNAS inhibit the secretion of lipids ( e .g ., cholesterol and fatty are single - stranded , highly specific , complementary acids ) and lipoproteins ( e . g . , VLDLs ) and components sequences that bind to the target mRNA and thereby pomote thereof ( e . g ., apoB and apoE ) by RPE cells into the Brm , the degradation of the mRNA by an RNase H . Small interfering sub - RPE - BL space and the subretinal space , and to clear RNAs ( siRNAs) are relatively short stretches of of double lipids ( e . g ., cholesterol and oxidized lipids ) and lipoproteins stranded RNA that are incorporated into the RNA - induced ( e . g ., VLDLs ) and components thereof (e . g ., apoB and silencing complex ( RISC ) present in the cytoplasm of cells apo E ) from the BrM , the sub -RPE -BL space and the sub and bind to the target mRNA , thereby resulting in degrada retinal space . For example , apoB is involved in the forma tion of the mRNA by a RISC - dependent mechanism . The tion of at least hepatic VLDL , which is the parent of at least greater the length of complementarity between the siRNA plasma LDL . Inhibition of apoB production by RPE cells and the target mRNA , the greater the specificity of the and inhibition of the uptake by RPE cells of fatty acids siRNA for the target mRNA . available to lipidate apoB could curtail the production of [0210 ] Cholesterol can also be cleared through , e .g ., the VLDLs , and hence possibly LDLs, by RPE cells . removal of HDL - cholesteryl ester by the gut. Lecithin [ 0207 ] Anti -dyslipidemic agents modulate inter alia the cholesterol acyltransferase (LCAT ) is a plasma enzyme that production , uptake and clearance of lipids , lipoproteins and converts free cholesterol into cholesteryl ester, which is then other substances that play a role in the formation of lipid sequestered into the core ofHDL particles . Therefore , LCAT containing deposits in the retina , the subretinal space , the activators increase HDL -cholesteryl ester level and are sub - RPE - BL space, and the choroid ( e . g . , the BrM ). Anti anti - dyslipidemic . Apolipoproteins A - I and E are major dyslipidemic apolipoprotein mimetics and statins are physiological activators of LCAT. Hence, LCAT activators described above. Another class of anti -dyslipidemic agents include without limitation apoA - I and apoE and derivatives , is fibrates, which activate peroxisome proliferator -activated fragments and analogs thereof, including apoA - I mimetics receptor -alpha ( PPAR - a ). Fibrates are hypolipidemic agents and apoE mimetics . that reduce fatty acid and triglyceride production , induce [0211 ] Acetyl -CoA carboxylase (ACC ) inhibitors can also lipoprotein lipolysis but stimulate the production of high be used as anti - dyslipidemic agents . ACC inhibitors inhibit density lipoprotein (HDL , which mediates reverse choles fatty acid and triglyceride ( TG ) synthesis and decrease terol transport ), increase VLDL and LDL removal from VLDL - TG secretion . Non - limiting examples of ACC inhibi plasma, and stimulate reverse cholesterol transport from tors include anthocyanins, avenaciolides , benzodioxepines peripheral cells or tissues to the circulation and ultimately { e . g ., 7 - ( 4 -propyloxy -phenylethynyl ) - 3 , 3 - dimethyl- 3 , 4 the liver , where cholesterol is metabolized and excreted into dihydro -2H -benzo [b ][ 1, 4 ]dioxepine benzothiophenes [ e .g ., the bile . Examples of fibrates include without limitation N - ethyl- N - ( 3 - { [ 4 - ( 3 , 3 - dimethyl - 1 - oxo - 2 -oxa - 7 - azaspiro bezafibrate , ciprofibrate , clinofibrate , clofibric acid , clofi [ 4 . 5 ] dec- 7 - yl) piperidin - 1 - yl) - carbonyl ) - 1 -benzothien - 2 - yl) brate , aluminum clofibrate ( alfibrate ), clofibride , etofibrate , urea] , bis -piperidinylcarboxamides (e .g ., CP -640186 ), chlo fenofibric acid , fenofibrate , gemfibrozil, ronifibrate , simfi roacetylated biotin , cyclodim , diclofop , haloxyfop , biphe brate , and analogs , derivatives and salts thereof. Other nyl- and 3 -phenyl pyridines, phenoxythiazoles { e . g ., 5 - ( 3 hypotriglyceridemic agents include omega -3 fatty acids acetamidobut- 1- ynyl) - 2 - ( 4 -propyloxyphenoxy ) thiazole ), ( e . g . , docosahexaenoic acid (DHA ) , docosapentaenoic acid piperazine oxadiazoles, (4 -piperidinyl ) -piperazines , sora [ DPA ], eicosapentaenoic acid [EPA ) , a - linolenic acid phens ( e . g . , soraphen spino - piperidines , spiro - pyrazolidin US 2018 /0296525 A1 Oct . 18 , 2018 21

ediones , spiro [ chroman - 2 , 4 '- piperidin ) - 4 -ones , 5 - ( tetradecy exenatide, liraglutide, lixisenatide, semaglutide, taspo loxy ) - 2 - furancarboxylic acid ( TOFA ), thiazolyl phenyl glutide, CNTO736 , CNTO3649 , HM11260C (LAPS -Exen ethers, thiophenes [ e . g ., 1 - ( 3 - { [ 4 - ( 3 , 3 - dimethyl- 1 - oxo - 2 din ) , NN9926 (OG9S7GT ) , TT401, ZYOG1, and analogs , oxa -7 -azaspiro [ 4 .5 ]dec -7 - yl) piperidin - 1 -yl ] -carbonyl ) - 5 derivatives and salts thereof. Because GLP - 1 , the endog (pyridin - 2 -yl ) -2 - thienyl) - 3 - ethylurea ), and analogs, deriva enous ligand of the GLP -1 receptor, is rapidly degraded by tives and salts thereof . dipeptidyl peptidase 4 (DPP - 4 ) , anti - dyslipidemic effects [ 0212 ] Anti -dyslipidemic agents also include inhibitors of similar to those of GLP - 1 receptor agonists can be achieved acyl- CoA cholesterol acyltransferase (ACAT ) (also called with the use of a DPP - 4 inhibitor, albeit with potentially sterol O - acyltransferase ( SOAT ]) , including ACAT1 lower potency. Non - limiting examples of DPP - 4 inhibitors (SOAT1 ) and ACAT2 (SOAT2 ) . ACAT inhibitors inhibit include alogliptin , anagliptin , dutogliptin , gemigliptin , lina cholesterol esterification and decrease the production and gliptin , saxagliptin , sitagliptin , teneligliptin , vildagliptin , secretion of VLDL and LDL apoB (or the production and berberine, lupeol, and analogs , derivatives and salts thereof. secretion of apoB - containing VLDLs and LDLs) . Examples [ 0215 ] Additional anti - dyslipidemic agents include inhibi of ACAT inhibitors include without limitation avasimibe , tors of the microsomal triglyceride transfer protein (MTTP ) , pactimibe , pellitorine , terpendole C , and analogs , deriva which is expressed predominantly in hepatocytes and tives and salts thereof. enterocytes but also in RPE cells . MTTP catalyzes the [0213 ] Other anti- dyslipidemic agents include inhibitors assembly of cholesterol, triglycerides and apoB to chylomi of stearoyl -CoA desaturase - 1 ( SCD - 1 ) (also called stearoyl crons and VLDLs. MTTP inhibitors inhibit the synthesis of COA delta - 9 desaturase ). SCD -1 is an endoplasmic reticu apoB - containing chylomicrons and VLDLs , and inhibit the lum enzyme that catalyzes the formation of a double bond in secretion of these lipoproteins. Examples of MTTP inhibi stearoyl- CoA and palmitoyl- CoA , the rate - limiting step in tors include , but are not limited to , microRNAs ( e . g . , the formation of the monounsaturated fatty acids oleate and miRNA - 30c ), MTTP - targeting anti- sense polynucleotides palmitoleate from stearoyl- CoA and palmitoyl - CoA , respec and anti- sense PNAs, implitapide , lomitapide, dirlotapide , tively . Oleate and palmitoleate are major components of mitratapide , CP -346086 , JTT- 130 , SLX - 4090 , and analogs , cholesterol esters , alkyl- diacylglycerol and phospholipids. derivatives and salts thereof. Systemic administration of an Examples of inhibitors of SCD - 1 activity or expression MTTP inhibitor may result in hepatic steatosis ( e . g ., accu include CAY- 10566 , CVT- 11127 , benzimidazole - carboxam mulation of triglycerides in the liver ), which can be averted ides ( e . g ., SAR - 224 ), hexahydro -pyrrolopyrroles ( e . g . , by , e . g . , local administration of the MTTP inhibitor, use of SAR -707 ) , 3 -( 2 -hydroxyethoxy ) -N -( 5 -benzylthiazol - 2 -yl ) an MTTP inhibitor that is not systemically absorbed ( e. g . , benzamides {e .g ., 3 - (2 -hydroxyethoxy ) -4 -methoxy - N -[ 5 SLX -4090 ) , or co - administration of a GLP - 1 receptor ago ( 3 - trifluoromethylbenzyl) thiazol- 2 - yl] benzamide and 4 - eth nist, or any combination or all thereof. Another option for ylamino - 3 - ( 2 - hydroxyethoxy ) - N - [ 5 - ( 3 avoiding hepatic steatosis is the use of miRNA - 30c . One trifluoromethylbenzyl) thiazol- 2 -yl ] benzamide ) , piperazin region of the sequence of miRNA - 30c decreases MTTP 1 -ylpyridazine -based compounds (e .g . , XEN - 103 ), expression and apoB secretion , and another region decreases spiropiperidine -based compounds { e. g ., 1' - { 6 - 5 - (pyridin - 3 fatty acid synthesis , with no deleterious effect to the liver. ylmethyl) - 1 , 3 , 4 - oxadiazol- 2 - yl] pyridazin - 3 - yl) - 5 - (trifluo [0216 ] MicroRNAs are relatively short non - coding RNAs romethyl) - 3 ,4 -dihydrospiro [chromene - 2, 4 '- piperidine ] and that target one or more mRNAs in the same pathway or 5 - fluoro - 1' - {6 - [ 5 - (pyridin - 3 -ylmethyl ) - 1 ,3 ,4 -oxadiazol - 2 different biological pathways and silence the mRNA ( S ) . yl] pyridazin -3 - yl -3 , 4 -dihydrospiro [chromene -2 ,4 ' -piperi MicroRNAs resemble siRNAs of the RNA interference dine ] } , 5 - alkyl- 4 , 5 -dihydro - 3H - spiro [ 1 , 5 -benzoxazepine - 2 , (RNAi ) pathway , except that miRNAs derive from regions 4 ' -piperidine ] -based compounds { e . g ., 6 - 15 of RNA transcripts that fold back on themselves to form ( cyclopropylmethyl) - 4 ,5 - dihydro - l ' H , 3H - spiro [ 1 , 5 short hairpins, whereas siRNAs derive from longer regions benzoxazepine - 2 , 4 - piperidin ) - 1 '- yl] - N - ( 2 -hydroxy - 2 of double -stranded RNA . Although either strand of the pyridin - 3 - ylethyl) pyridazine- 3 - carboxamide ) , miRNA duplex formed by the RNase III enzyme Dicer may benzoylpiperidine -based compounds { e . g ., 6 - [ 4 - ( 2 -methyl potentially act as a functional miRNA , only one strand is benzoyl) piperidin - 1 -yl ) pyridazine - 3 -carboxylic acid (2 -hy usually incorporated into the RISC . The mature miRNA droxy - 2 -pyridin - 3 - ylethyl ) amide ) , piperidine- aryl urea becomes part of an active RISC containing Dicer and many based compounds { e . g . , 4 - ( 2 - chlorophenoxy ) - N - [ 3 - (methyl associated proteins including Argonaute proteins ( e. g . , carbamoyl) phenyl] piperidine - 1 - carboxamide ) , 1 - ( 4 - phe Ago1/ 2 ) . Argonaute proteins are important for miRNA noxypiperidin - 1 - yl) - 2 - arylaminoethanone- based com induced silencing and bind the mature miRNA and orient it pounds, the cis - 9 , trans - 11 isomer and the trans - 10 ,cis - 12 for interaction with the target mRNA ( S ) . Certain Argonaute isomer of conjugated linoleic acid , substituted heteroaro proteins (e .g . , Ago2 ) cleave mRNAs directly . The mature matic compounds disclosed in WO 2009 / 129625 A1, SCD miRNA binds to the target mRNA ( S ) , resulting in silencing 1 - targeting anti - sense polynucleotides , SCD - 1 - targeting of the mRNA ( s ) via cleavage of the mRNA ( s ) , destabiliza anti - sense peptide -nucleic acids , SCD - 1 - targeting siRNAs, tion of the mRNA ( s ) through shortening of their poly ( A ) and analogs , derivatives and salts thereof. tail , and / or less efficient translation of the mRNA ( s ) into 102141 Another class of anti- dyslipidemic agents is gluca proteins by ribosomes . gon - like peptide - 1 (GLP - 1 ) receptor agonists . GLP - 1 recep [0217 ] Other kinds of anti- dyslipidemic agents include tor agonists reduce the production of apoB and VLDL anti - sense polynucleotides and anti- sense peptide -nucleic particles and hence VLDL - apoB and VLDL - TG , decrease acids (PNAs ) that target mRNA for apoB , including apoB48 the cellular content of cholesterol and triglycerides , and and apoB 100 . ApoB is important in the formation of VLDLS reduce or reverse hepatic steatosis (fatty liver) by decreasing and subsequently LDLs. Use of an anti- sense polynucleotide hepatic lipogenesis . Non - limiting examples of GLP - 1 recep - or PNA wholly or partially ( e . g ., at least about 50 % , 60 % , tor agonists include exendin - 4 , albiglutide , dulaglutide, 70 % , 80 % , 90 % or 95 % ) complementary to mRNA for apoB US 2018 /0296525 A1 Oct . 18 , 2018 blocks translational expression of apoB and hence the pro [0222 ] PPAR - a agonists and PPAR - y agonists can also be duction of VLDLs and LDLs. Examples of anti - sense poly used to treat AMD . The hypolipidemic effects of the PPAR nucleotides targeting mRNA for apoB include without limi a -activating fibrates are described above . Fibrates also tation mipomersen . Anti -sense polynucleotides and anti decrease the expression of vascular endothelial growth fac sense PNAs can also target mRNA for apoC -III . ApoC - III is tor (VEGF ) and VEGF receptor 2 (VEGFR2 ) , which play an a component of VLDLs , inhibits lipoprotein lipase and important role in the development of neovascularization , hepatic lipase , and acts to reduce hepatic uptake of triglyc including CNV . Examples of PPAR - a agonists include , but erides, thereby causing hypertriglyceridemia . are not limited to , fibrates and perfluoroalkanoic acids ( e . g . , [ 0218 ] Anti - sense polynucleotides and anti - sense PNAS perfluorooctanoic acid and perfluorononanoic acid ) . PPAR can regulate gene expression by targeting miRNAs as wells y - activating thiazolidinediones also have anti- dyslipidemic as mRNAs . For example , miRNA - 33a and miRNA - 33b effects. Like LXR , PPAR - y heterodimerizes with RXR . repress the expression of the ATP -binding cassette trans Thiazolidinediones decrease the level of lipids ( e . g ., fatty porter ABCA1 ( cholesterol efflux regulatory protein acids and triglycerides ), increase the level ofHDLs (which (CERPI ) , which mediates the efflux of cholesterol and mediate reverse cholesterol transport ) , and increase the phospholipids. Use of an anti - sense polynucleotide or PNA efflux of lipids ( e . g ., cholesterol ) from cells to the circulation wholly or partially ( e . g . , at least about 50 % , 60 % , 70 % , and ultimately the liver , where lipids are metabolized and 80 % , 90 % or 95 % ) complementary to miRNA -33a and /or excreted into the bile . Like fibrates, thiazolidinediones also miRNA - 33b increases reverse cholesterol transport and inhibit VEGF - induced angiogenesis . Examples of PPAR - Y HDL production and decreases VLDL - TG production and agonists include without limitation thiazolidinediones ( e . g . , fatty acid production and oxidation . Increased expression of ciglitazone , lobeglitazone , netoglitazone , pioglitazone, rivo ABCA1 is also protective against angiogenesis in AMD . As glitazone , rosiglitazone and troglitazone ), rhodanine, ber another example, overexpression of miRNA - 122 increases berine , honokiol, perfluorononanoic acid , and analogs , cholesterol synthesis , and hence use of an anti - sense poly derivatives and salts thereof. nucleotide or PNA targeting miRNA - 122 decreases choles [0223 ] Other anti -dyslipidemic PPAR modulators include terol synthesis , incuding in the liver . PPAR - 8 agonists . PPAR - 8 agonists increase HDL level , reduce VLDL level, and increase the expression of choles [ 0219 ] Peptide - nucleic acids present advantages as anti terol efflux transporters (e . g ., ABCA1) . Non -limiting sense DNA or RNA mimics . In addition to binding to RNA examples of PPAR -8 agonists include GFT505 (a dual or DNA targets in a sequence -specific manner with high PPAR - a / d agonist ) , GW0742 , GW501516 , sodelglitazar affinity, PNAs can possess high stability and resistance to (GW677954 ) ,MBX - 8025 , and analogs , derivatives and salts nucleases and proteases. thereof . [0220 ] Cholesterylester transfer protein (CETP ) inhibitors [ 0224 ] Anti -dyslipidemic agents also include inhibitors of can be used as anti - dyslipidemic agents . CETP transfers bromodomain and extra - terminal domain ( BET) proteins cholesterol from HDLs to VLDLs and LDLs . CETP inhibi such as BRD2, BRD3, BRD4 and BRDT. A non - limiting tors increase HDL -cholesterol level, decrease VLDL - cho example of a BET ( viz . , BRD4 ) inhibitor is apabetalone lesterol and LDL - cholesterol levels , and increase reverse (RVX - 208 ) , which increases HDL and HDL -cholesterol cholesterol transport from peripheral cells or tissues to the levels, increases cholesterol efflux and reverse cholesterol circulation and ultimately the liver , where cholesterol is transport, stimulates the production of apoA - I ( the main metabolized and excreted into the bile . Examples of CETP protein component of HDL ), and is also anti -inflammatory . inhibitors include, but are not limited to , anacetrapib , dal 0225 ]. Another way to increase cholesterol efflux from cetrapib , evacetrapib , torcetrapib , AMG 899 ( TA - 8995 ) and cells is to increase the level of cardiolipin in the inner analogs, derivatives and salts thereof. mitochondrial membrane . Increased cardiolipin content may [ 0221 ] Other anti- dyslipidemic agents that increase cellu also prevent or curtail mitochondrial dysfunction . A non lar lipid ( e . g . , cholesterol ) efflux include liver X receptor limiting example of agents that increase the level of cardio (LXR ) agonists and retinoid X receptor ( RXR ) agonists . lipin in the inner mitochondrial membrane is elamipretide LXR heterodimerizes with the obligate partner RXR . The MTP( - 131 ) , a cardiolipin peroxidase inhibitor and a mito LXR /RXR heterodimer can be activated with either an LXR chondria -targeting peptide . agonist or an RXR agonist . Activation of the LXR /RXR [0226 ]. If systemic administration of an inhibitor of a heterodimer decreases fatty acid synthesis , increases HDL lipid -modulating enzyme or an anti -dyslipidemic agent that cholesterol level and increases lipid ( e . g . , cholesterol ) efflux increases lipid efflux ( e . g ., reverse cholesterol transport) from cells to the circulation and ultimately the liver, where results in hepatic steatosis or abnormal levels of lipids in the lipids are metabolized and excreted into the bile . Non blood , or risks doing so , hepatic steatosis or abnormal levels limiting examples of LXR agonists include endogenous of lipids in the blood can be averted or treated by, e . g ., local ligands such as oxysterols ( e . g ., 22 ( R ) -hydroxycholesterol , administration of the enzyme inhibitor or the anti -dyslipi 24 ( S )- hydroxycholesterol , 27 -hydroxycholesterol and cho demic agent to the eye , co -use of an agent that reduces or lestenoic acid ), synthetic agonists such as acetyl- podocarpic reverses hepatic steatosis , or co - use of an agent that dimer, hypocholamide , N , N - dimethyl- 3 -hydroxy - cholena decreases lipid levels in the blood , or any combination or all mide ( DMHCA ) , GW3965 , T0901317 , and analogs, deriva thereof. Examples of agents that reduce or reverse hepatic tives and salts thereof. Non - limiting examples of RXR steatosis include without limitation agents that reduce agonists include endogenous ligands such as 9 -cis -retinoic hepatic lipogenesis , such as GLP - 1 receptor agonists , which acid , and synthetic agonists such as bexarotene , AGN can be administered , e . g . , systemically for this purpose . A 191659, AGN 191701 , AGN 192849, BMS649, LG100268 , non - limiting example of agents that decrease lipid levels in LG100754 , LGD346 , and analogs, derivatives and salts the blood is statins, which can be administered systemically thereof. for this purpose . US 2018 /0296525 A1 Oct. 18 , 2018 23

[0227 ] Other compounds that bind to and neutralize and /or zan , which promotes the release of lipofuscin from RPE facilitate clearance of lipids and toxic lipid byproducts ( e . g . , cells ; and retinol- binding protein 4 (RBP4 ) antagonists ( e. g ., oxidized lipids ) can also be used . For example , cyclodex A1120 , LBS -008 and compound 43 [ a cyclopentyl- fused trins have a hydrophilic exterior but a hydrophobic interior, pyrrolidine ] ), which inhibit the formation of lipofuscin and hence can form water- soluble complexes with hydro bisretinoids such as A2E . phobic molecules . Therefore , cyclodextrins, including a - cy [0232 ] Another potential way to prevent or curtail the clodextrins ( 6 -membered sugar ring molecules ), B - cyclo accumulation of lipofuscin bisretinoids ( e . g . , A2E ) is to dextrins (7 -membered sugar ring molecules ) , interfere with the visual/ light cycle in photoreceptors . For y - cyclodextrins ( 8 -membered sugar ring molecules ) and example , the visual/ light cycle modulator fenretinide derivatives thereof ( e . g ., methyl- 3 -cyclodextrin ) , can form reduces serum levels of retinol and RBP4 and inhibits retinol water - soluble inclusion complexes with lipids ( e . g ., choles binding to RBP4, which decreases the level of light cycle terol) and toxic lipid byproducts ( e . g ., oxidized lipids ) and retinoids and halts the accumulation of lipofuscin bis thereby can neutralize their effect and /or facilitate their retinoids ( e . g ., A2E ) . Other visual/ light cycle modulators removal. include without limitation inhibitors of the trans- to - cis [ 0228 ] Another kind of anti - dyslipidemic agents is endo retinol isomerase RPE65 ( e . g ., emixustat [ ACU - 4429 ) and plasmic reticulum ( ER ) modulators that restore proper ER retinylamine ) , which , by inhibiting the conversion of all function , including without limitation azoramide . The ER trans retinol to 11 - cis retinol in the RPE , reduce the amount plays an important role in lipid metabolism . ER dysfunction of retinol available and its downstream byproduct A2E . Like and chronic ER stress are associated with many pathologies, fenretinide , emixustat reduces the accumulation of lipofus including obesity and inflammation . Azoramide improves cin and A2E in the RPE . Treatment with a light cycle ER protein - folding ability and activates ER chaperone modulator may slow the rate of the patient' s rod -mediated capacity to protect cells against ER stress . dark adaptation . To speed up the rate of dark adaptation , a [0229 ] AMD reportedly is associated with extracellular dark adaptation agent can be administered . Non - limiting deposits of apoE and amyloid -beta ( AB ) , including in examples of dark adaptation agents include carotenoids drusen . Aß deposits reportedly are involved in inflammatory ( e. g ., carotenes, such as ß -carotene ), retinoids ( e .g ., all - trans events . For instance , amyloid - ß reportedly induces the pro retinol ( vitamin A ) , 11 - cis retinol, all - trans retinal ( vitamin duction of the pro - inflammatory cytokines interleukin - 1B A aldehyde ), 11 -cis retinal, all- trans retinoic acid ( tretinoin ] and tumor necrosis factor - a by macrophages and microglia , and esters thereof , 9 - cis - retinoic acid ?alitretinoin ) and esters which can increase the expression of complement factor B thereof, 11 -cis retinoic acid and esters thereof, 13 - cis -ret in RPE cells and may contribute to AMD progression . inoic acid ?isotretinoin ) and esters thereof, etretinate, acit Accordingly , anti -amyloid agents (e . g. , inhibitors of AB retin , adapalene , bexarotene and tazarotene ) , and analogs , formation or aggregation into plaques /deposits , and promot derivatives and salts thereof. ers of AB clearance ) can potentially be useful for treating [0233 ] Oxidative events play a significant role in the AMD . Examples of anti- amyloid agents ( e .g ., anti- AB pathogenesis of AMD . For instance , accumulation of per agents ) include without limitation anti - Aß antibodies ( e . g . , oxidized lipids can lead to inflammation and neovascular bapineuzumab , solanezumab , GSK - 933776 [ it also reduces ization . Furthermore, oxidative stress can compromise the complement C3a deposition in the BrM ], RN6G [PF regulation of the complement system by RPE cells ( the 4382923 ] , AN - 1792 , 2H6 and deglycosylated 2H6 ), anti complement system is discussed below ) . To prevent , delay apoE antibodies ( e . g . , HJ6 . 3 ) , apoE mimetics ( e . g . , AEM the onset of or slow the progression of AMD , antioxidants 28 ) , cystatin C , berberine , L -3 - n -butylphthalide , T0901317, can be administered . In addition , antioxidants can be neu and analogs, derivatives , fragments and salts thereof. roprotective by preventing or curtailing toxicity in the retina [0230 ] Elevated levels of other toxic byproducts are also and interfering with cell - death pathways. For example , the associated with AMD . For example , elevated levels of toxic mitochondria - targeting electron scavenger XJB - 5 - 131 aldehydes such as 4 -hydroxynonenal (HNE ) and malondi inhibits oxidation of cardiolipin , a mitochondria - specific aldehyde (MDA ) are present in patients with AMD , particu polyunsaturated phospholipid , thereby curtailing cell death , larly atrophic AMD . An agent that inhibits the formation of including in the brain . As another example , crocin and toxic aldehydes , binds to them and lowers their level , or crocetin , carotenoids found in saffron , can protect cells from promotes their breakdown or clearance , such as the aldehyde apoptosis . As yet another example , xanthophylls ( e . g . , lutein trap NS2, can be used to treat AMD . and zeaxanthin ) can protect against development of drusen [0231 ] In addition , with age lipofuscin and components like lesions at the RPE , loss of macular pigment and thereof ( e . g ., A2E ) reportedly accumulate in the RPE as a light- induced photoreceptor apoptosis . As still another byproduct of visual cycling . Lipofuscin is pro - inflammatory, example , carnosic acid , a benzenediol abietane diterpene and the lipofuscin bisretinoid A2E reportedly inhibits lyso found in rosemary and sage, can upregulate antioxidant somal degradative function and cholesterol metabolism in enzymes , protect retinal cells from hydrogen peroxide tox the RPE , induces the complement system and mediates blue icity , and increase the thickness of the outer nuclear layer . As light - induced apoptosis , and thus has been implicated in the a further example , curcuminoids (e .g ., curcumin ) found in atrophy and cell death of RPE cells . Accordingly, inhibitors turmeric can upregulate hemeoxygenase - 1 , thereby protect of lipofuscin or components thereof ( e . g ., A2E ), including ing RPE cells from hydrogen peroxide - induced apoptosis . inhibitors of their formation or accumulation and promoters As a yet further example, zinc increases catalase and glu of their breakdown or clearance , can potentially be useful for tathione peroxidase activity , thereby protecting RPE cells treating AMD . Examples of inhibitors of lipofuscin or and photoreceptors from hydrogen peroxide and tent- butyl components thereof ( e . g ., A2E ) include without limitation hydroperoxide, and protects photoreceptors and other retinal isotretinoin , which inhibits the formation of lipofuscin and cells from caspase -mediated cell death . As a still further A2E and the accumulation of lipofuscin pigments ; sorapra example , cyclopentenone prostaglandins ( e. g ., cyclopen US 2018 /0296525 A1 Oct . 18 , 2018 24 tenone 15 -deoxy - A -prostaglandin J2 [ 15d -PGJ2 ], a ligand [0241 ] 6 ) ß -carotene , vitamin C , vitamin E , lutein , zeax for PPAR - Y ) can protectRPE cells from oxidative injury by, anthin , omega - 3 fatty acids (DHA and EPA ) , zinc and e . g ., upregulating the synthesis of glutathione , an antioxi copper. dant. Cyclopentenone prostaglandins also possess anti -in Exemplary ICAPS® formulations include: flammatory property . As an additional example , N - acetyl [0242 ] 1) vitamin A , vitamin C , vitamin E , zinc and carnosine scavenges lipid peroxyl radicals in the eye , copper ; or thereby reducing cell damage . [0243 ] 2 ) vitamin A , vitamin B2, vitamin C , vitamin E , [0234 ] Non - limiting examples of antioxidants include lutein , zeaxanthin , zinc, copper and selenium . anthocyanins, apolipoprotein mimetics ( e . g . , apo A - I mimet Exemplary Ocuvite® formulations contain : ics and apoE mimetics ) , benzenediol abietane diterpenes [0244 ] 1 ) vitamin C , vitamin E , lutein , zeaxanthin , zinc ( e . g . , carnosic acid ) , carnosine, N - acetylcarnosine, carote and copper; or noids (e . g. , carotenes [e . g. , ß - carotene ], xanthophylls [ e .g ., [0245 ] 2 ) vitamin C , vitamin E , lutein , zeaxanthin , lutein , zeaxanthin and meso - zeaxanthin ), and carotenoids in omega - 3 fatty acids, zinc and copper; or saffron [ e . g ., crocin and crocetin ]) , curcuminoids ( e . g . , cur [0246 ] 3 ) vitamin A , vitamin C , vitamin E , lutein , zeax cumin , demethoxycurcumin and tetrahydrocurcumin ), anthin , zinc , copper and selenium . cyclopentenone prostaglandins ( e . g ., 15d -PGJ2 ) , flavonoids [0247 ] Alternative to or in addition to antioxidants , other { e . g . , flavonoids in Ginkgo biloba ( e . g ., myricetin and neuroprotectors (neuroprotectants ) can be administered to quercetin ), prenylflavonoids (e . g. , isoxanthohumol) , fla treat AMD . Neuroprotectors can be used , e . g ., to promote vones ( e . g ., apigenin ) , isoflavones ( e . g ., genistein ), flava the health and / or growth of cells in the retina , and / or to nones ( e . g ., naringenin ) and flavanols ( e . g . , catechin and prevent cell death regardless of the initiating event. For epigallocatechin - 3 - gallate ) } , glutathione , melatonin , ret instance , ciliary neurotrophic factor (CNTF ) rescues photo inoids, stilbenoids ( e . g . , resveratrol) , uric acid , vitamin A , receptors from degeneration . Likewise , brimonidine protects vitamin B ( thiamine ) , vitamin B , ( riboflavin ) , vitamin B2 retinal ganglion cells , bipolar cells and photoreceptors from (niacin ), vitamin B6 (e . g. , pyridoxal , pyridoxamine , 4 - pyri degeneration . As another example, glatiramer acetate doxic acid and pyridoxine) , vitamin B , ( folic acid ) , vitamin reduces retinal microglial cytotoxicity (and inflammation ). B12 ( cobalamin ), vitamin C , vitamin E ( e .g ., tocopherols and Examples of neuroprotectors include without limitation ber tocotrienols ) , selenium , zinc ( e . g . , zinc monocysteine ) , berine , glatiramer acetate , apoE mimetics ( e . g ., CN - 105 ) , inhibitors and scavengers of lipid peroxidation and byprod Az- adrenergic receptor agonists ( e . g ., apraclonidine and ucts thereof ( e . g ., vitamin E [ e . g ., a - tocopherol] , tirilazad , brimonidine ), serotonin 5 -HT14 receptor agonists ( e . g . , NXY- 059 , and cardiolipin peroxidation inhibitors [ e .g ., AL -8309B and azapirones [ e .g ., buspirone , gepirone and elamipretide, SkQ1 and XJB - 5 - 131 ]) , activators of nuclear tandospirone ]) , neuroprotectins ( e. g ., neuroprotectins A , B factor ( erythroid -derived 2 ) - like 2 (NFE2L2 or Nrf2 ) ( e . g ., and Di) , endogenous neuroprotectors { e . g ., carnosine , bardoxolone methyl, OT- 551, fumarates ?e . g . , dimethyl and CNTF , glial cell -derived neurotrophic factor GDNF( ) family monomethyl fumarate ), and dithiolethiones [ e . g . , oltipraz ] ) , ( e . g . , GDNF, artemin , neurturin and persephin ), and neuro superoxide dismutase (SOD ) mimetics { e . g ., OT- 551 ( a trophins ( e. g ., brain -derived neurotrophic factor [ BDNF ] , cyclopropyl ester prodrug of tempol hydroxylamine) , man nerve growth factor (NGF ), neurotrophin - 3 [NT - 3 ] and ganese (III ) - and zinc (III ) -porphyrin complexes ( e . g . , MnT neurotrophin - 4 [NT - 4 ] )} , prostaglandin analogs (e . g ., uno BAP, MnTMPyP and ZnTBAP ) , manganese ( II) penta prostone isopropyl [UF - 021 ] ) , and analogs, derivatives , azamacrocyclic complexes ( e . g . , M40401 and M40403 ) , and fragments and salts thereof. manganese (III )- salen complexes ( e .g ., those disclosed in [0248 ] Furthermore , other neuroprotectors that can be U . S . Pat. No . 7 , 122 ,537 ) } , and analogs , derivatives and salts used to treat AMD include agents that prevent the death of thereof. retina - associated cells ( e . g . , RPE cells and photoreceptors ) [ 0235 ] Antioxidants can be provided by way of, e . g ., a by apoptosis (programmed cell death ) and / or necrosis ( char dietary supplement, such as an AREDS or AREDS2 formu acterized by cell swelling and rupture ) . For example , nucleo lation , an ICAPS® formulation , an Ocuvite® formulation , side reverse transcriptase inhibitors (NRTIs ) block the death Saffron 2020TM or Phototrop® . If a supplement contains a of RPE cells via inhibition of P2X7 -mediated NLRP3 relatively high amount of zinc ( e . g ., zinc acetate , zinc oxide inflammasome activation of caspase - 1 , and reduce geo or zinc sulfate ) , copper ( e .g ., cupric oxide or cupric sulfate ) graphic atrophy and CNV . As another example , the first can optionally be co -administered with zinc to prevent apoptosis signal (Fas ) receptor inhibitor ONL - 1204 protects copper- deficiency anemia associated with high zinc intake . retinal cells , including photoreceptors, from apoptosis . If Saffron 2020TM contains saffron , resveratrol, lutein , zeaxan apoptosis is reduced ( e . g ., through inhibition of caspases ) , thin , vitamins A , B2, C and E , zinc and copper. Phototrop® necrosis may increase to compensate for the reduction in comprises acetyl- L - carnitine, omega - 3 fatty acids and coen apoptosis, so an effective strategy for preventing or curtail zyme Q . An exemplary Age -Related Eye Disease Study ing the death of retina - associated cells can involve inhibition ( AREDS ) formulation includes ß - carotene , vitamin C , vita of both apoptosis and necrosis . min E , zinc ( e . g . , zinc oxide ) and copper ( e . g . , cupric oxide ) . [0249 ] Examples of apoptosis inhibitors include without Exemplary AREDS2 formulations contain : limitation first apoptosis signal ( Fas ) receptor inhibitors [0236 ] 1 ) ß - carotene , vitamin C , vitamin E and zinc ; or ( e . g ., ONL - 1204 ) , cardiolipin peroxidation inhibitors ( e . g . , [0237 ] 2 ) vitamin C , vitamin E , zinc and copper ; or elamipretide, SkQ1 and XJB - 5 - 131) , tissue factor ( TF ) [ 0238 ] 3 ) vitamin C , vitamin E and zinc ; or inhibitors ( e . g . , anti - TF antibodies and fragments thereof [0239 ] 4 ) B - carotene , vitamin C , vitamin E , omega - 3 fatty and fusion proteins thereof ( e . g . , ICON - 1 ]) , inhibitors of acids (DHA and EPA ) , zinc and copper ; or inflammasomes, inhibitors of P2X7- mediated NLRP3 acti [0240 ] 5 ) ß -carotene , vitamin C , vitamin E , lutein , zeax vation of caspase - 1 ( e . g ., NRTIs, such as abacavir ( ABC ) , anthin , zinc and copper ; or lamivudine [3TC ] , stavudine [ d4T ], me- d4T and zidovudine US 2018 /0296525 A1 Oct . 18 , 2018 25

[ AZT] ) , other inhibitors of NLRP3 activation of caspase - 1 [ 0263 ] inhibitors of caspase - 13 , such as benzyloxycarbo ( e . g ., myxoma virus M013 protein ) , neuroprotectins , mem nyl- Leu -Glu (OMe ) -Glu ( OMe )- Asp ( OME) - fluoromethylke bers of the Bcl - 2 family ( e . g . , Bcl- 2 , Bcl -XL and Bcl - w ) , tone (SEQ . ID .NO . 32 , aka LEED - FMK or Z - LEED - FMK ) ; members of the inhibitor of apoptosis protein (IAP ) family and ( e . g . , cellular LAP 1 [ CIAP1 ] , CIAP2, X - linked IAP [ XIAP ] , NLR family apoptosis inhibitory protein [NAIP ] , and sur [0264 ] analogs , derivatives , fragments and salts thereof. vivin ) , and analogs , derivatives , fragments and salts thereof. [0265 ] Examples of necrosis inhibitors include without [ 0250 ] Apoptosis inhibitors also include inhibitors of cas limitation caspase inhibitors, inhibitors of receptor - interact pases , including but not limited to : ing protein (RIP ) kinases ( e . g ., necrostatins , such as necro [0251 ] inhibitors of the caspase family (pan caspase statins 1 , 5 and 7 ), Necrox compounds (e .g . , Necrox - 2 and inhibitors ), such as quinoline - 2 - carbonyl- Val- Asp (OMe ) - 2 , Necrox - 5 ), Nec - 1s , and analogs , derivatives and salts 6 - difluorophenoxymethylketone ( SEQ . ID . NO . 14 , also thereof . called Q - VD (OME ) - OPh by BioVision , Inc . of Milpitas , Calif . ) , tert -butyloxycarbonyl - Asp ( Me) - fluoromethylke [0266 ] Elevated levels of C - reactive protein (CRP ) are tone (SEO . ID . NO . 15 , aka Boc - D - FMK ) , benzyloxycar found in the blood and eyes of patients with AMD . Elevated CRP levels can increase VEGF production and thereby lead bonyl- Val- Ala - Asp (OME ) -NH2 ( SEQ . ID . NO . 16 , aka to neovascularization . In addition , CRP is implicated in the Z - VAD ), and benzyloxycarbonyl- Val- Ala -Asp ( OME) - fluo pathogenesis of inflammation , and inhibits cholesterol efflux romethylketone (SEQ . ID . NO . 17 , aka Z -VAD -FMK ) ; through down -regulation of the cholesterol efflux proteins [0252 ] inhibitors of caspase - 1, such as benzyloxycarbo ABCA1 and ABCG1. Moreover, monomeric CRP can bind nyl- Tyr - Val- Ala - Asp (OMe ) - fluoromethylketone (SEQ . ID . to the complement protein Clq and subsequently activate NO . 18 , aka Z - YVAD -FMK ) and cytokine response modi the classical complement pathway, which in tandem with the fier A ( crmA ) ; alternative complement pathway can result in the formation [ 0253 ] inhibitors of caspase - 2 , such as benzyloxycarbo of the membrane attack complex (MAC ) and eventually cell nyl- Val -Asp (OM ) - Val -Ala - Asp (OME ) - fluoromethylketone lysis . Accordingly , CRP inhibitors that curtail the level ( e . g . , ( SEQ . ID . NO . 19 , aka Z - VDVAD - FMK ) ; via decreased production or increased breakdown or clear [ 0254 ] inhibitors of caspase - 3 , such as quinoline- 2 -carbo ance ) or the activity of CRP can be used to treat AMD . nyl- Asp (OME ) - Glu ( OME) - Val- Asp ( OME) - 2 ,6 -difluorophe Examples of CRP inhibitors include without limitation noxymethylketone (SEQ . ID . NO . 20 , aka Q -DEVD -OPh ), DPP - 4 inhibitors , thiazolidinediones, stilbenoids , statins , benzyloxycarbonyl- Asp (OME ) -Glu (OMe ) - Val- Asp ( OMe) epigallocatechin - 3 - gallate (EGCG ), CRP - i2 , CRP -targeting fluoromethylketone (SEQ . ID . NO . 21, aka Z -DEVD - FMK ) , anti - sense polynucleotides and anti -sense PNAs, and ana benzyloxycarbonyl- Asp ( OMe) -Gln -Met - Asp (OMe ) - fluo logs , derivatives and salts thereof. romethylketone (SEQ . ID . NO . 22 , aka Z -DQMD -FMK ), [0267 ] The complement system of the innate immune XIAP and survivin ; system is implicated in the pathogenesis of AMD . For [0255 ] inhibitors of caspase -4 , such as benzyloxycarbo example , variants of the CFH gene resulting in defective or nyl- Leu -Glu (OME ) - Val -Asp (OME ) - fluoromethylketone deficient complement factor H (CFH ) are strongly associ ( SEQ . ID . NO . 23 , aka Z -LEVD - FMK ); ated with risk for AMD . Further, the alternative complement [ 0256 ] inhibitors of caspase - 5 , such as benzyloxycarbo pathway may be activated by the accumulation of apolipo nyl- Trp - Glu (OME ) - His - Asp ( Me) - fluoromethylketone proteins ( e . g . , apoE ) and lipofuscin or components thereof ( SEQ . ID . NO . 24 , aka Z - WEHD - FMK ) ; ( e . g . , A2E ) . In addition , the membrane attack complex (MAC , C5b - 9 ) has been documented on choroidal blood [ 0257] inhibitors of caspase -6 , such as benzyloxycarbo vessels , the Bruch ' s membrane (BrM ) and the RPE and is nyl- Val- Glu ( OME) - Ile - Asp ( OMe) - fluoromethylketone associated with abnormal RPE cells , suggesting that (SEQ . ID . NO . 25 , aka Z -VEID -FMK ) and crmA ; complement -mediated cell lysis may accelerate RPE dys [ 0258 ] inhibitors of caspase - 7, such as XIAP and survivin ; function and death in AMD . Moreover, there is a marked [ 0259 ] inhibitors of caspase - 8 , such as quinoline- 2 -carbo accumulation of the MAC in the BrM and the choriocapil nyl- Ile -Glu ( OMe ) - Thr- Asp (OME ) - 2 ,6 - difluorophenoxym laris endothelium of the aging macula . The complement ethylketone (SEQ . ID . NO . 26 , aka Q - IETD -OPh ) , benzy system also plays a significant role in inflammatory and loxycarbonyl- Ile -Glu (OMe ) - Thr - Asp (OME ) oxidative events . As an example , the anaphylatoxins C3a , fluoromethylketone (SEQ . ID . NO . 27 , aka Z - IETD - FMK ), C4a and C5a promote inflammation and generation of and crmA ; cytotoxic oxygen radicals and increase vascular permeabil [0260 ] inhibitors of caspase - 9 , such as quinoline - 2 - carbo ity . For instance , binding ofC3a and C5a to the C3a and C5a nyl- Leu -Glu ( Me) - His - Asp (OMe ) - 2 ,6 - difluorophenoxym receptors , respectively , leads to an inflammatory response , ethylketone (SEQ . ID . NO . 28 , aka Q - LEHD -OPh ) , benzy e . g ., by stimulating mast cell- mediated inflammation via histamine release . Activation of the complement cascade loxycarbonyl- Leu -Glu (OMe ) -His - Asp (OME ) and local inflammation are implicated in , e . g . , drusen for fluoromethylketone (SEQ . ID . NO . 29, aka Z -LEHD -FMK ) , mation , a hallmark of atrophic AMD that can lead to CIAP2 and XIAP ; neovascular AMD . In addition , the complement system is [ 0261 ] inhibitors of caspase - 10 , such as benzyloxycarbo implicated in neovascularization , including CNV . For nyl- Ala -Glu (OME ) - Val- Asp (OMe ) - fluoromethylketone instance , activation of the complement system may result in ( SEQ . ID . NO . 30 , aka AEVD - FMK or Z -AEVD - FMK ); formation of the MAC in the choriocapillary endothelium , [ 0262 ] inhibitors of caspase - 12 , such as benzyloxycarbo whose breakdown by the MAC can lead to hypoxia and thus nyl- Ala - Thr- Ala -Asp ( OME) - fluoromethylketone (SEQ . ID . CNV . Furthermore , some complement components ( e. g. , NO . 31 , aka Z -ATAD - FMK ) ; C5a ) exhibit pro - angiogenic properties — e . g . , the C5a recep US 2018 /0296525 A1 Oct . 18 , 2018

