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Us 2018 / 0296525 A1 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 EXT Subretinaldrusenoid deposit X 044 * * * . 1 . I . II IT . ! ! . WW . # # T . SA * * . .. -8200.000300 ! . ! ! 29 . www * * ! . BaselmoundoIS 288 FIG.1 WE LA BESSON BlindPre- 6003556 Qw878 $ MINIMURNucleus 700 MIUIUSIONDABAVITVAMOM19-3dd 0 W Patent Application Publication Oct. 18 , 2018 Sheet 2 of 4 US 2018 /0296525 A1 oil Red O Staining -56 % (p = 0. 007 ) p = 0 .84 ORO-score UNTY teretettet OOOOOOOOOOOOOOOOOOOOOOOOOOoodbodoodoodooDOO Injected Eyes neviririririnig Non -injected ??????????????????????? Eyes eccete Tiiiiii Treatment Group (L - 4F ) ControlGroup ( SL - 4F /Placebo ) FIG . 2 Patent Application Publication Oct . 18 , 2018 Sheet 3 of 4 US 2018 /0296525 A1 Filipin Staining FluorescenceIntensity (ArbitraryUnits,Mean4-SE) -68 % * p = 0 .037 many injected Eyes Non -Injected Injected Eyes Non - injected Eyes Treatment Group ( L -4F ) Control Group ( SL - 4F1Placebo ) FIG . 3 MAC ( c5b9 ) Staining -58 % * p < 0 .0016 p < 0 . 31 viiiiiiiiiii una FluorescenceIntensity(ArbitraryUnits+1-SE) kutukutukutukutukutukutukutukutukutukutukutu kutukutukutukutukutukutukutukutukutukutukutukutuku OOOOO OOOOOOOOOOOOOOOOOOOOOOOOOO injected Eyes Non - injected Injected Eyes Non -injected mmmmmmmmmmmmmmmmmmmmmmmmmm eyes Treatment Group (L -4F ) Control Group ( SL - 4F /Placebo ) FIG . 4 Patent Application Publication Oct . 18 , 2018 Sheet 4 of 4 US 2018 /0296525 A1 Complement Activator Factor D Staining iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii i iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii . ???????????????????????????????????? FluorescenceIntensity (ArbitraryUnits,Mean*-SE) 0 ~ 690 Die personale 0000000000000000000000000 Injected Eyes Non -injected Injected Eyes Non -injected Eyes Eyes Treatment Group (L -4F ) Control Group (L -4F / Placebo ) FIGR . 5 Bruch ' s Membrane Thickness in TEM - 24 % # p = 0 .0118 Bruch'sThickness(Mean+SE,um) ????????????????????????? Injected Eyes Non - injected Non - injected Eyes Eyes 10000000000000000000000000000000000000000000000000000000000000000000000 Treatment Group ( L -4F ) ControlGroup ( SL - 4F / Placebo ) FIG . 6 US 2018 /0296525 A1 Oct . 18 , 2018 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 ) of matrix 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 ] The present 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
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