tor mediates increased VEGF secretion in RPE cells. More bodies and fragments thereof ( e . g ., TNT- 009) , serpin 1 (or over, the MAC releases pro -angiogenic molecules ( e . g ., C1 inhibitor, which inhibits C1r, C1s , MASP - 1 and MASP PDGF and VEGF ) . 2 ), BCX - 1470 and nafamostat (both inhibit Cls and CFD ), [0268 ] Alternative to or in addition to inhibition of the SCR1 ( a soluble form of complement receptor 1 [CR1 ] that alternative complement pathway, inhibition of the lectin promotes the dissociation of C3bBb and the cleavage of C3b complement pathway (and / or classic complement pathway ) and C4b by CFI and inhibits the classic and alternative can be beneficial in the treatment of atrophic AMD and /or complement pathways) , TT30 (a fusion protein linking the neovascular AMD . For example , inhibition of a mannan C3 fragment -binding domain of complement receptor 2 binding lectin serine protease ( or mannose - associated serine [CR2 ] with the alternative pathway - inhibitory domain of protease (MASP ]) ( e . g ., MASP - 1 , - 2 or - 3 ) using , e . g . , an CFH which inhibits the C3 convertase, C3b , the alternative antibody or a fragment thereof ( e . g ., OMS721 , an anti pathway and MAC formation ), CFH -related protein 1 MASP - 2 antibody ) , can dampen amplification of comple (CFHR1 , which inhibits the C5 convertase , C5b deposition ment activation and sequelae thereof, such as inflammation . and MAC formation ) , anti - CFB antibodies and fragments In the lectin pathway , MASPs cleave C2 and C4 to form thereof ( e . g . , bikaciomab and TA106 ) , anti -CFD antibodies C2ac4b , a C3- convertase . At the border of the lectin and and fragments thereof (e .g . , lampalizumab [FCFD45148 ]) , alternative pathways , the C3 - convertase cleaves C3 into C3a other CFD inhibitors ( e . g . , ACH -4471 ) , anti - CFP (proper and C3b . C3b binds to C2aC4b to form a C5 - convertase , din ) antibodies and fragments thereof ( e . g ., NM9401 ) , C3 which cleaves C5 into C5a and C5b . C5 , C6 , C7 , C8 and convertase dissociation promoters or formation inhibitors C9 together form the membrane attack complex (MAC ), ( e . g ., CFH and fragments thereof ?e . g ., AMY- 201 ] , soluble which may result in cell lysis via cell swelling and bursting . complement receptor 1 [SCR1 such as CDX - 1135 ] and Complement factors H and I inactivate C3b and downregu fragments thereof ( e . g . , mirococept] , C4b - binding protein late the alternative pathway, thereby suppressing inflamma [ C4BP ] and decay accelerating factor [DAF ]) , anti- C3 anti tion , for example . By inhibiting the formation of the C3- con bodies and fragments thereof, compstatin and analogs and vertase C2aC4b , a MASP inhibitor can be useful for treating derivatives thereof ( e . g . , POT- 4 ( AL -78898A ) and Peptides atrophic AMD and / or neovascular AMD . I through IX disclosed in R . Gorham et al. , Exp . Eye Res. , [ 0269 ] Accordingly , AMD can be treated using inhibitors 116 : 96 - 108 (2013 ) } ( inhibit C3 , C3 convertase and MAC of the complement system or components ( e . g ., proteins and formation ), mycophenolic acid -glucosamine conjugates factors ) thereof ( e . g . , CFB , CFD , C2 , C2a , C2b , C4 , C4a , (downregulators of C3 ), other C3 inhibitors ( e. g ., AMY- 101 , C4b , C3- convertases [ e . g ., C2ac4b and C3bBb ] , C3 , C3a , APL - 2 , CB - 2782 and neurotropin ), 3E7 (an anti - C3b / iC3b C3b , C3a receptor, C3 [ H , 0 ] , C3 [ H , O ]Bb , C5 - convertases monoclonal antibody) , promoters of C3b and C4b cleavage [ e . g . , C2aC4bC3b and C3bBbC3b ] , C5 , C5a, C5b , C5a ( e . g . , CFI, CFH , C4BP, SCR1 and soluble membrane cofac receptors , C6 , C7 , C8 , C9 and MAC [C5b - 9 ] ) . As an tor protein [ SMCP ] ), anti -C5 antibodies and fragments illustrative example , compstatin inhibits activation of the thereof (e . g . , eculizumab [ inhibits C5 and MAC formation ) , complement system by binding to C3 , the converging pro Ergidina , Mubodina , ABP959 , ALXN1210 , LFG316 , tein of all three complement activation pathways , and inhib MEDI- 7814 and R07112689 [SKY59 ] ), anti -C5 aptamers iting the cleavage of C3 to C3a and C3b by C3 -convertases . ( e . g ., ARC1905 ?avacincaptad pegol or ZIMURA® ], an [ 0270 ] As another example, lampalizumab is an antigen inhibitor of C5 cleavage ) , other C5 inhibitors ( e . g . , binding fragment (Fab ) of a humanized monoclonal antibody RA101495 and Coversin ), anti -C5a antibodies and frag targeting complement factor D (CFD ) , the rate - limiting ments thereof (e . g. , IFX - 1 [CaCP - 29 ] and MEDI- 7814 ) , enzyme involved in the activation of the alternative comple anti - C5a aptamers ( e . g . , NOX -D19 ) , C5a receptor antago ment pathway (ACP ) . CFD cleaves CFB into the proteolyti nists ( e . g ., ADC - 1004 , CCX - 168 , JPE - 1375 , JSM -7717 , cally active factor Bb . Bb binds to spontaneously hydrolysed PMX -025 , Ac - F [OPdChaWR ] { PMX -53 } and PMX - 205 , C3 C3 ( H , O ) ], which leads to the formation of the C5 - con and anti- C5aR antibodies and fragments thereof ( e . g . , neu vertase C3bBbc3b . Hyperactivity of the ACP is implicated trazimab , NN8209 and NN8210 ]) , apo A - I mimetics (e . g ., in the development of AMD , including geographic atrophy L -4F , an inhibitor of complement activation ) , CD59 and (GA ). Lampalizumab inhibits complement activation and modified CD59 having a glycolipid anchor ( inhibit binding inflammation and can be used to treat or slow the progres of C9 to C5b - 8 complex and hence MAC formation ) , sion of AMD , including GA . Atrophic AMD patients with a tandospirone (reduces complement deposits ) , zinc ( inhibits mutation in complement factor I (CFI ) appear to exhibit a complement activation and MAC deposition ), KSI- 401 more positive response to lampalizumab treatment. In the (blocks activation of the complement system ), and analogs, MAHALO Phase II trial , patients receiving monthly intra derivatives, fragments and salts thereof. vitreal injections of 10 mg lampalizumab in one eye for 18 10272 ] Inflammation is also an important contributor to the months exhibited a reduction in the rate ofGA enlargement, pathogenesis of AMD , and AMD is associated with chronic and hence the area ofGA , in the injected eye by about 20 % inflammation in the region of the RPE , the BrM and the according to fundus autofluorescence compared to patients choroid . For example , inflammatory responses may be receiving a placebo . A subgroup of patients positive for CFI involved in drusen formation , and can upregulate the expres mutations and receiving monthly intravitreal injections of 10 sion of VEGF and other pro - angiogenic factors that cause mg lampalizumab for 18 months exhibited an enhanced neovascularization , including CNV . Inflammation can be reduction in the GA growth rate , and hence the area of GA , mediated by the cellular immune system ( e . g ., dendritic by about 44 % compared to placebo . CFI, a C3b /C4b inac cells ) and / or the humoral immune system ( e . g . , the comple tivator, regulates complement activation by cleaving cell ment system ). Inflammation can also be mediated by inflam bound or fluid - phase C3b and C4b . masomes, which are components of the innate immune [0271 ] Non - limiting examples of inhibitors of the comple system . For example , accumulation of material ( e . g ., lipo ment system or components thereof include anti- Cls anti protein - like particles , lipids and possibly lipofuscin or com US 2018 /0296525 A1 Oct . 18 , 2018 ponents thereof ( e . g . , A2E ]) in the BrM may activate the as Ac2 -26 and CGEN -855A ), and analogs, derivatives , NLRP3 inflammasome, leading to a chronic inflammatory fragments and salts thereof. Glucocorticoids also inhibit the response . In addition , assembly of inflammasomes ( e . g ., synthesis of prostaglandins by cyclooxygenases 1 and 2 NLRP3 ) in response to cell - stress signals activates caspases (COX - 1 and COX - 2 ) , akin to NSAIDs. ( e . g . , caspase - 1 ) , which results in inflammation ( e . g . , via [ 0277 ] Examples of non - steroidal anti - inflammatory drugs production of pro - inflammatory interleukin - 1B ) and ulti (NSAIDs ) include without limitation : mately cell death ( e . g . , of RPE cells) . [0278 ] acetic acid derivatives , such as aceclofenac , bro [0273 ] Many of the substances mentioned in this disclo mfenac , diclofenac , etodolac , indomethacin , ketorolac , sure possess anti - inflammatory property in addition to the nabumetone , sulindac , sulindac sulfide, sulindac sulfone and property or properties described for them . Other anti - inflam tolmetin ; matory agents include without limitation hydroxychloro 102791 anthranilic acid derivatives ( fenamates ) , such as quine, corticosteroids ( e . g . , fluocinolone acetonide and tri flufenamic acid , meclofenamic acid , mefenamic acid and amcinolone acetonide ) , steroids having little glucocorticoid tolfenamic acid ; activity ( e . g . , anecortave ?anecortave acetate ] ) , non - steroidal [0280 ] enolic acid derivatives ( oxicams) , such as droxi anti- inflammatory drugs ( e . g ., non - selective cyclooxygenase cam , isoxicam , lornoxicam , meloxicam , piroxicam and ten [COX ] 1 /COX - 2 inhibitors ?e . g ., aspirin and bromfenac ) and oxicam ; COX - 2 -selective inhibitors [ e . g ., coxibs ]) , mast cell stabi [0281 ] propionic acid derivatives, such as fenoprofen , lizers and inflammasome inhibitors . flurbiprofen , ibuprofen , dexibuprofen , ketoprofen , dexketo [ 0274 ] Examples of inhibitors of inflammasomes ( e . g ., profen , loxoprofen , naproxen and oxaprozin ; inhibitors of their assembly or function include without [ 0282 ] salicylates , such as diflunisal , salicylic acid , ace limitation NLRP3 (NALP3 ) inhibitors ( e. g. , interleukin - 4 tylsalicylic acid (aspirin ), choline magnesium trisalicylate , [ IL - 4 ], myxoma virus M013 protein , omega - 3 fatty acids, and salsalate ; anthraquinones [ e . g ., chrysophanol] , sesquiterpene lactones [0283 ] COX -2 -selective inhibitors , such as apricoxib , [ e . g ., parthenolide ] , sulfonylureas [ e . g . , glyburide ) , triterpe celecoxib , etoricoxib , firocoxib , fluorocoxibs (e . g ., fluoro noids [ e . g ., asiatic acid ] and vinyl sulfones [ e . g ., Bay coxibs A - C ), lumiracoxib , mavacoxib , parecoxib , rofecoxib , 11 - 7082 ]) , NLRP3 / AIM2 inhibitors ( e . g . diarylsulfonylu tilmacoxib (JTE -522 ) , valdecoxib , 4 - 0 -methylhonokiol , reas ?e . g . , CP -456 ,773 ] ) , NLRP1 inhibitors ( e . g . , Bcl- 2 , the niflumic acid , DuP -697 , CG100649 , GW406381 , NS - 398 , loop region of Bcl- 2 , and Bcl - X [L ]) , NLRP1B inhibitors SC - 58125 , benzothieno [ 3 , 2 - d ]pyrimidin - 4 - one sulfonamide ( e. g ., auranofin ), and analogs , derivatives, fragments and thio -derivatives , and COX - 2 inhibitors derived from Tribu salts thereof. Peptide 5 ( PeptagonTM ) is derived from the lus terrestris ; second extracellular loop of human Connexin43 (Cx43 ) . 10284 ] other kinds of NSAIDs, such as monoterpenoids Peptide5 blocks pathological Cx43 hemichannels , thereby ( e .g ., eucalyptol and phenols [ e. g ., carvacrol] ) , anilinopyri inhibiting the release of ATP and activation of the inflam dinecarboxylic acids ( e . g . , clonixin ) , sulfonanilides ( e . g . , masome pathway of inflammation . Inhibition of the inflam nimesulide ), and dual inhibitors of lipooxygenase (e .g ., masome pathway of inflammation reduces the release of 5 - LOX ) and cyclooxygenase ( e . g . , COX - 2 ) ( e . g ., chebulagic inflammatory cytokines and reduces tissue / cell damage , and acid , licofelone , 2 -( 3 , 4 , 5 - trimethoxyphenyl) - 4 - ( N -methylin hence Peptide5 also serves as a neuroprotector of retinal dol- 3 -yl ) thiophene, and di- tert -butylphenol - based com cells . pounds [ e . g . , DTPBHZ, DTPINH , DTPNHZ and [ 0275 ] Non - limiting examples of corticosteroids (includ DTPSAL ] ) ; and ing glucocorticoids but not mineralocorticoids ) include [0285 ] analogs, derivatives and salts thereof. hydrocortisone types ( e . g ., cortisone , hydrocortisone ( corti [0286 ] In non -central and central geographic atrophy ,mast sol] , prednisolone , methylprednisolone , prednisone and cells degranulate in the choroid , releasing histamine and tixocortol) , betamethasone types ( e . g ., betamethasone, dex other mediators of inflammation . Mast cell stabilizers block amethasone and fluocortolone ), halogenated steroids ( e .g ., a calcium channel essential for mast cell degranulation , alclometasone, beclometasone, beclometasone dipropionate stabilizing the mast cell and thereby preventing the release ?e . g ., AGN - 208397 ] , clobetasol, clobetasone, desoximeta of histamine and other inflammation mediators . Examples of sone , diflorasone , diflucortolone, fluprednidene, fluticasone , mast cell stabilizers include without limitation B2- adrenergic halobetasol [ulobetasol ] , halometasone and mometasone ), receptor agonists , cromoglicic acid , ketotifen , methylxan acetonides and related substances ( e . g . , amcinonide , budes thines , nedocromil , olopatadine , omalizumab , pemirolast , onide , ciclesonide , desonide, fluocinonide, fluocinolone quercetin , tranilast, and analogs , derivatives and salts acetonide, flurandrenolide [ fludroxycortide ], halcinonide, thereof. Examples of short - acting B2 - adrenergic agonists triamcinolone acetonide and triamcinolone ) , carbonates include without limitation bitolterol, fenoterol, isoprenaline ( e . g . , prednicarbate ), and analogs, derivatives and salts ( isoproterenol) , levosalbutamol ( levalbuterol) , orciprenaline thereof. (metaproterenol ) , pirbuterol, procaterol, ritodrine , salbuta [ 0276 ] A major mechanism of glucocorticoids ' anti -in mol ( albuterol) , terbutaline, and analogs, derivatives and flammatory effects is stimulation of the synthesis and func salts thereof. Non - limiting examples of long- acting tion of annexins (lipocortins ) , including annexin A1. Annex B2 -adrenergic agonists include arformoterol, bambuterol , ins , including annexin Al , suppress leukocyte inflammatory clenbuterol, formoterol, salmeterol, and analogs , derivatives events ( including epithelial adhesion , emigration , chemot and salts thereof. Examples of ultralong - acting B2 -adrener axis , phagocytosis and respiratory burst ), and inhibit phos gic agonists include without limitation carmoterol, inda pholipase A2 , which produces the potent pro - inflammatory caterol , milveterol, olodaterol, vilanterol, and analogs , mediators prostaglandins and leukotrienes . Therefore , anti derivatives and salts thereof. inflammatory agents include annexins ( e .g ., annexin A1) , [0287 ] In summary, examples of anti - inflammatory agents annexin mimetic peptides ( e .g ., annexin A1 mimetics , such include without limitation hydroxychloroquine , anti -amy US 2018 /0296525 A1 Oct . 18 , 2018 loid agents , antioxidants , apolipoprotein mimetics ( e . g . , cell differentiation , angiogenesis and apoptosis . For apoA - I mimetics and apoE mimetics ) , C - reactive protein example , as AMD progresses to the advanced stage , elevated inhibitors , complement inhibitors , inflammasome inhibitors , levels of MMPs can degrade the Bruch ' s membrane (BrM ) , neuroprotectors ( e . g ., glatiramer acetate ) , corticosteroids an ECM and part of the choroid . Endothelial cells migrate glucocorticoids, steroids having little glucocorticoid activity along the ECM to the site of injury , proliferate , form ( e . g . , anecortave ) , annexins ( e . g ., annexin Al) and mimetic endothelial tubes , and mature into new blood vessels that peptides thereof, non - steroidal anti - inflammatory drugs arise from capillaries in the choroid and grow through the (NSAIDs ) , tetracyclines ( e . g . , minocycline ) , mast cell sta fractured BrM . Furthermore , breakage in the Brm may bilizers , omega - 3 fatty acids and esters thereof, cyclopen allow endothelial cells to migrate into the sub -RPE -BL tenone prostaglandins , anti - angiogenic agents ( e . g . , anti space and form immature blood vessels that are leaky and VEGF/ VEGFR agents , tissue factor inhibitors and kallikrein tortuous and may extend into the subretinal space . The net inhibitors ), inhibitors of pro - inflammatory cytokines ( e . g ., result is neovascularization ( including CNV ) and develop IL - 2 , IL - 6 , IL - 8 and TNF - a ), inhibitors of signal transducer ment of neovascular AMD . MMPs can also cleave peptide and activator of transcription (STAT ) proteins or their acti bonds of cell - surface receptors , releasing pro -apoptotic vation { e . g . , suppressor of cytokine signaling ( SOLS ) ligands such as FAS . MMP inhibitors can be used , e .g ., to mimetic peptides ( e . g ., SOCS1 mimeties ?e . g . SOC1- KIR , inhibit angiogenesis and apoptosis , and to treat neovascular NewSOCS1 -KIR , PS - 5 and Tkip ] and SOCS3 mimeties ) , AMD ( including types 1 , 2 and / or 3 neovascularization ) or and immunosuppressants . atrophic AMD ( including non - central and/ or central geo [ 0288 ] Pro - inflammatory cytokines associated with the graphic atrophy ) . For example , doxycycline curtails loss of development and progression of AMD include without limi photoreceptors . Non -limiting examples of MMP inhibitors tation IL - 6 and IL - 8 . Therefore, inhibitors of the signaling , include tissue inhibitors of metalloproteinases ( e . g . , TIMPs production or secretion of IL -6 and IL - 8 can be used to treat 1 , 2 , 3 and 4 ) , tetracyclines ( e . g . , doxycycline, incyclinide atrophic AMD and /or neovascular AMD . Inhibitors of IL -6 and minocycline [ e. g ., NM108 ]) , dichloromethylenediphos include without limitation clazakizumab , elsilimomab , phonic acid , batimastat, cipemastat, ilomastat, marimastat , olokizumab , siltuximab and sirukumab , and inhibitors of the prinomastat , rebimastat , tanomastat, ABT -770 , MMI- 166 , IL - 6 receptor ( IL -6R ) include without limitation sarilumab MMI- 270 , Ro 28 - 2653 , RS - 130830 , CAS Reg . No . ( CRN ) and tocilizumab . Inhibitors of the production of IL - 6 include 239796 - 97 - 5 , CRN 420121 - 84 - 2 , CRN 544678 - 85 - 5 , CRN without limitation nafamostat, prostacyclin , tranilast, M013 556052 - 30 - 3 , CRN 582311 - 81 - 7 , CRN 848773 -43 - 3 , CRN protein , apoE mimetics ( e. g ., AEM - 28 and hEp ), omega -3 868368 - 30 - 3 , and analogs, derivatives, fragments and salts fatty acids and esters thereof, glucocorticoids , immuno thereof modulatory imides (e .g ., thalidomide , lenalidomide , [0291 ] Alternative to or in addition to MMP inhibitors , pomalidomide and apremilast ) , and TNF - a inhibitors ( in other kinds of inhibitors of cell migration can be utilized . fra ) . Inhibitors of the production of IL - 8 include without For example, rho kinase (ROCK ) inhibitors, including limitation alefacept, glucocorticoids and tetracyclines ( e . g ., ROCK1 and ROCK2 inhibitors, block cell migration , doxycycline , minocycline and tetracycline ). In addition , including endothelial cell migration in the early stages of statins inhibit the secretion of IL - 6 and IL - 8 from , e . g . , RPE neovascularization . Examples of ROCK inhibitors include cells . without limitation fasudil, netarsudil , ripasudil, AMA -0428 , [ 0289 ) Other therapeutic agents that can be used to treat GSK - 429286A , RKI- 1447 , Y - 27632 and Y -30141 . atrophic AMD and /or neovascular AMD include immuno 10292 ] In some circumstances, the use of an MMP acti suppressants . Immunosuppressants can have anti - inflamma vator rather than an MMP inhibitor may be desired . The tory property . Examples of immunosuppressants include , BrM undergoes constant turnover, mediated by MMPs and but are not limited to , glatiramer acetate, inhibitors of TIMPs . The Brm thickens progressively with age , partly interleukin - 2 ( IL - 2 ) signaling , production or secretion ( e . g ., because of increased levels of TIMPs and a resulting reduc antagonists of the IL - 2 receptor alpha subunit [e .g . , basil tion in ECM turnover . Thickening of ECM in the BrM with iximab and daclizumab ], glucocorticoids, mTOR inhibitors age may result in the BrM ' s retention of lipoproteins [ e .g ., rapamycin (sirolimus ), deforolimus ( ridaforolimus ), secreted by the RPE , eventually leading to the formation of everolimus, temsirolimus, umirolimus (biolimus A9 ) and BLind and drusen . The accumulation of lipid - rich BLind zotarolimus ) , and calcineurin inhibitors ?e . g . , cyclosporine , and basal laminar deposits (BLamD , which are excess pimecrolimus and tacrolimus ] ) , and inhibitors of tumour extracellular matrix in thickened RPE - BL ) lengthen the necrosis factors ( e . g . , TNF - a ) ( e . g ., adalimumab , certoli diffusion distance between the choriocapillaris and the RPE . zumab pegol, golimumab , infliximab , etanercept, bupro An MMP activator can be used to achieve greater BrM pion , ART- 621 , immunomodulatory imides and xanthine turnover and less thickening of the BrM , but not to the point derivatives ( e . g . , lisofylline , pentoxifylline and propentof where the BrM becomes so degraded that new blood vessels ylline ] ) . Immunosuppressants also include agents that sup can grow through the BrM . Examples of MMP activators press gene transcription related to inflammatory M1 mac include without limitation basigin ( extracellular matrix met rophages , such as TMi-018 . As a non - limiting example of alloproteinase inducer EMMPRIN ] or CD147 ) , concanava the potential benefits of the use of an immunosuppressant, an lin A , cytochalasin D , and analogs , derivatives , fragments immunosuppressant can reduce the number or frequency of and salts thereof. Similarly , an MMP activator, or a matrix administration of an anti - angiogenic agent ( e . g . , the number metalloproteinase , can be employed to reduce the thickness or frequency of injections of an anti- VEGF / VEGFR agent ) of BLamb persisting over the BrM . in the treatment of neovascular AMD . [0293 ] Angiogenesis is the underlying mechanism of neo [0290 ] Matrix metalloproteinases (MMPs ) degrade extra vascularization ( including types 1 , 2 and 3 ), which can occur cellular matrix (ECM ) proteins and play an important role in in the advanced stage of AMD to lead to neovascular AMD cell migration ( dispersion and adhesion ) , cell proliferation , and severe vision loss if left untreated . Neovascular AMD is US 2018 /0296525 A1 Oct . 18 , 2018 characterized by vascular growth and fluid leakage in the SF0166 , and anti- integrin antibodies and fragments thereof) , choroid , the sub -RPE -BL space , the subretinal space and the tissue factor ( TF ) inhibitors ( e . g ., anti - TF antibodies and neural retina . Leakage from blood vessels can be more fragments thereof and fusion proteins thereof ( e . g . , ICON responsible for vision loss associated with neovascular 1 ] ) , kallikrein inhibitors ( e . g ., avoralstat (BCX4161 ] , AMD than growth of new blood vessels . Vascular endothe BCX7353 , ecallantide [DX - 88 ] , KVD001, and anti -kal lial growth factors (VEGFs ) are pivotal in the pathogenesis likrein antibodies and fragments thereof (e .g . , DX - 2930 ]) , of neovascular AMD . VEGFs are potent, secreted endothe serine/ arginine -protein kinase 1 (SRPK1 ) inhibitors ( e . g ., lial- cell mitogens that stimulate the migration and prolifera SPHINX31 ) , Src kinase inhibitors ( e . g . , SKI- 606 and tion of endothelial cells, and increase the permeability of TG100572 ) , anecortave ( anecortave acetate ) , angiostatin new blood vessels, resulting in leakage of fluid , blood and ( e . g . , angiostatin K1- 3 ) , außz inhibitors ( e . g ., etaraci proteins from them . In addition , VEGFs increase the level of zumab ) , apoA - I mimetics ( e . g . , L -4F and L - 5F ) , apoE MMPs , which degrade the ECM further. Moreover , VEGFs mimetics ( e . g ., apo Edp ) , azurin (50 - 77 ) (p28 ) , berberine , enhance the inflammatory response . However, VEGFs or bleomycins, borrelidin , carboxyamidotriazole , cartilage -de receptors therefor are not the only potential targets for rived angiogenesis inhibitors ( e . g ., chondromodulin I and anti - angiogenic agents . For example , targeting integrins troponin I ), castanospermine , CM101, inhibitors of the associated with receptor tyrosine kinases using an integrin complement system , corticosteroids ( including glucocorti inhibitor ( e. g ., ALG - 1001 [LUMINATE® ]) inhibits the pro coids ), cyclopropene fatty acids (e . g ., sterculic acid ), a - di duction and growth of new blood vessels and reduces the fluoromethylornithine , endostatin , everolimus , fumagillin , permeability ( leakage ) of blood vessels. Angiogenesis can genistein , heparin , interferon - a , interleukin - 12 , interleukin also be inhibited through inhibition of other targets , includ 18 , itraconazole , KV11, linomide , MMP inhibitors , ing without limitation kinases ( e . g ., tyrosine kinases , such as 2 -methoxyestradiol , pigment epithelium - derived factor receptor tyrosine kinases ) and phosphatases ( e . g . , tyrosine (PEDF ) , platelet factor- 4 , PPAR - a agonists ( e . g . , fibrates ) , phosphatases , such as receptor tyrosine phosphatases) . PPAR Y- agonists ( e . g . , thiazolidinediones ) , prolactin , rapamycin ( sirolimus) , anti -angiogenic siRNA , sphin 10294 ] Anti -angiogenic agents can be used to prevent or gosine - 1 -phosphate inhibitors (e . g. , sonepcizumab ), curtail neovascularization ( including types 1 , 2 and 3 ) , and squalene , staurosporine , angiostatic steroids ( e . g . , tetrahy to reduce the permeability / leakage of blood vessels . For drocortisol) plus heparin , stilbenoids , suramin , SU5416 , example , interleukin - 18 ( IL - 18 ) eliminates VEGFs from the tasquinimod , tecogalan , tetrathiomolybdate, thalidomide eye , thereby inhibiting the formation of damaging blood and derivatives thereof ( e . g . , lenalidomide and pomalido vessels behind the retina . Non - limiting examples of anti mide ), thiabendazole , thrombospondins ( e . g . , thrombospon angiogenic agents include inhibitors of VEGFs { e . g ., squala din 1 ) , TNP -470 , tranilast , triterpenoids ?e . g . , oleanolic acid mine , ACU -6151 , LHA - 510 , PAN - 90806 , anti- VEGF anti analogs such as TP - 151 (CDDO ) , TP - 155 (CDDO methyl bodies and fragments thereof ( e . g . , bevacizumab ester ) , TP - 190 , TP - 218 , TP -222 , TP - 223 (CDDO carboxam [ AVASTIN® ], ranibizumab [LUCENTIS® ], brolucizumab ide ) , TP - 224 (CDDO monomethylamide) , TP - 225 , TP - 226 FRTH258 ) , ENV1305 , ESBA903 and ESBA1008 ) , anti VEGF immunoconjugates ( e . g ., KSI- 301) , anti- VEGF (CDDO dimethylamide ) , TP - 230 , TP - 235 (CDDO imida aptamers ( e .g ., pegaptanib [MACUGEN® ]) , anti -VEGF zolide ) , TP - 241, CDDO monoethylamide , CDDO mono designed ankyrin repeat proteins (DARPins ) ( e. g ., abicipar ( trifluoroethyl) amide and ( + ) - TBE - B ] , tumstatin and fusion pegol [ AGN - 150998 or MP0112 ] ) , soluble VEGFRs ( e . g . , proteins thereof ( e . g . , OCU200 ) , vasostatin , vasostatin 48 , VEGFR1) , and soluble fusion proteins containing one or Withaferin A , and analogs, derivatives , fragments and salts more extracellular domains of one or more VEGFRs ( e . g ., thereof. VEGFR1, VEGFR2 and VEGFR3 ) (e . g. , aflibercept [EY [02951 One or more anti -angiogenic agents can be admin LEA® ], conbercept and OPT- 302 ,) } , inhibitors of receptors istered at an appropriate time to prevent or reduce the risk of for VEGFs ( e . g . , VEGFR1 and VEGFR2) ( e . g . , axitinib , developing pathologies that can lead to severe vision loss . In fruquintinib , pazopanib , regorafenib , sorafenib , sunitinib certain embodiments , one or more anti - angiogenic agents [ e . g . , GB - 102 ] , tivozanib , isoxanthohumol, pristimerin , are administered prior to occurrence of scar formation KPI- 285 , PF - 337210 , PP1 , TG100572 , X - 82 , D - (LPR ) , and ( fibrosis ) or a substantial amount thereof. anti -VEGFR antibodies and fragments thereof ( e .g . , ramu [ 0296 ] The anti - angiogenic agents described herein may cirumab ] ) , inhibitors of platelet- derived growth factors have additional beneficial properties . For example, the anti (PDGFs ) { e . g ., squalamine, PP1, anti- PDGF aptamers ( e . g . , PDGF aptamer E10030 may also have an antifibrotic effect E10030 [FOVISTA® ] and pegpleranib ), anti- PDGF anti by reducing subretinal fibrosis , which can lead to central bodies and fragments thereof ( e. g ., rinucumab ), and soluble vision loss in about 10 - 15 % of people with neovascular PDGFRs or receptors therefor (PDGFRs ) ( e . g ., axitinib , AMD . pazopanib , sorafenib , sunitinib , X -82 , and anti -PDGFR anti [0297 ] In some embodiments , two or more anti - angio bodies and fragments thereof ( e .g ., REGN2176 -3 ]) , inhibi genic agents targeting different mechanisms of angiogenesis tors of fibroblast growth factors (FGFs ) ( e . g ., squalamine , are used to inhibit neovascularization ( including types 1 , 2 anti- FGF antibodies and fragments thereof, anti - FGF aptam and 3 ) , decrease the permeability /leakage of blood vessels ers and soluble FGFRs) or receptors therefor ( FGFRs ) ( e . g ., and treat neovascular AMD . In certain embodiments , the pazopanib and anti- EGFR antibodies and fragments two or more anti- angiogenic agents comprise an anti - VEGF/ thereof) , inhibitors of angiopoietins ( e . g . , anti- angiopoietin VEGFR agent ( e . g ., aflibercept, brolucizumab , bevacizumab antibodies and fragments thereof such as nesvacumab or ranibizumab ) and an agent targeting a different mecha [REGN910 ] and REGN910 - 3 , and soluble angiopoietin nism of angiogenesis . In some embodiments , the two or receptors) or receptors therefor ( e . g , antibodies and frag more anti - angiogenic agents comprise an anti -VEGF / ments thereof against angiopoietin receptors ) , inhibitors of VEGFR agent and an anti -PDGF / PDGFR agent, such as integrins (e . g . , ALG - 1001 [LUMINATE® ], JSM -6427 , bevacizumab or ranibizumab and E10030 , or aflibercept and US 2018 /0296525 A1 Oct . 18 , 2018 30

REGN2176 - 3 . E10030 blocks PDGF - B from binding to its ture and function and improves the transport of incoming natural receptor on pericytes, causing pericytes to be oxygen and micronutrients ( including vitamin A ) and out stripped from newly formed abnormal blood vessels . Left going waste between the choriocapillaris and the RPE and unprotected , the endothelial cells are highly vulnerable to thereby improves the health of RPE cells . Therefore , an the effects of an anti -VEGF agent. Because of this ability to advanced -stage AMD patient can first be treated with a strip pericytes , E10030 may have an effect on both immature lipid - clearing apo mimetic ?e . g . , an apoA - I mimetic ( e . g . , blood vessels and more mature blood vessels slightly later in L -4F ) and / or an apoE mimetic ( e . g ., AEM -28 - 14 ) ] and then the disease process . In further embodiments , the two or more receive RPE cell replacement ( e . g ., via one or more injec anti - angiogenic agents comprise an anti - VEGF /VEGFR tions into or implantations in , e . g . , the space below the agent and an anti - angiopoietin / angiopoietin receptor agent, retina ). The new RPE cells can prevent disease progression such as aflibercept and nesvacumab or REGN910 - 3 . by replacing dead and dying RPE cells . The RPE cells can [0298 ] Alternatively, an anti -angiogenic agent targeting be , e . g ., RPE cells derived from stem cells ( e . g . , human different mechanisms of angiogenesis can be employed to embryonic stem cells [hESC ) , human neural stem cells treat, e . g . , neovascular AMD . For example , a bispecific [ hNSC ] , human central nervous system stem cells [hCNS antibody or DARPin targeting VEGF /VEGFR and PDGF/ SC ) , bone marrow stem cells (BMSC ) , mesenchymal stem PDGFR , or a bispecific antibody or DARPin targeting cells (MSC , such as ischemic tolerant MSCs that are allo VEGF /VEGFR and angiopoietin / angiopoietin receptor, can geneic RPE progenitors ] and induced pluripotent stem cells be used . ( iPSC ) , including autologous stem cells and stem cells [0299 ] AMD can also be treated with other kinds of derived from donor cells ) or RPE cells obtained from the therapy, including laser photocoagulation therapy (LPT ), translocation of full - thickness retina . In certain embodi photodynamic therapy (PDT ) and radiation therapy (RT ). ments , the RPE cells are derived from human embryonic LPT employs , e . g ., an argon ( Ar) laser, a micropulse laser or stem cells (e . g ., CPCB -RPE1 cells , MA09 - ARPE cells or a nanosecond laser , or any combination thereof, and can OPREGEN® cells ) or induced pluripotent stem cells . reduce or eliminate drusen in patients with atrophic AMD or Human retinal progenitor cells ( e . g ., jCell cells ) can also be neovascular AMD . Laser surgery can also be employed to implanted or injected (e . g. , intravitreally ) to rescue and destroy abnormal blood vessels in the eye and generally is reactivate diseased photoreceptors , or to replace dead pho suitable if the growth of abnormal blood vessels is not too toreceptors, for treatment of AMD (and retinitis pigmen extensive and the abnormal blood vessels are not close to the tosa ) . Removal of lipid deposits in the eye by the apo fovea. PDT utilizes a laser in combination with a compound mimetic can lead to beneficial effects such as curtailment of ( e . g . , verteporfin ) that, upon activation by light of a particu local inflammation , oxidative stress and complement acti lar wavelength , injures target cells and not normal cells . A vation , which can aid in preventing or forestalling RPE cell steroid can optionally be administered in PDT. PDT is often atrophy and death . employed to treat polypoidal neovasculopathy, the most [0301 ] As an example of an RPE cell replacement therapy , common form of neovascularization in Asian populations . RPE cells can be introduced as a sheet on a polymer or other Examples of RT include without limitation external beam suitable carrier material that allows the cells to interdigitate irradiation , focal radiation ( e . g ., via intravitreal, transvitreal with remaining photoreceptors and to resume vital phago or transpupillary delivery ) ( e .g . , transvitreal delivery of cytosis and vitamin A transfer functions, among other func strontium 90 [°°Sr ] X - ray at 15 Gy or 24 Gy doses ) , and tions . A lipid -clearing apo mimetic [ e . g . , an apo A - I mimetic radiation in combination with an anti -VEGF / VEGFR agent ( e . g ., L - 4F ) and / or an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] ( e. g ., transvitreal delivery of 9°Sr X - ray at a single 24 Gy improves traffic of incoming oxygen and nutrients and dose combined with bevacizumab , or 16 Gy X -ray com outgoing waste across the BrM and thereby improves the bined with ranibizumab ) . PDT or RT can be provided to health of cells in the surrounding area . Optionally in com reduce neovascularization ( e . g . , CNV ) and limit vision loss bination with an agent ( e . g ., an MMP activator or a matrix or improve visual acuity in patients with neovascular AMD . metalloproteinase ) that reduces the thickness of basal lami In some embodiments , LPT, PDT or RT, or any combination nar deposits (BLamD ) persisting over the BrM , the apo or all thereof, is provided to a patient with neovascular AMD mimetic aids in the preparation of a suitable transplant bed who does not respond adequately to treatment with an for the sheet of RPE cells, which benefit from a clear path anti -angiogenic agent ( e. g. , an anti- VEGF /VEGFR agent) . from the choriocapillaris to the transplant scaffolding . [0300 ] Stem cell -derived retinal pigment epithelium [0302 ] As another example of an RPE cell replacement (RPE ) cells and photoreceptors can rescue the retina , replace therapy , cells can be introduced into the eye by a non lost retinal neurons, and restore or improve vision . Stem surgical method . Bone marrow cells can be re - programmed cell - derived RPE cells produce neurotrophic factors that to home in on the RPE layer and to take up residence among promote the survival of photoreceptors. Therefore , cell the native RPE cells . An apo mimetic [ e . g . , an apoA - I replacement therapies and stem cell - based therapies , such as mimetic ( e . g ., L -4F ) and/ or an apoE mimetic ( e . g . , AEM stem cell -derived RPE cells and photoreceptors , can be 28 - 14 ) ] , optionally in combination with an agent ( e . g . , an employed to treat AMD . As an illustrative example , an MMP activator or a matrix metalloproteinase ) that reduces apolipoprotein mimetic ?e . g . , an apoA - I mimetic ( e . g . , L - 4F ) the thickness of BLamD persisting over the BrM , increases and / or an apoE mimetic ( e . g . , AEM - 28 - 14 ) ] can be used in the transport of incoming oxygen and nutrients and outgoing combination with RPE cell replacement to treat, e . g ., waste across the BrM and thereby improves the health of advanced - stage AMD , including central geographic atrophy cells in the RPE layer. and neovascular AMD . RPE cells may atrophy and die as a [0303 ] RPE rejuvenation can also be practiced . For result of rampant lipid deposition in the sub - RPE - BL space example , free - floating cells ( e. g ., umbilical cells ) can be and over the BrM . Removal of lipid deposits from the injected to provide trophic support to existing cells ( e . g . , sub -RPE -BL space and the BrM normalizes the BrM struc neuronal and RPE cells ). A lipid - clearing apo mimetic [ e . g . , US 2018 /0296525 A1 Oct . 18 , 2018 31 an apoA - I mimetic ( e . g ., L -4F ) and / or an apoE mimetic improve the health of the endothelium and /or the blood flow ( e . g . , AEM - 28 - 14 ) ] improves traffic of incoming oxygen and of the vascular system of the eye , including the therapeutic nutrients and outgoing waste across the Brm and thereby agents described herein , can be administered at least in early improves the health of cells in the area of the choroidal AMD . watershed . Optionally in combination with an agent ( e .g ., an [0307 ] One or more therapeutic agents can be adminis MMP activator or a matrix metalloproteinase ) that reduces tered in the early stage, the intermediate stage or the the thickness of BLamD persisting over the BrM , the apo advanced stage ( atrophic and /or neovascular ) of AMD , or mimetic aids in the preparation of a suitable dispersion bed prior to development of AMD , or any combination or all for the injected cells . thereof, to treat or slow the progression of AMD , or to [0304 ] In addition , AMD can be treated by cell replace prevent or delay the onset of the next stage of AMD , or to ment therapies for the choriocapillaris . For example , the prevent or delay the onset of AMD . In some embodiments , choriocapillaris endothelium can be replaced with stem a single therapeutic agent is administered in the early stage , cell- derived choriocapillaris endothelial cells . the intermediate stage or the advanced stage (atrophic and /or [0305 ] Furthermore, AMD can be treated by gene therapy. neovascular ) of AMD , or prior to development of AMD , or For instance , a gene therapy ( e . g ., RST -001 ) can employ the any combination or all thereof . The single therapeutic agent photosensitivity gene channelrhodopsin 2 to create new can target one or more underlying factors of AMD . In certain photoreceptors in retinal ganglion cells . A lipid - clearing apo embodiments , the single therapeutic agent targets an mimetic [ e . g . , an apoA - I mimetic ( e. g . , L - 4F ) and /or an upstream factor of AMD , such as lipid accumulation . In apoE mimetic ( e . g ., AEM - 28 - 14 ) ] increases the transport of some embodiments , the single therapeutic agent is an anti incoming oxygen and nutrients and outgoing waste across dyslipidemic agent, such as an apolipoprotein mimetic ( e . g . , the BrM and thereby improves the health of RPE and an apo A - I mimetic such as L - 4F or an apoE mimetic such as photoreceptor cells . AEM - 28 - 14 ) or a statin ( e . g ., atorvastatin or simvastatin ) . [0306 ] Choroidal blood flow ( CBF ) decreases with age , [0308 ] Treatment of AMD using two or more therapeutic possibly due to a decrease in choriocapillaris diameter and agents , or two or more different kinds of therapeutic agents , density . Choriocapillaris vascular dropout/ loss and is described below . decreased CBF can occur early in the pathogenesis of AMD . VII. TREATMENT OF AMD USING In early AMD , the vascular density of the choriocapillaris is COMBINATIONS OF THERAPEUTIC AGENTS inversely correlated with the density of sub - RPE - BL depos its ( e . g . , drusen and BLinD ) , and the number of " ghost " [0309 ] A strategy for treating AMD is to target multiple vessels ( remnants of previously healthy capillaries ) is posi underlying factors of AMD using two or more therapeutic tively correlated with sub -RPE - BL deposit density . More agents . In some embodiments , two or more therapeutic over , decreased CBF is positively correlated with fundus agents described herein , or two or more different kinds of findings associated with an increased risk of choroidal therapeutic agents described herein , are used to treat AMD . neovascularization ( e . g . , drusen and pigmentary changes ) . [0310 ] In certain embodiments , the two or more therapeu Vascular endothelial- cell loss may result from activation of tic agents , or the two or more different kinds of therapeutic the complement system and formation of MACs in the agents , are not limited to , but can comprise : choriocapillaris , which can be inhibited by the use of a [0311 ] i ) antioxidants and / or vitamins, such as vitamin B6 complement inhibitor ( e . g . , an inhibitor of MAC formation , ( e . g ., pyridoxine ), vitamin B , ( e . g . , folic acid ) and vitamin deposition or function ). Endothelial dysfunction may also be B12 ( e . g ., cyanocobalamin ) ; or caused by : 1) a diminished amount of nitric oxide, which can [0312 ] ii ) antioxidants and /or vitamins, plus minerals , be due to a high level of dimethylarginine (which interferes such as Age -Related Eye Disease Study (AREDS ) formu with L - arginine -stimulated nitric oxide synthesis ) and can be lations ( e . g ., B - carotene, vitamin C , vitamin E , zinc [ e . g ., corrected by the use of an agent that increases the level of zinc oxide ) and copper [ e . g ., cupric oxide ]) , or Saffron nitric oxide ( e . g . , a stimulator of nitric oxide synthesis or an 2020 " (saffron , resveratrol, lutein , zeaxanthin , vitamins A , inhibitor of dimethylarginine formation ; 2 ) an increase in B2, C and E , zinc and copper ); or reactive oxygen species, which can impair nitric oxide [0313 ] iii) AREDS2 formulations, such as: synthesis and activity and can be inhibited by the use of an [0314 ] 1 ) B - carotene , vitamin C , vitamin E and zinc ; antioxidant ( e . g . , a scavenger of reactive oxygen species ) ; [0315 ] 2) vitamin C , vitamin E , zinc and copper ; and 3 ) inflammatory events , which can be inhibited by an [ 0316 ] 3 ) vitamin C , vitamin E and zinc; agent that inhibits endothelial inflammatory events ( e . g ., an [0317 ] 4 ) B - carotene , vitamin C , vitamin E , zinc , cop apoA - I mimetic such as Rev - D - 4F ) . Reduced CBF can be per, and omega - 3 fatty acids ; improved by using a vascular enhancer that increases CBF , [0318 ] 5 ) B -carotene , vitamin C , vitamin E , zinc , cop such as a vasodilator { e . g . , hyperpolarization -mediated ( cal per, lutein and zeaxanthin ; and cium channel blocker , e . g ., adenosine) , AMP -mediated [0319 ] 6 ) B - carotene , vitamin C , vitamin E , zinc , cop ( e . g . , prostacyclin ) , cGMP -mediated ( e . g . , nitric oxide or per , omega - 3 fatty acids, lutein and zeaxanthin ; or MC - 1101 [ which increases the generation of nitric oxide and [0320 ] iv ) a visual/ light cycle modulator and a dark adap also has anti - inflammatory and antioxidant properties] ), tation agent; or inhibition of a phosphodiesterase (PDE ) ( e . g . , moxaverine [0321 ] v ) an apoptosis inhibitor ( e . g ., a caspase inhibitor ) or sildenafil ?a PDE5 inhibitor ] ) , antagonism of a - 1A adren and a necrosis inhibitor ( e . g ., an RIP kinase inhibitor ); or ergic receptor (e .g ., nicergoline ), or inhibition of a comple [0322 ] vi ) an apolipoprotein mimetic (e .g ., an apoA -I ment polypeptide that causes smooth muscle contraction mimetic ) and an anti -angiogenic agent; or ( e . g ., C3a , C4a or C5a )} . Increasing CBF can prevent [0323 ] vii ) two or more anti - angiogenic agents , such as rupture of the BrM . To treat vascular loss and /or decreased two endogenous anti- angiogenic agents (e .g . , angiostatin CBF, one or more therapeutic agents that preserve or and endostatin ), or an anti - PDGF/ PDGFR agent and an US 2018 /0296525 A1 Oct . 18 , 2018 32 anti -VEGF /VEGFR agent ( e. g ., E10030 and ranibizumab , junction with niacin ( nicotinic acid ) , a cholesterol absorp or REGN2176 - 3 and aflibercept) , or an anti - angiopoietin / tion inhibitor ( e . g ., berberine , ezetimibe or SCH -48461 ) , a angiopoietin receptor agent and an anti - VEGF /VEGFR bile acid sequestrant ( e . g . , colesevelam , colestipol or agent (e .g ., nesvacumab or REGN910 - 3 and aflibercept) , or cholestyramine ), or omega - 3 fatty acids, or any combination a sphingosine - 1 -phosphate inhibitor and an anti - VEGF/ or all thereof. In still further embodiments , an MTTP VEGFR agent ( e . g . , sonepcizumab and aflibercept , bevaci inhibitor is administered . In yet further embodiments , an zumab or ranibizumab ); or anti - sense polynucleotide or PNA targeting mRNA for [ 03241 viii ) a complement inhibitor and an anti - angiogenic apoB , and / or an anti - sense polynucleotide or PNA targeting agent, such as an anti -CS agent ( e . g ., ARC1905 ) and an miRNA - 33a and/ or miRNA -33b , are administered . In addi anti -VEGF /VEGFR agent, or an anti- CS agent ( e . g ., tional embodiments , an LXR agonist and / or an RXR agonist ARC1905 ) , an anti -PDGF /PDGFR agent ( e . g ., E10030 ) and are administered . an anti - VEGF/ VEGFR agent; or (0331 ) Oxidative and inflammatory events also contribute [0325 ] ix ) an anti - inflammatory agent ( e. g ., an NSAID or to the pathogenesis of AMD , including atrophic AMD and a corticosteroid ) and an anti -angiogenic agent (e .g ., an neovascular AMD . Therefore , in some embodiments one, anti- VEGF /VEGFR agent) , such as bromfenac or triamci two or more antioxidants are administered at least in the nolone acetonide, and aflibercept , bevacizumab or ranibi early stage, the intermediate stage or the advanced stage zumab ; or (atrophic and / or neovascular ) of AMD , or any combination [0326 ] x ) an immunosuppressant ( e . g ., an IL - 2 inhibitor or or all thereof. In certain embodiments , the one or more a TNF - a inhibitor ) and an anti -angiogenic agent ( e . g ., an antioxidants include a vitamin , a pro - vitamin , a saffron anti -VEGF /VEGFR agent) , such as daclizumab , rapamycin , carotenoid or zinc , or any combination or all thereof. In adalimumab or infliximab , and aflibercept, bevacizumab or further embodiments , one , two or more anti- inflammatory ranibizumab ; or agents are administered at least in the early stage , the [ 0327 ] xi) laser therapy, photodynamic therapy or radia intermediate stage or the advanced stage ( atrophic and / or tion therapy and agent( s ) used therewith ; or neovascular ) of AMD , or any combination or all thereof. In [ 0328 ] xii ) any combinations of therapeutic agents previ certain embodiments, the one or more anti - inflammatory ously disclosed for the potential treatment of AMD . agents include an apolipoprotein mimetic ( e . g . , an apoA - I [0329 ] In some embodiments , two or more therapeutic mimetic such as L - 4F ) , a CRP inhibitor, a complement agents described herein , or two or more different kinds of inhibitor, an inflammasome inhibitor, a corticosteroid ( e. g. , therapeutic agents described herein , are administered , con fluocinolone acetonide ) or an NSAID ( e . g ., bromfenac ( or a currently or sequentially and in the same pharmaceutical salt thereof, such as sodium salt ] or a coxib ), or any composition or in different compositions, at least in the combination thereof. advanced stage of AMD , including atrophic AMD and /or neovascular AMD . In further embodiments , two or more [0332 ] In addition , activation of the complement system therapeutic agents described herein , or two or more different can lead to inflammation , oxidation , neovascularization and kinds of therapeutic agents described herein , are adminis cell lysis . Accordingly , in some embodiments one , two or tered , concurrently or sequentially and in the same pharma more complement inhibitors are administered at least in the ceutical composition or in different compositions, at least in early stage, the intermediate stage or the advanced stage the intermediate stage of AMD . In still further embodiments, ( atrophic and / or neovascular ) of AMD , or any combination two or more therapeutic agents described herein , or two or or all thereof. In certain embodiments , the one or more more different kinds of therapeutic agents described herein , complement inhibitors include a CFD inhibitor ( e . g . , lam are administered , concurrently or sequentially and in the palizumab ) , a C3 inhibitor ( e . g . , CB - 2782 ) , a C5 inhibitor same pharmaceutical composition or in different composi ( e . g ., ARC1905 or LFG316 ) , TT30 or zinc ( e . g ., zinc oxide tions , at least in the early stage of AMD . In additional or zinc sulfate ) , or any combination thereof, wherein copper embodiments , two or more therapeutic agents described ( e . g ., cupric oxide or cupric sulfate ) can optionally be herein , or two or more different kinds of therapeutic agents administered to prevent copper- deficiency anemia associ described herein , are administered , concurrently or sequen ated with high zinc intake . tially and in the same pharmaceutical composition or in [0333 ] Furthermore , the death of RPE cells and retinal different compositions, to treat or slow the progression of, or cells ( e . g ., photoreceptors ) by apoptosis , necrosis, cell lysis to prevent or delay the onset of, geographic atrophy ( includ or any other mechanism can result in RPE and retinal ing noncentral and /or central GA ) or neovascular AMD degeneration and atrophy. Thus, in some embodiments an ( including types 1 , 2 and / or 3 neovascularization ) . apoptosis inhibitor and /or a necrosis inhibitor are adminis [ 0330 ] Accumulation of lipid - containing material ( e . g . , tered at least in the early stage , the intermediate stage or the lipids , lipoproteins and apolipoproteins) occurs early in the advanced stage ( atrophic and / or neovascular ) of AMD , or pathogenesis of AMD (in particular, atrophic AMD ) . any combination or all thereof. In certain embodiments , the Accordingly, one , two, three or more anti - dyslipidemic apoptosis inhibitor includes a caspase inhibitor and / or an agents can be used to treat AMD . In some embodiments , NRTI, and the necrosis inhibitor includes an RIP kinase one , two , three or more anti - dyslipidemic agents are admin inhibitor. In additional embodiments , one, two or more istered at least in the early stage , the intermediate stage or neuroprotectors other than an antioxidant, an apoptosis the advanced stage (atrophic and / or neovascular ) of AMD , inhibitor , a necrosis inhibitor or a complement inhibitor are or any combination or all thereof. In certain embodiments , administered at least in the early stage , the intermediate one , two or more apolipoprotein mimetics ( e . g ., an apoA - I stage or the advanced stage ( atrophic and /or neovascular ) of mimetic such as L - 4F or D -4F , and / or an apoE mimetic such AMD , or any combination or all thereof. In certain embodi as AEM - 28 - 14 ) are administered . In further embodiments , a ments , the one or more neuroprotectors include glatiramer statin and /or a fibrate are administered , optionally in con acetate and / or a neurotrophic factor ( e . g . , CNTF ). US 2018 /0296525 A1 Oct . 18 , 2018 33

[0334 ] To treat or slow the progression of neovascular [ 0345 ] 6 ) an anti- dyslipidemic anti - sense polynucleotide AMD ( including types 1 , 2 and /or 3 neovascularization ), in or PNA ; some embodiments one , two or more anti - angiogenic agents [0346 ] 7 ) a CETP inhibitor ; are administered in advanced AMD . In certain embodi- (0347 ] 8 ) an LXR agonist ; ments , the one or more anti -angiogenic agents include an [0348 ] 9 ) an antioxidant; anti- VEGF/ VEGFR agent ( e. g ., aflibercept, brolucizumab , [0349 ] 10 ) a neuroprotector ; bevacizumab or ranibizumab , or any combination thereof) , [0350 ] 11) an anti - inflammatory agent ; an anti -PDGF /PDGFR agent ( e . g . , E10030 ) or an anti [0351 ] 12 ) a CRP inhibitor; angiogenic steroid ( e . g ., anecortave acetate ) , or any combi [0352 ] 13 ) a complement inhibitor; and nation or all thereof. In further embodiments , to prevent or 10353 ] 14 ) an MMP inhibitor. delay the onset of neovascular AMD , one , two or more 0354 ) In further embodiments , one, two , three , four or anti - angiogenic agents are administered in advanced AMD more , or any combination , of the therapeutic agents in the before the development of neovascular AMD and / or in following group are administered at least in intermediate intermediate AMD . In certain embodiments , the one or more AMD ( e . g . , to treat or slow the progression of non - central anti - angiogenic agents include an MMP inhibitor ( e . g . , a GA , and /or to prevent or delay the onset of central GA tetracycline or a “ mastat ” ) , an anti -angiogenic steroid ( e . g . , and /or neovascular AMD ) : anecortave acetate ) , an anti -PDGF /PDGFR agent ( e . g . , [0355 ] 1 ) an apolipoprotein mimetic ; E10030 ) or an anti - VEGF/ VEGFR agent ( e . g . , aflibercept or [0356 ] 2 ) a statin ; brolucizumab ) , or any combination thereof. 10357 ] 3 ) a fibrate ; [0335 ] To prevent, reduce the risk of developing , or delay 10358 ] 4 ) a GLP - 1 receptor agonist; the onset of AMD , one , two , three or more of the therapeutic [0359 ] 5 ) an MTTP inhibitor ; agents described herein can be administered prior to devel [0360 ] 6 ) an anti -dyslipidemic anti - sense polynucleotide opment of AMD . Examples of such therapeutic agents or PNA ; include , but are not limited to , anti -dyslipidemic agents , [0361 ] 7 ) a CETP inhibitor ; antioxidants , anti - inflammatory agents , and agents that pre 0362 ) 8 ) an LXR agonist ; serve or improve the health of the endothelium and / or the [0363 ] 9 ) an antioxidant; blood flow of the vascular system of the eye . Furthermore , [0364 ] 10 ) a neuroprotector; a secosteroid ( e . g . , vitamin D ) can be administered to lower [0365 ] 11 ) an apoptosis inhibitor and /or a necrosis inhibi the risk of AMD , e .g ., in women . tor ; [ 0336 ] In some embodiments , an anti- dyslipidemic agent [03661 12 ) an anti - inflammatory agent ; ( e . g . , an apolipoprotein mimetic [ e . g . , an apoA - I mimetic [0367 ] 13 ) a CRP inhibitor; such as L - 4F and / or an apoE mimetic such as AEM - 28 - 141 [ 0368 ] 14 ) a complement inhibitor; and and/ or a statin [ e . g ., atorvastatin or simvastatin ] ) is used in 10369 ) 15 ) an MMP inhibitor. conjunction with one or more additional therapeutic agents [0370 ] In yet further embodiments , one, two , three , four or in the early stage , the intermediate stage or the advanced more , or any combination , of the therapeutic agents in the stage (atrophic and / or neovascular ) of AMD , or any com following group are administered at least in advanced atro bination or all thereof. In certain embodiments, the anti phic AMD ( e . g ., to treat or slow the progression of central dyslipidemic agent and the one or more additional thera GA and / or to prevent or delay the onset of neovascular peutic agents have a synergistic effect . AMD ) , and /or in intermediate AMD ( e . g . , to treat or slow [0337 ] In some embodiments , the multi - drug treatment the progression of non - central GA , and / or to prevent or method described herein targets two , three , four, five or delay the onset of central GA and / or neovascular AMD ) : more underlying factors of AMD . In further embodiments , at [ 0371 ] 1 ) an apolipoprotein mimetic ; least two , three , four, five or more (if three or more thera [0372 ] 2 ) a statin ; peutic agents are administered ) , or all, of the therapeutic [0373 ] 3 ) a fibrate ; agents exert their pharmacological effect by different modes [0374 ] 4 ) an ACAT inhibitor ; of action or by action on different biological targets . 10375 ] 5 ) a GLP - 1 receptor agonist; [0338 ] The multi - drug approach to treating AMD can be [0376 ] 6 ) an MTTP inhibitor; designed so that different combinations of two , three , four , [0377 ] 7 ) an anti -dyslipidemic anti - sense polynucleotide five or more therapeutic agents can be used in the treatment or PNA ; of AMD , in different stages (including the early stage , the [0378 ] 8 ) an LXR agonist ; intermediate stage and the advanced stage ) of AMD , and for [0379 ] 9 ) an antioxidant; different phenotypes of AMD ( including geographic atrophy [0380 ] 10 ) a neuroprotector ; and neovascular AMD ) . [0381 ] 11) an apoptosis inhibitor and /or a necrosis inhibi [ 0339 ] In some embodiments , one , two , three, four or tor ; more , or any combination , of the therapeutic agents in the [ 0382 ] 12 ) an anti- inflammatory agent ; following group are administered at least in early AMD [0383 ] 13 ) a CRP inhibitor; and ( e . g ., to prevent or delay the onset of non - central geographic 10384 ] 14 ) a complement inhibitor. atrophy [GA ] ) : [0385 ] In still further embodiments , one, two, three , four [0340 ] 1 ) an apolipoprotein mimetic ; or more, or any combination , of the therapeutic agents in the following group are administered at least in advanced AMD [0341 ] 2 ) a statin ; to treat or slow the progression of neovascular AMD ( in [ 0342 ] 3 ) a fibrate ; cluding types 1, 2 and /or 3 neovascularization ), and /or in [0343 ] 4 ) a GLP - 1 receptor agonist ; advanced atrophic AMD and / or intermediate AMD to pre [0344 ] 5 ) an MTTP inhibitor; vent or delay the onset of neovascular AMD : US 2018 /0296525 A1 Oct . 18 , 2018 34

[ 0386 ] 1 ) an apolipoprotein mimetic ; mimetic [e . g. , an apoA -I mimetic and /or an apoE mimetic ], 10387 ] 2 ) a statin ; an LXR agonist and an MTTP inhibitor ( e . g . , miRNA -30c ] ; [0388 ] 3 ) a fibrate ; or an apolipoprotein mimetic ?e . g ., an apoA - I mimetic [ 0389 ] 4 ) an ACAT inhibitor ; and /or an apoE mimetic ] , an LXR agonist and an anti 103901 5 ) an MTTP inhibitor ; dyslipidemic anti -sense polynucleotide or PNA ) and an [0391 ] 6 ) an anti - dyslipidemic anti - sense polynucleotide antioxidant ( e . g . , vitamins , saffron carotenoids and /or zinc ) ; or PNA ; or [0392 ] 7 ) an LXR agonist ; [0411 ] 3 ) an anti -dyslipidemic agent (e . g. , a statin ; an [ 0393 ] 8 ) an antioxidant ; apolipoprotein mimetic [ e . g . , an apoA - I mimetic and / or an [0394 ] 9) a neuroprotector; apoE mimetic ] ; a GLP - 1 receptor agonist ; an anti -dyslipi [ 0395 ] 10 ) an anti - inflammatory agent ; demic anti -sense polynucleotide or PNA ; a CETP inhibitor; [ 0396 ]. 11 ) an immunosuppressant; an LXR agonist; an LXR agonist and a statin ; an LXR [0397 ] 12 ) a CRP inhibitor; agonist and a fibrate ; or an LXR agonist and an anti [ 0398 ] 13 ) a complement inhibitor ; and dyslipidemic anti -sense polynucleotide or PNA ) and an [0399 ] 14 ) an anti- angiogenic agent. anti - inflammatory agent ( e . g . , an NSAID , such as bromfenac [0400 ] In some embodiments, the following plurality of or a coxib ) ; or therapeutic agents is administered , concurrently or sequen [ 0412 ] 4 ) an anti - dyslipidemic agent ( e . g . , a statin , an tially and in the same composition or in different composi LXR agonist and / or an apolipoprotein mimetic [ e . g . , an tions , at least in early AMD : apo A - I mimetic and / or an apoE mimetic ] ) , an antioxidant [0401 ] 1 ) two or more anti - dyslipidemic agents ( e . g ., an ( e . g ., vitamins, saffron carotenoids and /or zinc ) , and an apolipoprotein mimetic ( e . g . , an apoA - I mimetic and / or an anti- inflammatory agent ( e . g . , an NSAID , such as bromfenac apoE mimetic ) , a statin and /or a fibrate ); or or a coxib ) ; or [0402 ] 2 ) an anti- dyslipidemic agent ( e . g ., a statin ; a statin [0413 ] 5) an anti- dyslipidemic agent (e . g ., a statin , an and an apolipoprotein mimetic [ e . g . , an apoA - I mimetic LXR agonist and /or an apolipoprotein mimetic [ e . g ., an and/ or an apoE mimetic ]; a statin and a fibrate ; a statin and apo A -I mimetic and / or an apoE mimetic ]) , an anti - inflam a GLP - 1 receptor agonist ; a statin and an MTTP inhibitor matory agent (e . g . , an NSAID , such as bromfenac or a ?e . g ., miRNA - 30c ]; or a statin and a CETP inhibitor ) and an coxib ) , and an MMP inhibitor ( e . g . , a “ mastat ” ) ; or antioxidant ( e . g . , vitamins , saffron carotenoids and / or zinc ) ; [0414 ] 6 ) an anti -dyslipidemic agent (e . g. , a statin , an or LXR agonist, and / or an apolipoprotein mimetic [ e . g ., an [0403 ] 3 ) an anti -dyslipidemic agent (e .g ., a statin ; an apoA - I mimetic and / or an apoE mimetic ]) and a comple MTTP inhibitor [ e .g ., miRNA - 30c] ; a statin and a fibrate ; a ment inhibitor ( e . g . , lampalizumab , zinc, TT30 , a C3 inhibi statin and a GLP - 1 receptor agonist; or a fibrate and a GLP - 1 tor and / or an anti- CS agent ) ; or receptor agonist ) and an anti - inflammatory agent ( e . g . , an [ 0415 ] 7 ) an anti - dyslipidemic agent ( e . g . , a statin , an NSAID , such as bromfenac or a coxib ) ; or LXR agonist, and / or an apolipoprotein mimetic [ e . g ., an 0404 ] 4 ) an anti - dyslipidemic agent ( e . g . , a statin and / or apoA - I mimetic and /or an apoE mimetic ] ) , and an apoptosis an MTTP inhibitor [ e . g ., miRNA - 30c ]) , an antioxidant ( e . g ., inhibitor ( e . g . , an NRTI) and /or a necrosis inhibitor ( e . g . , a vitamins, saffron carotenoids and/ or zinc ) , and an anti necrostatin ) ; or inflammatory agent ( e . g . , an NSAID , such as bromfenac or [0416 ] 8 ) an anti - dyslipidemic agent ( e . g . , a statin , an a coxib ) ; or LXR agonist, and / or an apolipoprotein mimetic [ e . g ., an [0405 ] 5 ) an anti- dyslipidemic agent ( e . g . , a statin and /or apo A - I mimetic and / or an apoE mimetic ]) , a complement a GLP - 1 receptor agonist) , an antioxidant ( e . g . , vitamins, inhibitor ( e . g . , lampalizumab , zinc , TT30 , a C3 inhibitor saffron carotenoids and / or zinc ) , and an MMP inhibitor ( e . g ., and/ or an anti -C5 agent) , and an apoptosis inhibitor ( e . g ., an a “ mastat” ) ; or NRTI) and / or a necrosis inhibitor ( e . g . , a necrostatin ) ; or [ 0406 ] 6 ) an anti -dyslipidemic agent ( e. g ., a statin ) , an [0417 ] 9 ) an anti- dyslipidemic agent ( e . g ., a statin and /or antioxidant ( e . g ., vitamins, saffron carotenoids and / or zinc ) , an apolipoprotein mimetic ?e . g . , an apoA - I mimetic and /or and a neuroprotector ( e . g . , glatiramer acetate ) ; or an apoE mimetic ]) , an antioxidant (e .g . , vitamins, saffron 04071 7 ) an anti -dyslipidemic agent ( e . g . , a statin ) , an carotenoids and / or zinc) , and a neuroprotector ( e . g . , CNTF antioxidant ( e . g . , vitamins , saffron carotenoids and / or zinc ) , and /or glatiramer acetate ) ; or a neuroprotector ( e . g . , glatiramer acetate ) , and an anti [0418 ] 10 ) an anti -dyslipidemic agent (e .g ., a statin and /or inflammatory agent ( e. g . , an NSAID , such as bromfenac or an apolipoprotein mimetic [ e . g ., an apoA - I mimetic and /or a coxib ) . an apoE mimetic ] ), an antioxidant ( e. g . , vitamins, saffron [0408 ] In further embodiments , the following plurality of carotenoids and / or zinc ) , an anti - inflammatory agent ( e . g . , therapeutic agents is administered , concurrently or sequen an NSAID , such as bromfenac or a coxib ) , and a neuropro tially and in the same composition or in different composi tector ( e . g ., CNTF and / or glatiramer acetate ). tions, at least in intermediate AMD : [0419 ] In yet further embodiments , the following plurality [0409 ] 1 ) two or more anti- dyslipidemic agents ( e. g. , a of therapeutic agents is administered , concurrently or statin and an apolipoprotein mimetic [e .g ., an apoA - I sequentially and in the same composition or in different mimetic and / or an apoE mimetic ); a statin and a fibrate ; or compositions , at least in advanced atrophic AMD to treat or a statin , a fibrate and a GLP - 1 receptor agonist ) ; or slow the progression of geographic atrophy ( including cen [ 0410 ] 2 ) an anti -dyslipidemic agent ( e. g. , a statin ; an tral GA ) , and /or to prevent or delay the onset of neovascular apolipoprotein mimetic [ e. g ., an apo A -I mimetic and /or an AMD : apoE mimetic ]; an LXR agonist; a statin and an LXR [0420 ] 1 ) a CRP inhibitor ( e . g . , a statin or a thiazolidin agonist ; an LXR agonist and a GLP - 1 receptor agonist ; an edione ) and a complement inhibitor ( e . g . , lampalizumab , LXR agonist and a CETP inhibitor; an apolipoprotein zinc , TT30 , a C3 inhibitor and / or an anti - C5 agent) ; or US 2018 /0296525 A1 Oct . 18 , 2018 35

[0421 ] 2 ) an anti -dyslipidemic agent ( e. g. , an apolipopro [0432 ] 13 ) a neuroprotector ( e. g ., CNTF and /or glatiramer tein mimetic [e . g ., an apoA -I mimetic and /or an apoE acetate ) and a complement inhibitor ( e . g . , lampalizumab , mimetic ) , a statin and / or an LXR agonist ) , and a comple zinc, TT30 , a C3 inhibitor and / or an anti- C5 agent) ; or ment inhibitor ( e . g . , lampalizumab , zinc , TT30 , a C3 inhibi [0433 ] 14 ) an anti -dyslipidemic agent (e . g. , an apolipo tor and /or an anti -C5 agent) ; or protein mimetic [ e . g . , an apoA - I mimetic and / or an apoE [0422 ] 3 ) an anti -dyslipidemic agent (e . g. , an apolipopro mimetic ), a statin and /or an LXR agonist) , a neuroprotector tein mimetic [e . g ., an apoA -I mimetic and /or an apoE ( e . g ., CNTF and / or glatiramer acetate ), and a complement mimetic ] , a statin and / or an LXR agonist ), and an antioxi inhibitor ( e . g . , lampalizumab , zinc, TT30 , a C3 inhibitor dant ( e . g ., vitamins, saffron carotenoids and /or zinc ) ; or and /or an anti -C5 agent) ; or [ 0423] 4 ) an anti - dyslipidemic agent ( e . g . , an apolipopro [ 0434 ] 15 ) an anti -dyslipidemic agent ( e . g ., an apolipo tein mimetic [ e . g . , an apoA - I mimetic and / or an apoE protein mimetic [ e . g ., an apoA - I mimetic and / or an apoE mimetic ] , a statin and /or an LXR agonist) and an anti mimetic ] , a statin and /or an LXR agonist ) , an antioxidant inflammatory agent ( e . g ., an apoA - I mimetic ?e. g ., L - 4F ], a ( e . g . , vitamins , saffron carotenoids and /or zinc ) , and a neu roprotector ( e . g . , CNTF and /or glatiramer acetate ) ; or corticosteroid [ e . g . , fluocinolone acetonide ] and /or an [0435 ) 16 ) an antioxidant ( e . g . , vitamins, saffron carote NSAID ( e .g . , bromfenac or a coxib ]) ; or noids and /or zinc ) , a neuroprotector ( e . g . , CNTF and /or [ 0424 ] 5 ) an anti -dyslipidemic agent ( e . g ., an apolipopro glatiramer acetate ) , and a complement inhibitor ( e . g . , lam tein mimetic [ e. g ., an apoA - I mimetic and /or an apoE palizumab , zinc , TT30 , a C3 inhibitor and / or an anti -C5 mimetic ) , a statin and /or an LXR agonist ) , an antioxidant agent ) ; or ( e . g . , vitamins , saffron carotenoids and /or zinc ) , and an [0436 ] 17 ) an anti -dyslipidemic agent ( e .g . , an apolipo anti- inflammatory agent ( e . g ., an apoA - I mimetic [ e . g . , protein mimetic [ e . g . , an apo A - I mimetic and/ or an apoE L - 4F ], a corticosteroid [ e . g . , fluocinolone acetonide ] and /or mimetic ] , a statin and / or an LXR agonist ) , an antioxidant an NSAID ( e . g ., bromfenac or a coxib ]) ; or ( e .g ., vitamins, saffron carotenoids and / or zinc ), a neuropro [0425 ] 6 ) an anti - dyslipidemic agent ( e . g . , an apolipopro tector ( e .g . , CNTF and /or glatiramer acetate ) , and a comple tein mimetic [ e . g ., an apoA - I mimetic and/ or an apoE ment inhibitor ( e . g . , lampalizumab , zinc , TT30 , a C3 inhibi mimetic ] , a statin and /or an LXR agonist ) , an antioxidant tor and /or an anti -C5 agent ) . ( e . g . , vitamins, saffron carotenoids and /or zinc ), and a CRP [0437 ] In other embodiments , the following plurality of inhibitor ( e . g . , a statin or a thiazolidinedione ) ; or therapeutic agents is administered , concurrently or sequen [0426 ] 7 ) an anti -dyslipidemic agent ( e. g. , an apolipopro tially and in the same composition or in different composi tein mimetic ( e . g . , an apoA - I mimetic and / or an apoE tions, at least in advanced AMD to treat or slow the mimetic ), a statin and /or an LXR agonist ), an antioxidant progression of neovascular AMD (including types 1, 2 ( e . g . , vitamins, saffron carotenoids and /or zinc ) , and a and /or 3 neovascularization ) , and / or to prevent or delay the complement inhibitor ( e. g ., lampalizumab , zinc, TT30 , a C3 onset of neovascular AMD : inhibitor and /or an anti -C5 agent) ; or [0438 ] 1) an anti -dyslipidemic agent ( e. g ., an apolipopro [ 0427] 8 ) an anti - dyslipidemic agent ( e . g . , an apolipopro tein mimetic ?e . g . , an apoA - I mimetic and / or an apoE tein mimetic [ e . g . , an apoA - I mimetic and / or an apoE mimetic ), a statin and / or an LXR agonist ) and an anti mimetic ) , a statin and /or an LXR agonist ) , an anti - inflam angiogenic agent ( e .g . , an anti- VEGF /VEGFR agent and /or matory agent (e .g ., an apoA -I mimetic [ e. g. , L -4F ], a cor an anti -PDGF / PDGFR agent) ; or ticosteroid [ e . g ., fluocinolone acetonide ) and /or an NSAID [0439 ] 2 ) an anti- inflammatory agent ( e . g . , an apoA - I [ e . g . , bromfenac or a coxib ] ) , and a complement inhibitor mimetic [ e . g . , L - 4F ], an NSAID [ e . g . , bromfenac or a coxib ] ( e . g . , lampalizumab , zinc , TT30 , a C3 inhibitor and /or an and / or a corticosteroid [ e . g . , triamcinolone acetonide ] ) or an anti- C5 agent ) ; or immunosuppressant ( e . g . , an IL - 2 inhibitor and / or a TNF - a [0428 ] 9 ) a CRP inhibitor ( e .g ., a statin or a thiazolidin inhibitor ) , and an anti - angiogenic agent ( e . g. , an anti - VEGF / edione ) , an anti -inflammatory agent ( e . g ., an apoA - I VEGFR agent and / or an anti -PDGF /PDGFR agent) ; or mimetic [ e . g . , L - 4F ], a corticosteroid [ e . g . , fluocinolone [0440 ] 3 ) an anti -dyslipidemic agent ( e. g ., an apolipopro acetonide ) and / or an NSAID ( e . g . , bromfenac or a coxib ] ) , tein mimetic [ e . g . , an apoA - I mimetic and /or an apoE mimetic ) , a statin and / or an LXR agonist) , an anti- inflam and a complement inhibitor ( e .g ., lampalizumab , zinc , TT30 , matory agent ( e . g ., an apoA - I mimetic [ e . g . , L -4F ], an a C3 inhibitor and /or an anti -C5 agent) ; or NSAID ( e. g ., bromfenac or a coxib ) and /or a corticosteroid [0429 ] 10 ) an anti -dyslipidemic agent ( e . g . , an apolipo Te . g . , triamcinolone acetonide ] ) or an immunosuppressant protein mimetic [ e . g . , an apoA - I mimetic and /or an apoE ( e .g ., an IL - 2 inhibitor and/ or a TNF - a inhibitor ) , and an mimetic ) , a statin and / or an LXR agonist ), and an apoptosis anti - angiogenic agent ( e . g . , an anti- VEGF /VEGFR agent inhibitor ( e . g ., an NRTI) and / or a necrosis inhibitor ( e . g . , a and / or an anti -PDGF / PDGFR agent ) ; or necrostatin ) ; or [0441 ] 4 ) an anti -dyslipidemic agent ( e. g. , an apolipopro [0430 ] 11) an anti -dyslipidemic agent (e .g ., an apolipo tein mimetic [ e . g . , an apoA - I mimetic and/ or an apoE protein mimetic [ e. g . , an apoA - I mimetic and /or an apoE mimetic ] , a statin and/ or an LXR agonist ) , an antioxidant mimetic ] , a statin and /or an LXR agonist ) , a complement ( e . g ., vitamins, saffron carotenoids and / or zinc ) , and an inhibitor ( e .g ., lampalizumab , zinc , TT30 , a C3 inhibitor anti - angiogenic agent ( e . g ., an anti - VEGF/ VEGFR agent and /or an anti - C5 agent) , and an apoptosis inhibitor ( e. g ., an and / or an anti -PDGF /PDGFR agent) ; or NRTI) and / or a necrosis inhibitor ( e . g ., a necrostatin ) ; or [0442 ] 5 ) a neuroprotector ( e . g ., CNTF and /or glatiramer [ 0431 ] 12 ) an anti- dyslipidemic agent ( e . g ., an apolipo acetate ) and an anti -angiogenic agent ( e . g ., an anti - VEGF / protein mimetic ?e . g . , an apoA - I mimetic and / or an apoE VEGFR agent and / or an anti - PDGF /PDGFR agent) ; or mimetic ) , a statin and / or an LXR agonist) and a neuropro 10443 ] 6 ) an anti - dyslipidemic agent ( e . g . , an apolipopro tector (e . g ., CNTF and /or glatiramer acetate ); or tein mimetic [e .g . , an apoA -I mimetic and /or an apoE US 2018 /0296525 A1 Oct . 18 , 2018 36 mimetic ) , a statin and /or an LXR agonist ) , a neuroprotector ramer acetate , an antioxidant and /or a neurotrophic factor ) ( e . g . , CNTF and / or glatiramer acetate ), and an anti- angio and / or an apoptosis inhibitor ( e . g . , an NRTI ) and /or a genic agent ( e . g ., an anti - VEGF /VEGFR agent and / or an necrosis inhibitor ( e . g . , a necrostatin ) are administered at anti -PDGF / PDGFR agent) ; or least in intermediate AMD and / or advanced AMD to treat [0444 ] 7 ) a complement inhibitor ( e . g ., a C3 inhibitor geographic atrophy ( including non -central GA and / or cen [ e . g . , CB - 2782 ] , an anti -C5 agent [ e . g ., ARC1905 or tral GA ); or LFG316 ] and / or a CFD inhibitor [ e . g . , lampalizumab ]) and an anti -angiogenic agent (e . g ., an anti - VEGF /VEGFR agent [0453 ] 3 ) an anti- dyslipidemic agent (e .g . , a statin and /or and / or an anti - PDGF/ PDGFR agent ) ; or an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and /or [0445 ] 8 ) an anti -dyslipidemic agent (e . g. , an apolipopro an apoE mimetic ] ) is administered at least in early AMD tein mimetic [ e . g ., an apoA - I mimetic and / or an apoE and /or intermediate AMD , a neuroprotector (e . g. , glatiramer mimetic ) , a statin and / or an LXR agonist ), a complement acetate , an antioxidant and/ or a neurotrophic factor ) and /or inhibitor ( e . g . , a C3 inhibitor [ e . g . , CB - 2782 ], an anti- C5 an apoptosis inhibitor ( e . g ., an NRTI) and / or a necrosis agent [ e . g ., ARC1905 or LFG316 ] and / or a CFD inhibitor inhibitor ( e . g . , a necrostatin ) are administered at least in [ e . g . , lampalizumab ] ) , and an anti -angiogenic agent ( e . g . , an intermediate AMD and/ or advanced AMD , and a comple anti- VEGF/ VEGFR agent and / or an anti- PDGF /PDGFR ment inhibitor (e . g. , lampalizumab , zinc, TT30 , a C3 inhibi agent ) ; or tor and / or a C5 inhibitor ) is administered at least in inter [0446 ] 9 ) a neuroprotector ( e . g . , CNTF and / or glatiramer mediate AMD and / or advanced AMD to treat geographic acetate ), a complement inhibitor ( e . g ., a C3 inhibitor [ e . g . , atrophy ( including non -central GA and / or central GA ) ; or CB - 2782 ], an anti- C5 agent [ e . g . , ARC1905 or LFG316 ] and / or a CFD inhibitor [ e . g . , lampalizumab ]) , and an anti [0454 ] 4 ) an antioxidant (e . g. , vitamins , saffron carote angiogenic agent ( e. g. , an anti- VEGF /VEGFR agent and / or noids and /or zinc ) is administered at least in early AMD an anti- PDGF / PDGFR agent ); or and / or intermediate AMD , a complement inhibitor ( e . g . , [ 0447] 10 ) an anti -dyslipidemic agent ( e . g . , an apolipo lampalizumab , zinc, TT30 , a C3 inhibitor and / or a C5 protein mimetic [ e. g ., an apoA -I mimetic and /or an apoE inhibitor ) is administered at least in intermediate AMD mimetic ) , a statin and / or an LXR agonist ) , a neuroprotector and / or advanced AMD , and an anti- angiogenic agent ( e . g ., ( e . g . , CNTF and / or glatiramer acetate ) , a complement an anti -VEGF / VEGFR agent and / or an anti - PDGF /PDGFR inhibitor ( e . g . , a C3 inhibitor [ e . g . , CB - 2782 ], an anti- C5 agent) is administered at least in advanced AMD to treat agent [ e . g ., ARC1905 or LFG316 ] and/ or a CFD inhibitor neovascular AMD (including types 1 , 2 and /or 3 neovascu ?e . g . , lampalizumab ]) , and an anti- angiogenic agent ( e . g ., an larization [NV ]) ; or anti -VEGF /VEGFR agent and /or an anti - PDGF/ PDGFR agent ) ; or [0455 ] 5 ) an anti- dyslipidemic agent ( e . g ., a statin and / or [ 0448 ] 11 ) a neuroprotector ( e . g ., CNTF and / or glatiramer an apolipoprotein mimetic [ e . g ., an apoA - I mimetic and / or acetate ) , an anti - inflammatory agent ( e . g ., an apoA - I an apoE mimetic ]) is administered at least in early AMD mimetic [ e . g . , L -4F ] , an NSAID [ e . g . , bromfenac or a coxib ] and / or intermediate AMD , an antioxidant ( e . g . , vitamins , and / or a corticosteroid [ e . g . , triamcinolone acetonide ] ) or an saffron carotenoids and / or zinc ) is administered at least in immunosuppressant ( e . g . , an IL - 2 inhibitor and / or a TNF - a early AMD and / or intermediate AMD , a complement inhibi inhibitor) , and an anti - angiogenic agent ( e . g . , an anti - VEGF / tor (e .g . , lampalizumab , zinc, TT30 , a C3 inhibitor and /or a VEGFR agent and / or an anti -PDGF / PDGFR agent ) ; or C5 inhibitor ) optionally is administered at least in interme [ 0449] 12 ) an anti -dyslipidemic agent ( e . g . , an apolipo diate AMD and / or advanced AMD , and an anti- angiogenic protein mimetic [ e. g ., an apoA -I mimetic and /or an apoE agent ( e . g . , an anti - VEGF/ VEGFR agent and / or an anti mimetic ) , a statin and / or an LXR agonist ) , a neuroprotector PDGF /PDGFR agent) is administered at least in advanced ( e . g . , CNTF and / or glatiramer acetate ) , an anti - inflammatory AMD to treat neovascular AMD ( including types 1 , 2 and /or agent (e . g. , an apo A -I mimetic [ e. g ., L -4F ], an NSAID ( e. g ., 3 neovascularization ) ; or bromfenac or a coxib ] and/ or a corticosteroid [ e . g . , triam cinolone acetonide ]) or an immunosuppressant ( e. g. , an IL - 2 [0456 ] 6 ) an anti- dyslipidemic agent ( e . g ., a statin and / or inhibitor and / or a TNF -a inhibitor ), and an anti -angiogenic an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and / or agent ( e . g ., an anti - VEGF /VEGFR agent and / or an anti an apoE mimetic ] ) is administered at least in early AMD PDGF /PDGFR agent) . and /or intermediate AMD , an antioxidant (e . g ., vitamins , [0450 ] In certain embodiments , the multi- drug approach to saffron carotenoids and /or zinc ) optionally is administered at treating AMD is selected from the following regimens: least in early AMD and / or intermediate AMD , an anti [0451 ] 1 ) an anti -dyslipidemic agent (e . g. , a statin and /or inflammatory agent ( e . g. , an apoA - I mimetic [ e. g ., L -4F ] , a an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and /or corticosteroid ?e . g ., triamcinolone acetonide ] and / or an an apoE mimetic ]) is administered at least in early AMD NSAID ( e . g ., bromfenac or a coxib ] ) is administered at least and / or intermediate AMD , and an antioxidant ( e . g ., vita in intermediate AMD and/ or advanced AMD , and an anti mins , saffron carotenoids and / or zinc ) and /or an anti - inflam angiogenic agent ( e . g . , an anti - VEGF /VEGFR agent and / or matory agent ( e . g ., an apoA - I mimetic [ e . g . , L - 4F ] , a cor an anti - PDGF /PDGFR agent) is administered at least in ticosteroid [ e . g . , triamcinolone acetonide) and /or an NSAID advanced AMD to treat neovascular AMD (including types [ e . g . , bromfenac or a coxib ] ) are administered at least in 1 , 2 and /or 3 neovascularization ) . early AMD and /or intermediate AMD ; or [0457 ] Table 2 provides examples of combinations of an [ 0452 ] 2 ) an anti- dyslipidemic agent ( e . g ., a statin and / or apo mimetic ( e . g . , an apo A - I mimetic such as L - 4F or D -4F , an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and / or or an apoE mimetic such as AEM -28 - 14 ) or/ and a statin an apoE mimetic ]) is administered at least in early AMD ( e . g . , atorvastatin ) with one additional therapeutic agent to and / or intermediate AMD , and a neuroprotector ( e . g ., glati treat exemplary eye disorders. US 2018 /0296525 A1 Oct . 18, 2018 37

TABLE 2 One additional therapeutic agent used in combination with an apo mimetic ( e . g . , an apo A - I mimetic such as L - 4F or D - 4F , or an apo E mimetic such as AEM - 28 - 14 ) or/ and a statin ( e . g . , atorvastatin ) Function Exemplary Active Agent Exemplary Eye Disorders Anti -dyslipidemic Omega - 3 fatty acid ( s ) Dry and wet AMD , macular edema CETP inhibitor Anacetrapib AMD ( including dry AMD ) Antioxidant Cardiolipin peroxidation Elamipretide AMD (including dry AMD ) , inhibitor (CPI ) mitochondrial eye diseases ( e . g . Leber 's hereditary optic neuropathy ) CPI SkQi AMD ( including dry AMD ) , uveitis , glaucoma, dry eye Anti- inflammatory Connexin43 hemichannel Peptide5 (Peptagon TM ) Wet AMD , diabetic retinopathy (DR ) , blocker diabetic macular edema (DME ) , ME Complement inhibitor KSI - 401 AMD ( including dry AMD and GA ) CFD inhibitor ACH -4471 AMD ( including dry AMD and GA) C3 inhibitor APL - 2 AMD ( including dry AMD and GA) C3 inhibitor CB - 2782 AMD ( including dry AMD and GA ) C5 inhibitor ARC1905 ( avacincaptad Dry and wet AMD , Stargardt disease , pegol or ZIMURA ® ) non - infectious uveitis , von Hippel Lindau disease Immunosuppressant Dexamethasone Dry and wet AMD , uveitis , DME Fluocinolone acetonide Dry and wet AMD , uveitis , DME mTOR inhibitor Rapamycin (sirolimus ) Dry and wet AMD Suppressor of M1- related TMi- 018 Dry AMD ( including GA ) , DR transcription Neuroprotector Brimonidine AMD ( including dry AMD and GA ) CNTF -releasing cells NT-501 Dry and wet AMD , macular telangiectasia Apoptosis / Fas inhibitor ONL - 1204 Dry & wet AMD, retinal detachment Visual cycle modulator RBP4 inhibitor LBS - 008 AMD ( including dry AMD ) , Stargardt disease RPE65 inhibitor Emixustat AMD ( including dry AMD ) , DR ( e . g . , proliferative DR ), Stargardt disease Anti - angiogenic VEGF inhibitor Abicipar pegol Wet AMD , DR , DME, post- retinal vein occlusion (RVO ) ME VEGF inhibitor Aflibercept ( EYLEA? ) Wet AMD, DR , DME, post- RVO ME VEGF inhibitor OPT- 302 Wet AMD , DR , DME , post -RVO ME VEGF inhibitor Bevacizumab ( AVASTIN ® ) Wet AMD , DR , DME , post - RVO ME VEGF inhibitor Brolucizumab Wet AMD , DR , DME , post - RVO ME VEGF inhibitor Ranibizumab (LUCENTIS ® ) Wet AMD , DR , DME , post -RVO ME VEGF inhibitor ENV1305 Wet AMD , DR , DME, post - RVO ME VEGF inhibitor KSI- 301 Wet AMD , DR , DME, post - RVO ME VEGF inhibitor ACU -6151 Wet AMD , DR , DME , post -RVO ME dry AMD ( including GA ) VEGF/ PDGF inhibitor Squalamine Wet AMD , DR , DME , post -RVO ME VEGF -signaling inhibitor OCU200 Wet AMD , DR , DME , post -RVO ME VEGFR tyrosine kinase ( TK ) KPI- 285 Wet AMD , DR , DME , post - RVO ME inhibitor VEGFR / PDGFR TK inhibitor Sunitinib ( e . g ., GB - 102 ) Wet AMD , DR , DME , post- RVO ME VEGFR / PDGFR TK inhibitor X - 82 Wet AMD , DR , DME , post -RVO ME VEGFR / PDGFR / FGFR TK Pazopanib Wet AMD , DR , DME, post - RVO ME inhibitor Integrin inhibitor ALG - 1001 (LUMINATE ® ) Wet AMD , DR , DME , post- RVO ME Integrin inhibitor SF0166 Wet AMD , DR , DME , post - RVO ME MMP inhibitor Minocycline ( e. g . , NM108 ) Wet AMD , DR , DME , post -RVO ME uveitis Tissue factor inhibitor ICON - 1 Wet AMD , DR , DME , post - RVO ME SRPK1 inhibitor SPHINX31 Wet AMD , DR , DME , post -RVO ME Kallikrein inhibitor KVD001 Wet AMD , DR , DME , post- RVO ME US 2018 /0296525 A1 Oct . 18, 2018 38

TABLE 2 - continued One additional therapeutic agent used in combination with an apo mimetic ( e . g . , an apo A - I mimetic such as L - 4F or D - 4F , or an apo E mimetic such as AEM - 28 - 14 ) or/ and a statin ( e . g . , atorvastatin ) Function Exemplary Active Agent Exemplary Eye Disorders Vascular modulator Vasodilator MC - 1101 AMD ( including dry AMD ) Q2- adrenergic receptor agonist Brimonidine Glaucoma Cell replacement hESC - derived RPE cells OPREGEN ® cells AMD ( including dry AMD and GA) hESC - derived RPE cells CPCB - RPE1 cells AMD ( including dry AMD and GA ) Human retinal progenitor jCell cells AMD ( including dry AMD and GA ) , cells retinitis pigmentosa

VIII. TREATMENT OF AMD WITH AN an apo mimetic and / or a statin ) . In some embodiments , the ANTI -DYSLIPIDEMIC AGENT AND AN anti -angiogenic agent ( e .g . , an anti - VEGF agent) is admin ANTI -ANGIOGENIC AGENT istered (e . g. , by intravitreal injection ) at least about 1 .5 , 2 , 3 , [0458 ] Some embodiments of the disclosure relate to a 4 , 5 or 6 ( e . g . , at least about 2 ) times less frequently than the method of treating AMD , comprising administering to a conventional or recommended dosing frequency for the subject in need of treatment a therapeutically effective anti -angiogenic agent in the absence of treatment with the amount of an anti - dyslipidemic agent and a therapeutically anti - dyslipidemic agent ( e. g . , an apo mimetic and /or a effective amount of an anti- angiogenic agent. statin ). In certain embodiments , the anti -angiogenic agent 10459 ) Examples of anti - dyslipidemic agents , including ( e . g . , an anti- VEGF agent) is administered locally to , into , in apolipoprotein mimetics and statins , include without limi or around the eye ( e . g ., by intravitreal injection ) once every tation those described elsewhere herein . In certain embodi 2 , 3 , 4 , 5 or 6 months. In further embodiments, treatment ments , the anti -dyslipidemic agent includes, or is , an apoA - I with the anti- dyslipidemic agent (e . g. , an apo mimetic mimetic ( e . g ., L - 4F or D -4F or a salt thereof) and / or an apoE and / or a statin ) reduces the total number of times ( e . g ., the mimetic ( e . g . , AEM - 28 - 14 or a salt thereof) . In further total number of injections ) the anti -angiogenic agent ( e. g. , embodiments , the anti - dyslipidemic agent includes , or is , a an anti- VEGF agent) is administered . In certain embodi statin ( e . g ., atovastatin and / or simvastatin or a salt thereof) . ments , the anti -angiogenic agent ( e . g ., an anti -VEGF agent ) All of the embodiments relating to the treatment of AMD is administered ( e . g . , by intravitreal injection ) no more than with an apolipoprotein mimetic which are described in about 20 , 18 , 15 , 12 or 10 times . In additional embodiments , Section IV and elsewhere herein , and all of the embodiments the anti - angiogenic agent ( e . g . , an anti -VEGF agent ) is relating to the treatment of AMD with a statin which are administered ( e . g ., by intravitreal injection ) in a dose at least described in Section V and elsewhere herein , also apply to about 10 % , 20 % , 30 % , 40 % , 50 % , 60 % , 70 % or 80 % ( e . g . , the treatmentof AMD with an anti -angiogenic agent and an at least about 20 % ) , or about 10 - 30 % , 30 - 50 % or 50 -70 % , apo mimetic and / or a statin . less than the conventional or recommended dose for the [0460 ] Examples of anti- angiogenic agents include with anti- angiogenic agent in the absence of treatment with the out limitation those described elsewhere herein . In some anti - dyslipidemic agent ( e . g . , an apo mimetic and /or a embodiments , the anti - angiogenic agent includes, or is , an statin ) . agent that inhibits the action of a vascular endothelial [0462 ] Treatment of AMD with the anti- dyslipidemic growth factor (an anti - VEGF agent) , including without agent ( e . g ., an apo mimetic and / or a statin ) and the anti limitation VEGF - A , VEGF -B and placental growth factor angiogenic agent ( e . g ., an anti - VEGF agent) may have a ( PGF ) . Non - limiting examples of anti -VEGF agents include synergistic effect. For instance , treatment with the anti those described elsewhere herein . In certain embodiments , dyslipidemic agent ( e . g . , an apo mimetic and /or a statin ) the anti - VEGF agent includes , or is , aflibercept (EYLEA? ) , may enhance the efficacy of the anti - angiogenic agent, brolucizumab , bevacizumab (AVASTIN® ) or ranibizumab and /or vice versa . As an example , the apoA - I mimetic L - 4F ( LUCENTIS® ) , or any combination thereof. In further can markedly reduce lipid deposits from the Bruch ' s mem embodiments , the anti - angiogenic agent includes, or is , an brane (BrM ) and structurally remodel the BrM to a normal agent that inhibits the action of a platelet- derived growth or healthier state , thereby reducing the susceptibility of the factor ( an anti- PDGF agent) , including without limitation BrM to penetration by new blood vessels growing from the PDGF - A , PDGF - B , PDGF - C , PDGF - D and PDGF - A / B . choroid through the BrM and into the sub - RPE - BL space Non - limiting examples of anti- PDGF agents include those and the subretinal space in types 1 and 2 neovascularization described elsewhere herein . In certain embodiments , the (NV ) . As another example , the ability of L -4F to reduce anti - PDGF agent includes , or is , E10030 ( FOVISTA? ) . inflammation (via inhibition of, e . g ., activation of the [ 0461] In some embodiments , the anti -angiogenic agent complement system and the formation of pro - inflammatory ( e . g . , an anti - VEGF agent) is administered in a frequency oxidized lipids ) , an important stimulus of NV , can decrease less than the conventional or recommended dosing fre the required number of administrations ( e . g ., by injection ) quency , and/ or in a dose less than the conventional or and /or dosage of the anti - angiogenic agent. As a further recommended dose , for the anti -angiogenic agent in the example , the statin atorvastatin can substantially reduce absence of treatment with the anti -dyslipidemic agent ( e .g . , drusen deposits , a rich source of lipids that can be oxidized US 2018 /0296525 A1 Oct . 18 , 2018 39 to pro - inflammatory and pro - angiogenic oxidized lipids. In [0467 ] In other embodiments , the anti- angiogenic agent addition , statins have antioxidant property . Synergism includes , or is , ranibizumab , and ranibizumab is adminis between the anti - dyslipidemic agent ( e . g ., an apo mimetic tered ( e . g . , by intravitreal injection ) in a dose of about and / or a statin ) and the anti -angiogenic agent can allow , but 0 .1 -0 . 2 mg, 0 .2 -0 .3 mg or 0 .3 -0 . 4 mg once every month . is not required for, e .g . , the anti -angiogenic agent to be [0468 ] In additional embodiments , the anti - angiogenic administered less frequently than the conventional or rec agent includes, or is , bevacizumab ( AVASTIN® ) , and beva ommended dosing frequency , and /or in a dose lower than the cizumab is administered ( e . g . , by intravitreal injection ) in a conventional or recommended dose , for the anti - angiogenic dose of about 0 . 1 - 0 . 3 mg, 0 . 3 - 0 . 5 mg, 0 . 5 - 0 .75 mg, 0 .75 - 1 agent in the absence of treatment with the anti -dyslipidemic mg or 1 - 1 . 25 mg once every 2 , 3 , 4 , 5 or 6 months , agent ( e . g ., an apo mimetic and /or a statin ) . optionally after being administered in a dose of about [0463 ] Administration of a lower dose of the anti- angio 0 . 1 - 0 . 3 mg, 0 . 3 - 0 . 5 mg, 0 . 5 - 0 .75 mg, 0 .75 - 1 mg or 1 - 1 . 25 genic agent can have benefits , such as a better safety profile mg once every month for the first 1 , 2 or 3 months or once due to fewer side effects . Less frequent administration ( e . g . , every 6 weeks for the first 1 . 5 or 3 months , compared to the by intravitreal injection ) of the anti- angiogenic agent can conventional or recommended dose and dosing frequency also have benefits , such as greater /better patient comfort , for bevacizumab for the treatment of AMD of about 1 . 25 mg convenience , compliance and health due to fewer invasive administered by intravitreal injection once every month in procedures being performed . Frequent administration can the absence of treatment with the anti- dyslipidemic agent tax both the care provider and the patientbecause of frequent ( e . g ., an apo mimetic and / or a statin ) . The intravitreal office visits for testing, monitoring and treatment. Further half - life of bevacizumab has been estimated to be about 9 . 8 more , the anti- angiogenic agent ( e . g ., an anti - VEGF agent ) days . may become less effective with repeated use , a phenomenon [0469 ] In other embodiments , the anti- angiogenic agent known as tachyphylaxis . Moreover, risks of intravitreal includes, or is , bevacizumab , and bevacizumab is adminis injections include elevated intraocular pressure , bacterial tered ( e . g . , by intravitreal injection ) in a dose of about and sterile endophthalmitis , cataract formation , hemorrhage 0 . 1 - 0 . 3 mg, 0 . 3 - 0 .5 mg, 0 . 5 - 0 .75 mg or 0 . 75 - 1 mg once and retinal detachment, and repeated injections can lead to every month . retinal thinning and geographic atrophy . [0470 ] In some embodiments , the duration /length of treat [0464 ] In certain embodiments , the anti- angiogenic agent ment with the anti -angiogenic agent ( e. g ., an anti -VEGF includes , or is , aflibercept (EYLEA ) , and aflibercept is agent ) is no more than about 36 , 30 , 24 , 18 or 12 months. In administered ( e . g ., by intravitreal injection ) in a dose of certain embodiments , the length of treatment with the anti about 1 - 1 . 5 mg or 1 . 5 - 2 mg once every 3 , 4 , 5 or 6 months, angiogenic agent ( e . g . , an anti - VEGF agent ) is no more than optionally after being administered in a dose of about 1 - 1 .5 about 24 , 18 or 12 months. In further embodiments , the mg or 1 .5 - 2 mg once every month for the first 1 , 2 or 3 length of treatment with the anti -angiogenic agent ( e . g . , an months or once every 6 weeks for the first 1 . 5 or 3 months , anti- VEGF agent ) is about 6 - 12 , 12 - 18 or 18 - 24 months . compared to the conventional or recommended dose and [ 0471 ] In some embodiments , the anti - angiogenic agent dosing frequency for aflibercept of 2 mg administered by ( e . g ., an anti- VEGF agent) is administered to treat or slow intravitreal injection once every 2 months after administra the progression of neovascular (wet ) AMD , including types tion of 2 mg once every month for the first 3 months in the 1 , 2 and 3 neovascularization (NV ) and including when absence of treatment with the anti- dyslipidemic agent ( e . g ., signs of active neovascularization are present. The presence an apo mimetic and /or a statin ) . The intravitreal half - life of of sub -RPE -BL , subretinal or intraretinal fluid , which can signify active neovascularization and leakage of fluid from aflibercept has been estimated to be about 9 . 0 days . new blood vessels , can be detected by techniques such as [0465 ] In other embodiments , the anti - angiogenic agent OCT- fluorescein angiography . In certain embodiments , the includes , or is , aflibercept, and aflibercept is administered anti- angiogenic agent ( e . g . , an anti - VEGF agent ) is admin ( e. g ., by intravitreal injection ) in a dose of about 1 -1 .25 mg, istered when the presence of subretinal or intraretinal fluid 1 . 25 - 1 . 5 mg or 1 . 5 - 1 . 75 mg in a frequency substantially is detected . An anti -angiogenic agent ( e . g ., an anti- VEGF similar to or the same as the conventional or recommended agent) can also be employed when sub -RPE -BL fluid is dosing frequency for aflibercept in the absence of treatment detected , although pigment epithelium detachment caused with the anti - dyslipidemic agent ( e . g . , an apo mimetic by sub -RPE - BL fluid can remain stable for a relatively long and / or a statin ) . time and may not require anti - angiogenic therapy. In further [0466 ] In further embodiments , the anti - angiogenic agent embodiments , the anti - angiogenic agent ( e . g ., an anti- VEGF includes, or is , ranibizumab (LUCENTIS® ) , and ranibi agent) is administered at least in the advanced stage of AMD zumab is administered ( e . g ., by intravitreal injection ) in a to prevent or delay the onset of neovascular AMD . In certain dose of about 0 . 1 - 0 . 2 mg, 0 . 2 -0 .3 mg, 0 .3 -0 . 4 mg or 0 .4 -0 .5 embodiments , the anti -angiogenic agent ( e . g . , an anti - VEGF mg once every 2 , 3 , 4 , 5 or 6 months, optionally after being agent ) is administered ( e . g . , by intravitreal injection ) less administered in a dose of about 0 . 1 - 0 . 2 mg, 0 .2 - 0 . 3 mg, frequently , and /or in a lower dose , to prevent or delay the 0 . 3 - 0 . 4 mg or 0 . 4 - 0 . 5 mg once every month for the first 1 , onset of neovascular AMD than to treat or slow the pro 2 or 3 months or once every 6 weeks for the first 1 . 5 or 3 gression of neovascular AMD . months , compared to the conventional or recommended [0472 ] In some embodiments , the anti- dyslipidemic agent dose and dosing frequency for ranibizumab of 0 . 5 mg ( e . g . , an apo mimetic and / or a statin ) is administered at least administered by intravitreal injection once every month in in the advanced stage of AMD to treat or slow the progres the absence of treatment with the anti -dyslipidemic agent sion of neovascular AMD , including types 1 , 2 and 3 NV. In ( e . g . , an apo mimetic and / or a statin ) . The intravitreal further embodiments , the anti - dyslipidemic agent ( e . g . , an half- life of ranibizumab has been estimated to be about 7 . 1 apo mimetic and / or a statin ) is administered at least in the days . advanced stage of AMD to treat or slow the progression of US 2018 /0296525 A1 Oct . 18 , 2018 40 central geographic atrophy (GA ) , and / or to prevent or delay improved patient compliance and health due to fewer inva the onset of neovascular AMD . In additional embodiments , sive procedures being performed . the anti - dyslipidemic agent ( e . g . , an apo mimetic and /or a [ 0476 ] In some embodiments , the composition containing statin ) is administered at least in the intermediate stage of the anti - dyslipidemic agent ( e . g ., an apo mimetic and/ or a AMD to treat or slow the progression of non -central GA , statin ) , and / or the composition containing the anti -angio and / or to prevent or delay the onset of central GA and / or genic agent ( e . g . , an anti -VEGF agent ), whether the same neovascular AMD . composition or separate compositions , are formulated as an [0473 ] In some embodiments , the anti -dyslipidemic agent injectable solution or suspension ( e . g. , for intravitreal, sub ( e . g . , an apo mimetic and /or a statin ) and /or the anti conjunctival, subretinal or sub - Tenon ' s injection ) . Examples angiogenic agent ( e . g ., an anti - VEGF agent ) are adminis of formulations for injection into the eye include without limitation those described elsewhere herein . In other tered locally to , into , in or around the eye . Potential routes , embodiments , the composition containing the anti - dyslipi sites and means of local administration are described else demic agent ( e. g . , an apo mimetic and / or a statin ) , and /or the wherein herein . In some embodiments , the anti -dyslipidemic composition containing the anti - angiogenic agent ( e . g . , an agent ( e . g ., an apo mimetic and / or a statin ) and / or the anti - VEGF agent ) , whether the same composition or sepa anti - angiogenic agent ( e . g ., an anti - VEGF agent ) are admin rate compositions, are formulated as an eye drop or an istered by injection ( e . g ., intravitreal, subconjunctival, sub implant ( e . g ., an intravitreal, subretinal or sub - Tenon ' s retinal or sub - Tenon 's injection ), eye drop or implant ( e. g. , implant) . Use of an eye drop , or implantation of the implant intravitreal , subretinal or sub - Tenon ' s implant ). In certain one , two or three times , can avoid potential issues associated embodiments , the anti- dyslipidemic agent (e . g ., an apo with repeated injections. In further embodiments , the com mimetic and / or a statin ) and the anti - angiogenic agent ( e . g . , position containing the anti - dyslipidemic agent ( e . g . , an apo an anti - VEGF agent) are administered by injection ( e . g ., mimetic and /or a statin ), and / or the composition containing intravitreal , subconjunctival, subretinal or sub - Tenon ' s the anti- angiogenic agent ( e . g ., an anti - VEGF agent) , injection ) or eye drop . In further embodiments , the anti whether the same composition or separate compositions, are dyslipidemic agent ( e . g . , an apo mimetic and /or a statin ) configured for sustained release of the anti - dyslipidemic and / or the anti -angiogenic agent ( e . g . , an anti - VEGF agent) agent and / or the anti -angiogenic agent. Non - limiting are administered via a sustained -release composition . Non examples of sustained -release compositions include those limiting examples of sustained - release compositions include described elsewhere herein . Use of a sustained -release com those described elsewhere herein . position can decrease the number of times a potentially [0474 ] In certain embodiments , the anti - dyslipidemic invasive procedure ( e . g . , intravitreal injection ) is performed agent ( e . g ., an apo mimetic and / or a statin ) is administered to administer a drug , and can improve the profile of the locally to , into , in or around the eye in the initial phase of amount of the drug delivered to the target site over a period treatment, and then the anti - dyslipidemic agent is adminis of time . tered systemically . As a non -limiting example , the initial [0477 ] In some embodiments , the composition containing administration ( s ) ( e . g . , the first one to five administrations ) the anti - dyslipidemic agent ( e . g . , an apo mimetic , or a statin of the anti - dyslipidemic agent ( e . g . , an apo mimetic and/ or in the same composition containing the anti -angiogenic a statin ) can be local via injection ( e . g . , intravitreal, sub agent) , and /or the composition containing the anti - angio conjunctival, subretinal or sub - Tenon ' s injection ), and then genic agent ( e . g . , an anti -VEGF agent) , whether the same subsequent administration ( s ) of the anti -dyslipidemic agent composition or separate compositions, comprise one or can be systemic , such as oral, parenteral ( e . g ., intravenous, more excipients that inhibit peptide /protein aggregation , subcutaneous or intramuscular ), or topical ( e . g ., intranasal or increase peptide / protein solubility , reduce solution viscosity pulmonary ) . In other embodiments , the anti -dyslipidemic or increase peptide/ protein stability , or any combination or agent ( e . g . , an apo mimetic and / or a statin ) is administered all thereof. Examples of such excipients include without only locally ( e . g . , by injection , eye drop or implant) . In yet limitation those described elsewhere herein , and the use of other embodiments , the anti -dyslipidemic agent ( e. g ., an apo such excipients can have benefits as described elsewhere mimetic and / or a statin ) is administered only systemically herein . For instance , such excipients can improve the inject ( e . g . , orally , parenterally or topically ) . ability of a composition , and thus can enable the use of a [ 0475 ] The anti -dyslipidemic agent ( e . g . , an apo mimetic needle with a smaller gauge for injection . Moreover, the use and / or a statin ) and the anti - angiogenic agent ( e . g . , an of such excipients can decrease the volume needed to anti -VEGF agent) can be administered via the same phar administer a given amount of a peptide or protein , and hence maceutical composition or separate pharmaceutical compo can reduce ocular pressure if the peptide or protein is sitions , where a composition further comprises one or more administered by injection into the eye . In addition , the use of pharmaceutically acceptable excipients or carriers . If the such excipients can allow a greater dose of a peptide or anti - dyslipidemic agent and the anti - angiogenic agent are protein to be administered for a given volume, which can administered via the same composition , such a composition permit the peptide or protein to be administered less fre can be prepared in advance or can be prepared by combining quently for a given total dose administered over a time the anti -dyslipidemic agent and the anti -angiogenic agent period . into the same formulation shortly or just before the formu [0478 ] In some embodiments , the anti - angiogenic agent lation is administered ( e . g . , by injection ) . Administration of ( e . g ., an anti -VEGF agent ) is administered ( e . g . , by intrav the anti- dyslipidemic agent and the anti -angiogenic agent in itreal injection ) in a dose higher than the conventional or the same composition decreases the number of times the recommended dose , and in a frequency less than the con patient is subjected to a potentially invasive procedure ( e . g ., ventional or recommended dosing frequency , for the anti intravitreal injection ) compared to separate administration angiogenic agent in the absence of treatment with the of the therapeutic agents , which can have benefits such as anti- dyslipidemic agent ( e . g ., an apo mimetic and / or a US 2018 /0296525 A1 Oct . 18 , 2018 statin ). In certain embodiments , the anti- angiogenic agent inhibitor such as ARC1905 or LFG316 , or a complement ( e . g . , an anti - VEGF agent) is administered ( e . g . , by intrav - factor D inhibitor such as lampalizumab ) . Use of the anti itreal injection ) in a dose at least about 10 % , 20 % , 30 % , dyslipidemic agent ( e . g . , an apo mimetic and /or a statin ) 50 % , 75 % , 100 % , 150 % or 200 % ( e . g . , at least about 30 % ) , may enhance the efficacy of one or more other therapeutic or about 10 - 30 % , 30 -50 % , 50 - 100 % , 100 - 150 % or 150 agents that , e . g . , reduce oxidative stress and /or reduce 200 % ( e. g ., about 50 - 100 % ) , higher than the conventional or inflammation . In certain embodiments , the additional thera recommended dose for the anti -angiogenic agent in the peutic agent includes , or is , ARC1905 or LFG316 . absence of treatment with the anti - dyslipidemic agent ( e . g . , [0483 ] In some embodiments , the anti - dyslipidemic agent an apo mimetic and / or a statin ) . In further embodiments , the ( e . g ., an apo mimetic and / or a statin ) and the anti - angiogenic anti - angiogenic agent ( e . g . , an anti - VEGF agent) is admin agent ( e . g . , an anti - VEGF agent) are used in conjunction istered ( e . g . , by intravitreal injection ) at least about 1 . 5 , 2 , 3 , with an anti - inflammatory agent ( e . g . , an NSAID such as 4 , 5 or 6 ( e . g . , at least about 2 ) times less frequently than the bromfenac , and /or a corticosteroid such as triamcinolone conventional or recommended dosing frequency for the acetonide ) or an immunosuppressant ( e . g ., an IL - 2 inhibitor anti - angiogenic agent in the absence of treatment with the such as daclizumab or rapamycin , or a TNF - a inhibitor such anti - dyslipidemic agent ( e . g . , an apo mimetic and /or a as infliximab ) to treat neovascular AMD . Inflammation is a statin ). stimulus of NV , and hence an anti - inflammatory agent or an [0479 ] In certain embodiments , the anti -angiogenic agent immunosuppressant can suppress NV . Therefore , use of an includes , or is , aflibercept (EYLEA ) , and aflibercept is anti- inflammatory agent or an immunosuppressant can administered ( e . g ., by intravitreal injection ) in a dose of reduce the number or frequency of administration (e . g. , about 2 . 2 - 2 .5 mg , 2 . 5 - 3 mg, 3 - 3 . 5 mg or 3 . 5 - 4 mg once injections ) of the anti- angiogenic agent . In further embodi every 3 , 4 , 5 or 6 months, optionally after being adminis ments, the anti -dyslipidemic agent ( e . g ., an apo mimetic tered in a dose of about 2. 2 -2 . 5 mg, 2 . 5 - 3 mg, 3 - 3 .5 mg or and /or a statin ) and the anti - angiogenic agent ( e . g . , an 3 . 5 - 4 mg once every month for the first 1 , 2 or 3 months or anti- VEGF agent ) are used in combination with a neuropro once every 6 weeks for the first 1 . 5 or 3 months , compared tector ( e . g ., an endogenous neuroprotector, such as CNTF ) . to the conventional or recommended dose and dosing fre Use of a neuroprotector can prevent or curtail degeneration quency for aflibercept of 2 mg administered by intravitreal of retinal cells (e .g ., photoreceptors ). injection once every 2 months after administration of 2 mg 10484 ] In some embodiments , the additional therapeutic once every month for the first 3 months in the absence of agent( s ) are administered at least in the advanced stage of treatment with the anti- dyslipidemic agent (e .g ., an apo AMD . In further embodiments, the additional therapeutic mimetic and /or a statin ). agent ( s ) are administered at least in the intermediate stage of [0480 ] In other embodiments , the anti- angiogenic agent AMD . In still further embodiments, the additional therapeu includes , or is , ranibizumab (LUCENTIS® ) , and ranibi tic agent( s ) are administered at least in the early stage of zumab is administered ( e . g . , by intravitreal injection ) in a AMD . In certain embodiments , the additional therapeutic dose of about 0 .55 -0 .75 mg , 0 .75 - 1 mg, 1 - 1 . 25 mg or agent( s ) administered at least in the early stage of AMD 1 .25 - 1 . 5 mg once every 2 , 3 , 4 , 5 or 6 months, optionally include , or are , an antioxidant ( e . g . , a vitamin , a saffron after being administered in a dose of about 0 .55 - 0 . 75 mg, carotenoid and / or zinc ) and / or an anti- inflammatory agent 0 .75 - 1 mg, 1- 1. 25 mg or 1. 25 - 1. 5 mg once every month for ( e. g ., an NSAID ), and the additional therapeutic agent( s ) are the first 1 , 2 or 3 months or once every 6 weeks for the first administered systemically ( e . g . , orally ) or locally ( e . g ., by 1 . 5 or 3 months, compared to the conventional or recom eye drop ) . mended dose and dosing frequency for ranibizumab of 0 . 5 [0485 ] An anti -dyslipidemic agent ( e .g ., an apoA - I mg administered by intravitreal injection once every month mimetic such as L - 4F or an apoE mimetic such as AEM in the absence of treatment with the anti -dyslipidemic agent 28 - 14 , and / or a statin such as atorvastatin or simvastatin ) in ( e . g . , an apo mimetic and / or a statin ) . combination with an anti -angiogenic agent ( e . g . , an anti [0481 ] In yet other embodiments , the anti - angiogenic VEGF agent such as aflibercept, brolucizumab , bevaci agent includes, or is , bevacizumab ( AVASTIN® ) , and beva zumab or ranibizumab , and / or an anti -PDGF agent such as cizumab is administered ( e . g ., by intravitreal injection ) in a E10030 ) can also be used to treat other eye diseases and dose of about 1 .4 - 1. 75 mg, 1 . 75 - 2 mg, 2 - 2 . 5 mg or 2 . 5 - 3 mg disorders in addition to AMD . Non - limiting examples of once every 2 , 3 , 4 , 5 or 6 months, optionally after being other eye diseases and disorders that can be treated with such administered in a dose of about 1. 4 - 1 . 75 mg, 1 . 75 - 2 mg, a combination include diabetic maculopathy (DMP ) ( includ 2 - 2 . 5 mg or 2 . 5 - 3 mg once every month for the first 1 , 2 or ing partial ischemic DMP ), diabetic macular edema (DME ) 3 months or once every 6 weeks for the first 1 . 5 or 3 months , ( including clinically significant DME (CSME ), focal DME compared to the conventional or recommended dose and and diffuse DME ), diabetic retinopathy ( including in dosing frequency for bevacizumab for the treatment of AMD patients with DME ) , retinal vein occlusion (RVO ) , central of about 1 .25 mg administered by intravitreal injection once RVO ( including central RVO with cystoid macular edema every month in the absence of treatment with the anti [ CME ]) , branch RVO ( including branch RVO with CME) , dyslipidemic agent ( e . g ., an apo mimetic and / or a statin ) . macular edema following RVO ( including central RVO and [ 0482] One or more other therapeutic agents described branch RVO ) , Irvine -Gass Syndrome (postoperative macu herein can be used in combination with the anti - dyslipi lar edema ) , and uveitis ( including uveitis posterior with demic agent ( e. g ., an apo mimetic and /or a statin ) and the CME ) . Beneficial properties of an anti - dyslipidemic agent anti - angiogenic agent ( e . g ., an anti - VEGF agent) for the ( e . g ., an apo mimetic and / or a statin ) , such as the strong treatment of AMD . In some embodiments , the additional anti - inflammatory property of apo A - I mimetics and apoE therapeutic agent( s ) include , or are, an antioxidant ( e . g . , mimetics and the antioxidant property of statins , can vitamins, saffron carotenoids and / or zinc ) and /or a comple - increase the effectiveness of an anti - angiogenic agent ( e . g ., ment inhibitor ( e . g . , a C3 inhibitor such as CB - 2782 , a C5 an anti -VEGF agent) in the treatment of such eye diseases US 2018 /0296525 A1 Oct . 18 , 2018 and disorders . Embodiments relating to the treatment of embodiments , the anti - dyslipidemic agent ( e . g ., an apo AMD using a combination of an anti -dyslipidemic agent mimetic and /or a statin ) and the complement inhibitor ( e . g . , ( e . g . , an apo mimetic and /or a statin ) and an anti - angiogenic a C3 inhibitor, a C5 inhibitor and /or a CFD inhibitor ) are agent (e . g. , an anti- VEGF agent) also apply to the treatment administered at least in the early stage of AMD or the initial of other eye diseases and disorders using such a combina phase of intermediate AMD to prevent or delay the onset of tion . non - central GA . In certain embodiments, the complement inhibitor ( e . g . , a C3 inhibitor , a C5 inhibitor and / or a CFD IX . TREATMENT OF AMD WITH AN inhibitor ) and /or the anti -dyslipidemic agent (e .g ., an apo ANTI -DYSLIPIDEMIC AGENT AND A mimetic and/ or a statin ) are administered less frequently , COMPLEMENT INHIBITOR and /or in a lower dose , to prevent or delay the onset of [0486 ] Further embodiments of the disclosure relate to a non - central or central GA than to treat or slow the progres method of treating AMD , comprising administering to a sion of central GA . subject in need of treatment a therapeutically effective amount of an anti - dyslipidemic agent and a therapeutically [ 0490 ] In certain embodiments , treatment with the anti effective amount of a complement inhibitor . dyslipidemic agent ( e . g ., an apo mimetic and / or a statin ) and [0487 ] Examples of anti- dyslipidemic agents, including the complement inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor apolipoprotein mimetics and statins, include without limi and / or a CFD inhibitor ) slows the progression of central GA tation those described elsewhere herein . In certain embodi and / or non - central GA ( e . g . , reduces the rate of GA pro ments , the anti -dyslipidemic agent includes, or is , an apoA - I gression , or reduces the GA lesion area or size ) by at least mimetic (e . g. , L -4F or D -4F or a salt thereof ) and /or an apoE about 10 % , 20 % , 30 % , 40 % , 50 % , 60 % , 70 % or 80 % ( e . g . , mimetic ( e . g . , AEM - 28 - 14 or a salt thereof ). In further by at least about 20 % or 40 % ) , or by about 20 -40 % , 40 -60 % embodiments , the anti - dyslipidemic agent includes, or is , a or 60 - 80 % . In further embodiments , treatment with the statin ( e .g . , atovastatin and /or simvastatin or a salt thereof) . anti -dyslipidemic agent ( e . g . , an apo mimetic and /or a statin ) All of the embodiments relating to the treatment of AMD and the complement inhibitor ( e . g ., a C3 inhibitor, a C5 with an apolipoprotein mimetic which are described in inhibitor and /or a CFD inhibitor ) slows the progression of Section IV and elsewhere herein , and all of the embodiments central GA and /or non - centralGA ( e . g ., reduces the rate of relating to the treatment of AMD with a statin which are GA progression , or reduces the GA lesion area or size ) at described in Section V and elsewhere herein , also apply to the treatment of AMD with a complement inhibitor and an least about 10 % , 20 % , 30 % , 50 % , 100 % , 150 % , 200 % or apo mimetic and /or a statin . 300 % (e .g ., at least about 20 % or 30 % ), or about 10 - 30 % , [0488 ] Non - limiting examples of complement inhibitors 30 - 50 % , 50 - 100 % , 100 - 200 % or 200 - 300 % ( e . g . , about include those described elsewhere herein . In some embodi 50 - 100 % ) , more than treatment with the complement inhibi ments , the complement inhibitor includes , or is , a CFD tor in the absence of treatment with the anti -dyslipidemic inhibitor ( e . g . , lampalizumab ) , a C3 inhibitor ( e . g . , agent . CB - 2782 ) or a C5 inhibitor ( e . g . , LFG316 or ARC1905 [0491 ] Treatment of AMD , including central and non [ZIMURA® ) , or any combination or all thereof. In certain central GA , with the anti - dyslipidemic agent ( e .g . , an apo embodiments , the complement inhibitor includes, or is , mimetic and / or a statin ) and the complement inhibitor ( e . g . , lampalizumab . In some embodiments , the subject has a a C3 inhibitor, a C5 inhibitor and / or a CFD inhibitor ) may mutation in the gene encoding complement factor I ( CFI) , have a synergistic effect. For instance , treatment with the which may be a biomarker for a more positive response to anti - dyslipidemic agent may enhance the efficacy of the treatment with lampalizumab . CFI, a C3b /C4b inactivator , complement inhibitor, and / or vice versa . As an example , the regulates complement activation by cleaving cell -bound or apoA - I mimetic L - 4F can clear lipid barrier from the fluid -phase C3b and C4b . Bruch ’ s membrane , which improves the exchange of oxygen [ 0489 ] In some embodiments , the anti -dyslipidemic agent and nutrients ( including vitamin A ) from the choriocapillaris ( e . g . , an apo mimetic and / or a statin ) and the complement to RPE cells and photoreceptors , thereby curtailing the death inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor and /or a CFD of RPE and photoreceptor cells . As another example , the inhibitor) are administered to treat geographic atrophy (GA ). ability of L - 4F to reduce inflammation can decrease the In some embodiments , the anti- dyslipidemic agent ( e . g ., an required number of administrations ( e . g . , by injection ) and / apo mimetic and / or a statin ) and the complement inhibitor or dosage of the complement inhibitor . As a further example , ( e . g . , a C3 inhibitor, a C5 inhibitor and / or a CFD inhibitor ) the statin atorvastatin can substantially reduce drusen depos are administered to prevent, delay the onset of, or slow the its , which improves the exchange of incoming oxygen and progression of central GA . In certain embodiments , the nutrients and outgoing waste between the choriocapillaris anti -dyslipidemic agent (e . g ., an apo mimetic and / or a statin ) and RPE cells and reduces the risk of drusenoid pigment and the complement inhibitor ( e . g . , a C3 inhibitor , a C5 epithelial detachments . In addition , statins have antioxidant inhibitor and/ or a CFD inhibitor ) are administered at least in property . Synergism between the anti - dyslipidemic agent the advanced stage of atrophic ( dry ) AMD to treat or slow and the complement inhibitor can allow , but is not required the progression of central GA , and / or to prevent or delay the for, e . g . , the complement inhibitor to be administered less onset of neovascular AMD . In further embodiments , the frequently than the conventional or recommended dosing anti - dyslipidemic agent ( e . g ., an apo mimetic and/ or a statin ) frequency , and / or in a dose lower than the conventional or and the complement inhibitor ( e . g ., a C3 inhibitor, a C5 recommended dose , for the complement inhibitor in the inhibitor and /or a CFD inhibitor ) are administered at least in absence of treatment with the anti - dyslipidemic agent. the intermediate stage of AMD to treat or slow the progres Administration of a lower dose of the complement inhibitor sion of non - central GA , and /or to prevent or delay the onset can have benefits , such as a better safety profile due to fewer of central GA and/ or neovascular AMD . In additional side effects . Less frequent administration ( e . g ., by intravit US 2018 /0296525 A1 Oct . 18 , 2018 43 real injection ) of the complement inhibitor can have signifi inhibitor, a C5 inhibitor and /or a CFD inhibitor ) is about cant benefits for the patient as well as the care provider , as 6 - 12 , 12 - 18 or 18 - 24 months . described elsewhere herein . [ 0496 ] In some embodiments , the anti- dyslipidemic agent [ 0492 ] In some embodiments , the complement inhibitor ( e . g . , an apo mimetic and / or a statin ) and / or the complement ( e. g ., a C3 inhibitor, a C5 inhibitor and /or a CFD inhibitor ) inhibitor ( e . g . , a C3 inhibitor , a C5 inhibitor and / or a CFD is administered in a frequency less than the conventional or inhibitor ) are administered locally to , into , in or around the recommended dosing frequency , and /or in a dose less than eye . Potential routes , sites and means of local administration the conventional or recommended dose , for the complement are described elsewherein herein . In some embodiments , the inhibitor in the absence of treatment with the anti -dyslipi anti- dyslipidemic agent ( e . g . , an apo mimetic and / or a statin ) demic agent ( e . g . , an apo mimetic and / or a statin ) . In some and /or the complement inhibitor ( e . g ., a C3 inhibitor, a C5 embodiments , the complement inhibitor ( e . g . , a C3 inhibitor , inhibitor and / or a CFD inhibitor ) are administered by injec a C5 inhibitor and /or a CFD inhibitor ) is administered ( e . g . , tion ( e . g ., intravitreal, subconjunctival, subretinal or sub by intravitreal injection ) at least about 1 . 5 , 2 , 3 , 4 , 5 or 6 Tenon 's injection ), eye drop or implant (e . g. , intravitreal, ( e . g . , at least about 2 ) times less frequently than the con subretinal or sub - Tenon ' s implant) . In certain embodiments , ventional or recommended dosing frequency for the comple the anti - dyslipidemic agent ( e . g . , an apo mimetic and / or a ment inhibitor in the absence of treatment with the anti statin ) and the complement inhibitor ( e . g ., a C3 inhibitor, a dyslipidemic agent ( e . g ., an apo mimetic and / or a statin ) . In C5 inhibitor and / or a CFD inhibitor ) are administered by certain embodiments, the complement inhibitor ( e . g ., a C3 injection ( e . g ., intravitreal, subconjunctival , subretinal or inhibitor, a C5 inhibitor and / or a CFD inhibitor ) is admin sub - Tenon ' s injection ) or eye drop . In further embodiments , istered locally to , into , in or around the eye ( e . g . , by the anti - dyslipidemic agent ( e . g . , an apo mimetic and / or a intravitreal injection ) once every 2 , 3 , 4 , 5 or 6 ( e . g . , once statin ) and/ or the complement inhibitor ( e . g . , a C3 inhibitor, every 2 ) months . In further embodiments , treatment with the a C5 inhibitor and/ or a CFD inhibitor) are administered via anti -dyslipidemic agent ( e . g ., an apo mimetic and /or a statin ) a sustained -release composition . Non - limiting examples of reduces the total number of times ( e .g ., the total number of sustained -release compositions include those described else injections ) the complement inhibitor ( e . g . , a C3 inhibitor, a where herein . C5 inhibitor and / or a CFD inhibitor) is administered . In [0497 ] In certain embodiments , the anti - dyslipidemic certain embodiments, the complement inhibitor ( e . g ., a C3 agent ( e . g ., an apo mimetic and /or a statin ) is administered inhibitor , a C5 inhibitor and / or a CFD inhibitor) is admin locally to , into , in or around the eye in the initial phase of istered locally ( e . g ., by intravitreal injection ) no more than treatment, and then the anti - dyslipidemic agent is adminis about 20 , 18 , 15 , 12 or 10 times. In additional embodiments , tered systemically . As a non - limiting example, the initial the complement inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor administration (s ) ( e .g ., the first one to five administrations) and / or a CFD inhibitor ) is administered ( e . g . , by intravitreal of the anti - dyslipidemic agent ( e . g . , an apo mimetic and / or injection ) in a dose at least about 10 % , 20 % , 30 % , 40 % , a statin ) can be local via injection ( e . g ., intravitreal, sub 50 % , 60 % , 70 % or 80 % (e . g. , at least about 20 % ), or about conjunctival, subretinal or sub - Tenon ' s injection ) , and then 10 - 30 % , 30 - 50 % or 50 - 70 % , less than the conventional or subsequent administration ( s ) of the anti -dyslipidemic agent recommended dose for the complement inhibitor in the can be systemic , such as oral, parenteral ( e . g ., intravenous, absence of treatment with the anti -dyslipidemic agent ( e. g ., subcutaneous or intramuscular ) , or topical ( e . g . , intranasal or an apo mimetic and / or a statin ). pulmonary ) . In other embodiments , the anti - dyslipidemic agent ( e .g . , an apo mimetic and /or a statin ) is administered [0493 ] In certain embodiments , the complement inhibitor only locally ( e . g ., by injection , eye drop or implant) . In yet includes , or is , lampalizumab , and lampalizumab is admin other embodiments , the anti -dyslipidemic agent (e .g ., an apo istered ( e . g ., by intravitreal injection ) in a dose of about 4 - 6 mimetic and /or a statin ) is administered only systemically mg, 6 - 8 mg or 8 - 10 mg once every 2 , 3, 4 , 5 or 6 months, ( e . g . , orally , parenterally or topically ) . optionally after being administered in a dose of about 4 - 6 [0498 ] The anti -dyslipidemic agent (e .g ., an apo mimetic mg, 6 -8 mg or 8 - 10 mg once every month for the first 1 , 2 and / or a statin ) and the complement inhibitor ( e . g . , a C3 or 3 months or once every 6 weeks for the first 1 . 5 or 3 inhibitor , a C5 inhibitor and / or a CFD inhibitor) can be months, compared to the conventional or recommended administered via the same pharmaceutical composition or dose and dosing frequency for lampalizumab of about 10 mg separate pharmaceutical compositions, where a composition administered by intravitreal injection once every month in further comprises one or more pharmaceutically acceptable the absence of treatment with the anti -dyslipidemic agent excipients or carriers. If the anti - dyslipidemic agent and the ( e . g ., an apo mimetic and /or a statin ). complement inhibitor are administered via the same com [0494 ] In other embodiments , the complement inhibitor position , such a composition can be prepared in advance or includes , or is , lampalizumab , and lampalizumab is admin can be prepared by combining the anti - dyslipidemic agent istered ( e . g ., by intravitreal injection ) in a dose of about 3 - 5 and the complement inhibitor into the same formulation mg, 5 -7 mg or 7 - 9 mg once every month (4 weeks ) or 1 .5 shortly or just before the formulation is administered ( e . g . , months (6 weeks ). by injection ) . Administration of the anti -dyslipidemic agent [0495 ] In some embodiments , the duration / length of treat and the complement inhibitor in the same composition ment with the complement inhibitor ( e . g . , a C3 inhibitor, a decreases the number of times the patient is subjected to a C5 inhibitor and /or a CFD inhibitor ) is no more than about potentially invasive procedure ( e . g ., intravitreal injection ) 36 , 30 , 24 , 18 or 12 months. In certain embodiments , the compared to separate administration of the therapeutic length of treatment with the complement inhibitor ( e . g ., a C3 agents , which can have significant benefits for the patient inhibitor, a C5 inhibitor and /or a CFD inhibitor) is no more and the care provider as described elsewhere herein . than about 24 , 18 or 12 months. In further embodiments, the 10499 ] In some embodiments , the composition containing length of treatmentwith the complement inhibitor ( e . g . , a C3 the anti- dyslipidemic agent ( e . g . , an apo mimetic and / or a US 2018 /0296525 A1 Oct . 18 , 2018 44 statin ), and /or the composition containing the complement injection ) in a dose at least about 10 % , 20 % , 30 % , 50 % , inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor and /or a CFD 75 % , 100 % , 150 % or 200 % ( e . g ., at least about 30 % ) , or inhibitor ) , whether the same composition or separate com about 10 - 30 % , 30 - 50 % , 50 - 100 % , 100 - 150 % or 150 - 200 % positions , are formulated as an injectable solution or sus ( e . g . , about 50 - 100 % ) , higher than the conventional or pension (e . g. , for intravitreal, subconjunctival , subretinal or recommended dose for the complement inhibitor in the sub - Tenon ' s injection ). Examples of formulations for injec absence of treatment with the anti - dyslipidemic agent ( e . g . , tion into the eye include without limitation those described an apo mimetic and /or a statin ) . In further embodiments , the elsewhere herein . In other embodiments , the composition complement inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor containing the anti- dyslipidemic agent (e . g. , an apo mimetic and / or a CFD inhibitor ) is administered ( e . g . , by intravitreal and / or a statin ) , and /or the composition containing the injection ) at least about 1. 5 , 2 , 3 , 4 , 5 or 6 ( e . g ., at least about complement inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor 2 ) times less frequently than the conventional or recom and / or a CFD inhibitor) , whether the same composition or mended dosing frequency for the complement inhibitor in separate compositions , are formulated as an eye drop or an the absence of treatment with the anti- dyslipidemic agent implant ( e . g ., an intravitreal, subretinal or sub - Tenon ' s ( e . g . , an apo mimetic and /or a statin ) . implant ) . Use of an eye drop , or implantation of the implant (0502 ] In certain embodiments , the complement inhibitor one , two or three times, can avoid potential issues associated includes, or is , lampalizumab , and lampalizumab is admin with repeated injections. In further embodiments , the com istered ( e . g . , by intravitreal injection ) in a dose of about position containing the anti- dyslipidemic agent ( e . g . , an apo 12 - 14 mg, 14 - 16 mg, 16 - 18 mg or 18 - 20 mg once every 2 , mimetic and /or a statin ), and /or the composition containing 3 , 4 , 5 or 6 months, optionally after being administered in a the complement inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor dose of about 12 - 14 mg, 14 - 16 mg, 16 - 18 mg or 18 - 20 mg and / or a CFD inhibitor ) , whether the same composition or once every month for the first 1 , 2 or 3 months or once every separate compositions, are configured for sustained release 6 weeks for the first 1 . 5 or 3 months , compared to the of the anti -dyslipidemic agent and /or the complement inhibi conventional or recommended dose and dosing frequency tor. Non -limiting examples of sustained - release composi for lampalizumab of about 10 mg administered by intravit tions include those described elsewhere herein . Use of a real injection once every month in the absence of treatment sustained - release composition can decrease the number of with the anti - dyslipidemic agent ( e . g . , an apo mimetic times a potentially invasive procedure ( e . g ., intravitreal and /or a statin ). injection ) is performed to administer a drug , and can [0503 ] In additional embodiments , the anti- dyslipidemic improve the profile of the amount of the drug delivered to agent ( e . g . , an apo mimetic and / or a statin ) and the comple the target site over a period of time. ment inhibitor are administered at least in the advanced [0500 ] In some embodiments , the composition containing stage of AMD further to prevent or delay the onset of the anti- dyslipidemic agent ( e . g . , an apo mimetic , or a statin neovascular (wet ) AMD , and / or to treat or slow the progres in the same composition containing the complement inhibi sion of wet AMD , including types 1 , 2 and 3 neovascular tor ) , and/ or the composition containing the complement ization . The complement inhibitor used to treat wet AMD inhibitor ( e . g . , a C3 inhibitor , a C5 inhibitor and / or a CFD can be the same as , different from , or in addition to the inhibitor ), whether the same composition or separate com complement inhibitor used to treat dry AMD ( including positions , comprise one or more excipients that inhibit geographic atrophy ). In certain embodiments , the comple peptide/ protein aggregation , increase peptide/ protein solu ment inhibitor includes , or is , a C5 inhibitor such as bility , reduce solution viscosity or increase peptide/ protein ARC1905 ( ZIMURA® ) or LFG316 . In some embodiments , stability , or any combination or all thereof. Examples of such an anti -angiogenic agent is used in conjunction with the excipients include without limitation those described else anti - dyslipidemic agent ( e . g ., an apo mimetic and / or a statin ) where herein , and the use of such excipients can have and the complement inhibitor to treat wet AMD . In certain benefits as described elsewhere herein . For instance, such embodiments , the anti - angiogenic agent includes , or is , an excipients can improve the injectability of a composition , anti - VEGF agent ( e . g ., aflibercept EYLEA® ) , broluci and thus can enable the use of a needle with a smaller gauge zumab , bevacizumab [ AVASTIN® ] or ranibizumab [ LU for injection . Moreover , the use of such excipients can CENTIS® ) , or any combination thereof) and / or an anti decrease the volumeneeded to administer a given amount of PDGF agent ( e . g . , E10030 [ FOVISTA® ]) . a peptide or protein , and hence can reduce ocular pressure if [0504 ] In some embodiments , the anti -angiogenic agent the peptide or protein is administered by injection into the ( e . g ., an anti - VEGF agent ) and / or the complement inhibitor eye. In addition , the use of such excipients can allow a ( e . g . , a C5 inhibitor such as ARC1905 ) are administered in greater dose of a peptide or protein to be administered for a a frequency less than the conventional or recommended given volume, which can permit the peptide or protein to be dosing frequency , and / or in a dose less than the conventional administered less frequently for a given total dose admin or recommended dose , for the anti - angiogenic agent and /or istered over a time period . the complement inhibitor in the absence of treatment with [0501 ] In some embodiments , the complement inhibitor the anti - dyslipidemic agent ( e . g . , an apo mimetic and / or a ( e . g . , a C3 inhibitor, a C5 inhibitor and / or a CFD inhibitor ) statin ) . In certain embodiments , the anti- angiogenic agent is administered ( e . g . , by intravitreal injection ) in a dose ( e . g . , an anti - VEGF agent) and / or the complement inhibitor higher than the conventional or recommended dose, and in ( e . g . , a C5 inhibitor such as ARC1905 ) are administered a frequency less than the conventional or recommended ( e. g ., by intravitreal injection ) at least about 1. 5 , 2 , 3, 4 , 5 or dosing frequency , for the complement inhibitor in the 6 ( e . g . , at least about 2 ) times less frequently than the absence of treatment with the anti- dyslipidemic agent ( e . g . , conventional or recommended dosing frequency for the an apo mimetic and/ or a statin ) . In certain embodiments , the anti - angiogenic agent and / or the complement inhibitor in the complement inhibitor ( e . g . , a C3 inhibitor, a C5 inhibitor absence of treatment with the anti - dyslipidemic agent ( e . g . , and / or a CFD inhibitor ) is administered ( e .g . , by intravitreal an apo mimetic and/ or a statin ) . In further embodiments , the US 2018 /0296525 A1 Oct . 18 , 2018 45 anti - angiogenic agent ( e . g ., an anti -VEGF agent) and / or the relating to the treatment of AMD with a statin which are complement inhibitor ( e . g . , a C5 inhibitor such as described in Section V and elsewhere herein , also apply to ARC1905 ) are administered ( e . g ., by intravitreal injection ) the treatment of AMD with an antioxidant ( and optionally a in a dose at least about 10 % , 20 % , 30 % , 40 % , 50 % , 60 % , mineral) and an apo mimetic and /or a statin . 70 % or 80 % ( e. g ., at least about 20 % ), or about 10 -30 % , 10509 ] Examples of antioxidants include without limita 30 -50 % or 50 -70 % , less than the conventional or recom tion those described elsewhere herein . In certain embodi mended dose for the anti -angiogenic agent and/ or the ments , the antioxidant comprises one or more vitamins ( e. g ., complement inhibitor in the absence of treatment with the vitamin B6 , vitamin C and vitamin E ) , one or more carote anti - dyslipidemic agent ( e . g . , an apo mimetic and /or a noids ( e . g . , xanthophylls ( e . g . , lutein , zeaxanthin and meso statin ) . Non - limiting examples of dosing frequencies and zeaxanthin ] and carotenoids in saffron [ e . g . , crocin and dosages for aflibercept, bevacizumab and ranibizumab are crocetin ] ) , or zinc, or any combination or all thereof, such as provided elsewhere herein . an AREDS or AREDS2 formulation , an ICAPS® formula [0505 ) One or more other therapeutic agents described tion , an Ocuvite® formulation or Saffron 2020TM described herein can be used in combination with the anti - dyslipi elsewhere herein . In addition to their ability to reduce demic agent ( e . g . , an apo mimetic and / or a statin ) and the oxidative stress , antioxidants can have other beneficial prop complement inhibitor for the treatment of dry or wet AMD . erties. For instance, saffron carotenoids have anti- inflamma In some embodiments , the additional therapeutic agent( s ) tory and cell -protective , as well as antioxidant, effects . include , or are , an antioxidant ( e . g . , vitamins , saffron caro 10510 ] In some embodiments , the antioxidant ( e . g . , vita tenoids and / or zinc ) , an anti - inflammatory agent ( e . g ., an mins and / or carotenoids) is administered in a dose less than NSAID such as bromfenac , and / or a corticosteroid such as the conventional or recommended dose , and/ or in a fre fluocinolone acetonide or triamcinolone acetonide ) , or a quency less than the conventional or recommended dosing neuroprotector ( e .g ., an endogenous neuroprotector such as frequency , for the antioxidant in the absence of treatment CNTF ), or any combination or all thereof. Use of the with the anti - dyslipidemic agent ( e . g ., an apo mimetic anti -dyslipidemic agent (e . g ., an apo mimetic and / or a statin ) and /or a statin ) . Administration of a lower dose of an may enhance the efficacy of one or more other therapeutic antioxidant can have benefits for the subject, such as fewer agents that, e . g . , reduce oxidative stress , reduce inflamma side effects . For example , higher intake of B - carotene can tion or curtail degeneration of RPE cells and retinal cells increase the risk of lung cancer in smokers . As another (e .g ., photoreceptors ) , or any combination or all thereof . example , higher intake of vitamin E can increase the risk of [0506 ] In some embodiments , the additional therapeutic heart failure in at -risk subjects . In some embodiments , the agent( s ) are administered at least in the advanced stage of antioxidant ( e . g . , vitamins and / or carotenoids ) is adminis AMD . In further embodiments , the additional therapeutic tered in a dose at least about 10 % , 20 % , 30 % , 40 % , 50 % , agent ( s ) are administered at least in the intermediate stage of 60 % , 70 % or 80 % ( e . g . , at least about 20 % ), or about AMD . In still further embodiments, the additional therapeu 10 - 30 % , 30 -50 % or 50 - 70 % , less than the conventional or tic agent( s ) are administered at least in the early stage of recommended dose for the antioxidant in the absence of AMD . In certain embodiments , the additional therapeutic treatment with the anti -dyslipidemic agent ( e . g . , an apo agent( s ) administered at least in the early stage of AMD mimetic and / or a statin ) . In further embodiments , the anti include , or are, an antioxidant ( e . g ., a vitamin , a saffron oxidant ( e . g . , vitamins and / or carotenoids ) is administered at carotenoid and / or zinc) and /or an anti - inflammatory agent least about 2 , 3 , 5 , 7 or 10 ( e . g ., at least about 2 ) times less ( e . g . , an NSAID ) , and the additional therapeutic agent( s ) are frequently than the conventional or recommended dosing administered systemically ( e . g ., orally ) or locally ( e . g . , by frequency for the antioxidant in the absence of treatment eye drop ). with the anti -dyslipidemic agent (e . g. , an apo mimetic and / or a statin ) . In certain embodiments , the antioxidant X . TREATMENT OF AMD WITH AN ( e . g . , vitamins and / or carotenoids ) is administered , whether ANTI- DYSLIPIDEMIC AGENT AND AN systemically ( e . g ., orally ) or locally in a non - invasive man ANTIOXIDANT ner ( e . g ., by eye drop ), once every two or three days [ 0507] Additional embodiments of the disclosure relate to compared to the conventional or recommended dosing fre a method of treating AMD , comprising administering to a quency for the antioxidant of at least one time every day subject in need of treatment a therapeutically effective orally in the absence of treatment with the anti -dyslipidemic amount of an anti - dyslipidemic agent and a therapeutically agent (e .g ., an apo mimetic and / or a statin ) . effective amount of an antioxidant. In addition , a mineral [0511 ] Treatment of AMD with the anti -dyslipidemic ( e . g ., zinc or selenium , each of which can also function as an agent ( e . g ., an apo mimetic and /or a statin ) and the antioxi antioxidant ) can be used in conjunction with an anti - dys dant ( e . g . , vitamins and / or carotenoids ) may have a syner lipidemic agent and an antioxidant to treat AMD . gistic effect . For instance , treatment with the anti - dyslipi [ 0508 ] Examples of anti -dyslipidemic agents , including demic agent may enhance the efficacy of the antioxidant, apolipoprotein mimetics and statins, include without limi and /or vice versa . As an example, the apoA - I mimetic L - 4F tation those described elsewhere herein . In certain embodi can markedly reduce lipid deposits from the Bruch ' s mem ments , the anti - dyslipidemic agent includes , or is , an apoA - I brane and the sub -RPE - BL space , thereby decreasing the mimetic ( e . g ., L - 4F or D -4F or a salt thereof) and / or an apoE amount of lipids susceptible to oxidation . As another mimetic ( e . g . , AEM - 28 - 14 or a salt thereof) . In further example , the ability of L - 4F to curtail the oxidation of lipids embodiments, the anti - dyslipidemic agent includes, or is , a and to clear pro - inflammatory oxidized lipids can decrease statin ( e . g ., atovastatin and / or simvastatin or a salt thereof) . the required dosage and / or frequency of administration of All of the embodiments relating to the treatment of AMD the antioxidant. As a further example , the statin atorvastatin with an apolipoprotein mimetic which are described in can substantially reduce drusen deposits , a rich source of Section IV and elsewhere herein , and all of the embodiments lipids available for oxidation . In addition , statins have US 2018 /0296525 A1 Oct . 18 , 2018 46 antioxidant property . Synergism between the anti -dyslipi - ( e . g ., orally or intravenously ) . In certain embodiments , the demic agent and the antioxidant can allow , but is not antioxidant ( e . g ., vitamins and /or carotenoids ) is adminis required for, e .g . , the antioxidant to be administered in a tered systemically ( e . g . , orally ) . In some embodiments , the dose lower than the conventional or recommended dose , anti - dyslipidemic agent ( e . g ., an apo mimetic and/ or a statin ) and / or in a frequency less than the conventional or recom and / or the antioxidant ( e . g ., vitamins and / or carotenoids ) are mended dosing frequency , for the antioxidant in the absence administered via a sustained - release composition . of treatment with the anti -dyslipidemic agent . [0515 ] In certain embodiments , the anti- dyslipidemic [0512 ] In some embodiments , the anti - dyslipidemic agent agent ( e . g ., an apo mimetic and /or a statin ) is administered ( e . g ., an apo mimetic and /or a statin ) and the antioxidant locally to , into , in or around the eye in the initial phase of ( e . g ., vitamins and/ or carotenoids ) are administered at least treatment, and then the anti - dyslipidemic agent is adminis in the advanced stage of AMD to treat or slow the progres tered systemically . As a non - limiting example, the initial sion of central geographic atrophy (GA ) and / or neovascular administration ( s ) ( e . g . , the first one to five administrations ) AMD ( including types 1 , 2 and 3 NV ) , and / or to prevent or of the anti- dyslipidemic agent ( e . g ., an apo mimetic and /or delay the onset of neovascular AMD . Use of the antioxidant a statin ) can be local via injection ( e .g . , intravitreal, sub can inhibit the formation of oxidized lipids, which can be conjunctival, subretinal or sub - Tenon ' s injection ) , and then strongly pro - inflammatory and hence pro - angiogenic . In subsequent administration ( s ) of the anti -dyslipidemic agent further embodiments , the anti -dyslipidemic agent ( e. g ., an can be systemic , such as oral, parenteral ( e . g . , intravenous , apo mimetic and/ or a statin ) and the antioxidant ( e . g ., subcutaneous or intramuscular ), or topical ( e . g . , intranasal or vitamins and /or carotenoids ) are administered at least in the pulmonary ) . In other embodiments , the anti- dyslipidemic intermediate stage of AMD to treat or slow the progression agent ( e . g ., an apo mimetic and / or a statin ) is administered of non - central GA, and /or to prevent or delay the onset of only locally ( e .g . , by injection , eye drop or implant) . In yet central GA and/ or neovascular AMD . In yet further embodi other embodiments , the anti -dyslipidemic agent (e . g ., an apo ments , the anti -dyslipidemic agent ( e . g . , an apo mimetic mimetic and / or a statin ) is administered only systemically and /or a statin ) and the antioxidant ( e. g ., vitamins and /or ( e . g . , orally , parenterally or topically ) . carotenoids) are administered at least in the early stage of [ 0516 ] The anti -dyslipidemic agent ( e . g ., an apo mimetic AMD or the initial phase of intermediate AMD to prevent or and /or a statin ) and the antioxidant ( e . g . , vitamins and /or delay the onset of non - central GA . In additional embodi carotenoids ) can be administered via the same pharmaceu ments , the antioxidant (e . g. , vitamins and /or carotenoids) , tical composition or separate pharmaceutical compositions . and optionally the anti -dyslipidemic agent (e .g ., an apo If the anti -dyslipidemic agent and the antioxidant are admin mimetic and/ or a statin ) , are administered at least in the early istered in the same composition , such a composition can be stage of AMD . prepared in advance or can be prepared by combining the [0513 ] In certain embodiments , treatment with the anti anti- dyslipidemic agent and the antioxidant into the same dyslipidemic agent ( e . g . , an apo mimetic and /or a statin ) and formulation shortly or just before the formulation is admin the antioxidant ( e . g . , vitamins and /or carotenoids ) slows the istered ( e . g . , by injection ) . In some embodiments , the anti progression of central GA and / or non -central GA ( e . g . , dyslipidemic agent and the antioxidant are locally adminis reduces the rate ofGA progression , or reduces the GA lesion tered in the same composition to , into , in or around the eye , area or size ) by at least about 10 % , 20 % , 30 % , 40 % , 50 % , such as by injection (e . g ., intravitreal, subconjunctival, 60 % , 70 % or 80 % ( e .g ., by at least about 20 % ) , or by about subretinal or sub - Tenon ' s injection ) , eye drop or implant 20 -40 % , 40 -60 % or 60 -80 % . In further embodiments , treat ( e. g ., intravitreal, subretinal or sub - Tenon 's implant) . ment with the anti -dyslipidemic agent ( e . g ., an apo mimetic 105171 One or more other therapeutic agents described and / or a statin ) and the antioxidant ( e . g . , vitamins and /or herein can be used in conjunction with the anti -dyslipidemic carotenoids) slows the progression of central GA and /or agent ( e . g ., an apo mimetic and /or a statin ) and the antioxi non -central GA ( e . g ., reduces the rate of GA progression , or dant ( e .g ., vitamins and /or carotenoids ) for the treatment of reduces the GA lesion area or size ) at least about 10 % , 20 % , atrophic (dry ) or neovascular (wet ) AMD . In some embodi 30 % , 50 % , 100 % , 150 % , 200 % or 300 % ( e. g ., at least about ments, the additional therapeutic agent ( s ) include , or are , an 20 % or 30 % ) , or about 10 - 30 % , 30 -50 % , 50 - 100 % , 100 anti- angiogenic agent ( e . g . , an anti -VEGF agent, such as 200 % or 200 - 300 % ( e . g ., about 50 - 100 % ) , more than treat aflibercept, brolucizumab , bevacizumab or ranibizumab , ment with the antioxidant in the absence of treatment with and / or an anti -PDGF agent such as E10030 ), a complement the anti -dyslipidemic agent . inhibitor ( e. g ., a C3 inhibitor such as CB -2782 , a C5 [0514 ] The anti - dyslipidemic agent ( e . g ., an apo mimetic inhibitor such as ARC1905 or LFG316 , and /or a comple and / or a statin ) and the antioxidant ( e . g . , vitamins and / or ment factor D inhibitor such as lampalizumab ) , an anti carotenoids ) can be administered by any suitable method . In inflammatory agent ( e . g ., an NSAID such as bromfenac , some embodiments , the anti - dyslipidemic agent ( e . g ., an apo and / or a corticosteroid such as fluocinolone acetonide or mimetic and /or a statin ) and /or the antioxidant ( e . g ., vita triamcinolone acetonide ) , or a neuroprotector ( e . g . , glati mins and / or carotenoids) are administered locally to , into , in ramer acetate and/ or CNTF ) , or any combination or all or around the eye , such as by injection ( e . g . , intravitreal, thereof . Use of the anti - dyslipidemic agent ( e . g ., an apo subconjunctival, subretinal or sub - Tenon ' s injection ) , eye mimetic and / or a statin ) may enhance the efficacy of one or drop or implant ( e . g . , intravitreal , subretinal or sub - Tenon ' s more other therapeutic agents that, e . g . , curtail the growth implant] ) . In certain embodiments , the anti -dyslipidemic and leakage of new blood vessels , reduce inflammation , agent ( e . g . , an apo mimetic and / or a statin ) is administered reduce oxidative stress , or curtail degeneration of RPE cells locally ( e . g . , by injection , eye drop or implant ). In other and retinal cells ( e . g . , photoreceptors ) , or any combination embodiments , the anti - dyslipidemic agent ( e . g ., an apo or all thereof. mimetic and / or a statin ) and /or the antioxidant ( e . g ., vita [0518 ] In some embodiments , the additional therapeutic mins and/ or carotenoids) are administered systemically agent is administered at least in the advanced stage of AMD . US 2018 /0296525 A1 Oct . 18 , 2018 47

In certain embodiments , the additional therapeutic agent AMD ( including non - central and / or central geographic atro includes , or is , an anti- angiogenic agent ( e . g ., an anti - VEGF phy ) or neovascular AMD ( including types 1 , 2 and / or 3 agent) and optionally a neuroprotector ( e .g . , an endogenous neovascularization ) , or the vision improvement can occur in neuroprotector such as CNTF ) and is administered at least in a subject with atrophic AMD or neovascular AMD . the advanced stage of AMD to treat or slow the progression of wet AMD , including types 1 , 2 and 3 neovascularization . [0522 ] One or more of the therapeutic agents described In other embodiments , the additional therapeutic agent herein can also be used to treat other eye diseases and includes , or is , a complement inhibitor ( e . g . , a C3 inhibitor , disorders in addition to AMD . Non -limiting examples of a C5 inhibitor and / or a CFD inhibitor ) and/ or a neuropro other eye diseases and disorders that can be treated with one tector ( e . g ., an endogenous neuroprotector such as CNTF ) ormore therapeutic agents described herein include juvenile and is administered at least in the advanced stage of AMD macular degeneration ( e . g ., Stargardt disease ), macular to treat or slow the progression of central geographic atro telangiectasia , maculopathy ( e .g ., age - related maculopathy phy (GA ). TARM ) and diabetic maculopathy (DMP ] [ including partial 0519 ] In further embodiments , the additional therapeutic ischemic DMP ] ) , macular edema ( e . g . , diabetic macular agent is administered at least in the intermediate stage of edema [DME ] [ including clinically significant DME , focal AMD . In certain embodiments , the additional therapeutic DME and diffuse DME] , Irvine -Gass Syndrome [postopera agent includes , or is , a complement inhibitor ( e . g ., a C3 tive macular edema] , and macular edema following RVO inhibitor, a C5 inhibitor and / or a CFD inhibitor ) and / or a [ including central RVO and branch RVO ]) , retinopathy (e . g ., neuroprotector ( e . g ., glatiramer acetate and / or CNTF ) and is diabetic retinopathy [ including in patients with DME ] , administered at least in the intermediate stage of AMD to treat or slow the progression of non - central GA , and / or to Purtscher' s retinopathy and radiation retinopathy ), retinal prevent or delay the onset of central GA, or is administered artery occlusion (RAO ) (e .g . , central and branch RAO ), at least in the early stage of AMD or the initial phase of retinal vein occlusion (RVO ) ( e . g ., central RVO [ including intermediate AMD to prevent or delay the onset of non central RVO with cystoid macular edema { CME } ] and central GA . In still further embodiments , the additional branch RVO [ including branch RVO with CME ]) , glaucoma therapeutic agent is administered at least in the early stage ( including low - tension , normal- tension and high -tension of AMD . In certain embodiments , the additional therapeutic glaucoma) , ocular hypertension , retinitis (e . g. , Coats ' dis agent administered at least in the early stage of AMD ease [ exudative retinitis ] and retinitis pigmentosa ), chori includes , or is , an anti - inflammatory agent ( e . g ., an NSAID ) , oretinitis , choroiditis ( e . g ., serpiginous choroiditis ) , uveitis and the additional therapeutic agent is administered systemi ( including anterior uveitis , intermediate uveitis , posterior cally ( e . g . , orally ) or locally ( e . g ., by eye drop ) . uveitis with or without CME, and pan -uveitis ) , retinal detachment (e . g . , in von Hippel -Lindau disease ), retinal XI. TREATMENT OF AMD AND OTHER EYE pigment epithelium (RPE ) detachment, and diseases asso DISEASES ciated with increased intra - or extracellular lipid storage or [0520 ] One or more of the therapeutic agents described accumulation in addition to AMD . herein ( e . g . , an anti -dyslipidemic agent such as an apolipo [0523 ] In some embodiments , an apolipoprotein mimetic protein mimetic le . g . , an apoA - I mimetic and / or an apoE . ( e. g ., an apoA - I mimetic [e .g . , L -4F ] and /or an apoE mimetic ] and/ or a statin , optionally in combination with one mimetic ?e . g ., AEM - 28 - 141) , either alone or in combination or more other therapeutic agents ) can be used to treat with one or more other therapeutic agents , is used to treat an age - related macular degeneration (AMD ) and any symp - eye disease or disorder other than AMD . In certain embodi toms or complications associated with AMD . Examples of ments , an apo mimetic having anti - inflammatory property such symptoms and complications include without limita ( e . g . , an apoA - I mimetic ?e . g ., L - 4F ] and / or an apoE tion accumulation of lipids ( including neutral lipids and mimetic [ e . g . , AEM - 28 - 14 ]) , either alone or in combination modified lipids ) on the BrM , thickening of the Brm , accu with another therapeutic agent , is administered to treat an mulation of lipid -rich debris , deposition of lipid - rich debris inflammatory eye disease or disorder, such as uveitis . In ( including basal linear deposits and drusen ) between the such a case , the apo mimetic ( e . g . , L - 4F ) acts as an anti RPE - BL and the BrM ICL , formation of a diffusion barrier inflammatory agent and can be utilized in place of, e . g . , a between the RPE and the choriocapillaris , degeneration of steroidal or non -steroidal anti- inflammatory drug. The use of photoreceptors , geographic atrophy (including non - central an apo mimetic ( e. g ., an apoA - I mimetic [e . g. , L - 4F ] and /or and central GA ) , RPE atrophy , neovascularization ( includ an apoE mimetic ?e . g ., AEM - 28 - 14 ]) in conjunction with an ing types 1, 2 and 3 NV ) , leakage , bleeding and scarring in anti - angiogenic agent ( e . g ., an anti- VEGF agent) to treat eye the eye , and vision impairment and loss. diseases and disorders in addition to AMD is described [ 0521 ] As a non - limiting example , some embodiments of elsewhere herein . In further embodiments , an apo mimetic the disclosure relate to a method of preventing , delaying the ( e .g ., an apoA - I mimetic [e .g . , L -4F ] and /or an apoE onset of, slowing the progression of or reducing the extent mimetic ?e . g . , AEM - 28 - 14 ]) , in conjunction with an anti of vision impairment or loss associated with AMD , or VEGF agent, a neuroprotector, a kinase inhibitor or c - pep improving vision ( e . g ., visual acuity ) in a subject with AMD , tide (connecting peptide ), or any combination or all thereof, comprising administering to a subject a therapeutically is administered to treat diabetic retinopathy . Embodiments effective amount of an anti -dyslipidemic agent ( e . g ., an relating to the treatment of AMD using an apo mimetic [ e . g . , apolipoprotein mimetic such as an apoA - I mimetic ?e . g ., an apoA - I mimetic ( e . g . , L -4F ) and / or an apoE mimetic L -4F ] and /or an apoE mimetic [ e . g . , AEM - 28 - 14 ] , and / or a ( e . g . , AEM - 28 - 14 ) ] alone or in combination with another statin ?e . g . , atorvastatin and / or simvastatin ) ) . One or more therapeutic agent ( e . g . , an anti - angiogenic agent [ e . g . , an other therapeutic agents can optionally be administered . The anti - VEGF agent] , a complement inhibitor or an antioxi vision impairment or loss can be associated with atrophic dant) and described elsewhere herein also apply to the US 2018 /0296525 A1 Oct . 18, 2018 48 treatment of other eye diseases and disorders using an apo contact lens. In some embodiments , one or more , or all, of mimetic alone or in combination with that given type of the therapeutic agent ( s ) are administered by intravitreal therapeutic agent. ( e . g ., micro - intravitreal) , subconjunctival, subretinal or sub Tenon ' s injection or implantation . As an example , in certain XII. ADMINISTRATION OF THERAPEUTIC embodiments one or more apolipoprotein mimetics ( e . g . , an AGENTS apo A - I mimetic ( e . g . , L -4F ) and / or an apoE mimetic ( e . g ., [0524 ] The therapeutic agents described herein can be AEM - 28 - 14 ) ] are injected into the vitreous humor , under administered to a subject by any suitable method , including neath the conjunctiva , below the retina or into the sub any suitable means for local or systemic administration . In Tenon ' s capsule of the eye at least one time every 4 weeks certain embodiments , the therapeutic agents are adminis ( 1 month ) , 6 weeks , 8 weeks ( 2 months) , 10 weeks, 12 tered by intravitreal injection or implant, subconjunctival weeks ( 3 months ) , 4 months , 5 months or 6 months for a injection or implant, subretinal injection or implant, sub period of time (e . g. , about 6 months , 12 months, 18 months, Tenon 's injection or implant, peribulbar injection , eye drop , or 24 months or longer as determined by the treating oral ingestion , or intravenous injection or infusion . physician to treat, e . g . , atrophic AMD ( including non - central [ 0525 ] In some embodiments , one or more , or all , of the and / or central geographic atrophy ) and / or neovascular therapeutic agent( s ) are administered locally. Local admin AMD . istration of a therapeutic agent can deliver the agent to the [0529 ] A method that can administer a therapeutic agent target site ( s ) more effectively , avoid first -pass metabolism less frequently than intravitreal injection is a posterior and require a lower administration dose of the agent, and juxtascleral depot. For example , Retaane® is a blunt, tinted , thereby can reduce any side effect caused by the agent. As posterior juxtascleral depot cannula that delivers a certain the pathological events of AMD occur in the eye , the amount ( e . g . , about 15 mg ) of anecortave acetate onto the therapeutic agent( s ) used to treat AMD can be locally sclera directly behind the macula while leaving the globe administered to the eye for more effective treatment. For intact . Anecortave acetate can be administered once every 6 example , the lipid -containing material (e . g ., lipids , lipopro months using this delivery method , compared to monthly or teins and apolipoproteins ) that accumulates in the Bruch ' s bimonthly intravitreal injections of ranibizumab or afliber membrane (BrM ), the sub -RPE - BL space and the subretinal cept, respectively . Moreover, the posterior juxtascleral depot space appears to be of intraocular origin (e . g ., secreted by method greatly decreases the risk of intraocular infection , retinal pigment epithelium [RPE ] cells ). Therefore , a more endophthalmitis and detachment of the retina . effective reduction in the accumulation of such material can [0530 ] Although local administration of a therapeutic involve local administration of one or more anti -dyslipi agent to the eye for the treatment of AMD or another eye demic agents to the target sites in the eye . disorder may have advantages such as greater efficacy and [0526 ] Potential routes /modes of local administration reduced side effects , systemic administration of a therapeu include without limitation intraaqueous ( the aqueous tic agent may be desired in certain circumstances . As an humor ) , peribulbar, retrobulbar , suprachoroidal, subcon example , oral administration of a therapeutic agent can junctival, intraocular, periocular, subretinal, intrascleral, increase patient compliance due to ease of use and non posterior juxtascleral, trans - scleral, sub - Tenon ' s , intravitreal invasiveness if , e . g ., a topical formulation for local delivery and transvitreal. Subretinal administration administers a ( e . g . , eye drop or contact lens ) cannot be developed for that therapeutic agent below the retina , such as, e .g ., the sub therapeutic agent. As another example , a pathological event retinal space , the RPE , the sub -RPE -BL space or the chor of AMD may have a non - local component. For instance , the oid , or any combination or all thereof . Potential sites of local amount of lipid - containing material RPE cells secrete into administration include, but are not limited to , the anterior the BrM , the sub -RPE -BL space and the subretinal space chamber (aqueous humor ) and the posterior chamber of the may be affected in part by the uptake of plasma lipids (e . g. , eye , the vitreous humor ( vitreous body ) , the retina ( includ cholesterol and fatty acids) and lipoproteins ( e . g . , LDLs ) by ing the macula and /or the photoreceptor layer ), the subreti RPE cells . In such a case, it may be desirable to administer nal space, the RPE , the sub - RPE - BL space , the choroid systemically one or more anti- dyslipidemic agents that ( including the BrM and the choriocapillaris endothelium ), decrease the production of such lipids and lipoproteins by the sclera, and the sub - Tenon ' s capsule / space . the liver. [ 0527 ] In some embodiments , a therapeutic agent is deliv [0531 ] In some embodiments, one or more of the thera ered across the sclera and the choroid to the vitreous humor , peutic agent ( s ) are administered systemically . Potential from where it can diffuse to the target tissue (s ), e .g . , the routes of systemic administration include without limitation retina ( e . g . , photoreceptors ) , the subretinal space , the RPE , oral, parenteral ( e . g . , intradermal, subcutaneous , intramus the sub -RPE - BL space or the Brm , or any combination or all cular, intravascular, intravenous, intraarterial, intramedul thereof. In other embodiments , a therapeutic agent is deliv lary and intrathecal) , intracavitary , intraperitoneal, and topi ered across the sclera and the choroid to the target tissue ( s ) , cal ( e . g ., transdermal, transmucosal, intranasal ?e . g . , by e . g ., the retina (e . g ., photoreceptors ) , the subretinal space , nasal spray or drop ), pulmonary [ e . g . , by oral or nasal the RPE and /or the sub -RPE - BL space , from where it can inhalation ] , buccal, sublingual, rectal and vaginal) . diffuse to the BrM if the BrM is a target tissue. In further (0532 ) In certain embodiments , one or more anti - dyslipi embodiments , a therapeutic agent is administered intraocu demic agents are administered systemically . For example, in larly into the anterior or posterior chamber of the eye , the certain embodiments a fibrate and /or a statin are adminis vitreous humor, the retina or the subretinal space , for tered orally , and /or a GLP - 1 receptor agonist is administered example . subcutaneously . In further embodiments , one or more anti [0528 ] Potential means of local administration include oxidants are administered systemically . As an example , in without limitation injection , implantation , and means for certain embodiments vitamins , saffron carotenoids and / or local topical administration to the eye , such as eye drop and zinc are administered orally . In yet further embodiments , US 2018 /0296525 A1 Oct . 18 , 2018 49 one or more anti - inflammatory agents are administered the age, body weight, general health , gender and diet of the systemically . For example, in certain embodiments an subject, and the response of the subject to the treatment, and NSAID ( e . g . , a coxib ) is administered orally, and /or a can be determined by the treating physician . In some complement inhibitor ( e . g . , an anti - C5 antibody , such as embodiments , the dosing regimen of one or more , or all, of LFG316 ) is administered intravenously . the therapeutic agent ( s ) comprises one or more loading [0533 ] In some embodiments , one or more polypeptide doses followed by one or more maintenance doses . The one therapeutic agents ( e . g . , an endogenous angiogenesis inhibi or more loading doses are designed to establish a relatively tor such as a soluble VEGFR [ e . g . , VEGFR1 ], or angiostatin high or therapeutically effective level of the therapeutic and / or endostatin ) are administered by means of a viral ( e . g . , agent at the target site ( s ) relatively quickly , and the one or adenoviral or lentiviral ) vector expressing the polypeptide more maintenance doses are designed to establish a thera therapeutic agent( s ). As an example , AVA - 101 comprises an peutically effective level of the therapeutic agent for the adeno - associated virus 2 (AAV2 ) vector containing a gene period of treatment. The loading dose can be provided , e . g ., that encodes soluble VEGFR1 ( FLT- 1 ) . Local administration by administering a dose that is greater than ( e . g . , 2 , 3 , 4 or of AVA - 101 into the eye ( e . g ., the RPE or choriocapillary 5 times greater than ) the maintenance dose , or by adminis endothelium ) results in expression of soluble VEGFR1 by t ering a dose substantially similar to the maintenance dose the host retinal cells . The soluble VEGFR1 protein binds to more frequently ( e .g ., 2 , 3 , 4 or 5 times more frequently ) at VEGF in the extracellular space, which prevents VEGF the beginning of treatment. As an example , for the treatment from binding to membrane -bound VEGFRs and thereby of neovascular AMD ( including types 1 , 2 and /or 3 neovas inhibits angiogenesis . AVA - 101 can be administered as , e . g ., cularization ) , in certain embodiments three loading doses of a single subretinal injection for the treatment of, e . g . , the anti -angiogenic agent aflibercept are administered by neovascular AMD ( including types 1 , 2 and / or 3 neovascu intravitreal injection (about 2 mg monthly for 3 months) larization ), which precludes the need for multiple or frequent followed by a maintenance dose (about 2 mg) once every 2 injections . months for a period of time as determined by the treating [0534 ] In additional embodiments , one or more polypep physician . tide therapeutic agents ( e . g . , a neuroprotector [ e . g ., ciliary [ 0537 ] In the early , intermediate and advanced stages of neurotrophic factor ] or an anti - angiogenic agent ?e . g . , an AMD , and in atrophic AMD and neovascular AMD , the anti -VEGF agent, such as a soluble VEGFR ] ) are adminis progression and treatment of AMD can be monitored using tered by means of genetically engineered cells (e .g ., NTC various methods known in the art (called “ diagnostic " 201 cells ) producing the polypeptide therapeutic agent( s ) methods herein for simplicity ) . Such methods include with and encapsulated in polymeric particles or a polymeric out limitation structural SDOCT (which reveals drusen and implant. As an example , an expression vector containing a RPE and can quantify total drusen volume and monitor gene encoding ciliary neurotrophic factor (CNTF ) is trans progression of the disease ) , hyperspectral autofluorescence fected into RPE cells to produce genetically engineered (which can detect fluorophores unique to drusen and basal NTC -201 cells . The NTC - 201 cells are encapsulated , e .g ., in linear deposits ) , color fundus photography, quantitative fun a semipermeable hollow fiber -membrane capsule that is dus autofluorescence (IAF ) and OCT- fluorescein angiogra contained in a scaffold of six strands of polyethylene phy (FA ) , and can examine parameters such as cone -medi terephthalate yarn . The capsule and the scaffold maintain the ated vision ( e. g . , best - corrected visual acuity (BCVA , which cells ( e . g ., growth support and delivery of nutrients ) . After persists until late in the disease ] , visual acuity with an Early implantation of the encapsulated cell- based drug - delivery Treatment Diabetic Retinopathy Study (ETDRS ) chart or a system in , e . g ., the vitreous cavity ( e . g . , via access through Snellen chart , contrast sensitivity with a Pelli- Robson chart , the sclera ) , the NTC - 201 cells produce and secrete CNTF low - luminance visual acuity [ visual acuity measured with a through the semipermeable capsule . Such an encapsulated neutral - density filter to reduce retinal illuminance , and cell technology ( e . g ., NT- 501 ) provides a controlled , con development of metamorphopsia ) and rod -mediated vision tinuous and sustained delivery of CNTF , and prolongs the ( e . g ., dark adaptation kinetics (which is a sensitive measure half - life of CNTF from about 1 - 3 min to about 20 - 50 of macular function that tracks with progression of the months. Intraocular delivery of CNTF using such an encap disease ] ) . For example , treatment is expected to keep stable , sulated cell technology can , e . g ., reduce photoreceptor loss or to improve , photopic (daylight ) vision mediated by cone associated with the degeneration of cells of the retina , and photoreceptors and scotopic (night ) vision mediated by rod hence can be used to prevent, delay the onset of or slow the photoreceptors . As another example , the health of RPE cells progression of, e . g ., geographic atrophy ( including central can be assessed with qAF, where stability of or increase in GA ) , neovascular AMD and / or vision loss . qAF intensity can indicate stable or improved RPE health , as [ 0535 ] One or more polypeptide therapeutic agents can a reduction in qAF intensity can signify degeneration of also be delivered via administration of naturally occuring RPE cells . QAF can be used to quantify the area or size of cells that produce and release such agents. For example , geographic atrophy, and hence to monitor the progression of cells derived from umbilical cord tissue can rescue photo non - centralGA or central GA , as was done in the MAHALO receptors and visual functions , reportedly through the pro Phase II study on lampalizumab . The health of RPE cells can duction and release of neuroprotectors such as neurotrophic also be assessed with SDOCT, where the presence of hyper factors . reflective foci located vertically above drusen within the [ 05361. The therapeutically effective amount and the fre retina indicates migratory RPE cells , which signifies that the quency of administration of, and the duration of treatment RPE layer is about to disintegrate just before atrophy of RPE with , a particular therapeutic agent for the treatment of AMD cells and photoreceptors. Poor RPE health can be an indi or another eye disorder may depend on various factors , cator of poor visual outcome in atrophic AMD and neovas including the eye disease , the severity of the disease , the cular AMD . As a further example , OCT- FA can detect the potency of the therapeutic agent, themode of administration , presence of sub - RPE -BL , subretinal or intraretinal fluid , US 2018 /0296525 A1 Oct . 18 , 2018 which can signify active neovascularization and leakage of During the second phase of treatment, the anti -dyslipidemic fluid from new blood vessels . agent can be injected less frequently ( e . g ., once every 6 or [0538 ] Employment of diagnostic methods allows the 8 weeks ), and in the same dose per injection as the initial course of treatment of early , intermediate or advanced AMD , dose per injection or in a higher dose per injection so that a or atrophic AMD or neovascular AMD , using one or more substantially similar total dose is administered over a certain therapeutic agents ( e. g ., an anti- dyslipidemic agent such as time period . The second phase of treatment can last for a an apo mimetic or a statin , an anti -angiogenic agent or a selected period of time. During an optional third phase of complement inhibitor, or any combination or all thereof ) , to treatment, the anti - dyslipidemic agent can be injected even be monitored and adjusted . As an example , an anti- dyslipi less frequently (e .g . , once every 10 or 12 weeks ), and in the demic agent ( e . g . , an apo mimetic such as an apoA - I same dose per injection as the initial dose per injection or in mimetic [e . g. , L -4F ] or an apoE mimetic [ e .g ., AEM -28 -14 ], a higher dose per injection so that a substantially similar or a statin such as atorvastatin or simvastatin ) can be total dose is administered over a certain time period . The administered by injection ( e . g . , intravitreal, subconjunctival, optional third phase of treatment can last for a selected subretinal or sub - Tenon ' s injection for the treatment of period of time. And so on . Such a treatment regimen can be early, intermediate or advanced AMD , or atrophic AMD or called a “ treat - and - extend ” regimen . In the initial/ first phase , neovascular AMD . During the initial phase of treatment, the the second phase , the optional third phase and any additional anti -dyslipidemic agent can be administered in a certain optional phase of treatment , one or more diagnostic methods frequency of injections and in a certain dose per injection . If can be performed to monitor the progression and treatment one or more diagnostic methods show substantial improve of AMD and possibly to adjust the treatment depending on ment in the disease , or stability in the disease after a the results of the diagnostic tests . For example , if one or significant length of treatment ( e . g . , SDOCT shows substan more diagnostic methods show a worsening of the disease tial reduction of soft drusen volume, or stability in soft ( e .g ., SDOCT shows an increase in soft drusen volume) , the drusen volume after a significant length of treatment ) , the anti- dyslipidemic agent can be injected more frequently anti - dyslipidemic agent can be injected less frequently and / and /or in a higher dose per injection . In contrast, if one or or in a lower dose per injection , or the anti -dyslipidemic more diagnostic methods show stability or an improvement agent can be injected less frequently and in a higher dose per in the disease ( e . g ., SDOCT shows stability or a reduction of injection so that a substantially similar total dose is admin soft drusen volume) , the anti- dyslipidemic agent can be istered over a certain time period . On the other hand , if one injected less frequently and/ or in a lower dose per injection , or more diagnostic methods show a worsening of the dis or the anti -dyslipidemic agent can be injected less frequently ease , or no change in the disease ( particularly in a more and in a higher dose per injection so that a substantially severe form of the disease , such as non -central or central similar total dose is administered over a certain time period . geographic atrophy or neovascular AMD ) after the initial Unlike an as - needed regimen , a treat- and -extend regimen phase of treatment ( e . g . , SDOCT shows an increase in soft does not involve routine diagnostic visits , but the therapeutic drusen volume, or no change in soft drusen volume after the agent is administered in routine treatment visits ( whose initial phase of treatment ), the anti - dyslipidemic agent can frequency decreases in the second phase and the optional be injected more frequently and /or in a higher dose per third phase of treatment) , even though the therapeutic agent, injection . If one or more diagnostic methods show stark or the dose administered , might not be medically needed at improvement in the disease ( e . g . , SDOCT shows elimination that time. Frequent clinic visits (whether for monitoring of all or most soft drusen ) , treatment with the anti -dyslipi and / or treatment) and frequent ( e . g ., monthly ) injections can demic agent can be paused or stopped . However, if one or have negative consequences , such as decreased patient com more diagnostic methods show return of the disease after a pliance , adverse medical effects ( e . g . tachyphylaxis ) , and certain period of time ( e . g ., SDOCT shows an appreciable or increased healthcare cost . A potential advantage of a treat significant amount of soft drusen ) , treatment with the anti and - extend regimen over an as -needed regimen is that it can dyslipidemic agent, such as the treatment regimen that had decrease the total number of clinic visits made for monitor resulted in the stark improvement, can be resumed . The ing and treatment. progression and treatment of AMD can be monitored using [ 0540 ] As a non - limiting example of a treat - and -extend diagnostic methods to adjust the treatment accordingly . Such regimen , for the treatment of neovascular AMD an anti a treatment regimen can be called an “ as -needed ” or “ pro re angiogenic agent ( e . g ., an anti - VEGF agent such as afliber nata” regimen . An as -needed regimen involves routine clinic cept, bevacizumab or ranibizumab ) , whether alone or in visits ( e . g . , once every 4 , 6 or 8 weeks ) so that one or more combination with one or more other therapeutic agents ( e . g . , diagnostic methods can be performed to monitor the pro an anti - inflammatory agent and /or an anti- dyslipidemic gression and treatment of AMD , although the therapeutic agent ) can be injected ( e . g . , intravitreally ) once every 4 , 6 or agent might not be administered during a clinic visit depend 8 weeks until achievement of a maximal effect, such as ing on the results of the diagnostic tests . substantially complete resolution of subretinal fluid and / or [ 0539 ] As another example of treatment of early , interme intraretinal fluid without new retinal hemorrhage, or no diate or advanced AMD , or atrophic AMD or neovascular further reduction of subretinal fluid and / or intraretinal fluid AMD , with an anti - dyslipidemic agent ( e . g . , an apo mimetic in OCT- FA for at least two consecutive clinic visits in the such as an apoA - I mimetic [ e . g ., L -4F ] or an apoE mimetic absence of new retinal hemorrhage . In such a case , the [ e . g ., AEM - 28 - 14 ), or a statin such as atorvastatin or sim anti- angiogenic agent can be injected less frequently the vastatin ) administered by injection ( e . g ., intravitreal , sub interval between injections can be extended by, e . g . , about 2 conjunctival , subretinal or sub - Tenon ' s injection ), the anti or 4 weeks ) . If the disease remains stable , the interval dyslipidemic agent can be administered in a certain between injections can be extended by , e . g . , about 2 or 4 frequency of injections ( e . g . , once monthly ) and in a certain weeks at a time, and the total extension period can be up to , dose per injection during the initial phase of treatment. e. g ., about 3 , 4 , 5 or 6 months. If the patient shows a US 2018 /0296525 A1 Oct . 18 , 2018 51 relatively mild deterioration in the disease ( e . g . , reappear Co . ( 2007 ) ; and Pharmaceutical Preformulation and Formu ance of a relatively small amount of subretinal fluid and /or lation , Gibson , Ed ., CRC Press LLC (Boca Raton , Fla . intraretinal fluid or a relatively small increase in the amount [ 2004 ]) . thereof) , the interval between injections of the anti- angio 0544 ) Compositions and formulations , such as injectable genic agent can be shortened by, e . g ., about 1 or 2 weeks . If and eye drop formulations, for use in the disclosure can be the disease deterioration is severe , frequent injections ( e . g ., prepared in sterile form . Sterile pharmaceutical formulations once every 4 , 6 or 8 weeks ) of the anti -angiogenic agent can are compounded or manufactured according to pharmaceu be resumed . Similar principles are also applicable to a tical- grade sterilization standards known to those of skill in treat - and - extend regimen for the treatment of atrophic AMD the art, such as those disclosed in or required by the United or neovascular AMD with any other kind of therapeutic States Pharmacopeia Chapters 797 , 1072 and 1211; Califor agent, including without limitation an anti - dyslipidemic nia Business & Professions Code 4127 . 7 ; 16 California agent ( e . g ., an apo mimetic such as an apoA - I mimetic [ e . g ., Code of Regulations 1751; and 21 Code of Federal Regu L -4F ] or an apoE mimetic ?e . g . , AEM - 28 - 14 ) , or a statin lations 211 . such as atorvastatin or simvastatin ) and a complement [0545 ] As an illustrative example , one or more therapeutic inhibitor ( e . g ., a C3 inhibitor such as CB -2782 , a C5 agents can be formulated for delivery into the eye ( e . g . , inhibitor such as ARC1905 or LFG316 , or a complement intravitreal, subconjunctival, subretinal or sub - Tenon ' s factor D inhibitor such as lampalizumab ) . injection or eye drop ) . Excipients and carriers that can be [ 0541 ] Alternative to an as -needed regimen or a treat - and used to make such formulations include without limitation extend regimen , for the treatment of early , intermediate or solvents ( e . g ., aqueous solvents , such as water, saline and advanced AMD , or atrophic AMD or neovascular AMD , a phosphate - buffered saline ) , isotonic / iso -osmotic agents therapeutic agent ( e .g ., an anti -dyslipidemic agent, an anti ( e . g ., NaCl and sugars [ e . g ., sucrose ]) , pH adjusters ( e . g . , angiogenic agent or a complement inhibitor ) can be admin sodium dihydrogen phosphate and disodium hydrogen phos istered in substantially the same frequency of administration phate ) , and emulsifiers ( e . g . , non - ionic surfactants , such as and in substantially the same dose per administration for polysorbates [ e. g. , polysorbate 20 ]) . If the one or more substantially the entire length of treatment selected by the therapeutic agents include a peptide or protein , such formu treating physician or until one or more diagnostic methods lations ( and any other kinds of formulations ) can contain one indicate that the disease has been successfully treated or more substances that inhibit peptide /protein aggregation , according to any selected outcome measure ( s ) . Such a increase peptide / protein solubility , reduce solution viscosity treatment regimen can be called a " fixed -routine ” regimen . or increase peptide/ protein stability , or any combination or all thereof, such as non -hydrophobic amino acids ( e. g . , arginine and histidine ) , polyols ( e . g . , myo - inositol and sor XIII . PHARMACEUTICAL COMPOSITIONS , bitol) , sugars ( e . g . , glucose , lactose , sucrose and trehalose ) , DELIVERY SYSTEMS AND KITS osmolytes ( e. g ., trehalose, amino acids [ e. g ., glycine, proline and sarcosine ) , and betaines [ e . g . , trimethylglycine ] ), non [ 0542 ] A therapeutic agent can be administered as a phar ionic surfactants ( e . g . , alkyl polyglycosides ) , and Pro Tek® maceutical composition comprising one or more pharma alkylsaccarides (e . g ., a disaccharide [ e . g ., maltose or ceutically acceptable carriers or excipients . If two or more sucrose ] coupled to a long -chain fatty acid or a correspond therapeutic agents are used for the treatment of AMD or ing long - chain alcohol) . Because such substances increase another eye disease , they can be administered in the same peptide / protein solubility , they can be used to increase pharmaceutical composition or separate pharmaceutical peptide / protein concentration and hence decrease the vol compositions . ume needed to administer a given amount of the peptide or [0543 ] Pharmaceutically acceptable carriers and excipi protein , which can have beneficial effects such as reduced ents include pharmaceutically acceptable materials , vehicles ocular pressure ( e . g ., in intravitreal injection ) . In addition , and substances . Non - limiting examples of excipients include such substances can be employed to stabilize peptides and liquid and solid fillers , diluents , binders , lubricants , glidants , proteins during the preparation , storage and reconstitution of surfactants , dispersing agents , disintegration agents , emul lyophilized peptides and proteins. sifying agents , wetting agents , suspending agents , thicken [0546 ] In some embodiments , one or more , or all , of the ers , solvents , isotonic / iso - osmotic agents , buffers , pH therapeutic agent( s ) independently are delivered from a adjusters , absorption - delaying agents , sweetening agents , sustained -release composition . As used herein , the term flavoring agents , coloring agents, stabilizers, preservatives , " sustained -release composition " encompasses sustained -re antioxidants , antimicrobial agents , antibacterial agents , anti lease , prolonged - release , extended - release , slow - release and fungal agents , adjuvants , encapsulating materials and coat controlled - release compositions, systems and devices . Use ing materials . The use of such excipients in pharmaceutical of a sustained - release composition can have benefits , such as formulations is known in the art. Except insofar as any an improved profile of the amount of the drug delivered to conventional carrier or excipient is incompatible with a the target site over a time period , and improved patient therapeutic agent, the disclosure encompasses the use of compliance and health due to fewer invasive procedures conventional carriers and excipients in formulations con ( e . g . , injections into the eye ) being performed for adminis taining the therapeutic agents described herein . See, e .g ., tration of the drug . In some embodiments , the sustained Remington : The Science and Practice of Pharmacy , 21st Ed . , release composition is a drug - encapsulation system , such as , Lippincott Williams & Wilkins (Philadelphia , Pa . [ 2005 ]) ; e .g ., nanoparticles, microparticles, a cylinder or a capsule Handbook of Pharmaceutical Excipients , 5th Ed ., Rowe et made of, e . g ., a biodegradable polymer and /or a hydrogel. In al. , Eds . , The Pharmaceutical Press and the American Phar certain embodiments , the sustained - release composition maceutical Association ( 2005 ) ; Handbook of Pharmaceuti - comprises a hydrogel. Non - limiting examples of polymers cal Additives , 3rd Ed ., Ash and Ash , Eds. , Gower Publishing of which a hydrogel can be composed include polyvinyl US 2018 /0296525 A1 Oct . 18 , 2018 alcohol, acrylate polymers ( e. g ., sodium polyacrylate ), and droxypropionate ) , poly ( hydroxybutyrates ), poly ( 3 - hydroxy other homopolymers and copolymers having a large number butyrate ) , poly ( 4 -hydroxybutyrate ) , poly of hydrophilic groups ( e . g ., hydroxyl and /or carboxylate (hydroxypentanoates ) , poly ( 3 -hydroxypentanoate ), poly groups) . In other embodiments , the sustained - release drug (hydroxyvalerates ), poly ( 3 -hydroxyvalerate ), poly (4 encapsulation system comprises a membrane - enclosed res hydroxyvalerate ) , poly (hydroxyoctanoates ), poly ( 2 ervoir , wherein the reservoir contains a drug and the mem hydroxyoctanoate ) , poly ( 3 -hydroxyoctanoate ) , brane is permeable to the drug . polysalicylate/ polysalicylic acid , polycarbonates , poly ( trim [0547 ] In certain embodiments , the sustained -release com ethylene carbonate ), poly ( ethylene carbonate ), poly (propyl position is composed of a hydrogel formed by combining a ene carbonate ), tyrosine -derived polycarbonates, L -tyro cellulosic polymer ( e . g ., hydroxypropylmethyl cellulose or sine - derived polycarbonates, polyiminocarbonates , poly a derivative thereof) and polystyrene nanoparticles . Such a hydrogel can be locally administered to the eye by , e . g ., eye (DTH iminocarbonate ), poly (bisphenol A iminocarbonate ) , drop , injection or implantation . The polymer chains of the poly ( amino acids ), poly ( ethyl glutamate ), poly (propylene cellulosic polymer and the polystyrene nanoparticles can fumarate ), polyanhydrides , polyorthoesters, poly (DETOSU form relaxed bonds under pressure , which allows the hydro 1 , 6HD ), poly (DETOSU - L -CDM ) , polyurethanes, polyphos gel to flow readily when pushed through a needle , but can phazenes, polyimides, polyamides , nylons, nylon 12 , poly form solidified bonds within seconds of release of the oxyethylated castor oil , poly ( ethylene glycol) , pressure , which allows the hydrogel to transform into a polyvinylpyrrolidone , poly ( L - lactide - co - D - lactide ), poly ( L drug - carrying capsule in the eye . In certain embodiments , lactide - co - D , L - lactide ) , poly ( D - lactide - co - D , L - lactide ) , the hydrogel is loaded with a peptide or protein , such as an poly ( lactide - co - glycolide) , poly (lactide - co - e - caprolactone ) , apolipoprotein mimetic or an anti - VEGFNVEGFR agent. poly ( glycolide - co - e - caprolactone ) , poly (lactide - co - diox The peptide or protein can be released from the hydrogel as anone) , poly ( glycolide- co -dioxanone ), poly ( lactide- co - trim the edges of the hydrogel are gradually eroded by exposure ethylene carbonate ), poly ( glycolide - co - trimethylene car to water in the eye , which allows the peptide or protein to be bonate ), poly ( lactide -co - ethylene carbonate ), poly released from the hydrogel over the course of months and ( glycolide -co -ethylene carbonate ), poly ( lactide -co possibly years . propylene carbonate ), poly ( glycolide -co -propylene [0548 ] OTX - TKI is a sustained -release implant composed carbonate ) , poly ( lactide- co - 2 -methyl - 2 - carboxyl- propylene of a bioresorbable hydrogel and containing particles of a carbonate ) , poly ( glycolide - co - 2 -methyl - 2 - carboxyl -propyl receptor tyrosine kinase inhibitor (e .g ., a VEGFR TKI for ene carbonate ) , poly ( lactide -co -hydroxybutyrate ) , poly ( lac the treatment of, e . g ., wet AMD ) in an injectable fiber. tide - co -3 -hydroxybutyrate ), poly (lactide -co - 4 -hydroxybu OTX - TKI can be implanted by , e . g . , intravitreal injection tyrate ) , poly ( glycolide- co -hydroxybutyrate ), poly and can deliver the drug to the target tissues over a period (glycolide -co - 3 -hydroxybutyrate ) , poly ( glycolide - co - 4 of about 6 months . Similarly , OTX - IVT is a sustained hydroxybutyrate ) , poly ( lactide -co -hydroxyvalerate ), poly release , intravitreal implant designed to deliver an anti (lactide - co - 3 - hydroxyvalerate ), poly ( lactide- co - 4 VEGF agent ( e . g ., aflibercept ) over a period of about 4 - 6 hydroxyvalerate ) , poly ( glycolide - co - hydroxyvalerate ) , poly months . The OTX - TKI or OTX - IVT sustained - release (glycolide -co - 3 -hydroxyvalerate ), poly ( glycolide -co - 4 implant can be adapted to deliver other kinds of therapeutic hydroxyvalerate ) , poly ( 3 -hydroxybutyrate - co - 4 agents alternative to or in addition to a TKI or an anti- VEGF hydroxybutyrate ), poly ( hydroxybutyrate - co agent, such as an apo mimetic (e .g ., an apoA - Imimetic such hydroxyvalerate ) , poly ( 3 -hydroxybutyrate - co - 3 as L -4F or an apoE mimetic such as AEM - 28 - 14 ) or a statin hydroxyvalerate ) , poly ( 3 -hydroxybutyrate -co - 4 ( e . g . , atorvastatin ) . hydroxyvalerate ) , poly (4 -hydroxybutyrate -co - 3 [ 0549 ] In some embodiments , the sustained -release com hydroxyvalerate ) , poly ( 4 -hydroxybutyrate - co - 4 position is a polymeric implant (e .g ., a cylinder, a capsule or hydroxyvalerate ), poly ( e -caprolactone - co - fumarate ), poly any other suitable form ) or polymeric nanoparticles or ( ? -caprolactone -co - propylene fumarate ), poly ( ester -co microparticles , wherein the polymeric particles can be deliv ether ) , poly ( lactide - co - ethylene glycol) , poly ( glycolide - co ered , e . g . , by eye drop or injection or from an implant. In ethylene glycol) , poly ( e - caprolactone - co - ethylene glycol) , some embodiments , the polymeric implant or polymeric poly ( ester -co -amide ) , poly (DETOSU - 1 ,6HD -CO -DETOSU nanoparticles or microparticles are composed of a biode t -CDM ) , poly ( lactide - co -cellulose ester ) , poly ( lactide - co gradable polymer ( one or more biodegradable homopoly cellulose acetate ), poly (lactide -co - cellulose butyrate ), poly mers , one or more biodegradable copolymers , or a mixture ( lactide - co - cellulose acetate butyrate ) , poly (lactide - co thereof) . In certain embodiments , the biodegradable poly cellulose propionate ), poly ( glycolide -co - cellulose ester ) , mer comprises lactic acid and / or glycolic acid [ e . g ., an poly ( glycolide - co -cellulose acetate ) , poly ( glycolide - co - cel L - lactic acid -based copolymer, such as poly ( L - lactide- co lulose butyrate ) , poly ( glycolide- co - cellulose acetate glycolide) or poly ( L -lactic acid - co - D , L - 2 -hydroxyoctanoic butyrate ), poly ( glycolide- co -cellulose propionate ), poly ( lac acid ) ] . The biodegradable polymer of the polymeric implant tide -co -glycolide -co -e - caprolactone ) , poly ( lactide -co -gly or polymeric nanoparticles or microparticles can be selected colide -co -trimethylene carbonate ), poly ( lactide - co - e - capro so that the polymer substantially completely degrades lactone -co - trimethylene carbonate ), poly ( glycolide- co - e around the time the period of treatment is expected to end , caprolactone - co -trimethylene carbonate ) , poly ( 3 and so that the byproducts of thepolymer ' s degradation , like hydroxybutyrate - co - 3 -hydroxyvalerate - co - 4 the polymer , are biocompatible . hydroxybutyrate ) , poly ( 3 -hydroxybutyrate -co - 4 [ 0550 ] Non -limiting examples of biodegradable polymers hydroxyvalerate - co -4 -hydroxybutyrate ), collagen , casein , include polyesters , poly ( a -hydroxyacids ) , polylactide , polysaccharides , cellulose , cellulose esters , cellulose polyglycolide, poly ( e -caprolactone ) , polydioxanone, poly acetate , cellulose butyrate , cellulose acetate butyrate , cellu (hydroxyalkanoates ) , poly (hydroxypropionates ), poly (3 -hy lose propionate , chitin , chitosan , dextran , starch , modified US 2018 /0296525 A1 Oct . 18 , 2018 53 starch , and copolymers and blends thereof , wherein lactide and polyvinyl alcohol on the other end , and which releases includes L - lactide , D - lactide and D , L - lactide . a very small amount of the corticosteroid fluocinolone [ 0551] As an illustrative example , sustained -release com acetonide for up to 3 years . Another example of a sustained positions comprising one or more peptides or proteins ( e . g . , release polymeric implant is OZURDEX® . OZURDEX® is an apoliprotein mimetic [ e. g ., an apo A - I or apoE mimetic ] a biodegradable , intravitreal implant that delivers an and / or an antibody or fragment thereof ?e . g . , an anti - VEGF extended release of the corticosteroid dexamethasone using antibody or fragment thereof ] ) for injection ( e . g . , intravit the NOVADUR® solid polymer delivery system . Other real, subconjunctival, subretinal or sub - Tenon ' s injection ) therapeutic agents that can be delivered via a sustained can be composed of one or more biodegrable polymers , such release , biodegradable intravitreal implant include without as hexyl- substituted poly ( lactic acid ) (hexPLA ) . HexPLA is limitation the neuroprotector brimonidine . a hydrophobic polyester having a semi- solid aggregate state , (0555 ) A further example of a sustained - release ocular which facilitates formulation . The peptide/ protein can be drug - delivery system is that described in U . S . Pat. No . micronized and incorporated into a liquid hexPLA polymer 6 ,375 , 972 to Guo et al. Guo ' s system comprises an inner matrix by cryo -milling , forming a homogeneous and inject drug core containing a drug , and an inner tube impermeable able suspension . The peptide/ protein can have good com to passage of the drug , wherein the inner tube has first and patibility with the hexPLA polymer , good storage stability second ends and covers at least a portion of the inner drug ( e . g . , at about 4° C . for an extended period [ e . g . , about 3 core , and the inner tube is sized and formed of a material so months or longer ] ) , and better stability inside the polymer that the inner tube is dimensionally stable to accept the inner when shielded from the surrounding aqueous medium . For drug core without changing shape . An impermeable member mulations of the peptide /protein with hexPLA can have a is positioned at the inner tube ' s first end and prevents drug loading of, e . g . , about 1 - 5 % or 5 - 10 % , and the hexPLA passage of the drug out of the inner drug core through the can have a molecular weight (MW ) of, e. g ., about 1000 inner tube' s first end . A permeable member is positioned at 2000 g /mol , 2000 - 3000 g /mol or 3000 - 4000 g /mol . The the inner tube 's second end and allows diffusion of the drug formulations can form spherical depots in an aqueous out of the inner drug core through the inner tube 's second medium ( e . g ., a buffer ) and release the peptide / protein for an end . Guo ' s sustained -release system can be applied by extended period ( e . g ., about 1 , 2 , 3 , 4 , 5 or 6 months) . The injection or implantation to the vitreous humor , under the release rate of the peptide /protein can be influenced by the retina or onto the sclera , for example . polymer viscosity based on the polymer MW , and by the [0556 ] An additional example of a controlled - release ocu drug loading to a lesser extent, which permits fine - tuning of lar drug - delivery system is that described in U . S . Pat. No . the drug - release profile . The peptide /protein can maintain its 6 ,413 ,540 to Yaacobi. Yaacobi ' s system comprises a body structure when incorporated into the polymer matrix , and having a scleral surface for placement proximate to the can maintain its biological activity ( e . g ., high affinity for its sclera , and a well having an opening to the scleral surface biological target ) after being released from the polymer and an inner core containing a drug . The system delivers the matrix . drug at a controlled rate through the sclera to or through the [ 0552] Alternative to being released from polymeric nano choroid and to the retina . particles or microparticles, a solid therapeutic agent can be [0557 ] Another exemplary ocular drug -delivery device is administered in the form of nanoparticles or microparticles an osmotic pump , such as that described by Ambati et al. comprising primarily or consisting essentially of the thera Ambati ' s osmotic pump delivered separately IgG and an peutic agent. Compared to the agent being substantially anti - ICAM - 1 monoclonal antibody across the sclera to the completely dissolved in an aqueous medium upon adminis choroid and the retina , with negligible systemic absorption . tration , the agent in the form of such nanoparticles or J . Ambati et al. , Invest . Opthalmol. Vis. Sci . , 41: 1186 - 91 microparticles would substantially completely dissolve over (2000 ) . time after administration , and thereby would have a longer [0558 ] Another system for controlled delivery of a drug to duration of action and require fewer administrations ( e . g ., the posterior segment of the eye is described in M . Bhat injections ). Furthermore , such nanoparticles or micropar tacharya et al. , J . Controlled Release ( 2017 ), doi: 10 .1016 / ticles may form a depot for prolonged delivery of the j. jconrel. 2017 .02 .013 . The N - terminus of a peptide -based therapeutic agent. Such nanoparticles or microparticles can cleavable linker ( PCL ) is conjugated to a cell - penetrating optionally contain a relatively small amount of one or more peptide (CPP , e . g ., a charged peptide ), and the C - terminus of excipients . Nanoparticles or microparticles comprising pri the PCL is conjugated to a peptide drug . The peptide drug marily or consisting essentially of a therapeutic agent can be can be , e . g ., an apo mimetic such as an apoA - I mimetic ( e . g . , administered locally by , e . g , injection ( e . g . , intravitreal, 4F ) or an apoE mimetic such as AEM - 28 - 14 . To increase subconjunctival, subretinal or sub - Tenon 's injection ) , eye resistance to proteolysis , one or more , or all, of the amino drop or implant ( e . g ., intravitreal, subretinal or sub - Tenon ' s acid residues of the peptide drug can have the D - stereo implant) . chemistry ( e. g ., D - 4F having all D -amino acids ). The PCL [ 0553 ] In some embodiments , a sustained - release compo is sensitive to an enzyme ( e . g . , cathepsin D ) that is expressed sition releases a low or relatively low , but therapeutically at a relatively high level in the target cells ( e . g . , RPE cells ) . effective , dose of one or more therapeutic agents over a The CPP -PCL -peptide drug conjugate can be , e . g ., intrav period of about 1 week , 2 weeks , 4 weeks ( 1 month ) , 6 itreally injected , and is taken up by target RPE cells via weeks, 8 weeks ( 2 months ), 10 weeks, 3 months, 6 months, endocytosis . In the lysosome of RPE cells , cathepsin D 1 year , 1 .5 years , 2 years , 2 .5 years , 3 years or longer. cleaves the PCL , thereby releasing the peptide drug in the 0554 ] An example of a sustained - release polymeric RPE cells . The amino acid sequence of the PCL controls the implant is ILUVIEN® . ILUVIEN® is an intravitreal cleavage / release rate of the peptide drug . The RPE cells act implant in the form of a tiny tube which is made of a as intracellular drug depots that deliver the peptide drug to polyimide and sealed with a silicone adhesive on one end the surrounding tissues, including the neural retina and the US 2018 /0296525 A1 Oct . 18 , 2018 54

Bruch ' s membrane , in a controlled and sustained manner. appropriate fraction thereof, of each of the one , two or more Alternative to a peptide drug , the PCL can be conjugated to therapeutic agents . An example of a unit dosage form is a any kind of drug ( e . g . , a small molecule such as a statin ) that tablet , capsule , or pill for oral administration . Another can be attached to an amino acid . Furthermore , the CPP or example of a unit dosage form is a single - use vial, ampoule another kind of cell - targeting moiety can be designed to or pre - filled syringe containing a composition of one , two or target different types of cells . Alternatively , a CPP or a more therapeutic agents and excipients dissolved or sus cell- targeting moiety need not be employed and the PCL can pended in a suitable carrier ( e . g ., an aqueous solvent) . The be conjugated to , e . g . , a biodegradable polymer, such as a vial or ampoule can be included in a kit containing imple polymeric implant or polymeric nanoparticles or micropar - ments for administering the composition ( e . g ., a syringe , a ticles, where the amino acid sequence of the PCL can be filter or filter needle , and an injection needle for injecting the designed to control the enzymatically assisted release of the composition ) . The kit can also contain instructions for peptide or non - peptide drug in the target tissue or environ storing and administering the composition . ment. [0563 ] Alternatively , a composition comprising one, two [0559 ] Drug - eluting contact lenses can also be used as or more therapeutic agents can be presented in a kit , wherein sustained -release drug -delivery systems. Such contact the one, two or more therapeutic agents , excipients and lenses can be regarded as implantable devices or as com carriers ( e . g . , solvents ) are provided in two or more separate positions for topical administration . The release duration of containers ( e . g . , ampoules , vials , tubes , bottles or syringes ) drug -eluting contact lenses can be increased by, e . g ., and need to be combined to prepare the composition to be molecular imprinting , dispersion of barriers or nanopar administered . In some embodiments , two or more therapeu ticles /microparticles , increasing drug binding to a polymer, tic agents ( e . g ., an apoA - I mimetic and /or an apoE mimetic or sandwiching a polymer [ e. g ., poly (lactide -co - glycolide )] plus an anti -angiogenic agent, a neuroprotector, an anti layer in a lens , or any combination or all thereof. Contact inflammatory agent, a complement inhibitor, an antioxidant lenses can provide extended drug release for, e . g . , hours to or an agent that curtails lipid production ) are combined into days as desired , and can increase patient compliance due to the same formulation shortly or just before the formulation their ease of use and minimal invasiveness . is administered ( e . g . , by injection ) . The one , two or more [ 0560 ] In some embodiments , one or more therapeutic therapeutic agents can be provided in any suitable form ( e . g ., agents (e . g ., polynucleotides [ ? . g . , anti- sense polynucle in a stable medium or lyophilized ) . The kit can contain otides or PNAs) and / or polypeptides ( e . g . , apolipoprotein implements for administering the composition ( e . g ., a mimetics ]) independently are contained in nanoparticles , syringe , a filter or filter needle , and an injection needle for microparticles or liposomes having a lipid bilayer. In certain injecting a solution or suspension ) . The kit can also contain embodiments , the lipid bilayer is composed of one or more instructions for storing the contents of the kit , and for phospholipids. Non - limiting examples of phospholipids preparing and administering the composition . include phosphatidic acids ( e . g ., DMPA , DPPA and DSPA ) , [0564 ] A kit can contain all active and inactive ingredients phosphatidylcholines ( e . g . , DDPC , DEPC , DLPC , DMPC , in unit dosage form or the active ingredient( s ) and inactive DOPC , DPPC , DSPC , PLPC and POPC ) , phosphatidyletha ingredients in two or more separate containers , and can nolamines (e . g ., DMPE , DOPE , DPPE and DSPE ) , phos contain instructions for using the pharmaceutical composi phatidylglycerols (e .g ., DMPG , DPPG , DSPG and POPG ), tion to treat AMD or other eye diseases . and phosphatidylserines ( e . g . , DOPS ) . Nanoparticles , microparticles or liposomes having a lipid bilayer composed XIV . SALT FORMS of a fusogenic lipid (e . g. , DPPG ) can fuse with the plasma [0565 ] Compounds/ molecules ( e. g. , apolipoprotein membrane of cells and thereby deliver a therapeutic agent mimetics such as L -4F and AEM - 28 - 14 , and statins such as into those cells . The nanoparticles , microparticles or lipo atorvastatin ) may exist in a non - salt form ( e . g . , a free base somes having a lipid bilayer can be administered locally or or a free acid , or having no basic or acidic atom or functional systemically . group ) or as salts if they can form salts . Compounds that can [0561 ] In some embodiments , an anti -angiogenic agent form salts can be used in the non - salt form or in the form of ( e . g . , an anti- VEGF /VEGFR agent ) and an anti - inflamma pharmaceutically acceptable salts . If a compound has , e . g . , tory agent ( e . g . , an apolipoprotein mimetic [ e . g . , an apoA - I a basic nitrogen atom , the compound can form an addition mimetic ] , a CRP inhibitor, a complement inhibitor, an salt with an acid ( e . g . , a mineral acid ( such as HC1, HBr, HI, inflammasome inhibitor, a corticosteroid or an NSAID , or nitric acid , phosphoric acid or sulfuric acid ] or an organic any combination or all thereof) are contained in the same or acid ( such as a carboxylic acid or a sulfonic acid ] ) . Suitable different liposomes, nanoparticles or microparticles com acids for use in the preparation of pharmaceutically accept posed of a biodegradable polymer or a lipid bilayer , and are able salts include without limitation acetic acid , 2 , 2 - dichlo administered for the treatment of, e . g . , neovascular AMD roacetic acid , acylated amino acids, adipic acid , alginic acid , ( including types 1 , 2 and / or 3 neovascularization ) . In certain ascorbic acid , L - aspartic acid , benzenesulfonic acid , benzoic embodiments , the liposomes, nanoparticles or micropar acid , 4 -acetamidobenzoic acid , boric acid , ( + ) - camphoric ticles are administered locally , e . g . , by eye drop or injection acid , camphorsulfonic acid , ( + ) - ( 1S ) -camphor - 10 - sulfonic ( e . g . , intravitreal, subconjunctival, subretinal or sub - Tenon ' s acid , capric acid , caproic acid , caprylic acid , cinnamic acid , injection ). citric acid , cyclamic acid , cyclohexanesulfamic acid , dode [ 0562 ] A composition comprising one, two or more thera cylsulfuric acid , ethane - 1 , 2 - disulfonic acid , ethanesulfonic peutic agents can be presented in unit dosage form as a acid , 2 -hydroxyethanesulfonic acid , formic acid , fumaric single dose wherein all active and inactive ingredients are acid , galactaric acid , gentisic acid , glucoheptonic acid , combined in a suitable system , and components do not need D - gluconic acid , D -glucuronic acid , L - glutamic acid , alpha to be mixed to form the composition to be administered . The oxo - glutaric acid , glycolic acid , hippuric acid , hydrobromic unit dosage form can contain an effective dose, or an acid , hydrochloric acid , hydroiodic acid , ( + )- DL -lactic acid , US 2018 /0296525 A1 Oct . 18 , 2018 55

( + ) - L -lactic acid , lactobionic acid , lauric acid , maleic acid , 1 -1 .5 mg , 0. 1 -0 . 3 mg, 0 .3 - 0 .5 mg, 0 . 5 -0 .75 mg, 0 .75 - 1 ( - ) - L -malic acid , malonic acid , ( + ) -DL -mandelic acid , mg , 1 - 1. 25 mg or 1 .25 - 1. 5 mg (e .g . , about 0 .1 -0 . 5 mg or methanesulfonic acid , naphthalene - 2 - sulfonic acid , naphtha 0 . 5 - 1 mg) per administration ( e . g . , per injection ). lene - 1 , 5 - disulfonic acid , 1 -hydroxy - 2 - naphthoic acid , nico [ 0575 ] 8 . Themethod of any one of the preceding embodi tinic acid , nitric acid , oleic acid , orotic acid , oxalic acid , ments , wherein the apo mimetic ( e. g ., L - 4F ) is adminis palmitic acid , pamoic acid , perchloric acid , phosphoric acid , tered locally in a total dose of about 0 . 5 or 1 - 5 mg, 5 - 10 propionic acid , L -pyroglutamic acid , pyruvic acid , saccharic mg, 0 . 5 or 1- 3 mg, 3 -5 mg, 5 - 7 .5 mg or 7 .5 - 10 mg (e . g ., acid , salicylic acid , 4 - amino - salicylic acid , sebacic acid , about 0 . 5 - 3 mg or 3 - 5 mg ) over a period of about 6 stearic acid , succinic acid , sulfuric acid , tannic acid , ( + ) months. DL -tartaric acid , ( + ) - L - tartaric acid , thiocyanic acid , p -tolu [ 0576 ] 9 . The method of any one of the preceding embodi enesulfonic acid , undecylenic acid , and valeric acid . ments, wherein the apo mimetic (e . g ., L -4F ) is adminis [0566 ] If a compound has an acidic group ( e . g . , a carboxyl tered locally in a total dose of about 1 or 2 - 20 mg or 5 - 15 group ), the compound can form an addition salt with a base . mg for the whole treatment regimen . Pharmaceutically acceptable base addition salts can be [0577 ] 10 . The method of embodiment 9 , wherein the apo formed with , e . g . , metals ( e . g . , alkali metals or alkaline earth mimetic ( e . g . , L - 4F ) is administered locally in a total dose metals ) or amines ( e . g ., organic amines ) . Non - limiting of about 1 - 5 mg, 5 - 10 mg, 10 - 15 mg, 15 - 20 mg, 1 - 3 mg, examples of metals useful as cations include alkali metals 3 - 5 mg, 5 - 7 . 5 mg, 7 . 5 - 10 mg, 10 - 12 . 5 mg , 12 . 5 - 15 mg, ( e. g ., lithium , sodium , potassium and cesium ), alkaline earth 15 - 17. 5 mg or 17. 5 - 20 mg ( e . g ., about 1 - 5 mg or 5 - 10 mg) metals ( e . g ., magnesium and calcium ) , aluminum and zinc . for the whole treatment regimen . Metal cations can be provided by way of, e . g . , inorganic [ 0578 ] 11 . The method of any one of the preceding bases, such as hydroxides, carbonates and hydrogen carbon embodiments, wherein the dose per administration , the ates. Non - limiting examples of organic amines useful for total dose over a period of about 6 months , and the total forming base addition salts include chloroprocaine, choline , dose for the whole treatment regimen are per treated eye . cyclohexylamine , dibenzylamine , N , N -dibenzylethylenedi [0579 ] 12 . The method of any one of the preceding amine, dicyclohexylamine , diethanolamine, ethylenedi embodiments , wherein the apo mimetic ( e . g . , L -4F ) is amine, N - ethylpiperidine , histidine , isopropylamine , administered locally by injection ( e . g . , intravitreal, sub N -methylglucamine , procaine, pyrazine , triethylamine and conjunctival, subretinal or sub - Tenon 's injection ), eye trimethylamine . Pharmaceutically acceptable salts are dis drop or implant ( e. g ., intravitreal , intraaqueous, subretinal cussed in detail in Handbook of Pharmaceutical Salts , Prop or sub - Tenon ' s implant ) . erties, Selection and Use , P . Stahl and C . Wermuth , Eds. , [ 0580 ] 13 . The method of embodiment 12 , wherein the Wiley - VCH ( 2011 ). apo mimetic ( e. g ., L -4F ) is administered locally by injec XV . REPRESENTATIVE EMBODIMENTS tion ( e . g . , intravitreal, subconjunctival, subretinal or sub [ 0567 ] The following embodiments of the disclosure are Tenon 's injection ). provided by way of example only : [0581 ] 14 . The method of embodiment 13, wherein the [ 0568 ] 1 . A method of treating age - related macular degen apo mimetic ( e . g . , L - 4F ) is administered locally by injec eration ( AMD ), comprising administering to a subject in tion ( e . g . , intravitreal injection ) in a dose concentration need of treatment a therapeutically effective amount of an from about 1 , 2 , 3 , 4 or 5 mg/ mL to about 12 or 15 mg/mL . apolipoprotein ( apo ) mimetic or a pharmaceutically [0582 ] 15 . The method of embodiment 14 , wherein the acceptable salt thereof, wherein the apo mimetic is admin apo mimetic ( e. g ., L -4F ) is administered locally by injec istered locally to , into , in or around the eye in a dose from tion ( e . g. , intravitreal injection ) in a dose concentration of about 0 . 1 or 0 . 3 mg to about 1 . 5 mg per administration , about 1 - 4 mg/ mL , 4 - 8 mg/ mL , 8 - 12 mg/mL , 1 - 5 mg/mL , and / or in a total dose from about 0 . 5 or 1 mg to about 10 5 - 10 mg/mL , 10 - 15 mg/mL , 1 - 3 mg/ mL , 3 - 5 mg/mL , mg over a period of about 6 months. 5 - 7 . 5 mg/ mL , 6 - 8 mg/ mL , 7 . 5 - 10 mg/ mL , 10 - 12 . 5 [ 0569 ] 2 . The method of embodiment 1 , wherein the apo mg /mL or 12 . 5 - 15 mg/ mL (e . g. , about 1- 5 mg/ mL , 5 - 10 mimetic comprises, or is , an apoA - I mimetic or a salt mg/ mL or 6 - 8 mg/mL ). thereof. [0583 ] 16 . The method of any one of embodiments 13 to [ 0570 ] 3 . The method of embodiment 2 , wherein the 15 , wherein the apo mimetic ( e . g . , L -4F ) is locally admin apoA - I mimetic comprises , or is , 4F or a variant or a salt istered by injection ( e . g . , intravitreal injection ) in a dose ( e . g ., acetate salt ) thereof. volume of about 50 - 150 uL or 50 - 100 uL . [ 0571) 4 . The method of embodiment 3 , wherein the [0584 ] 17 . The method of embodiment 16 , wherein the apoA - I mimetic comprises, or is , L - 4F or D -4F or a salt apo mimetic ( e . g . , L -4F ) is administered locally by injec thereof, each optionally having a protecting group at the tion ( e . g . , intravitreal injection ) in a dose volume of about N - terminus and / or the C - terminus [ e . g . , AC -DWFKAFY 50 - 75 4 , 75 - 1004, 100 - 125 uL or 125 - 150 UL , or about 50 DKVAEKFKEAF -NH2 (SEQ . ID . NO . 13 ) ] . UL , 75 uL , 100 uL , 125 uL or 150 uL ( e . g ., about 100 UL ) . [ 0572 ] 5 . Themethod of any one of the preceding embodi [ 0585 ) 18 . The method of any one of embodiments 13 to ments , wherein the apo mimetic comprises, or is , an apoE 17 , wherein the apo mimetic ( e . g . , L -4F ) is locally admin mimetic or a salt thereof. istered by injection ( e . g ., intravitreal injection ) once every [0573 ] 6 . The method of embodiment 5 , wherein the apoE month ( 4 weeks ) or 1 . 5 months ( 6 weeks ) . mimetic comprises , or is , AEM - 28 - 14 or a variant or a salt [ 0586 ] 19 . The method of any one of embodiments 13 to thereof. 17 , wherein the apo mimetic ( e . g . , L -4F ) is locally admin [ 0574 ] 7 . Themethod of any one of the preceding embodi istered by injection (e . g. , intravitreal injection ) once every ments , wherein the apo mimetic ( e . g ., L -4F ) is adminis 2 months (8 weeks ), 2 . 5 months ( 10 weeks) or 3 months tered locally in a dose of about 0 . 1 - 0 . 5 mg, 0 . 5 - 1 mg, ( 12 weeks ). US 2018 /0296525 A1 Oct . 18 , 2018 56

[0587 ] 20 . The method of any one of embodiments 13 to Tenon ' s injection ) less frequently ( e . g . , an injection every 17 , wherein the apo mimetic ( e . g . , L -4F ) is locally admin about 3 , 4 or 6 months) , in a smaller total number of istered by injection ( e . g ., intravitreal injection ) once every injections ( e . g . , about 1 , 2 or 3 injections) or in a higher 4 , 5 or 6 months . dose per injection ( e . g ., about 0 . 5 - 1 mg or 1 - 1 .5 mg per [0588 ] 21 . The method of any one of embodiments 13 to injection ), or any combination or all thereof, in early 20 , wherein the apo mimetic (e . g. , L -4F ) is locally admin AMD . istered in a total of about 15 or less , 12 or less , 9 or less , [0599 ] 32 . The method of any one of the preceding 6 or less , or 3 or less injections ( e . g ., intravitreal injec embodiments, wherein the apo mimetic ( e . g . , L - 4F ) is tions ) . administered locally ( e .g . , by intravitreal injection ) more [0589 ] 22 . The method of embodiment 21, wherein the frequently (which can result in a greater total number of apo mimetic ( e . g ., L - 4F ) is administered locally in a total administrations ) and / or in a higher dose (higher dose per of about 15 , 14 , 13 , 12 , 11, 10 , 9 , 8 , 7 , 6 , 5 , 4 or 3 (e . g. , administration and / or higher total dose for the entire about 3 - 6 or 7 - 10 ) injections ( e . g ., intravitreal injections ) . treatment regimen ) the later the stage of AMD or themore [ 0590 ] 23 . The method of any one of the preceding severe the AMD condition . embodiments , wherein the apo mimetic ( e . g . , L -4F ) is [ 0600 ] 33 . The method of any one of the preceding administered locally ( e . g . , by intravitreal injection ) in a embodiments, wherein the apo mimetic ( e . g ., L - 4F ) is higher dose and /or more frequently in the initial phase of administered locally ( e. g ., by intravitreal injection ) in a treatment. fixed - routine regimen , an as- needed regimen or a treat [ 0591 ] 24 . The method of any one of the preceding and - extend regimen . embodiments , wherein the treatment regimen with the apo [0601 ] 34 . The method of any one of the preceding mimetic ( e . g . , L -4F ) lasts for about 36 months or less , 30 embodiments, wherein the apo mimetic ( e . g . , L - 4F) is months or less, 24 months or less, 18 months or less , 12 administered locally via a composition comprising about months or less , or 6 months or less . 75 - 95 % ( e . g ., about 90 % ) of the apo mimetic and about [ 0592] 25 . The method of embodiment 24 , wherein the 5 - 25 % ( e . g . , about 10 % ) of the corresponding apolipo treatment regimen with the apo mimetic ( e . g ., L -4F ) lasts protein ( e . g . , apoA - I ) or an active portion or domain for about 6 - 12 , 12 - 18 , 18 - 24 , 24 - 30 or 30 - 36 ( e . g ., for thereof by weight or molarity relative to their combined about 6 - 12 or 12 - 24 ) months. amount. [ 0593 ] 26 . The method of any one of the preceding [ 0602 ] 35 . The method of any one of the preceding embodiments , wherein the apo mimetic ( e .g ., L -4F ) is embodiments, wherein the apo mimetic ( e . g ., L - 4F ) is administered at least in the advanced stage of AMD ( e . g ., administered locally as a composition comprising one or to treat central geographic atrophy [GA ] and /or to prevent more excipients that inhibit peptide/ protein aggregation , or forestall neovascular AMD , and /or to treat neovascular increase peptide/ protein solubility, reduce solution vis AMD ) . cosity or increase peptide/ protein stability , or any com [0594 ] 27 . The method of embodiment 26 , wherein the bination or all thereof . apo mimetic ( e . g . , L -4F ) is administered locally by injec [0603 ] 36 . The method of any one of the preceding tion ( e . g . , intravitreal, subconjunctival , subretinal or sub embodiments , wherein the apo mimetic ( e . g . , L - 4F ) is Tenon ' s injection ) once every about 4 - 8 weeks or 4 -6 administered locally via a sustained -release composition . weeks , in a total of about 8 - 12 injections or more, in a [0604 ] 37 . The method of any one of the preceding dose up to about 1 - 1 . 5 mg per injection , or in a total dose embodiments , further comprising administering one or up to about 15 - 20 mg for the entire treatment regimen , or more additional therapeutic agents . any combination or all thereof, in advanced AMD . [0605 ] 38 . The method of embodiment 37 , wherein the [0595 ] 28 . The method of any one of the preceding one or more additional therapeutic agents are selected embodiments , wherein the apo mimetic ( e . g . , L - 4F ) is from anti - dyslipidemic agents; PPAR - a agonists , PPAR - 8 administered at least in the intermediate stage of AMD agonists and PPAR - y agonists ; anti - amyloid agents and ( e . g . , to treat non - centralGA and /or to prevent or forestall inhibitors of other toxic substances ( e . g . , aldehydes ) ; central GA and / or neovascular AMD , or administered in inhibitors of lipofuscin or components thereof; antioxi the initial phase of intermediate AMD to prevent or dants ; neuroprotectors ( neuroprotectants ) ; apoptosis forestall non - central GA ) . inhibitors and necrosis inhibitors ; C -reactive protein [0596 ] 29 . The method of embodiment 28 , wherein the inhibitors ; inhibitors of the complement system or com apo mimetic ( e . g ., L - 4F ) is administered locally by injec ponents ( e . g ., proteins ) thereof ; inhibitors of inflam tion ( e . g . , intravitreal, subconjunctival , subretinal or sub masomes ; anti - inflammatory agents ; immunosuppres Tenon ' s injection ) once every about 4 - 12 or 4 - 8 weeks , in sants ; modulators (inhibitors and activators) of matrix a total of about 4 - 8 injections or more, in a dose up to metalloproteinases and other inhibitors of cell migration ; about 0 . 5 - 1 mg or 1 - 1 . 5 mg per injection , or in a total dose anti - angiogenic agents ; laser therapies , photodynamic up to about 10 - 15 mg or more for the entire treatment therapies and radiation therapies ; agents that preserve or regimen , or any combination or all thereof, in intermedi improve the health of the endothelium and /or the blood ate AMD . flow of the vascular system of the eye ; cell ( e . g ., RPE cell ) [0597 ] 30 . The method of any one of the preceding replacement therapies ; and combinations thereof. embodiments , wherein the apo mimetic ( e .g . , L -4F ) is 106061 39 . The method of embodiment 38 , wherein the administered at least in the early stage of AMD (e .g ., to one or more additional therapeutic agents comprise an prevent or forestall non - central GA ) . anti -dyslipidemic agent, an antioxidant, an anti - inflam [0598 ] 31 . The method of embodiment 30 , wherein the matory agent, a complement inhibitor, a neuroprotector or apo mimetic ( e . g ., L - 4F ) is administered locally by injec an anti -angiogenic agent, or any combination or all tion (e .g ., intravitreal, subconjunctival, subretinal or sub thereof. US 2018 /0296525 A1 Oct . 18 , 2018 57

[ 0607 ] 40 . The method of any one of embodiments 37 to injection ) once every month ( 4 weeks ), 1. 5 months (6 39 , wherein the one or more additional therapeutic agents weeks ), 2 months ( 8 weeks ), 2 . 5 months ( 10 weeks ) or 3 comprise a statin ( e . g ., atorvastatin or a salt thereof and / or months ( 12 weeks ) . simvastatin ). [0619 ] 52 . The method of embodiment 51, wherein the [0608 ] 41. A method of treating age - related macular statin , whether or not in the form of a sustained - release degeneration ( AMD ), comprising administering locally a composition , is injected into the eye in a total of about therapeutically effective amount of a statin or a pharma 3 - 6 , 6 - 9 , 9 - 12 or 12 - 15 injections. ceutically acceptable salt thereof to , into , in or around the [0620 ] 53 . The method of any one of embodiments 41 to eye of a subject in need of treatment . 49 , wherein the statin ( e . g . , atorvastatin and / or simvasta [ 0609 ] 42 . The method of embodiment 41, wherein the tin ) is administered locally via a sustained -release implant statin is selected from atorvastatin , cerivastatin , fluvasta (e . g. , intravitreal, intraaqueous, subretinal, sub - Tenon ' s or tin , mevastatin , monacolins ( e . g . , monacolin K ?lovasta posterior juxtascleral implant) , and wherein the implant is tin ]) , pitavastatin , pravastatin , rosuvastatin , simvastatin , implanted in or around the eye: and analogs , derivatives , salts and combinations thereof. 10621 ] once every about 3 months , 4 months , 6 months , 1 [ 0610 ] 43. The method of embodiment 41 or 42, wherein year, 1 . 5 years or 2 years ; and the statin comprises, or is , a substantially hydrophobic / [ 0622] one or more ( e . g ., two , three , four or more) times lipophilic statin or a salt thereof. for the entire treatment regimen . [0611 ] 44 . The method of any one of embodiments 41 to [0623 ] 54 . The method of any one of embodiments 41 to 43 , wherein the statin comprises , or is , atorvastatin or a 53 , wherein the statin ( e . g ., atorvastatin and / or simvasta salt ( e . g ., calcium salt ) thereof, and /or simvastatin . tin ) is administered only locally (e .g ., via eye drop , [0612 ] 45 . The method of any one of embodiments 41 to injection or an implant ) for the entire treatment regimen . 44 , wherein the statin ( e . g . , atorvastatin and / or simvasta [0624 ] 55 . The method of any one of embodiments 41 to tin ) is administered locally by eye drop , injection ( e . g . , 53 , wherein the statin ( e . g . , atorvastatin and / or simvasta intravitreal , subconjunctival , subretinal or sub - Tenon ' s tin ) is administered locally in the initial phase of treat injection ) , or implant ( e . g . , intravitreal, intraaqueous , sub ment, and then the statin is administered systemically retinal or sub - Tenon 's implant) . ( e . g ., orally , parenterally or topically ) . [0613 ] 46 . The method of any one of embodiments 41 to [0625 ] 56 . The method of embodiments 55 , wherein the 45 , wherein the statin ( e . g . , atorvastatin and /or simvasta statin ( e . g . , atorvastatin and / or simvastatin ) is adminis tin ) is administered locally in a dose from about 10 -500 tered systemically (e . g ., orally ) in a dose of about 5 - 80 ug , 50 - 500 ug , 100 - 500 ug, 10 - 50 ug, 50 - 100 ug , 100 - 200 mg, 10 - 80 mg, 10 - 40 mg, 40 - 80 mg or 20 -60 mg one or ug , 200 - 300 ug, 300 -400 ug or 400 - 500 ug per adminis more times ( e. g ., twice ) daily or once every two days tration ( e. g ., by eye drop or injection ) . ( e .g ., once daily ) . [ 0614 ] 47 . The method of any one of embodiments 41 to [ 0626 ] 57 . The method of any one of embodiments 41 to 46 , wherein the statin ( e . g . , atorvastatin and / or simvasta 56 , wherein the treatment regimen with the statin ( e . g . , tin ) is administered locally ( e . g . , by eye drop , injection or atorvastatin and/ or simvastatin ) lasts for about 6 - 12 implant ) in a total dose of about 0 . 1 or 0 . 3 - 15 mg, 0 . 5 or months, 12 - 18 months , 18- 24 months , 2 - 3 years or longer. 1 - 10 mg, 0 . 1 or 0 . 3 - 1 mg , 1 - 5 mg, 5 - 10 mg or 10 - 15 mg [ 0627 ] 58 . The method of any one of embodiments 41 to over a period of about 1 month . 57 , wherein the statin ( e . g . , atorvastatin and / or simvasta [0615 ] 48 . The method of any one of embodiments 41 to tin ) is administered at least in the advanced stage of AMD 47 , wherein the statin ( e . g . , atorvastatin and / or simvasta ( e . g . , to treat central geographic atrophy [GA ] and / or to tin ) is administered locally ( e . g . , by eye drop , injection or prevent or forestall neovascular AMD , and / or to treat implant ) in a total dose of about 0 . 5 or 2 - 100 mg, 5 or neovascular AMD ) . 10 - 100 mg, 5 or 10 - 50 mg, 0 . 5 - 2 mg, 2 - 10 mg, 0 . 5 - 5 mg, [0628 ] 59 . The method of any one of embodiments 41 to 5 - 10 mg, 10 -50 mg or 50 - 100 mg over a period of about 58 , wherein the statin ( e . g ., atorvastatin and/ or simvasta 6 months . tin ) is administered at least in the intermediate stage of [0616 ] 49 . The method of any one of embodiments 41 to AMD ( e . g . , to treat non - central GA and /or to prevent or 48 , wherein the statin ( e . g ., atorvastatin and /or simvasta forestall central GA and /or neovascular AMD , or admin tin ) is administered locally ( e . g ., by eye drop , injection or istered in the initial phase of intermediate AMD to prevent implant ) in a total dose of about 1 or 4 - 200 mg, 5 or or forestall non -central GA ) . 10 - 200 mg, 5 or 10 - 150 mg, 5 or 10 - 100 mg, 1 - 5 mg, 5 - 10 [0629 ] 60 . The method of any one of embodiments 41 to mg, 1 - 10 mg, 10 -50 mg, 50 - 100 mg, 100 - 150 mg or 59 , wherein the statin ( e . g . , atorvastatin and / or simvasta 150 - 200 mg for the entire treatment regimen . tin ) is administered at least in the early stage of AMD [0617 ] 50 . The method of any one of embodiments 41 to ( e. g ., to prevent or forestall non -central GA ). 49 , wherein the statin ( e . g ., atorvastatin and /or simvasta [0630 ] 61 . The method of any one of embodiments 41 to tin ) is administered locally by eye drop one or more ( e . g . , 60 , wherein the statin ( e . g ., atorvastatin and / or simvasta two, three , four or more ) times daily , once every two days, tin ) is administered locally or systemically in a higher once every three days , twice a week or once a week ( e . g . , dose (higher dose per administration and / or higher total twice or thrice daily ). dose over a certain timeperiod or for the entire treatment [0618 ] 51. The method of any one of embodiments 41 to regimen ) and /or more frequently (which can result in a 49 , wherein the statin (e . g ., atorvastatin and / or simvasta greater total number of administrations , the later the stage tin ), whether or not in the form of a sustained -release of AMD or the more severe the AMD condition . composition , is administered locally by injection ( e . g . , [ 0631 ] 62 . The method of any one of embodiments 41 to intravitreal, subconjunctival, subretinal or sub - Tenon 's 61 , wherein the statin (e . g ., atorvastatin and /or simvasta US 2018 /0296525 A1 Oct . 18 , 2018 58

tin ) is administered at least prior to signs of AMD to [0642 ] 73 . A method of treating age -related macular prevent or delay the onset of AMD . degeneration ( AMD ) , comprising administering to a sub [ 0632 ] 63 . The method of embodiment 62 , wherein the ject in need of treatment a therapeutically effective statin is administered locally or systemically in a non amount of an anti -angiogenic agent, and a therapeutically invasive manner (e .g . , by eye drop or orally ). effective amount of an apolipoprotein ( apo ) mimetic or a [ 0633 ] 64 . The method of any one of embodiments 41 to pharmaceutically acceptable salt thereof according to any 63 , wherein the subject has the at - risk complement factor one of embodiments 1 to 40 and / or a therapeutically H genotype CC ( Y402H ). effective amount of a statin or a pharmaceutically accept [ 0634 ] 65 . The method of any one of embodiments 41 to able salt thereof according to any one of embodiments 41 64 , wherein the statin ( e . g ., atorvastatin and /or simvasta to 70 . tin ) is administered locally or systemically in a fixed [0643 ] 74 . The method of embodiment 73 , wherein the routine regimen , an as- needed regimen or a treat- and apo mimetic comprises , or is , an apoA -I mimetic ( e . g . , extend regimen . L - 4F or D -4F or a salt thereof) and /or an apoE mimetic [ 0635 ] 66 . The method of any one of embodiments 41 to ( e . g . , AEM -28 - 14 or a salt thereof) . 65 , wherein the statin (e . g. , atorvastatin and /or simvasta [0644 ] 75 . The method of embodiment 73 or 74 , wherein tin ) is administered locally or systemically via a sus the statin comprises, or is , atorvastatin or a salt ( e . g . , tained - release composition . calcium salt ) thereof, and/ or simvastatin . [ 0636 ] 67 . The method of any one of embodiments 41 to [ 0645 ) 76 . The method of any one of embodiments 73 66 , further comprising administering one or more addi to75 , wherein the anti - angiogenic agent comprises , or is , tional therapeutic agents . an agent that inhibits the action of a vascular endothelial [0637 ] 68 . The method of embodiment 67 , wherein the growth factor ( an anti - VEGF agent ) , and /or an agent that one or more additional therapeutic agents are selected inhibits the action of a platelet -derived growth factor ( an from anti -dyslipidemic agents ; PPAR -a agonists , PPAR - 8 anti- PDGF agent ). agonists and PPAR - y agonists ; anti -amyloid agents and [0646 ] 77 . The method of embodiment 76 , wherein the inhibitors of other toxic substances ( e . g . , aldehydes ) ; anti - VEGF agent is selected from squalamine , PAN inhibitors of lipofuscin or components thereof; antioxi 90806 , anti -VEGF antibodies and fragments thereof ( e . g . , dants ; neuroprotectors (neuroprotectants ) ; apoptosis bevacizumab [ AVASTIN ® ], ranibizumab [LUCEN inhibitors and necrosis inhibitors ; C - reactive protein TIS® ], brolucizumab , ESBA1008 and ESBA903 ) , anti inhibitors ; inhibitors of the complement system or com VEGF aptamers (e . g. , pegaptanib [MACUGEN® ]) , anti ponents ( e . g . , proteins ) thereof; inhibitors of inflam VEGF designed ankyrin repeat proteins (DARPins ) ( e . g . , masomes; anti - inflammatory agents ; immunosuppres abicipar pegol) , soluble receptors for VEGFs ( e . g . , sants ; modulators (inhibitors and activators) of matrix VEGFR1) , soluble fusion proteins containing one ormore metalloproteinases and other inhibitors of cell migration ; extracellular domains of one or more VEGFRs ( e . g . , anti - angiogenic agents ; laser therapies , photodynamic aflibercept [EYLEA® ] and conbercept) , and combina therapies and radiation therapies; agents that preserve or tions thereof. improve the health of the endothelium and /or the blood [0647 ] 78 . The method of embodiment 77 , wherein the flow of the vascular system of the eye ; cell ( e . g . , RPE cell ) anti - VEGF agent comprises, or is , aflibercept , broluci replacement therapies; and combinations thereof. zumab , bevacizumab or ranibizumab , or any combination [ 0638 ] 69 . The method of embodiment 68 , wherein the thereof. one or more additional therapeutic agents comprise an [0648 ] 79 . The method of any one of embodiments 73 to anti - dyslipidemic agent, an antioxidant, an anti - inflam 78 , wherein the anti - angiogenic agent ( e . g ., an anti- VEGF matory agent, a complement inhibitor, a neuroprotector or agent ) is administered in a frequency less than the con an anti -angiogenic agent, or any combination or all ventional or recommended dosing frequency , and /or in a thereof. dose less than the conventional or recommended dose , for [ 0639 ] 70 . The method of any one of embodiments 67 to the anti -angiogenic agent in the absence of treatment with 69 , wherein the one or more additional therapeutic agents the apo mimetic ( e . g . , L -4F ) and/ or the statin ( e . g . , comprise an apolipoprotein mimetic ( e . g . , an apoA - I atorvastatin ) . mimetic such as L -4F or D -4F or a salt thereof, and / or an [ 0649 ] 80 . The method of embodiment 79 , wherein the apoE mimetic such as AEM -28 - 14 or a salt thereof) . anti -angiogenic agent ( e .g ., an anti -VEGF agent) is [0640 ] 71 . A method of preventing , delaying the onset of , administered ( e . g . , by intravitreal injection ) at least about slowing the progression of or reducing the extent of vision 1 . 5 , 2 , 3 , 4 , 5 or 6 ( e . g ., at least about 2 ) times less impairment or loss associated with age - related macular frequently than the conventional or recommended dosing degeneration (AMD ) , or improving vision in a subject frequency for the anti -angiogenic agent in the absence of with AMD , comprising administering to a subject in need treatment with the apo mimetic ( e . g ., L - 4F ) and /or the of treatment a therapeutically effective amount of an statin ( e . g ., atorvastatin ) . apolipoprotein mimetic or a pharmaceutically acceptable 106501 81. The method of embodiment 79 or 80 , wherein salt thereof according to any one of embodiments 1 to 40 , the anti - angiogenic agent ( e . g ., an anti - VEGF agent) is and / or a therapeutically effective amount of a statin or a administered ( e . g ., by intravitreal injection ) in a dose at pharmaceutically acceptable salt thereof according to any least about 10 % , 20 % , 30 % , 40 % , 50 % , 60 % , 70 % or one of embodiments 41 to 70 . 80 % ( e . g ., at least about 20 % ) , or about 10 - 30 % , 30 - 50 % [ 0641 ] 72 . The method of embodiment 71, wherein the or 50 - 70 % , less than the conventional or recommended AMD is atrophic AMD ( including noncentral and /or dose for the anti - angiogenic agent in the absence of central geographic atrophy ) or neovascular AMD ( includ treatment with the apo mimetic ( e . g ., L - 4F ) and /or the ing types 1 , 2 and / or 3 neovascularization ) . statin (e . g ., atorvastatin ). US 2018 /0296525 A1 Oct . 18 , 2018 59

[0651 ] 82 . The method of any one of embodiments 79 to [0667 ] ranibizumab is administered ( e . g . , by intravitreal 81 , wherein treatment with the apo mimetic ( e . g ., L -4F ) injection ) in a dose of about 0 . 1 - 0 . 2 mg, 0 . 2 - 0 . 3 mg or and /or the statin ( e . g . , atorvastatin ) reduces the total 0 . 3 - 0 . 4 mg once every month . number of times ( e . g ., the total number of injections ) the (0668 ] 89 . The method of any one of embodiments 79 to anti - angiogenic agent ( e . g . , an anti -VEGF agent ) is 84 , wherein : administered . [ 0669 ] the anti - angiogenic agent comprises , or is , bevaci [ 0652 ] 83 . The method of embodiment 82 , wherein the zumab ( AVASTIN ) ; and anti -angiogenic agent ( e . g . , an anti - VEGF agent) is [0670 ] bevacizumab is administered ( e . g ., by intravitreal administered ( e . g . , by intravitreal injection ) no more than injection ) in a dose of about 0 . 1 - 0 . 3 mg, 0 . 3 - 0 . 5 mg, 0 . 5 - 0 . 75 about 20 , 18 , 15 , 12 or 10 times . mg, 0 . 75 - 1 mg or 1 - 1 . 25 mg once every 2 , 3 , 4 , 5 or 6 [0653 ] 84 . The method of any one of embodiments 79 to months, optionally after being administered in a dose of 83, wherein treatment with the anti- angiogenic agent about 0 . 1 - 0 . 3 mg, 0 . 3 - 0 . 5 mg, 0 . 5 - 0 .75 mg, 0 .75 - 1 mg or ( e . g ., an anti -VEGF agent) , and the apo mimetic ( e . g . , 1 - 1 .25 mg once every month for the first 1 , 2 or 3 months or L - 4F ) and / or the statin ( e . g . , atorvastatin ) , has a syner once every 6 weeks for the first 1 . 5 or 3 months , gistic effect. [ 0671 ] compared to the conventional or recommended dose and dosing frequency for bevacizumab for the [ 0654 ) 85 . The method of any one of embodiments 79 to treatment of AMD of about 1 .25 mg administered by 84 , wherein : intravitreal injection once every month in the absence [ 0655 ] the anti -angiogenic agent comprises, or is , afliber of treatment with the apo mimetic (e . g. , L -4F ) and /or cept (EYLEA® ); and the statin ( e . g . , atorvastatin ) . [0656 ] aflibercept is administered (e . g ., by intravitreal [0672 ] 90 . The method of any one of embodiments 79 to injection ) in a dose of about 1 - 1 . 5 mg or 1 . 5 - 2 mg once every 84, wherein : 3 , 4 , 5 or 6 months , optionally after being administered in a [ 0673 ] the anti -angiogenic agent comprises , or is , bevaci dose of about 1 - 1 . 5 mg or 1 . 5 - 2 mg once every month for the zumab ; and first 1 , 2 or 3 months or once every 6 weeks for the first 1 . 5 [0674 ] bevacizumab is administered (e . g ., by intravitreal or 3 months, injection ) in a dose of about 0 . 1 - 0 . 3 mg, 0 . 3 - 0 . 5 mg, 0 . 5 - 0 .75 [0657 ] compared to the conventional or recommended mg or 0 .75 - 1 mg once every month . dose and dosing frequency for aflibercept of 2 mg 0675 ] 91. The method of any one of embodiments 79 to administered by intravitreal injection once every 2 84 , wherein the anti - angiogenic agent ( e . g ., an anti - VEGF months after administration of 2 mg once every month agent) is administered ( e . g . , by intravitreal injection ) once for the first 3 months in the absence of treatment with every 2 , 3 , 4 , 5 or 6 months . the apo mimetic ( e . g . , L - 4F ) and / or the statin ( e . g . , 0676 ) 92 . The method of any one of embodiments 73 to atorvastatin ) . 91, wherein the anti - angiogenic agent ( e . g . , an anti -VEGF [ 0658 ] 86 . The method of any one of embodiments 79 to agent) is administered locally to , into , in or around the 84 , wherein : eye , such as by injection ( e. g . , intravitreal, subconjuncti [ 0659 ] the anti -angiogenic agent comprises, or is , afliber val, subretinal or sub - Tenon ' s injection ), eye drop or cept; and implant ( e . g . , intravitreal, intraaqueous , subretinal or sub [ 0660 ] aflibercept is administered ( e .g ., by intravitreal Tenon ' s implant) . injection ) in a dose of about 1 - 1 .25 mg, 1 .25 - 1 . 5 mg or [ 0677 ] 93 . The method of any one of embodiments 73 to 1 . 5 - 1 .75 mg in a frequency substantially similar to or the 92, wherein the anti- angiogenic agent ( e . g ., an anti - VEGF same as the conventional or recommended dosing frequency agent ) is administered to treat or slow the progression of for aflibercept in the absence of treatment with the apo neovascular (wet ) AMD , including types 1, 2 and 3 mimetic ( e . g . , L -4F ) and / or the statin ( e. g . , atorvastatin ) . neovascularization . [ 0661 ] 87 . The method of any one of embodiments 79 to [0678 ] 94 . The method of any one of embodiments 73 to 84 , wherein : 93 , wherein the anti - angiogenic agent ( e . g ., an anti - VEGF agent) is administered at least in the advanced stage of [ 0662 ] the anti- angiogenic agent comprises, or is , ranibi AMD to prevent, delay the onset of, or slow the progres zumab (LUCENTIS ) ; and sion to neovascular AMD . [0663 ] ranibizumab is administered ( e . g ., by intravitreal [ 0679 ] 95 . The method of any one of embodiments 73 to injection ) in a dose of about 0 . 1 - 0 . 2 mg, 0 . 2 - 0 . 3 mg, 0 . 3 - 0 . 4 94 , wherein the apo mimetic ( e . g . , L -4F ) and /or the statin mg or 0 . 4 - 0 . 5 mg once every 2 , 3 , 4 , 5 or 6 months , ( e . g . , atorvastatin ) are administered at least in the optionally after being administered in a dose of about advanced stage of AMD . 0 . 1 - 0 . 2 mg, 0 . 2 - 0 . 3 mg, 0 . 3 - 0 . 4 mg or 0 . 4 - 0 . 5 mg once every [0680 ] 96 . The method of embodiment 95, wherein the month for the first 1 , 2 or 3 months or once every 6 weeks apo mimetic ( e . g . , L - 4F ) and / or the statin ( e. g . , atorvas for the first 1. 5 or 3 months, tatin ) are administered to treat central geographic atrophy, 106641 compared to the conventional or recommended and /or to prevent, delay the onset of, or slow the progres dose and dosing frequency for ranibizumab of 0 . 5 mg sion of neovascular AMD ( including types 1 , 2 and 3 administered by intravitreal injection once every month neovascularization ) . in the absence of treatment with the apo mimetic ( e . g . , 10681 ] 97 . The method of any one of embodiments 73 to L - 4F ) and /or the statin ( e . g . , atorvastatin ) . 96 , wherein the anti- angiogenic agent ( e . g ., an anti - VEGF [ 0665 ] 88 . The method of any one of embodiments 79 to agent) is administered in a fixed - routine regimen , an 84 , wherein : as- needed regimen or a treat - and - extend regimen . [ 0666 ] the anti - angiogenic agent comprises , or is , ranibi- (0682 ] 98 . The method of any one of embodiments 73 to zumab ; and 97 , wherein the anti - angiogenic agent ( e . g . , an anti- VEGF US 2018 /0296525 A1 Oct . 18 , 2018 60

agent) , and the apo mimetic ( e . g . , L -4F ) and /or the statin ( e . g ., CFH and fragments thereof ( e . g . , AMY - 201 ] , ( e . g ., atorvastatin ), are administered in separate compo soluble complement receptor 1 [SCR1 such as CDX - 1135 ] sitions . and fragments thereof ( e . g . , mirococept] , C4b - binding [ 0683] 99 . The method of any one of embodiments 73 to protein [C4BP ] and decay accelerating factor [DAF ]) , C3 97 , wherein the anti -angiogenic agent ( e . g . , an anti - VEGF convertase inhibitors ( e . g ., TT30 and compstatin and agent ) , and the apo mimetic ( e . g . , L - 4F ) and / or the statin analogs and derivatives thereof (e . g. , POT- 4 ]) , anti - C3 ( e . g ., atorvastatin ) , are administered in the same compo antibodies and fragments thereof , other C3 inhibitors sition . ( e . g . , AMY- 101, APL - 2 , CB - 2782 , compstatin and ana [0684 ] 100 . A method of treating age- related macular logs and derivatives thereof [ e . g . , POT- 4 ), mycophenolic degeneration ( AMD ), comprising administering to a sub acid - glucosamine conjugates [downregulate C3] and neu ject in need of treatment a therapeutically effective rotropin ), anti -C3b /iC3b antibodies and fragments thereof amount of a complement inhibitor , and a therapeutically ( e . g ., 3E7 ) , other C3b inhibitors ( e . g . , TT30 ), promoters effective amount of an apolipoprotein ( apo ) mimetic or a of C3b and C4b cleavage ( e . g ., CFI, CFH , C4BP, SCR1 pharmaceutically acceptable salt thereof according to any and soluble membrane cofactor protein [SMCP ]) , C5 one of embodiments 1 to 40 and / or a therapeutically convertase inhibitors ( e . g ., CFHR1) , anti -C5 antibodies effective amount of a statin or a pharmaceutically accept and fragments thereof ( e . g . , eculizumab , Ergidina ,Mubo able salt thereof according to any one of embodiments 41 dina , ABP959 , ALXN1210 , LFG316 , MEDI- 7814 and to 70 . RO7112689 [SKY59 ] ), anti- C5 aptamers ( e . g ., ARC1905 [0685 ] 101. The method of embodiment 100 , wherein the [ avacincaptad pegol or ZIMURA® ]) , other C5 inhibitors apo mimetic comprises , or is , an apoA - I mimetic ( e . g ., ( e . g ., RA101495 and Coversin ), anti- C5a antibodies and L - 4F or D -4F or a salt thereof ) and / or an apoE mimetic fragments thereof ( e . g ., IFX - 1 [CaCP - 29 ] and MEDI ( e . g . , AEM -28 - 14 or a salt thereof) . 7814 ), anti - C5a aptamers (e .g . , NOX -D19 ), C5a receptor [ 0686 ] 102 . The method of embodiment 100 or 101 , antagonists { e .g ., ADC - 1004 , CCX - 168 , JPE - 1375 , JSM wherein the statin comprises, or is , atorvastatin or a salt 7717 , PMX -025 , Ac - F [OPdCha WR ] (PMX -53 ) and ( e . g . , calcium salt ) thereof, and /or simvastatin . PMX - 205 , and anti- C5aR antibodies and fragments 10687 ] 103 . The method of any one of embodiments 100 thereof ( e . g ., neutrazimab , NN8209 and NN8210 ) } , other to 102 , wherein the complement inhibitor, and the apo inhibitors of the alternative complement pathway ( e . g ., mimetic ( e . g . , L - 4F ) and /or the statin ( e . g ., atorvastatin ) , KSI -401 and zinc ) , other inhibitors of the classic comple are administered to treat geographic atrophy (GA ) . ment pathway (e . g. , serpin 1 [inhibits C1r and C1s ]) , [0688 ] 104 . The method of embodiment 103 , wherein the inhibitors of the lectin complement pathway (e .g . , inhibi complement inhibitor, and the apo mimetic ( e . g ., L - 4F ) tors of mannose -associated serine proteases [MASPs ) , and / or the statin ( e . g . , atorvastatin ) , are administered to such as anti- MASP antibodies and fragments thereof [ e . g ., prevent, delay the onset of, or slow the progression of OMS721 ] and serpin 1 [inhibits MASP - 1 and MASP -2 ]) , central GA and / or non - central GA . other inhibitors of membrane attack complex (MAC ) [0689 ] 105 . The method of embodiment 103 or 104 , formation ( e . g . , zinc , CD59 and modified CD59 having a wherein the complement inhibitor, and the apo mimetic glycolipid anchor ), and analogs , derivatives , fragments , ( e . g ., L - 4F ) and /or the statin ( e . g . , atorvastatin ), are salts and combinations thereof. administered at least in the advanced stage of atrophic [0693 ] 109 . The method of embodiment 108 , wherein the (dry ) AMD to treat or slow the progression of centralGA , complement inhibitor comprises , or is , a CFD inhibitor and /or to prevent or delay the onset of neovascular AMD . (e . g. , lampalizumab ), a C3 inhibitor (e . g. , CB - 2782 ) or a 10690 ) 106 . The method of any one of embodiments 103 C5 inhibitor ( e . g ., LFG316 or ARC1905 ) , or any combi to 105 , wherein the complement inhibitor , and the apo nation or all thereof . mimetic ( e . g . , L - 4F ) and /or the statin (e . g ., atorvastatin ), [ 0694 ] 110 . The method of embodiment 109, wherein the are administered at least in the intermediate stage of AMD complement inhibitor comprises , or is , lampalizumab . to treat or slow the progression of non -central GA , and / or [ 0695 ] 111. The method of embodiment 110 , wherein the to prevent or delay the onset of central GA and / or neo subject has a mutation in the gene encoding complement vascular AMD . factor I (CFI ) . [0691 ] 107 . The method of any one of embodiments 103 [0696 ] 112 . The method of any one of embodiments 100 to 106 , wherein the complement inhibitor, and the apo to 111 , wherein treatment with the complement inhibitor mimetic ( e . g . , L - 4F ) and /or the statin ( e . g ., atorvastatin ) , ( e . g . , a C3 inhibitor, a C5 inhibitor and / or a CFD inhibi are administered at least in the early stage of AMD or the tor) , and the apo mimetic (e . g ., L - 4F ) and / or the statin initial phase of intermediate AMD to prevent or delay the ( e . g . , atorvastatin ) , slows the progression of central GA onset of non -central GA . and/ or non -central GA ( e . g ., reduces the rate of GA [0692 ] 108 . The method of any one of embodiments 100 progression , or reduces the GA lesion area or size ) by at to 107 , wherein the complement inhibitor is selected from least about 10 % , 20 % , 30 % , 40 % , 50 % , 60 % , 70 % or anti -C1s antibodies and fragments thereof (e . g ., TNT 80 % ( e . g . , by at least about 20 % or 40 % ), or by about 009 ) , other Cls inhibitors ( e . g ., BCX - 1470 , nafamostat 20 -40 % , 40 -60 % or 60 - 80 % . and serpin 1 [C1 inhibitor ]) , anti- complement factor B [0697 ] 113 . The method of any one of embodiments 100 (CFB ) antibodies and fragments thereof ( e . g . , bikaciomab to 112 , wherein treatment with the complement inhibitor and TA106 ), anti -CFD antibodies and fragments thereof (e . g ., a C3 inhibitor, a C5 inhibitor and /or a CFD inhibi ( e . g ., lampalizumab ) , other CFD inhibitors ( e . g . , ACH tor ), and the apo mimetic ( e . g ., L -4F ) and / or the statin 4471, BCX - 1470 and nafamostat) , anti - CFP ( properdin ) ( e . g . , atorvastatin ) , slows the progression of central GA antibodies and fragments thereof ( e . g ., NM9401) , C3 and / or non -central GA ( e . g ., reduces the rate of GA convertase dissociation promoters or formation inhibitors progression , or reduces the GA lesion area or size) at least US 2018 /0296525 A1 Oct . 18 , 2018

about 10 % , 20 % , 30 % , 50 % , 100 % , 150 % , 200 % or [0708 ] 121. The method of any one of embodiments 114 300 % ( e . g . , at least about 20 % or 30 % ) , or about 10 - 30 % , to 119 , wherein : 30 - 50 % , 50 - 100 % , 100 - 200 % or 200 - 300 % ( e .g . , about [ 0709 ] the complement inhibitor comprises , or is , lampali 50 - 100 % ) , more than treatment with the complement zumab ; and inhibitor in the absence of treatment with the apo mimetic [0710 ] lampalizumab is administered (e . g. , by intravitreal and / or the statin . injection ) in a dose of about 3 - 5 mg, 5 - 7 mg or 7 - 9 mg once [ 0698 ] 114 . The method of any one of embodiments 100 every month (4 weeks ) or 1 .5 months (6 weeks) . to 113 , wherein the complement inhibitor ( e . g . , a C3 [ 0711 ] 122 . Themethod of any one of embodiments 114 to inhibitor, a C5 inhibitor and / or a CFD inhibitor ) is admin 120 , wherein the complement inhibitor ( e . g ., a C3 inhibi istered in a frequency less than the conventional or tor, a C5 inhibitor and / or a CFD inhibitor ) is administered recommended dosing frequency , and / or in a dose less than ( e . g ., by intravitreal injection ) once every 2 , 3 , 4 , 5 or 6 the conventional or recommended dose , for the comple ( e . g . , once every 2 ) months. ment inhibitor in the absence of treatment with the apo [0712 123 . The method of any one of embodiments 100 mimetic ( e . g . , L - 4F ) and / or the statin ( e . g . , atorvastatin ) . to 122 , wherein the complement inhibitor ( e . g ., a C3 [ 0699 ] 115 . The method of embodiment 114 , wherein the inhibitor, a C5 inhibitor and /or a CFD inhibitor) is admin complement inhibitor ( e . g ., a C3 inhibitor, a C5 inhibitor istered locally to , into , in or around the eye , such as by and /or a CFD inhibitor ) is administered (e . g ., by intrav injection ( e . g . , intravitreal , subconjunctival, subretinal or itreal injection ) at least about 1 . 5 , 2 , 3 , 4 , 5 or 6 ( e . g ., at sub - Tenon ' s injection ) , eye drop or implant ( e . g . , intrav least about 2 ) times less frequently than the conventional itreal , intraaqueous, subretinal or sub - Tenon 's implant) . or recommended dosing frequency for the complement [0713 ] 124 . The method of any one of embodiments 100 inhibitor in the absence of treatmentwith the apo mimetic to 123 , wherein the complement inhibitor ( e. g ., a C3 ( e. g ., L - 4F ) and /or the statin ( e. g ., atorvastatin ). inhibitor, a C5 inhibitor and /or a CFD inhibitor) , and the [0700 ] 116 . The method of embodiment 114 or 115 , apo mimetic ( e . g . , L -4F ) and / or the statin ( e . g . , atorvas wherein the complement inhibitor ( e . g . , a C3 inhibitor, a tatin ) , are administered in separate compositions. C5 inhibitor and /or a CFD inhibitor ) is administered ( e. g ., [0714 ] 125 . The method of any one of embodiments 100 by intravitreal injection ) in a dose at least about 10 % , to 123 , wherein the complement inhibitor ( e . g ., a C3 20 % , 30 % , 40 % , 50 % , 60 % , 70 % or 80 % (e . g ., at least inhibitor , a C5 inhibitor and /or a CFD inhibitor ) , and the about 20 % ) , or about 10 - 30 % , 30 - 50 % or 50 - 70 % , less apo mimetic ( e . g . , L - 4F ) and / or the statin ( e . g . , atorvas than the conventional or recommended dose for the tatin ) , are administered in the same composition . complement inhibitor in the absence of treatment with the [0715 ] 126 . The method of any one of embodiments 100 apo mimetic ( e . g ., L - 4F ) and / or the statin ( e . g ., atorvas to 125 , wherein the complement inhibitor, and the apo tatin ) . mimetic ( e . g ., L -4F ) and / or the statin ( e . g ., atorvastatin ) , [0701 ] 117 . The method of any one of embodiments 114 to are administered at least in the advanced stage of AMD to 116 , wherein treatment with the apo mimetic ( e . g ., L -4F ) prevent, delay the onset of, or slow the progression of and / or the statin ( e . g . , atorvastatin ) reduces the total neovascular AMD , including types 1 , 2 and 3 neovascu number of times ( e . g ., the total number of injections) the larization . complement inhibitor (e . g. , a C3 inhibitor, a C5 inhibitor [ 0716 ] 127. Themethod of embodiment 126 , further com and /or a CFD inhibitor ) is administered . prising administering a therapeutically effective amount [0702 ] 118 . The method of embodiment 117 , wherein the of an anti -angiogenic agent . complement inhibitor ( e . g ., a C3 inhibitor, a C5 inhibitor 107171. 128 . The method of embodiment 127 , wherein the and /or a CFD inhibitor) is administered (e . g. , by intrav anti - angiogenic agent comprises , or is , an anti - VEGF itreal injection ) no more than about 20 , 18 , 15 , 12 or 10 agent ( e . g ., aflibercept [EYLEA® ], brolucizumab , beva times . cizumab [ AVASTIN® ] or ranibizumab [LUCENTIS® ] , [ 0703 ) 119 . Themethod of any one of embodiments 114 to or any combination thereof) and /or an anti - PDGF agent 118 , wherein treatment with the complement inhibitor ( e . g . , E10030 [FOVISTA® ]) . ( e . g ., a C3 inhibitor , a C5 inhibitor and / or a CFD inhibi [0718 ] 129. The method of any one of embodiments 126 tor) , and the apo mimetic (e . g. , L - 4F ) and /or the statin to 128 , wherein the complement inhibitor comprises , or ( e . g . , atorvastatin ) , has a synergistic effect. is , a C3 inhibitor ( e . g . , CB - 2782 ) and /or a C5 inhibitor [0704 ] 120 . The method of any one of embodiments 114 ( e . g . , ARC1905 [ ZIMURA® ] or LFG316 ) . to 119, wherein : [0719 ] 130 . The method of any one of embodiments 100 [0705 ] the complement inhibitor comprises, or is , lampali to 129 , wherein the complement inhibitor ( e . g ., a CFD zumab ; and inhibitor [ e . g . , lampalizumab ], a C3 inhibitor [ e . g . , [ 0706 ] lampalizumab is administered (e .g ., by intravitreal CB - 2782 ] or a C5 inhibitor [ e . g . , ARC1905 or LFG316 ] , injection ) in a dose of about 4 - 6 mg, 6 - 8 mg or 8 - 10 mg once or any combination or all thereof) is administered in a every 2 , 3 , 4 , 5 or 6 months , optionally after being admin fixed - routine regimen , an as -needed regimen or a treat istered in a dose of about 4 -6 mg, 6 - 8 mg or 8 - 10 mg once and -extend regimen . every month for the first 1 , 2 or 3 months or once every 6 [0720 ] 131. A method of treating age -related macular weeks for the first 1 . 5 or 3 months, degeneration ( AMD ) , comprising administering to a sub [0707 ] compared to the conventional or recommended ject in need of treatment a therapeutically effective dose and dosing frequency for lampalizumab of about amount of an antioxidant, and a therapeutically effective 10 mg administered by intravitreal injection once every amount of an apolipoprotein ( apo ) mimetic or a pharma month in the absence of treatment with the apo mimetic ceutically acceptable salt thereof according to any one of ( e . g ., L - 4F ) and /or the statin ( e . g ., atorvastatin ) . embodiments 1 to 40 and /or a therapeutically effective US 2018 /0296525 A1 Oct . 18 , 2018 62

amount of a statin or a pharmaceutically acceptable salt tional or recommended dose for the antioxidant in the thereof according to any one of embodiments 41 to 70 . absence of treatment with the apo mimetic ( e . g . , L - 4F ) [0721 ] 132 . The method of embodiment 131 , wherein the and/ or the statin ( e . g . , atorvastatin ) . apo mimetic comprises, or is , an apoA - I mimetic ( e . g . , [0727 ] 138 . The method of embodiment 136 or 137 , L - 4F or D -4F or a salt thereof) and /or an apoE mimetic wherein the antioxidant ( e . g . , vitamins and / or carote ( e . g . , AEM - 28 - 14 or a salt thereof) . noids) is administered at least about 2 , 3 , 5 , 7 or 10 ( e . g . , [ 0722 ] 133 . The method of embodiment 131 or 132 , at least about 2 ) times less frequently than the conven wherein the statin comprises, or is , atorvastatin or a salt tional or recommended dosing frequency for the antioxi ( e . g . , calcium salt ) thereof, and / or simvastatin . dant in the absence of treatment with the apo mimetic [ 0723 ] 134 . The method of any one of embodiments 131 ( e . g . , L -4F ) and/ or the statin ( e . g . , atorvastatin ) . to 133 , wherein the antioxidant is selected from antho [0728 ] 139 . The method of embodiment 138 , wherein the cyanins , benzenediol abietane diterpenes ( e . g ., carnosic antioxidant ( e . g ., vitamins and /or carotenoids ) is admin acid ), carnosine , N - acetylcarnosine , carotenoids ( e . g . , istered once every two or three days compared to the carotenes [ e .g ., ß - carotene ], xanthophylls [ e. g ., lutein , conventional or recommended dosing frequency for the zeaxanthin and meso - zeaxanthin ] , and carotenoids in saf antioxidant of at least one time every day in the absence fron [ e . g . , crocin and crocetin ] ) , curcuminoids ( e . g . , cur of treatment with the apo mimetic (e . g ., L - 4F ) and / or the cumin ), cyclopentenone prostaglandins (e .g . , 15d - PGJ2) , statin ( e . g ., atorvastatin ) . flavonoids { e . g . , flavonoids in Ginkgo biloba ( e . g . , [0729 ] 140 . The method of any one of embodiments 131 myricetin and quercetin ), prenylflavonoids ( e .g ., isoxan to 139 , wherein the antioxidant ( e . g ., vitamins and / or thohumol) , flavones ( e . g ., apigenin ), isoflavones ( e . g . , carotenoids ) , and the apo mimetic ( e . g ., L -4F ) and / or the genistein ) , flavanones ( e . g ., naringenin ) and flavanols statin ( e . g ., atorvastatin ) , are administered at least in the ( e . g ., catechin and epigallocatechin - 3 - gallate ) } , gluta advanced stage of AMD to treat or slow the progression thione, melatonin , retinoids, stilbenoids ( e .g ., resveratrol) , of central geographic atrophy (GA ) and / or neovascular uric acid , vitamin A , vitamin B ( thiamine ) , vitamin B , AMD ( including types 1, 2 and 3 NV ) , and /or to prevent ( riboflavin ), vitamin B3 (niacin ), vitamin B6 ( e . g . , pyri or delay the onset of neovascular AMD . doxal , pyridoxamine , 4 -pyridoxic acid and pyridoxine ), [0730 ] 141 . The method of any one of embodiments 131 vitamin B , ( folic acid ) , vitamin B12 (cobalamin ), vitamin to 140 , wherein the antioxidant ( e . g . , vitamins and /or C , vitamin E (e . g ., tocopherols and tocotrienols) , sele carotenoids) , and the apo mimetic ( e. g ., L -4F ) and /or the nium , zinc ( e . g . , zinc monocysteine ) , inhibitors and scav statin ( e . g . , atorvastatin ) , are administered at least in the engers of lipid peroxidation and byproducts thereof ( e . g . , intermediate stage of AMD to treat or slow the progres vitamin E ?e . g . , a - tocopherol ] , tirilazad , NXY- 059 , and sion of non - central GA , and/ or to prevent or delay the cardiolipin peroxidation inhibitors [ e . g . , elamipretide , onset of central GA and / or neovascular AMD . SkQ1 and XJB - 5 - 131 ] ) , activators of nuclear factor [ 0731 ] 142. The method of any one of embodiments 131 (erythroid - derived 2 )- like 2 (NFE2L2 or Nrf2 ) ( e. g. , bar to 141, wherein the antioxidant ( e . g . , vitamins and /or doxolone methyl, OT- 551 , fumarates [ e . g ., dimethyl and carotenoids ) , and the apo mimetic ( e . g ., L -4F ) and / or the monomethyl fumarate ) , and dithiolethiones [ e . g ., oltip statin (e . g ., atorvastatin ), are administered at least in the raz ] ) , superoxide dismutase (SOD ) mimetics { e . g ., early stage of AMD or the initial phase of intermediate OT- 551 , manganese ( III ) - and zinc ( III ) - porphyrin com AMD to prevent or delay the onset of non - central GA . plexes ( e . g . , MnTBAP, MnTMPyP and ZnTBAP ) , man - f0732 ] 143 . The method of any one of embodiments 131 ganese ( II ) penta - azamacrocyclic complexes ( e . g . , to 142 , wherein the antioxidant ( e . g ., vitamins and /or M40401 and M40403 ) , and manganese ( III) - salen com carotenoids ) , and optionally the statin ( e . g . , atorvastatin ) plexes ( e . g . , those disclosed in U . S . Pat . No. 7 , 122, 537 ) } , and / or the apo mimetic ( e . g . , L - 4F ) , are administered at and analogs , derivatives , salts and combinations thereof. least in the early stage of AMD . 10724 ] 135 . The method of embodiment 134 , wherein the f0733 ] 144 . The method of any one of embodiments 140 antioxidant comprises one or more vitamins ( e . g ., vitamin to 143 , wherein treatment with the antioxidant ( e . g . , B6 , vitamin C and vitamin E ), one or more carotenoids vitamins and /or carotenoids ) , and the apo mimetic ( e . g . , ( e. g ., xanthophylls [ e .g ., lutein , zeaxanthin and meso L - 4F ) and /or the statin (e .g . , atorvastatin ), slows the zeaxanthin ] and carotenoids in saffron ?e . g . , crocin and progression of central GA and / or non - central GA ( e . g . , crocetin ] ), or zinc , or any combination or all thereof, such reduces the rate of GA progression , or reduces the GA as an AREDS or AREDS2 formulation , an ICAPS® lesion area or size ) by at least about 10 % , 20 % , 30 % , formulation , an Ocuvite® formulation or Saffron 2020? . 40 % , 50 % , 60 % , 70 % or 80 % ( e . g ., by at least about [0725 ] 136 . The method of any one of embodiments 131 20 % ) , or by about 20 -40 % , 40 -60 % or 60 -80 % . to 135 , wherein the antioxidant ( e . g . , vitamins and / or [0734 ] 145 . The method of any one of embodiments 140 carotenoids ) is administered in a dose less than the to 144 , wherein treatment with the antioxidant ( e . g . , conventional or recommended dose , and /or in a frequency vitamins and / or carotenoids ) , and the apo mimetic ( e . g . , less than the conventional or recommended dosing fre L - 4F ) and / or the statin (e . g ., atorvastatin ), slows the quency , for the antioxidant in the absence of treatment progression of central GA and / or non - central GA ( e . g . , with the apo mimetic ( e . g ., L - 4F ) and / or the statin ( e . g . , reduces the rate of GA progression , or reduces the GA atorvastatin ) . lesion area or size ) at least about 10 % , 20 % , 30 % , 50 % , 0726 ] 137 . The method of embodiment 136 , wherein the 100 % , 150 % , 200 % or 300 % ( e . g . , at least about 20 % or antioxidant ( e . g . , vitamins and/ or carotenoids ) is admin 30 % ), or about 10 - 30 % , 30 -50 % , 50 - 100 % , 100 -200 % or istered in a dose at least about 10 % , 20 % , 30 % , 40 % , 200 - 300 % ( e . g ., about 50 - 100 % ) , more than treatment 50 % , 60 % , 70 % or 80 % ( e . g ., at least about 20 % ) , or with the antioxidant in the absence of treatment with the about 10 - 30 % , 30 -50 % or 50 - 70 % , less than the conven apo mimetic and /or the statin . US 2018 /0296525 A1 Oct . 18 , 2018

[0735 ] 146 . The method of any one of embodiments 136 lations ( e . g . , ß -carotene , vitamin C , vitamin E , zinc [ e . g ., to 145 , wherein treatment with the antioxidant ( e . g ., zinc oxide ) and copper [ e . g ., cupric oxide ]) , or Saffron vitamins and / or carotenoids ) , and the apo mimetic ( e . g ., 2020® ( saffron , resveratrol, lutein , zeaxanthin , vitamins A , L -4F ) and /or the statin ( e. g ., atorvastatin ), has a syner B2, C and E , zinc and copper ); or gistic effect. [0762 ) iii ) AREDS2 formulations , such as : [0736 ] 147 . The method of any one of embodiments 131 [0763 ] 1) B -carotene , vitamin C , vitamin E and zinc ; to 146 , wherein the antioxidant ( e . g . , vitamins and /or [0764 ] 2) vitamin C , vitamin E , zinc and copper ; carotenoids ) is administered systemically ( e . g . , orally ) , or [0765 ] 3 ) vitamin C , vitamin E and zinc ; locally to , into , in or around the eye ( e . g ., by injection [0766 ] 4 ) ß -carotene , vitamin C , vitamin E , zinc, cop [ e . g ., intravitreal, subconjunctival, subretinal or sub - Ten per, and omega - 3 fatty acids ; on ' s injection ] , eye drop or implant ?e . g ., intravitreal, [0767 ] 5 ) B - carotene, vitamin C , vitamin E , zinc , cop subretinal or sub - Tenon ' s implant ]) . per, lutein and zeaxanthin ; and [0737 ] 148 . The method of any one of embodiments 131 [0768 ] 6 ) B - carotene , vitamin C , vitamin E , zinc , cop to 147 , wherein the antioxidant ( e . g . , vitamins and /or per, omega - 3 fatty acids , lutein and zeaxanthin ; or carotenoids) , and the apo mimetic ( e . g ., L -4F ) and / or the 107690 iv ) a visual/ light cycle modulator and a dark adap statin ( e .g ., atorvastatin ) , are administered in separate tation agent ; or compositions. [0770 ] V ) an apoptosis inhibitor ( e . g . , a caspase inhibitor ) [0738 ] 149 . The method of any one of embodiments 131 and a necrosis inhibitor ( e . g ., an RIP kinase inhibitor ) ; or to 147 , wherein the antioxidant ( e . g ., vitamins and/ or [0771 ] vi) an apolipoprotein mimetic ( e . g . , an apoA - I carotenoids ) , and the apo mimetic ( e . g . , L - 4F ) and / or the mimetic ) and an anti -angiogenic agent ; or statin ( e . g . , atorvastatin ) are administered in the same [0772 ] vii ) two or more anti -angiogenic agents , such as composition . two endogenous anti - angiogenic agents ( e . g . , angiostatin [ 0739 ] 150 . A method of treating age - related macular and endostatin ) , or an anti -PDGF /PDGFR agent and an degeneration ( AMD ) , comprising administering to a sub anti - VEGF /VEGFR agent ( e . g ., E10030 and ranibizumab , ject in need of treatment a therapeutically effective or REGN2176 - 3 and aflibercept ) , or an anti -angiopoietin / amount of a plurality of therapeutic agents selected from : angiopoietin receptor agent and an anti- VEGF /VEGFR [0740 ] 1 ) anti- dyslipidemic agents ; agent ( e . g . , nesvacumab or REGN910 - 3 and aflibercept ), or [ 0741] 2 ) PPAR - a agonists , PPAR - d agonists and PPAR - Y a sphingosine - 1 - phosphate inhibitor and an anti - VEGF/ agonists ; VEGFR agent (e . g. , sonepcizumab and aflibercept, bevaci [ 0742 ] 3 ) anti - amyloid agents and inhibitors of other toxic zumab or ranibizumab ) ; or substances ( e . g . , aldehydes ) ; [0773 ] viii ) a complement inhibitor and an anti - angiogenic [0743 ] 4 ) inhibitors of lipofuscin or components thereof; agent , such as an anti -C5 agent ( e . g . , ARC1905 ) and an [0744 ] 5 ) visual/ light cycle modulators and dark adapta anti- VEGF / VEGFR agent, or an anti -C5 agent ( e. g ., tion agents; ARC1905 ) , an anti- PDGF /PDGFR agent ( e . g ., E10030 ) and [ 0745 ] 6 ) antioxidants ; an anti - VEGF /VEGFR agent ; or [0746 ] 7 ) neuroprotectors ( neuroprotectants ); [0774 ) ix ) an anti- inflammatory agent ( e . g . , an NSAID or [0747 ] 8 ) apoptosis inhibitors and necrosis inhibitors; a corticosteroid ) and an anti -angiogenic agent ( e . g ., an [0748 ] 9 ) C - reactive protein (CRP ) inhibitors ; anti - VEGF /VEGFR agent) , such as bromfenac or triamci [0749 ] 10 ) inhibitors of the complement system or com nolone acetonide , and aflibercept, bevacizumab or ranibi ponents ( e. g . , proteins ) thereof; zumab ; or 10750 ) 11 ) inhibitors of inflammasomes ; [0775 ] x ) an immunosuppressant ( e . g . , an IL - 2 inhibitor or [0751 ] 12 ) anti -inflammatory agents ; a TNF -a inhibitor) and an anti -angiogenic agent ( e. g ., an [0752 ] 13 ) immunosuppressants ; anti -VEGF /VEGFR agent) , such as daclizumab , rapamycin , 10753] 14 ) modulators ( inhibitors and activators ) ofmatrix adalimumab or infliximab , and aflibercept, bevacizumab or metalloproteinases (MMPs ) and other inhibitors of cell ranibizumab ; or migration ; [0776 ] xi) laser therapy , photodynamic therapy or radia [ 0754 ] 15 ) anti - angiogenic agents ; tion therapy and agent( s ) used therewith ; or [ 0755 ] 16 ) laser therapies, photodynamic therapies and [0777 ] xii ) any combinations of therapeutic agents previ radiation therapies ; ously disclosed for the potential treatment of AMD . [ 0756 ] 17 ) agents that preserve or improve the health of [0778 ] 151. The method of embodiment 150 , further com the endothelium and /or the blood flow of the vascular prising administering one , two or more therapeutic agents , system of the eye ; and concurrently or sequentially and in the same composition [ 0757 ] 18 ) cell ( e . g . , RPE cell) replacement therapies ; or in different compositions, at least in the early stage of [ 0758 ] wherein two or more therapeutic agents are admin AMD . istered , concurrently or sequentially and in the same com [0779 ] 152. The method of embodiment 151, wherein the position or in different compositions , at least in the inter one , two or more therapeutic agents administered at least mediate stage and / or the advanced stage of AMD ; in early AMD comprise one or more therapeutic agents [0759 ] with the proviso that the plurality of therapeutic that maintain or improve the health of the endothelium agents is not limited to but can comprise : and / or the blood flow of the vascular system of the eye . 10760 ) i ) antioxidants and / or vitamins, such as vitamin B 10780 ) 153 . The method of embodiment 152 , wherein the ( e . g ., pyridoxine) , vitamin B , ( e . g . , folic acid ) and vitamin one or more therapeutic agents that maintain or improve B12 (e . g . , cyanocobalamin ) ; or the health of the endothelium and / or the blood flow of the 10761] ii ) antioxidants and / or vitamins, plus minerals , vascular system of the eye comprise a complement inhibi such as Age -Related Eye Disease Study (AREDS ) formu tor ( e. g . , a MAC inhibitor ) , an agent that inhibits endothe US 2018 /0296525 A1 Oct. 18 , 2018 64

lial inflammatory and /or oxidative events ( e .g ., an apoA - I at least in advanced atrophic AMD (e . g. , to treat or slow mimetic such as Rev - D - 4F ) , or an agent that improves the progression of centralGA and /or to prevent or delay choroidal or retinal blood flow ( e. g. , MC -1101 ) , or any the onset of neovascular AMD ) , and/ or in intermediate combination or all thereof. AMD ( e . g . , to treat or slow the progression of non - central [0781 ] 154 . The method of any one of embodiments 150 GA, and / or to prevent or delay the onset of central GA to 153 , wherein the plurality of therapeutic agents com and /or neovascular AMD ): prises an anti -dyslipidemic agent, an antioxidant, an anti [0815 ] 1 ) an apolipoprotein mimetic ; inflammatory agent, a complement inhibitor, a neuropro [0816 ] 2 ) a statin ; tector or an anti - angiogenic agent, or any combination or 0817 ] 3 ) a fibrate ; all thereof. [0818 ] 4 ) an ACAT inhibitor; [ 0782 ] 155 . The method of any one of embodiments 150 [0819 ] 5 ) a GLP - 1 receptor agonist ; to 154 , wherein the plurality of therapeutic agents is [0820 ] 6 ) an MTTP inhibitor ; administered to treat or slow the progression of geo [0821 ] 7) an anti- dyslipidemic anti -sense polynucleotide graphic atrophy (GA ) ( including noncentral and / or central or PNA ; GA ) or neovascular AMD ( including types 1 , 2 and / or 3 f0822 ] 8 ) an LXR agonist; neovascularization (NV1 ) , and / or to prevent or delay the [0823 ] 9 ) an antioxidant ; onset of GA ( including noncentral and / or central GA ) [0824 ) 10 ) a neuroprotector ; and / or neovascular AMD . [ 0783 ] 156 . The method of any one of embodiments 150 [0825 ]. 11 ) an apoptosis inhibitor and /or a necrosis inhibi to 155 , wherein one , two or more , or any combination , of tor; the therapeutic agents in the following group are admin [0826 ] 12 ) an anti - inflammatory agent; istered at least in early AMD ( e . g . , to prevent or delay the [0827 ) 13 ) a CRP inhibitor; and onset of non - central GA ) : [0828 ] 14 ) a complement inhibitor. [ 0784 ] 1 ) an apolipoprotein mimetic ; [0829 ] 159 . The method of any one of embodiments 150 [0785 ] 2 ) a statin ; to 158 , wherein two or more, or any combination , of the [ 0786 ] 3 ) a fibrate ; therapeutic agents in the following group are administered 107871. 4 ) a GLP - 1 receptor agonist ; at least in advanced AMD to treat or slow the progression 10788 ] 5 ) an MTTP inhibitor ; of neovascular AMD ( including types 1 , 2 and / or 3 [ 0789] 6 ) an anti -dyslipidemic anti- sense polynucleotide neovascularization ) , and /or in advanced atrophic AMD or PNA ; and / or intermediate AMD to prevent or delay the onset of [0790 ] 7 ) a CETP inhibitor, neovascular AMD : 10791 ] 8 ) an LXR agonist ; [ 0830 ] 1 ) an apolipoprotein mimetic ; [0792 ] 9) an antioxidant; [0831 ] 2 ) a statin ; [ 0793 ] 10 ) a neuroprotector; [0832 ] 3 ) a fibrate ; [ 0794 ] 11) an anti - inflammatory agent ; 10833 ] 4 ) an ACAT inhibitor ; [ 0795 ) 12 ) a CRP inhibitor; [0834 ] 5 ) an MTTP inhibitor; [0796 ] 13 ) a complement inhibitor, and [0835 ] 6 ) an anti - dyslipidemic anti - sense polynucleotide [0797 ] 14 ) an MMP inhibitor . or PNA ; [0798 ] 157 . The method of any one of embodiments 150 [0836 ] 7) an LXR agonist ; to 156 , wherein two or more , or any combination , of the [0837 ] 8 ) an antioxidant ; therapeutic agents in the following group are administered [ 0838 ] 9 ) a neuroprotector; at least in intermediate AMD ( e . g ., to treat or slow the [0839 ] 10 ) an anti - inflammatory agent; progression of non - centralGA , and / or to prevent or delay [ 0840 ] 11 ) an immunosuppressant; the onset of central GA and /or neovascular AMD ) : 10841 ) 12 ) a CRP inhibitor; [0799 ] 1 ) an apolipoprotein mimetic ; [0842 ] 13 ) a complement inhibitor ; and [ 0800 ] 2 ) a statin ; 0843 ] 14 ) an anti -angiogenic agent. [ 0801] 3 ) a fibrate ; [0844 ] 160 . The method of any one of embodiments 150 0802 ] 4 ) a GLP - 1 receptor agonist ; to 159 , wherein the following plurality of therapeutic [0803 ] 5 ) an MTTP inhibitor; agents is administered , concurrently or sequentially and in [ 0804 ] 6 ) an anti- dyslipidemic anti - sense polynucleotide the same composition or in different compositions, at least or PNA ; in early AMD : [ 0805 ] 7 ) a CETP inhibitor; [0845 ] 1 ) two or more anti -dyslipidemic agents ( e . g ., an [0806 ] 8 ) an LXR agonist ; apolipoprotein mimetic ( e. g . , an apoA - I mimetic and / or an [0807 ] 9 ) an antioxidant; apoE mimetic ), a statin and /or a fibrate ); or [ 0808 ] 10 ) a neuroprotector; [0846 ] 2 ) an anti- dyslipidemic agent ( e . g ., a statin ; a statin [ 0809 ] 11 ) an apoptosis inhibitor and / or a necrosis inhibi and an apolipoprotein mimetic [ e . g . , an apoA - I mimetic tor ; and /or an apoE mimetic ]; a statin and a fibrate ; a statin and [ 0810 ) 12 ) an anti -inflammatory agent ; a GLP - 1 receptor agonist; a statin and an MTTP inhibitor [0811 ] 13 ) a CRP inhibitor ; ?e . g . , miRNA - 30c ] ; or a statin and a CETP inhibitor ) and an [0812 ] 14 ) a complement inhibitor ; and antioxidant (e . g. , vitamins , saffron carotenoids and /or zinc ); 108131 15 ) an MMP inhibitor. or [ 0814 ] 158 . The method of any one of embodiments 150 [ 0847 ] 3 ) an anti - dyslipidemic agent ( e . g . , a statin ; an to 157 , wherein two or more , or any combination , of the MTTP inhibitor [ e . g ., miRNA -30c ] ; a statin and a fibrate ; a therapeutic agents in the following group are administered statin and a GLP - 1 receptor agonist; or a fibrate and a GLP - 1 US 2018 /0296525 A1 Oct . 18 , 2018 65 receptor agonist ) and an anti -inflammatory agent ( e. g ., an ment inhibitor ( e .g . , lampalizumab , zinc , TT30 , a C3 inhibi NSAID , such as bromfenac or a coxib ) ; or tor and /or an anti -C5 agent) ; or [0848 ] 4 ) an anti- dyslipidemic agent ( e . g ., a statin and /or [ 0859 ] 7 ) an anti -dyslipidemic agent ( e . g . , a statin , an an MTTP inhibitor [ e . g . ,miRNA - 30c ] ) , an antioxidant ( e . g ., LXR agonist, and / or an apolipoprotein mimetic [ e . g ., an vitamins, saffron carotenoids and / or zinc ) , and an anti apoA - I mimetic and /or an apoE mimetic ] ) , and an apoptosis inflammatory agent ( e . g ., an NSAID , such as bromfenac or inhibitor ( e . g . , an NRTI ) and / or a necrosis inhibitor ( e . g . , a a coxib ); or necrostatin ) ; or [ 0849 ] 5 ) an anti- dyslipidemic agent (e .g . , a statin and /or [0860 ] 8 ) an anti - dyslipidemic agent ( e . g ., a statin , an a GLP - 1 receptor agonist) , an antioxidant ( e . g . , vitamins, LXR agonist, and/ or an apolipoprotein mimetic [ e . g ., an saffron carotenoids and /or zinc ) , and an MMP inhibitor ( e . g ., apo A - I mimetic and/ or an apoE mimetic ] ) , a complement a “ mastat” ) ; or inhibitor ( e . g . , lampalizumab , zinc , TT30 , a C3 inhibitor [ 0850 ] 6 ) an anti- dyslipidemic agent ( e . g ., a statin ), an and /or an anti -CS agent) , and an apoptosis inhibitor ( e. g ., an antioxidant ( e . g ., vitamins , saffron carotenoids and / or zinc ) , NRTI) and / or a necrosis inhibitor ( e . g . , a necrostatin ) ; or and a neuroprotector ( e . g . , glatiramer acetate ) ; or [0861 ] 9 ) an anti- dyslipidemic agent ( e . g ., a statin and /or an apolipoprotein mimetic [ e. g ., an apoA -I mimetic and /or [ 0851] 7 ) an anti - dyslipidemic agent ( e . g ., a statin ) , an an apoE mimetic ]) , an antioxidant (e . g ., vitamins, saffron antioxidant ( e . g . , vitamins, saffron carotenoids and / or zinc ) , carotenoids and /or zinc ) , and a neuroprotector ( e . g ., CNTF a neuroprotector ( e . g . , glatiramer acetate ), and an anti and /or glatiramer acetate ); or inflammatory agent ( e . g . , an NSAID , such as bromfenac or [0862 ] 10 ) an anti -dyslipidemic agent (e .g ., a statin and /or a coxib ) . an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and /or [ 0852] 161. The method of any one of embodiments 150 an apoE mimetic ] ) , an antioxidant ( e . g . , vitamins, saffron to 160 , wherein the following plurality of therapeutic carotenoids and / or zinc ) , an anti - inflammatory agent ( e . g ., agents is administered , concurrently or sequentially and in an NSAID , such as bromfenac or a coxib ) , and a neuropro the same composition or in different compositions, at least tector (e .g . , CNTF and /or glatiramer acetate ). in intermediate AMD : [0863 ] 162. The method of any one of embodiments 150 [0853 ] 1 ) two or more anti -dyslipidemic agents ( e . g . , a to 161 , wherein the following plurality of therapeutic statin and an apolipoprotein mimetic [ e . g . , an apoA - I agents is administered , concurrently or sequentially and in mimetic and /or an apoE mimetic ] ; a statin and a fibrate ; or the same composition or in different compositions, at least a statin , a fibrate and a GLP - 1 receptor agonist ); or in advanced atrophic AMD to treat or slow the progres [ 0854 ] 2 ) an anti -dyslipidemic agent ( e . g ., a statin ; an sion of GA (including central GA ) , and /or to prevent or apolipoprotein mimetic ( e . g . , an apoA - I mimetic and / or an delay the onset of neovascular AMD : apoE mimetic ] ; an LXR agonist ; a statin and an LXR [0864 ] 1 ) a CRP inhibitor (e . g ., a statin or a thiazolidin agonist; an LXR agonist and a GLP - 1 receptor agonist; an edione ) and a complement inhibitor ( e . g . , lampalizumab , LXR agonist and a CETP inhibitor ; an apolipoprotein zinc , TT30 , a C3 inhibitor and / or an anti -C5 agent ) ; or mimetic ?e . g . , an apoA - I mimetic and/ or an apoE mimetic ] , 08651 2 ) an anti -dyslipidemic agent ( e . g ., an apolipopro an LXR agonist and an MTTP inhibitor ?e . g . , miRNA -30c ] ; tein mimetic ?e . g ., an apoA - I mimetic and /or an apoE or an apolipoprotein mimetic [ e. g ., an apoA - I mimetic mimetic ) , a statin and / or an LXR agonist ), and a comple and / or an apoE mimetic ], an LXR agonist and an anti ment inhibitor (e . g. , lampalizumab , zinc , TT30 , a C3 inhibi dyslipidemic anti -sense polynucleotide or PNA ) and an tor and /or an anti -CS agent ) ; or antioxidant ( e . g . , vitamins , saffron carotenoids and / or zinc ) ; [0866 ] 3 ) an anti -dyslipidemic agent ( e. g ., an apolipopro or tein mimetic [ e . g ., an apoA - I mimetic and / or an apoE [0855 ] 3 ) an anti- dyslipidemic agent (e .g ., a statin ; an mimetic ), a statin and /or an LXR agonist ), and an antioxi apolipoprotein mimetic [ e . g ., an apo A - I mimetic and / or an dant ( e . g ., vitamins, saffron carotenoids and /or zinc ) ; or apoE mimetic ] ; a GLP - 1 receptor agonist ; an anti - dyslipi [0867 ] 4 ) an anti - dyslipidemic agent ( e . g ., an apolipopro demic anti- sense polynucleotide or PNA ; a CETP inhibitor; tein mimetic [ e . g ., an apoA - I mimetic and /or an apoE an LXR agonist ; an LXR agonist and a statin ; an LXR mimetic ) , a statin and / or an LXR agonist ) and an anti agonist and a fibrate ; or an LXR agonist and an anti inflammatory agent ( e . g ., an apo A - I mimetic [ e . g ., L -4F ], a dyslipidemic anti - sense polynucleotide or PNA ) and an corticosteroid [ e . g . , fluocinolone acetonide ] and /or an anti - inflammatory agent ( e . g . , an NSAID , such as bromfenac NSAID ( e .g ., bromfenac or a coxib ]) ; or OLor a coxib ) ; or [ 0868 ] 5 ) an anti - dyslipidemic agent ( e . g . , an apolipopro [ 0856 ] 4 ) an anti -dyslipidemic agent ( e . g ., a statin , an tein mimetic [ e . g . , an apoA - I mimetic and /or an apoE LXR agonist and / or an apolipoprotein mimetic [ e . g ., an mimetic ), a statin and /or an LXR agonist ), an antioxidant apoA - I mimetic and / or an apoE mimetic ] ) , an antioxidant ( e . g . , vitamins , saffron carotenoids and / or zinc ) , and an ( e . g . , vitamins, saffron carotenoids and /or zinc ) , and an anti- inflammatory agent ( e . g . , an apoA - I mimetic [ e . g . , anti - inflammatory agent ( e . g . , an NSAID , such as bromfenac L -4F ] , a corticosteroid [ e . g . , fluocinolone acetonide ] and / or or a coxib ) ; or an NSAID ( e . g . , bromfenac or a coxib ]) ; or [0857 ] 5 ) an anti -dyslipidemic agent ( e . g . , a statin , an [0869 ] 6 ) an anti -dyslipidemic agent ( e. g ., an apolipopro LXR agonist and /or an apolipoprotein mimetic [ e . g . , an tein mimetic [ e . g ., an apoA - I mimetic and/ or an apoE apo A - I mimetic and / or an apoE mimetic ] ) , an anti - inflam mimetic ], a statin and / or an LXR agonist) , an antioxidant matory agent ( e . g ., an NSAID , such as bromfenac or a ( e . g . , vitamins, saffron carotenoids and /or zinc) , and a CRP coxib ) , and an MMP inhibitor ( e . g . , a " mastat” ) ; or inhibitor ( e . g . , a statin or a thiazolidinedione ); or [0858 ] 6 ) an anti -dyslipidemic agent (e . g. , a statin , an [0870 ] 7 ) an anti -dyslipidemic agent ( e. g ., an apolipopro LXR agonist , and /or an apolipoprotein mimetic [ e . g . , an tein mimetic [ e .g . , an apoA - I mimetic and /or an apoE apo A - I mimetic and /or an apoE mimetic ]) and a comple - mimetic ] , a statin and /or an LXR agonist ) , an antioxidant US 2018 /0296525 A1 Oct. 18 , 2018 66

( e . g ., vitamins , saffron carotenoids and / or zinc ) , and a neovascular AMD (including types 1 , 2 and /or 3 neovas complement inhibitor (e . g. , lampalizumab , zinc , TT30 , a C3 cularization ), and / or to prevent or delay the onset of inhibitor and / or an anti - CS agent) ; or neovascular AMD : [ 0871 ] 8 ) an anti- dyslipidemic agent ( e . g ., an apolipopro [0882 ] 1 ) an anti- dyslipidemic agent ( e . g . , an apolipopro tein mimetic [ e . g . , an apoA - I mimetic and / or an apoE tein mimetic [ e . g ., an apoA - I mimetic and/ or an apoE mimetic ), a statin and/ or an LXR agonist) , an anti -inflam mimetic ) , a statin and /or an LXR agonist) and an anti matory agent ( e . g ., an apoA - I mimetic [e . g ., L -4F ], a cor angiogenic agent ( e . g . , an anti -VEGF /VEGFR agent and /or ticosteroid [e . g ., fluocinolone acetonide ] and /or an NSAID an anti - PDGF/ PDGFR agent) ; or [ e . g ., bromfenac or a coxib ] ) , and a complement inhibitor [ 0883 ] 2 ) an anti - inflammatory agent ( e . g ., an apoA - I ( e . g . , lampalizumab , zinc, TT30 , a C3 inhibitor and /or an mimetic ?e . g ., L - 4F ], an NSAID ( e . g . , bromfenac or a coxib ] anti - CS agent) ; or and / or a corticosteroid [ e . g ., triamcinolone acetonide ] ) or an [ 0872 ] 9 ) a CRP inhibitor ( e . g . , a statin or a thiazolidin immunosuppressant ( e . g ., an IL - 2 inhibitor and / or a TNF - a edione ), an anti - inflammatory agent ( e. g . , an apoA - I inhibitor ) , and an anti - angiogenic agent ( e . g ., an anti -VEGF / mimetic [ e . g ., L - 4F ], a corticosteroid [ e . g ., fluocinolone VEGFR agent and /or an anti - PDGF /PDGFR agent ) ; or acetonide ) and / or an NSAID ( e . g . , bromfenac or a coxib ] ) , [0884 ] 3 ) an anti -dyslipidemic agent ( e . g . , an apolipopro and a complement inhibitor ( e . g . , lampalizumab , zinc , TT30 , tein mimetic [ e . g . , an apoA - I mimetic and/ or an apoE a C3 inhibitor and / or an anti -C5 agent“ ) ,; or mimetic ] , a statin and / or an LXR agonist ) , an anti - inflam [ 0873 ] 10 ) an anti- dyslipidemic agent ( e . g . , an apolipo matory agent ( e. g. , an apo A - I mimetic [ e. g. , L -4F ] , an protein mimetic [ e. g . , an apoA - I mimetic and / or an apoE NSAID [ e . g . , bromfenac or a coxib ) and /or a corticosteroid mimetic ) , a statin and /or an LXR agonist ), and an apoptosis [ e. g. , triamcinolone acetonide] ) or an immunosuppressant inhibitor ( e . g . , an NRTI) and / or a necrosis inhibitor ( e . g ., a ( e . g . , an IL - 2 inhibitor and /or a TNF - a inhibitor ) , and an necrostatin ); or anti -angiogenic agent ( e . g . , an anti -VEGF /VEGFR agent [0874 ] 11) an anti -dyslipidemic agent ( e . g ., an apolipo and / or an anti - PDGF /PDGFR agent) ; or protein mimetic ( e. g . , an apoA - I mimetic and /or an apoE [0885 ] 4 ) an anti -dyslipidemic agent (e .g ., an apolipopro mimetic ), a statin and / or an LXR agonist ) , a complement tein mimetic [ e . g . , an apoA - I mimetic and /or an apoE inhibitor (e . g ., lampalizumab , zinc , TT30 , a C3 inhibitor mimetic ) , a statin and / or an LXR agonist ) , an antioxidant and/ or an anti- C5 agent) , and an apoptosis inhibitor ( e . g . , an ( e . g . , vitamins, saffron carotenoids and /or zinc) , and an NRTI) and /or a necrosis inhibitor ( e . g ., a necrostatin ) ; or anti -angiogenic agent ( e. g . , an anti -VEGF /VEGFR agent [ 0875 ] 12 ) an anti- dyslipidemic agent ( e . g . , an apolipo and / or an anti- PDGF / PDGFR agent ); or protein mimetic [ e . g . , an apoA - I mimetic and / or an apoE [0886 ] 5 ) a neuroprotector (e .g ., CNTF and /or glatiramer mimetic ) , a statin and /or an LXR agonist ) and a neuropro acetate ) and an anti - angiogenic agent ( e . g . , an anti -VEGF / tector ( e . g . , CNTF and /or glatiramer acetate ) ; or VEGFR agent and /or an anti- PDGF / PDGFR agent) ; or [0876 ] 13 ) a neuroprotector ( e . g ., CNTF and / or glatiramer [ 0887 ] 6 ) an anti- dyslipidemic agent ( e . g ., an apolipopro acetate ) and a complement inhibitor ( e . g ., lampalizumab , tein mimetic ?e . g . , an apoA - I mimetic and /or an apoE zinc, TT30 , a C3 inhibitor and /or an anti- C5 agent) ; or mimetic ] , a statin and /or an LXR agonist) , a neuroprotector [ 0877 ] 14 ) an anti- dyslipidemic agent ( e . g . , an apolipo ( e . g ., CNTF and / or glatiramer acetate ) , and an anti - angio protein mimetic [ e . g . , an apoA - I mimetic and / or an apoE genic agent ( e . g . , an anti - VEGF /VEGFR agent and /or an mimetic ) , a statin and /or an LXR agonist ) , a neuroprotector anti - PDGF / PDGFR agent) ; or ( e . g . , CNTF and /or glatiramer acetate ) , and a complement [0888 ] 7 ) a complement inhibitor ( e. g ., a C3 inhibitor inhibitor (e . g . , lampalizumab , zinc , TT30 , a C3 inhibitor ?e . g ., CB - 2782 ] , an anti -C5 agent [ e . g . , ARC1905 or and / or an anti -C5 agent ) ; or LFG316 ] and / or a CFD inhibitor [ e . g . , lampalizumab ] ) and [ 0878 ] 15 ) an anti -dyslipidemic agent ( e . g . , an apolipo an anti -angiogenic agent ( e . g ., an anti - VEGF/ VEGFR agent protein mimetic [e .g ., an apoA - I mimetic and /or an apoE and / or an anti -PDGF / PDGFR agent) ; or mimetic ) , a statin and / or an LXR agonist ) , an antioxidant [ 0889 ] 8 ) an anti - dyslipidemic agent ( e . g ., an apolipopro ( e . g . , vitamins , saffron carotenoids and /or zinc ) , and a neu tein mimetic ?e . g ., an apoA - I mimetic and / or an apoE roprotector ( e . g ., CNTF and /or glatiramer acetate ); or mimetic ), a statin and /or an LXR agonist ), a complement 10879 ] 16 ) an antioxidant ( e . g ., vitamins , saffron carote inhibitor ( e . g . , a C3 inhibitor [ e . g ., CB -2782 ] , an anti - CS noids and /or zinc ), a neuroprotector ( e . g . , CNTF and /or agent [ e . g . , ARC1905 or LFG316 ] and/ or a CFD inhibitor glatiramer acetate ) , and a complement inhibitor ( e . g . , lam [ e . g ., lampalizumab ] ) , and an anti -angiogenic agent ( e . g ., an palizumab , zinc , TT30 , a C3 inhibitor and / or an anti - C5 anti- VEGF /VEGFR agent and/ or an anti- PDGF/ PDGFR agent ) ; or agent ); or [ 0880 ] 17) an anti -dyslipidemic agent ( e . g . , an apolipo [ 0890 ] 9 ) a neuroprotector ( e . g . , CNTF and / or glatiramer protein mimetic [e . g. , an apo A -I mimetic and /or an apoE acetate ) , a complement inhibitor ( e . g . , a C3 inhibitor ?e . g . , mimetic ], a statin and / or an LXR agonist ) , an antioxidant CB - 2782 ) , an anti -CS agent ?e . g . , ARC1905 or LFG3161 ( e . g . , vitamins, saffron carotenoids and / or zinc ) , a neuropro and /or a CFD inhibitor [ e . g ., lampalizumab ] ) , and an anti tector (e . g ., CNTF and / or glatiramer acetate ) , and a comple angiogenic agent (e . g ., an anti -VEGF / VEGFR agent and /or ment inhibitor (e . g ., lampalizumab , zinc, TT30 , a C3 inhibi an anti -PDGF / PDGFR agent) ; or tor and /or an anti - CS agent ) . [ 0891 ] 10 ) an anti - dyslipidemic agent ( e . g ., an apolipo [0881 ] 163. The method of any one of embodiments 150 protein mimetic [ e . g ., an apoA - I mimetic and /or an apoE to 162, wherein the following plurality of therapeutic mimetic ], a statin and /or an LXR agonist) , a neuroprotector agents is administered , concurrently or sequentially and in ( e . g ., CNTF and / or glatiramer acetate ), a complement the same composition or in different compositions , at least inhibitor (e .g . , a C3 inhibitor [ e .g ., CB -2782 ] , an anti- CS in advanced AMD to treat or slow the progression of agent [ e. g ., ARC1905 or LFG316 ] and /or a CFD inhibitor US 2018 /0296525 A1 Oct . 18 , 2018 67

[ e. g ., lampalizumab ]) , and an anti -angiogenic agent ( e. g ., an an apoE mimetic ]) is administered at least in early AMD anti -VEGF / VEGFR agent and /or an anti - PDGF/ PDGFR and /or intermediate AMD , an antioxidant ( e . g . , vitamins , agent) ; or saffron carotenoids and / or zinc ) is administered at least in [ 0892 ] 11) a neuroprotector ( e .g ., CNTF and /or glatiramer early AMD and / or intermediate AMD , a complement inhibi acetate ) , an anti- inflammatory agent ( e . g ., an apoA - I tor ( e . g . , lampalizumab , zinc , TT30 , a C3 inhibitor and / or a mimetic [e . g. , L -4F ], an NSAID ( e. g ., bromfenac or a coxib ] C5 inhibitor ) optionally is administered at least in interme and / or a corticosteroid [ e . g . , triamcinolone acetonide ] ) or an diate AMD and /or advanced AMD , and an anti - angiogenic immunosuppressant ( e . g . , an IL - 2 inhibitor and / or a TNF - a agent ( e . g . , an anti - VEGF / VEGFR agent and / or an anti inhibitor ), and an anti -angiogenic agent ( e . g . , an anti -VEGF PDGF /PDGFR agent) is administered at least in advanced VEGFR agent and /or an anti - PDGF /PDGFR agent ) ; or AMD to treat neovascular AMD ( including types 1 , 2 and / or [0893 ] 12 ) an anti- dyslipidemic agent (e . g. , an apolipo 3 NV ) ; or protein mimetic [ e . g . , an apoA - I mimetic and / or an apoE [0900 ) 6 ) an anti- dyslipidemic agent ( e . g ., a statin and /or mimetic ) , a statin and / or an LXR agonist ) , a neuroprotector an apolipoprotein mimetic [ e. g ., an apoA - I mimetic and /or ( e . g . , CNTF and / or glatiramer acetate ) , an anti - inflammatory an apoE mimetic ]) is administered at least in early AMD agent (e . g. , an apo A -I mimetic [ e. g ., L -4F ], an NSAID [ e. g ., and / or intermediate AMD , an antioxidant ( e . g . , vitamins, bromfenac or a coxib ) and / or a corticosteroid ?e . g . , triam saffron carotenoids and /or zinc ) optionally is administered at cinolone acetonide ] ) or an immunosuppressant ( e . g . , an IL - 2 least in early AMD and /or intermediate AMD , an anti inhibitor and /or a TNF - a inhibitor ), and an anti - angiogenic inflammatory agent ( e .g ., an apo A - I mimetic [ e. g ., L -4F ], a agent ( e . g ., an anti - VEGF /VEGFR agent and / or an anti corticosteroid [ e .g ., triamcinolone acetonide ] and /or an PDGF/ PDGFR agent ) . NSAID ( e . g ., bromfenac or a coxib ] ) is administered at least 10894 164 . The method of any one of embodiments 150 in intermediate AMD and / or advanced AMD , and an anti to 163, wherein : angiogenic agent (e . g . , an anti - VEGF /VEGFR agent and /or [0895 ] 1 ) an anti - dyslipidemic agent ( e .g . , a statin and /or an anti - PDGF /PDGFR agent) is administered at least in an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and / or advanced AMD to treat neovascular AMD ( including types an apoE mimetic ]) is administered at least in early AMD 1 , 2 and /or 3 NV ) . and / or intermediate AMD , and an antioxidant ( e . g . , vita [0901 ] 165 . A method of treating an eye disorder , com mins, saffron carotenoids and/ or zinc ) and /or an anti - inflam prising administering to a subject in need of treatment a matory agent ( e . g . , an apo A - I mimetic [ e . g . , L -4F ] , a cor therapeutically effective amount of an apolipoprotein ticosteroid ( e . g ., triamcinolone acetonide ) and /or an NSAID (apo ) mimetic or a pharmaceutically acceptable salt [ e . g . , bromfenac or a coxib ]) are administered at least in thereof or/ and a therapeutically effective amount of a early AMD and / or intermediate AMD ; or statin or a pharmaceutically acceptable salt thereof, and a [0896 ] 2 ) an anti -dyslipidemic agent ( e .g ., a statin and /or therapeutically effective amount of one additional thera an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and / or peutic agent selected from the therapeutic agents listed in an apoE mimetic ]) is administered at least in early AMD Table 2 . and / or intermediate AMD , and a neuroprotector ( e . g ., glati [0902 ] 166 . The method of embodiment 165 , wherein the ramer acetate , an antioxidant and /or a neurotrophic factor) apo mimetic is an apoA - I mimetic (e . g. , L -4F or D -4F or and /or an apoptosis inhibitor ( e. g ., an NRTI) and / or a a salt thereof) or an apoE mimetic ( e . g . , AEM - 28 - 14 or a necrosis inhibitor ( e . g . , a necrostatin ) are administered at salt thereof) . least in intermediate AMD and / or advanced AMD to treat 109031. 167 . The method of embodiment 165 or 166 , geographic atrophy ( including non -central GA and /or cen wherein the statin is atorvastatin or a salt thereof or tral GA ) ; or simvastatin . [0897 ] 3 ) an anti -dyslipidemic agent (e . g. , a statin and /or [0904 ] 168 . The method of any one of embodiments 165 an apolipoprotein mimetic [ e . g . , an apoA - I mimetic and / or to 167 , wherein the one additional therapeutic agent is an apoE mimetic ]) is administered at least in early AMD each one of the therapeutic agents listed in Table 2 in a and / or intermediate AMD , a neuroprotector ( e . g ., glatiramer plurality of different combinations of an apo mimetic acetate , an antioxidant and / or a neurotrophic factor ) and / or or/ and a statin and one additional therapeutic agent . an apoptosis inhibitor ( e . g ., an NRTI) and / or a necrosis [0905 ] 169. The method of any one of embodiments 165 inhibitor ( e . g ., a necrostatin ) are administered at least in to 168 , wherein the eye disorder is AMD . intermediate AMD and / or advanced AMD , and a comple ment inhibitor ( e . g ., lampalizumab , zinc , TT30 , a C3 inhibi XVI. EXAMPLES tor and /or a C5 inhibitor ) is administered at least in inter mediate AMD and /or advanced AMD to treat geographic [0906 ] The following examples are intended only to illus atrophy ( including non - central GA and / or central GA ) ; or trate the disclosure. Other assays, procedures , methodolo [ 0898 ] 4 ) an antioxidant ( e . g . , vitamins, saffron carote gies, techniques , conditions and reagents may alternatively noids and /or zinc ) is administered at least in early AMD be used as appropriate , and other studies may be conducted . and / or intermediate AMD , a complement inhibitor ( e . g . , lampalizumab , zinc , TT30 , a C3 inhibitor and / or a C5 Example 1 inhibitor ) is administered at least in intermediate AMD and / or advanced AMD , and an anti -angiogenic agent ( e . g . , Reduction of Lipid Deposits from Bruch ' s an anti -VEGF /VEGFR agent and /or an anti - PDGF/ PDGFR Membrane in Geriatric Monkeys by L - 4F agent ) is administered at least in advanced AMD to treat [0907 ] The macaque study was conducted according to neovascular AMD ( including types 1 , 2 and/ or 3 NV ) ; or accepted guidelines. Nine female geriatric macaques 0899 ] 5 ) an anti -dyslipidemic agent ( e . g . , a statin and / or (Macaca fascicularis , all more than 20 years of age ) with an apolipoprotein mimetic [ e . g ., an apoA - I mimetic and / or naturally occuring age - related maculopathy ( exhibiting age US 2018 /0296525 A1 Oct . 18 , 2018 related drusenoid macular changes /maculopathy resembling 70 % ethanol for 45 min . After being washed with deionized early AMD in humans ) were intravitreally injected with a water for 5 min , the specimens were treated with cholesterol sterile balanced salt solution (BSS ) of the apoA - I mimetic esterase ( 8 . 12 units /mL ) diluted in 0 . 1 M potassium phos L - 4F , AC - DWFKAFYDKVAEKFKEAF - NH , acetate salt phate buffer (PPB , pH 7 . 4 ) for 3 . 5 hr at 37° C . The (SEQ . ID . NO . 13 ) ( n = 7 ) , or a placebo ( a sterile BSS of specimens were then washed sequentially with PPB and scrambled L -4F [ SL - 4F ] having the same amino acids but in with phosphate buffered saline (PBS ) twice for 3 min , a non - functional order ) ( n = 2 ) . One eye per animal received followed by a wash with cold (4° C . ) PBS overnight. Filipin 6 monthly injections of the same escalating dosages of L - 4F staining was then performed with 250 ug /mL filipin (Sigma or scrambled L - 4F ( total of625 ug) in a 50 uL volume. The Aldrich Biochemie GmbH , Hamburg , Germany ) , diluted in second eye per animal was not injected and was just N , N - dimethylformamide (Merck Millipore , Darmstadt, Ger observed . The injected eye exhibited worse drusenoid many ) , for 60 min at RT with light shielding . The specimens changes than the uninjected eye per animal at baseline . Table were then washed sequentially with PBS and deionized 1 shows the dosing regimen used in the macaque study . water, mounted with a mounting solution (Mowiol® , Carl Roth GmbH , Karlsruhe , Germany ) , covered with a glass TABLE 1 cover slip , and examined using an inverted fluorescence microscope (DMI 6000 from Leica Microsystems, Wetzlar, Amount Injected Concentration Volume Germany ) . Filipin fluorescence was observed using a UV Day (ug ) (mg /mL ) Injected filter set ex * hem = 350 nm / 455 nm ) . As a negative control, cholesterol esterase was replaced by PBS , which prevented Placebo 25 0 .5 50 uL the release of cholesterol from cholesteryl ester and subse ( scrambled L -4F ) 50 1 . 0 one eye only quent binding by filipin . Semiquantitative analysis of fluo ( n = 2 ) 100 2 . 0 85 125 2. 5 rescence intensity of filipin at three separate regions of the 113 150 3. 0 BrM was done on three different slides from the same eye ( a 141 175 3 . 5 total of 9 different regions from each eye) . L - 4F 1 25 0. 5 50 uL ( n = 7 ) 50 1 . 0 one eye only [0911 ] Assays for immunohistochemistry of the mem 100 2. 0 brane attack complex MAC( , C5b - 9 ) and complement factor 125 2 . 5 D (CFD ) were performed identically except for employment 113 150 3 . 0 of monoclonal antibodies specific for each complement 141 175 3 . 5 component. Specimens were treated with 10 ug/ mL protease K ( Sigma - Aldrich Biochemie GmbH , Hamburg , Germany ) [ 0908 ] Clinical laboratory tests including serology, hemo in PBS for antigen retrieval for 30 min at RT. Subsequently grams and liver enzymes were conducted , and ophthalmic the sections were blocked with a solution of goat serum ( 5 % examinations were also performed , including fundus pho goat serum , 0 . 3 % Triton X - 100 in PBS ) for 60 min at RT. tographs, optical coherence tomography (OCT ) , intraocular The specimens were then reacted with a first antibody pressure testing and blood sampling . After 7 months, all against either C5b - 9 ( diluted 1 : 30 in PBS , mouse monoclo animals were sacrificed and eyes were immediately prepared nal antibody , Dako Deutschland GmbH , Hamburg , Ger for histology . Histochemistry was performed with oil red 0 many ) or complement factor D ( diluted 1 : 200 in PBS ,mouse for neutral lipids and filipin for esterified cholesterol. Immu monoclonal antibody , Santa Cruz Biotechnology , Dallas , nohistochemistry was performed against complement factor Tex . , USA ) overnight at 4° C . After being washed with PBS , D (CFD ) and the membrane attack complex (MAC , C5b - 9 ) , the specimens were reacted with a second antibody (diluted both being markers of activation of the alternative comple 1 : 200 in PBS , Alexa Fluor 488 anti -mouse , Life Technolo ment pathway . gies Deutschland GmbH , Darmstadt, Germany ) for 1 hr at [ 0909 ] For staining with oil red O (ORO ), specimens were 37° C . After the specimens were washed with PBS three treated with a 0. 3 % oil red O (Sigma - Aldrich Biochemie times , nucleus staining was conducted with DAPI ( 1 ug /mL , GmbH , Hamburg , Germany ) solution ( in 99 % isopropanol) Life Technologies GmbH , Darmstadt , Germany ) for 10 min . for 30 min at room temperature (RT ) , followed by immer The specimens then were washed with PBS three times , sion in a 60 % isopropanol solution for 12 min . After the mounted with anti -fade solution (Mowiol® , Carl Roth specimens were washed with deionized water for 3 min , GmbH , Karlsruhe , Germany ), and covered with a glass counter - staining was conducted with hematoxylin (Carl cover slip for microscopic examination . Fluorescence Roth GmbH , Karlsruhe , Germany ) . The specimens were microscopy was conducted using an inverted fluorescence then mounted with mounting solution (Aquatex from Merck microscope (DMI 6000 from Leica Microsystems, Wetzlar, Millipore, Darmstadt, Germany ), covered with a glass cover Germany ) and a filter set for dex / em = 470 nm / 525 nm . For slip (Menzel - Graeser GmbH ), and examined using a fully the semiquantitative analysis of fluorescence intensity of automated inverted light microscope for life science (DMI C 5b - 9 , 3 - 5 different regions in one slide were analyzed for 6000 from Leica Microsystems Wetzlar, Germany ) . Image 3 different slides from each eye ( a total of 9 - 15 different analysis was performed by grading the intensity of ORO regions from each eye ). For the semiquantitative analysis of staining (red color) of the Bruch ' s membrane (BrM ) with fluorescence intensity of complement factor D , 3 distinct scores ranging from 0 to 4 , according to a qualitative regions for each eye were evaluated . evaluation assessed in four different regions in two separate [ 0912 ] Both control animals injected with the placebo slices from each eye ( a total of 8 different regions from each ( scrambled L -4F ) exhibited in both eyes an intense and eye ) . Qualitative ORO staining scores at the BrM and the specific staining of the Bruch ' s membrane ( BrM ) and cho choroid : 0 = no staining ; 1 = + ; 2 = + + ; 3 = + + + ; 4 = + + + + . riocapillaris with oil red O for neutral lipids and filipin for [ 0910 ] For staining with filipin , specimens were washed esterified cholesterol. For example , staining with oil red O once with deionized water for 5 min and then treated with showed that in both control animals , a large amount of lipids US 2018 /0296525 A1 Oct . 18 , 2018 69 was present in and on the BrM . By contrast, in staining with [ 0917 ] In summary , the apoA - I mimetic L -4F functioned oil red O eyes injected with L - 4F exhibited a reduction of as an effective lipid scavenger and removed lipid deposits lipid deposits from the BrM by about 56 % after 6 months from the BrM in a monkey model of age - related maculopa compared to eyes injected with placebo . FIG . 2 shows the thy. Removal of lipid deposits from the BrM restored BrM scoring of staining of neutral lipids in and on the Bruch ' s integrity as examined by electron microscopy . In addition , membrane with oil red O (ORO ) in the injected eye and the downstream effects of lipid deposition such as local inflam fellow non - injected eye of macaques receiving 6 monthly mation were reduced , as demonstrated by the marked reduc intravitreal injections of L - 4F or placebo ( scrambled L -4F ) . tion of complement activation in eyes injected with L -4F . Semiquantitative evaluation of filipin fluorescence revealed a reduction of esterified cholesterol in the BrM by about Example 2 68 % in eyes injected with L - 4F compared to placebo injected eyes. FIG . 3 shows the intensity of staining of Phase I/ II Safety /Efficacy Studies of L -4F Alone esterified cholesterol in the Bruch ’ s membrane with filipin in the injected eye and the fellow non - injected eye of macaques [0918 ] Randomized , open - label, dose - escalation Phase receiving 6 monthly intravitreal injections of L -4F or pla I / II studies are conducted to evaluate the safety, tolerability , cebo ( scrambled L - 4F ) . pharmacokinetics and effective dose of L - 4F or a variant [ 0913] Through semiquantitative analysis of fluorescence ( e . g ., D -4F ) or a salt ( e . g . , acetate salt ) thereof administered intensity of the respective specific antibodies, eyes injected ( e . g . , by intravitreal injection ) to patients with AMD ( e . g ., with L - 4F exhibited a decreased level of MAC (C5b - 9 ) in intermediate -stage AMD ) . Soft drusen are a high -risk factor the BrM and the choriocapillaris by about 58 % and a for progression of AMD and are clinically well - recognized decreased level of complement factor D by about 41% lipid - rich sub - RPE - BL deposits that are hallmarks for AMD . compared to eyes injected with the scrambled peptide . FIG . The cumulative dose of L -4F until drusen reduction as well 4 shows the intensity of staining of the membrane attack the maximum tolerated dose provide important information complex (MAC , C5b - 9 ) in the Bruch ' s membrane and the about the optimum L - 4F dose ( s ) in other studies , including choriocapillaris in the injected eye and the fellow non those where L - 4F ( or a variant or salt thereof) is adminis injected eye of macaques receiving 6 monthly intravitreal tered in combination with one or more other therapeutic injections of L -4F or placebo (scrambled L - 4F ) . FIG . 5 agents ( e . g . , an anti - angiogenic agent or a complement shows the intensity of staining of complement factor D in the inhibitor) for the treatment of neovascular (wet ) AMD or injected eye and the fellow non - injected eye of macaques atrophic (dry ) AMD . receiving 6 monthly intravitreal injections of L - 4F or pla [0919 ] In Phase I/ II studies, L - 4F or a variant (e . g. , D -4F ) or a salt ( e . g . , acetate salt ) thereof is administered in a certain cebo ( scrambled L -4F ) . frequency ( e . g ., monthly or bimonthly ) by intravitreal injec [ 0914 ) Lipid deposition in the Bruch ' s membrane contrib tion into one eye in certain doses ( e . g ., escalating doses from utes to thickening of the BrM . Bruch ' s membrane thickness about 0 . 1 mg to about 1 . 5 mg) for a certain period of time was measured at the temporal outer macula of enucleated ( e . g ., about 6 , 9 or 12 months) . The other eye is not injected eyes examined by electron microscopy post -mortem . Eyes and serves as intra - individual control eye . Post - treatment injected with L - 4F exhibited reduction of BrM thickness evaluation is conducted up to , e . g . , about 12 months. Pri ( 1 . 31 um + SE 0 . 11 ) by about 24 % compared to eyes injected mary outcome measures include , e . g ., reduction of soft with placebo ( 1 .73 umuSE 0 .02 ) . FIG . 6 shows the thickness drusen ( e . g ., reduction of total drusen volume by about 30 % of the Bruch ' s membrane measured at the temporal outer as quantified by spectral domain optical coherence tomog macula in the injected eye and the fellow non - injected eye raphy (SDOCT ) and stability of or increase in quantitative of macaques receiving 6 monthly intravitreal injections of fundus autofluorescence (qAF ) intensity (time frame of, e. g . , L - 4F or placebo ( scrambled L -4F ) . about 15 months) . Secondary outcome measures include , [0915 ] L -4F had similar effects on the fellow non - injected e . g . , stability or improvement of vision , such as metamor eye as on the injected eye after 6 monthly intravitreal phopsia , dark adaptometry and best- corrected visual acuity injections ( see FIGS . 2 - 6 ) . Without intending to be bound by theory , L -4F intravitreally injected into one eye reached the (BCVA ) from baseline at, e. g . , about 9 and 15 months . BrM and from there could have entered the choriocapillaris and hence systemic circulation and ultimately the fellow Example 3 non - injected eye. Also without intending to be bound by theory, the magnitude of L - 4F ' s therapeutic effects in the Phase I / II Safety /Efficacy Studies of a Statin Alone fellow non - injected eye could have been due in part to the [0920 ] Randomized , open - label, dose - escalation Phase relatively small body weight of the macaques relative to eye I / II studies are conducted to evaluate the safety , tolerability , size and the primarily vegetarian diet of the macaques , pharmacokinetics and effective dose of a statin ( e . g ., ator which exhibited no atherosclerosis , a potential target for vastatin [ LIPITOR® ] or a salt [ e . g . , calcium salt ] thereof, or L - 4F in systemic circulation . simvastatin (ZOCOR® ] ) administered ( e . g ., by intravitreal [ 0916 ] L - 4F was well tolerated in all of the macaques , as injection or eye drop ) to patients with AMD ( e . g ., interme none of the macaques intravitreally injected with L - 4F diate - stage AMD ) . Soft drusen are a high - risk factor for experienced any significant adverse event or side effect. For progression of AMD and are clinically well- recognized example , 6 monthly intravitreal injections of L - 4F did not lipid - rich sub - RPE -BL deposits that are hallmarks for AMD . increase the blood level of high - sensitivity C - reactive pro The cumulative dose of the statin until drusen reduction as tein (hsCRP ) compared to the blood level of hsCRP on the well the maximum tolerated dose provide important infor day prior to the first injection of L - 4F . Circulating hsCRP, mation about the optimum statin dose ( s ) in other studies , which is mainly produced in the liver, is a non - specific including those where the statin or a salt thereof is admin marker for systemic inflammation . istered in combination with one or more other therapeutic US 2018 /0296525 A1 Oct. 18 , 2018 70 agents ( e .g ., an anti -angiogenic agent or a complement Goals include decreasing the dosage and the number of inhibitor ) for the treatment of neovascular AMD or atrophic injections of the anti- angiogenic agent required for curtail AMD . ing neovascularization . [0921 ] In Phase I /II studies , the statin or a salt thereof is Example 5 administered in a certain frequency ( e . g ., monthly intravit Phase II Efficacy Study of an Anti -Dyslipidemic real injection or daily eye drop ) into one eye in certain doses Agent in Combination with a Complement Inhibitor ( e . g . , escalating doses from about 100 ug to about 500 ug for [0923 ] A Phase II study is conducted to evaluate prelimi intravitreal injection or from about 10 ug to about 100 ug for nary and confirmatory efficacy of an anti -dyslipidemic agent eye drop ) for a certain period of time ( e . g ., about 6 , 9 or 12 ( e . g ., an apoA - I mimetic such as L - 4F or a salt thereof, or a months) . The other eye is not administered and serves as statin such as atorvastatin or a salt thereof ) thereof in intra - individual control eye . Post- treatment evaluation is combination with a complement inhibitor ( e . g ., a CFD conducted up to , e . g . , about 12 months . Primary outcome inhibitor such as lampalizumab , a C3 inhibitor such as measures include , e . g . , reduction of soft drusen ( e . g ., reduc CB - 2782 , or a C5 inhibitor such as ARC1905 [ ZIMURA® ] tion of total drusen volume by about 30 % ) as quantified by or LFG316 ) in patients who have intermediate - stage or SDOCT and stability of or increase in qAF intensity ( time advanced - stage atrophic ( dry ) AMD and exhibit non -central frame of, e . g ., about 15 months ) . Secondary outcome mea or central geographic atrophy (GA ) . The drugs are admin sures include , e . g . , stability or improvement of vision , such istered ( e . g ., by intravitreal injection ) in a certain frequency as metamorphopsia , dark adaptometry and BCVA from ( e . g ., monthly or bimonthly ) to assess their efficacy in baseline at, e . g . , about 9 and 15 months . slowing the progression of non -central or central GA ( e .g ., reduce the rate of GA progression , or reduce the GA lesion Example 4 area or size ) . Post - treatment evaluation is performed . The drugs are administered into the worse eye , and the other eye Phase II Efficacy Study of an Anti- Dyslipidemic is not administered and serves as intra - individual control Agent in Combination with an Anti- Angiogenic eye . Goals include decreasing the dosage and the number of Agent injections of the complement inhibitor required for slowing the progression of non -central or central GA . [ 0922 ] A Phase II study is conducted to evaluate prelimi [0924 ] It is understood that, while particular embodiments nary and confirmatory efficacy of an anti - dyslipidemic agent have been illustrated and described , various modifications ( e . g ., an apoA - I mimetic such as L - 4F or a salt thereof, or a may be made thereto and are contemplated herein . It is also statin such as atorvastatin or a salt thereof) in combination understood that the disclosure is not limited by the specific with an anti - angiogenic agent ( e . g . , an anti - VEGF agent examples provided herein . The description and illustration such as aflibercept [EYLEA® ], brolucizumab , bevacizumab of embodiments and examples of the disclosure herein are TAVASTIN® ] or ranibizumab [LUCENTIS 1 , or an anti not intended to be construed in a limiting sense . It is further PDGF agent such as E10030 [ FOVISTA® ]) in patients who understood that all aspects of the disclosure are not limited have neovascular (wet ) AMD . The drugs are administered to the specific depictions, configurations or relative propor ( e . g . , by intravitreal injection ) in a certain frequency ( e . g ., tions set forth herein , which may depend upon a variety of monthly or bimonthly ) until exudation from neovascular conditions and variables . Various modifications and varia ization ( e. g ., type 1 , 2 or 3 neovascularization ) stops. Post tions in form and detail of the embodiments and examples of treatment evaluation is performed . The drugs are adminis - the disclosure will be apparent to a person skilled in the art . tered into the worse eye , and the other eye is not It is therefore contemplated that the disclosure also covers administered and serves as intra - individual control eye . any and all such modifications , variations and equivalents .

SEQUENCE LISTING

< 160 > NUMBER OF SEQ ID NOS : 32 < 210 > SEQ ID NO 1 < 211 > LENGTH : 23 2 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term NH2 < 400 > SEQUENCE : 1 Cys Gly Val Leu Glu Ser Phe Lys Ala Ser Phe Leu Ser Ala Leu Glu 1 10 15 Glu Trp Thr Lys Lys Leu Gin 20

< 210 > SEQ ID NO 2 US 2018 /0296525 A1 Oct . 18, 2018

- continued < 211 > LENGTH : 16 < 212 > TYPE : PRT ? ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 400 > SEQUENCE : 2 Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu 10 15

< 210 > SEQ ID NO 3 < 211 > LENGTH : 16 TYPE : PRT < 213 > ORGANISM : Artificial Sequence FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 400 > SEQUENCE : 3 Asp Tri Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu 10 15

< 210 > SEQ ID NO 4 < 211 > LENGTH : 18 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence V 20? > FEATURE : < 223??? > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 400 > SEQUENCE : 4 Asp Tri Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu 10 15 Ala Phe

< 210 > SEQ ID NO 5 < 211 > LENGTH : 37 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < NNN220NNEPP > FEATURE : < 223WoWNA > OTHER INFORMATION : Description of Artificial Sequence : Synthetic polypeptide < 400 > SEQUENCE : 5 Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu 15 Ala Phe Pro Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys 20 25 30 Leu Lys Glu Ala Phe 35

< 210 > SEQ ID NO 6 < 211 > LENGTH : 37 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic polypeptide < 400 > SEQUENCE : 6 Asp Trp Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu 10 15 US 2018 /0296525 A1 Oct . 18, 2018

- continued Phe Phe Pro Asp Typ Leu Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys 20 25 30 Leu Lys Glu Phe Phe 35

< 210 > SEQ ID NO 7 < 211?? > LENGTH : 37 < 212 > TYPE : PRT < 213???? > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223??? > OTHER INFORMATION : Description of Artificial Sequence : Synthetic polypeptide < 400 > SEQUENCE : 7 Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu Lys Glu 10 15 Ala Phe Pro Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys 20 25 30 Leu Lys Glu Ala Phe 35

< 210 > SEQ ID NO 8 < 211 > LENGTH : 37 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220? > FEATURE : < 223??? > OTHER INFORMATION : Description of Artificial Sequence : Synthetic polypeptide < 400 > SEQUENCE : 8 Asp Lys Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Trp Ala Lys Glu 10 15 Ala Phe Pro Asp Lys Leu Lys Ala Phe Tyr Asp Lys Val Phe Glu Tri 20 25 30 Leu Lys Glu Ala Phe 35

< 210 > SEQ ID NO 9 < 211 > LENGTH : 37 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic polypeptide < 400 > SEQUENCE : 9 Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala Phe Lys Glu 10 15 Phe Leu Pro Asp Lys Trp Lys Ala Val Tyr Asp Lys Phe Ala Glu Ala 20 25 30 Phe Lys Glu Phe Leu 35

< 210 > SEQ ID NO 10 < 211 > LENGTH : 37 < 212 > TYPE : PRT V< 213 > ORGANISM : Artificial Sequence V< 220 > FEATURE : V< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic polypeptide < 400 > SEQUENCE : 10 US 2018 /0296525 A1 Oct . 18, 2018 73

- continued

Asp Tri Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu 15 Ala Phe Pro Asp Trp Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys 20 25 30 Phe Lys Glu Ala Phe 35

< 210 > SEQ ID NO 11 < 211 > LENGTH : 18 < 212 > TYPE : PRT < 213?? > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223?? > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES < 222 > LOCATION : ( 11 ) . . ( 11 ) < 223 > OTHER INFORMATION : Aib < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 17 ) . . ( 17 ) < 223 > OTHER INFORMATION : Aib < 400 > SEQUENCE : 11 Asp Tri Phe Lys Ala Phe Tyr Asp Lys Val Xaa Glu Lys Phe Lys Glu 10 15

Xaa Phe

< 210 > SEQ ID NO 12 < 211 > LENGTH : 18 < 212 > TYPE : PRT 13 > ORGANISM : Artificial Sequence < 220 > FEATURE : OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term Ac 20 > FEATURE : < 221 > NAME /KEY : MOD _ RES 2 > LOCATION : ( 11 ) . . ( 11 ) < 223 > OTHER INFORMATION : Aib < 220 > FEATURE : < 221 > NAME / KEY : MOD RES < 222 > LOCATION : ( 17 ) . . ( 17 ) < 223 > OTHER INFORMATION : Aib < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term NH2 < 400 > SEQUENCE : 12 Asp Tri Phe Lys Ala Phe Tyr Asp Lys Val Xaa Glu Lys Phe Lys Glu 10 15 Xaa Phe

< 210 > SEQ ID NO 13 < 211 > LENGTH : 18 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220M??? > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term Ac < 220????? > FEATURE : < 223 > OTHER INFORMATION : C - term NH2 < 400 > SEQUENCE : 13 US 2018 /0296525 A1 Oct . 18, 2018 |_ 74

- continued

Asp Tri Phe Lys Ala Phe Tyr Asp Lys Val Ala Glu Lys Phe Lys Glu 10 15

Ala Phe

< 210 > SEQ ID NO 14 < 211 > LENGTH : 2 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term quinoline - 2 - carbonyl < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : 23MOM > OTHER INFORMATION : C - term 2 , 6 - difluorophenoxymethylketone < 400 > SEQUENCE : 14 Val Asp

< 210 > SEQ ID NO 15 < 211 > LENGTH : 1 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term tert - butyloxycarbonyl < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES

? V LOCATION : ( 1 ) . . ( 1 )

? V OTHER INFORMATION : OMe modified residue

? V MO FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 15 Asp

< 210 > SEQ ID NO 16 11 > LENGTH : 3 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide V< 220 > FEATURE : V< 223 > OTHER INFORMATION : N - term benzyloxycarbonyl V< 220 > FEATURE : V< 221 > NAME / KEY : MOD _RES

V < 222M??? > LOCATION : ( 3 ) . . ( 3 ) V< 223 > OTHER INFORMATION : OMe modified residue

V < 220??? > FEATURE : V< 223 > OTHER INFORMATION : C - term NH2 < 400 > SEQUENCE : 16 Val Ala Asp

< 210 > SEQ ID NO 17 < 211 > LENGTH : 3 < 212 > TYPE : PRT US 2018 /0296525 A1 Oct . 18, 2018 75

- continued

V< 213 > ORGANISM : Artificial Sequence V< 220 > FEATURE : V< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term benzyloxycarbonyi < 220 > FEATURE : < 221 > NAME / KEY : MOD _RES < 222 > LOCATION : ( 3 ) . . ( 3 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 17 Val Ala Asp

< 210 > SEQ ID NO 18 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _RES < 222 > LOCATION : ( 4 ) . . ( 4 ) 23 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 18 Tyr Val Ala Asp

< 210 > SEQ ID NO 19 < 211 > LENGTH : 5 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term benzyloxycarbonyl 20 > FEATURE : < 221 > NAME /KEY : MOD _ RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME / KEY : MOD _RES < 222 > LOCATION : ( 5 ) . . ( 5 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 19 Val Asp Val Ala Asp

< 210 > SEQ ID NO 20 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term quinoline - 2 - carbonyl US 2018 /0296525 A1 Oct . 18, 2018

- continued < 220 > FEATURE : V 1 > NAME / KEY : MOD RES V LOCATION : ( 1 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term 2 , 6 - difluorophenoxymethylketone < 400 > SEQUENCE : 20 Asp Glu Val Asp

< 210 > SEQ ID NO 21 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : ? 3 > OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES ? LOCATION : ( 1 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES 22 > LOCATION : ( 4 ) . . ( 4 ) ? > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 21 Asp Glu Val Asp

< 210 > SEQ ID NO 22 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term benzyloxycarbonyi < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES < 222 > LOCATION : ( 1 ) . . ( 1 ) < 223 > OTHER INFORMATION : OMe modified residue 20 > FEATURE : < 221 > NAME / KEY : MOD _RES > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 22 Asp Gln Met Asp

< 210 > SEQ ID NO 23 V< 211 > LENGTH : 4

V < 212M??? > TYPE : PRT V< 213 > ORGANISM : Artificial Sequence

V < 220??? > FEATURE : V< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide US 2018 /0296525 A1 Oct . 18, 2018 77

- continued < 220 > FEATURE : OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue 20 > FEATURE : < 221 > NAME / KEY : MOD _RES > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 23 Leu Glu Val Asp

< 210 > SEQ ID NO 24 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 24 Trp Glu His Asp

< 210 > SEQ ID NO 25 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 25 Val Glu Ile Asp

< 210 > SEQ ID NO 26 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 2 20 > FEATURE : US 2018 /0296525 A1 Oct . 18, 2018

- continued < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term quinoline - 2 - carbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue 20 > FEATURE : < 223 > OTHER INFORMATION : C - term 2 , 6 - difluorophenoxymethylketone < 400 > SEQUENCE : 26 Ile Glu Thr Asp

< 210 > SEQ ID NO 27 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : 23 > OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES 22 > LOCATION : ( 2 ) . . ( 2 ) ? 3 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 27 Ile Glu Thr Asp

< 210 > SEQ ID NO 28 < 211 > LENGTH : 4 < 212 > TYPE : PRT 3 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223NNPP > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term quinoline - 2 - carbonyl 20 > FEATURE : < 221 > NAME / KEY : MOD _RES > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue 20 > FEATURE : < 221 > NAME / KEY : MOD _RES < 222 > LOCATION : ( 4 ) . . ( 4 ) 3 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term 2 , 6 - difluorophenoxymethylketone < 400 > SEQUENCE : 28 Leu Glu His Asp

< 210 > SEQ ID NO 29 < 211 > LENGTH : 4 < 212 > TYPE : PRT US 2018 /0296525 A1 Oct . 18, 2018 79

- continued

V< 213 > ORGANISM : Artificial Sequence V< 220 > FEATURE : V< 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term benzyloxycarbonyi < 220 > FEATURE : < 221 > NAME / KEY : MOD _RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 29 Leu Glu His Asp 1

< 210 > SEQ ID NO 30 < 211 > LENGTH : 4 < 212 > TYPE : PRT 13 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 2 ) . . ( 2 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue 20 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 30 Ala Glu Val Asp

< 210 > SEQ ID NO 31 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : 23 > OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME /KEY : MOD _ RES < 222 > LOCATION : ( 4 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 31 Ala Thr Ala Asp

< 210 > SEQ ID NO 32 < 211 > LENGTH : 4 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 2 20 > FEATURE : US 2018 /0296525 A1 Oct . 18, 2018 80

- continued < 223 > OTHER INFORMATION : Description of Artificial Sequence : Synthetic peptide < 220 > FEATURE : < 223 > OTHER INFORMATION : N - term benzyloxycarbonyl < 220 > FEATURE : < 221 > NAME / KEY : MOD _ RES < 222 > LOCATION : ( 2 ) . . ( 4 ) < 223 > OTHER INFORMATION : OMe modified residue < 220 > FEATURE : < 223 > OTHER INFORMATION : C - term fluoromethylketone < 400 > SEQUENCE : 32 Leu Glu Glu Asp

1 . A method of treating age - related macular degeneration one , two , three , four or more times for the entire treatment ( AMD ) , comprising administering locally a therapeutically regimen. effective amount of a statin or a pharmaceutically acceptable 14 . The method of claim 1 , wherein the statin is admin salt thereof to , into , in or around the eye of a subject in need istered only locally for the entire treatment regimen . of treatment. 15 . (canceled ) 2 . The method of claim 1 , wherein the statin is selected 16 . (canceled ) from atorvastatin , cerivastatin , fluvastatin , mevastatin , 17 . The method of claim 1 ,wherein the treatment regimen monacolins, lovastatin , pitavastatin , pravastatin , rosuvasta with the statin lasts for about 6 - 12 months , 12 - 18 months , tin , simvastatin , and salts and combinations thereof. 18 - 24 months , 2 - 3 years or longer. 3 . ( canceled ) 18 . The method of claim 1 , wherein the statin is admin 4 . The method of claim 2 , wherein the statin comprises , or istered at least in the advanced stage of AMD . is , atorvastatin or a salt thereof, and /or simvastatin . 19 . The method of claim 1 , wherein the statin is admin 5 . The method of claim 1 , wherein the statin is adminis - istered at least in the intermediate stage of AMD . tered locally by eye drop , injection or implant. 20 . The method of claim 1 , wherein the statin is admin 6 . The method of claim 1 , wherein the statin is adminis istered at least in the early stage of AMD . tered locally in a dose of about 10 -500 ug , 50 - 500 ug 21 . (canceled ) 100 - 500 ug , 10 - 50 ug, 50 - 100 ug , 100 - 200 ug , 200 - 300 ug , 22 . The method of claim 1 , wherein the statin is admin 300 -400 ug or 400 -500 ug per administration ( e . g . , by eye istered at least prior to signs of AMD to prevent or delay the drop or injection ) onset of AMD . 7 . The method of claim 1 , wherein the statin is adminis 23 - 26 . ( canceled ) tered locally in a total dose of about 0 . 1 or 0 . 3 - 15 mg, 0 . 5 27 . The method of claim 1 , further comprising adminis or 1 - 10 mg, 0 . 1 or 0 . 3 - 1 mg, 1 - 5 mg, 5 - 10 mg or 10 - 15 mg tering one or more additional therapeutic agents . over a period of about 1 month . 28 . The method of claim 27 , wherein the one or more 8 . The method of claim 1 , wherein the statin is adminis additional therapeutic agents are selected from anti - dyslipi tered locally in a total dose of about 0 . 5 or 2 - 100 mg, 5 or demic agents ; PPAR - a agonists , PPAR - 8 agonists and 10 - 100 mg, 5 or 10 - 50 mg, 0 . 5 - 2 mg, 2 - 10 mg, 0 . 5 - 5 mg, PPAR - y agonists ; anti - amyloid agents and inhibitors of other 5 - 10 mg, 10 -50 mg or 50 - 100 mg over a period of about 6 toxic substances; inhibitors of lipofuscin or components months. thereof; antioxidants ; neuroprotectors (neuroprotectants ) ; 9 . The method of claim 1 , wherein the statin is adminis apoptosis inhibitors and necrosis inhibitors ; C - reactive pro tered locally in a total dose of about 1 or 4 - 200 mg, 5 or tein inhibitors ; inhibitors of the complement system or 10 -200 mg, 5 or 10 - 150 mg, 5 or 10 - 100 mg, 1 - 5 mg, 5 - 10 components thereof; inhibitors of inflammasomes ; anti- in mg , 1 - 10 mg, 10 - 50 mg , 50 - 100 mg, 100 - 150 mg or 150 -200 flammatory agents ; immunosuppressants ; modulators ( in mg for the entire treatment regimen . hibitors and activators ) of matrix metalloproteinases and 10 . The method of claim 1 , wherein the statin is admin other inhibitors of cell migration ; anti - angiogenic agents ; istered locally by eye drop one, two, three , four or more laser therapies , photodynamic therapies and radiation thera times daily . pies ; agents that preserve or improve the health of the 11 . The method of claim 1 , wherein the statin in the form endothelium and/ or the blood flow of the vascular system of of a sustained - release composition is administered locally by the eye ; cell replacement therapies; and combinations injection once every month ( 4 weeks ), 1 . 5 months ( 6 weeks) , thereof. 2 months (8 weeks ), 2. 5 months ( 10 weeks) or 3 months ( 12 29 . The method of claim 28 , wherein the one or more weeks) . additional therapeutic agents comprise an anti - dyslipidemic 12 . ( canceled ) agent, an antioxidant, an anti -inflammatory agent, a comple 13 . The method of claim 1 , wherein the statin is admin ment inhibitor, a neuroprotector or an anti -angiogenic agent , istered locally via a sustained -release implant, and wherein or any combination or all thereof. the implant is implanted in or around the eye : 30 . The method of claim 27 , wherein the one or more once every about 3 months , 4 months, 6 months, 1 year, additional therapeutic agents comprise an apoA - I mimetic 1. 5 years or 2 years ; and and / or an apoE mimetic . US 2018 /0296525 A1 Oct . 18, 2018 81

31 . Themethod of claim 30 , wherein the apo A -I mimetic is L -4F or D - 4F or a salt thereof, and the apoE mimetic is AEM - 28 - 14 or a salt thereof.