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Taking a Dermatological Approach to Treating Ocular Surface Diseases

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Taking a Dermatological Approach to Treating Ocular Surface Diseases Taking a Dermatological Approach to treating Ocular Surface Diseases MARC GLEESON | CHIEF EXECUTIVE OFFICER OIS@SECO 2020 for Meibomian Gland Dysfunction, Contact Lens Discomfort & Blepharitis Copyright© Azura Ophthalmics | Confidential Meibomian Gland Contact Lens Blepharitis Demodex Dysfunction Discomfort Patient Administered Patient Administered Patient Administered Rx Proven activity against Rx Chronic Treatment Rx Chronic Treatment Treatment applied to Demodex applied to the eyelid applied to the eyelid the eyelid Allows continuation of New Chemical Entity In Office Physician Only Contact Lens Wear Administered Rx Treatment Lid Margin Involvement Hyperkeratinization of the Gland Orifice +/- Inflammation Copyright© Azura Ophthalmics | Confidential (MGD) Reduced secretion of lipids leads to instability of the tear film Modified sebaceous (oil-producing) and drying of the ocular surface, leading to damage and the glands responsible for secreting the signs and symptoms of dry eye disease (DED). outer lipid layer (meibum) of the tear film, which lubricates the ocular Obstructive MGD is the most common cause of evaporative surface during blinking and protects dry DED,1,3 and clinical signs of obstructive MGD are present against tear evaporation1,2 in 86% of DED patients4 MGD traditionally regarded as a hypersecretory disorder associated with bacterial infection and inflammation,1 which has guided the approach to treatment, often unsuccessfully 1Blackie et al. Cornea. 2010 | 2Knop et al. Invest Ophthalmol Vis Sci. 2011 | 3Baudouin et al. Br J Ophthalmol. 2016 | 4Lemp et al. Ocul Surf. 2009. Copyright© Azura Ophthalmics | Confidential A GUIDING LIGHT FOR THE DEVELOPMENT OF RX TREATMENTS FOR MGD Comedonal lesions in acne are inspissated hair follicles, filled with corneocytes, sebum, and other debris Keratolytic treatments are used to shed dead corneocytes, loosen the sebum plug, and prevent the formation of inflammatory papules and pustules Examples of keratoloytics included alpha- and beta-hydroxy acids, as well as topical retinoids Topical retinoids convey a concentration- dependent reduction in comedonal lesions, much like selenium sulfide in the treatment of MGD Copyright© Azura Ophthalmics | Confidential BLOCKED ORIFICES, THICK LIPIDS AND LIPID DEFICIENCY Loss of the tear lipid layer Clinical Manifestation Clinically the Meibomian glands Destabilises the tear film are blocked, damaged and/or meibum production in altered Histopathology: gland Results in loss of aqueous ‘blockage” at the orifice and/or layer by evaporation duct, damage and/or functional alteration to the meibomian acinar cells, and gland atrophy Functionally there is reduced Together these result in an lipid production and/or irregular ocular surface and secretion symptoms of dry eye Copyright© Azura Ophthalmics | Confidential A GUIDING LIGHT FOR THE DEVELOPMENT OF RX TREATMENTS FOR MGD Meibomian Glands Acne – Keratin plug Condition – medical use and Sebaceous Glands • Acne • Psoriasis come from the same removal of keratin plug reduction of hyperkeratosis embryonic source • Seborrheic dermatitis • Dandruff reduction of hyperkeratosis reduction of hyperkeratosis, keratin breakdown Keratolytic agents (representative agents) • Salicylic acid • Urea • Selenium disulfide • Retinoic acid As in diseases of the lid margin, secretory gland hyperkeratinization plays an important role in various skin disorders, and agents that reduce hyperkeratinization of the skin/sebaceous glands are effective in treating these conditions 1Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011 Mar 30;52(4):1938-78. | 2Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, diagnosis, classification, and grading. Ocul Surf. 2003 Jul;1(3):107-26. | 3Gutgesell VJ, Stern GA, Hood CI. Histopathology of meibomian gland dysfunction. Am J Ophthalmol. 1982;94:383-387. | 4Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf. 2004;2:149-165. Copyright© Azura Ophthalmics | Confidential BLOCKED GLANDS AT THE GLAND ORIFICE AND THICK LIPIDS Normal Glands Blocked Glands MGD Pathomechanism • Hyperkeratinization of the orifice and the ductal epithelium results in luminal plugging1 Gland Orifice • Orifice Blockage (Gland Orifice Obstruction)1 • Formation of keratinized epithelial debris (keratin strands Normal Meibum Altered Meibum MGD Pathomechanism crosslinked linked by strong disulfide bonds)3,4 increases the normal melting point of meibum1 • Basal acinar cells have sparse cytoplasm containing a large number of keratin filament bundles that contribute to meibum1 Meibum Meibum Viscosity (Increased Meibum Keratin)1 • Altered Meibum Quality and Thickness 1 Knop E, Knop N, Millar T, Obata H, Sullivan DA. IOVS, Special Issue 2011. 1938-1978 | 2Korb DR, Henriquez AS.. J Am Optom Assoc. 1980;51:243–251 | 3Tomlinson et al. Invest Ophthalmol Vis Sci. 2011 | 4Ong et al. Curr Eye Res. 1991 | 5 Obata et al. 2002;:ARVO E-Abstract 60 Copyright© Azura Ophthalmics | Confidential UNBLOCKING GLANDS AND DISRUPTION OF KERATIN PLAQUES WITHIN MEIBUM MATRIX Keratins are helical structural proteins Disulfide bonds are that make up hair, comparatively strong nails, feathers, horn and require considerable and skin thermal energy to break, >144 ˚C Extremely resilient and insoluble Disulfide bond cross Readily achieved Disulfide bond disruption linking hardens chemically in hair by ammonium structures to give For ocular use require thioglycolate is the basis strength and mild disulphide bond for permanent wave durability disrupting agent “perm” hair styling Bunick and Milstone Journal of Investigative Dermatology 2017, Volume 137, 142-150: The X-Ray Crystal Structure of the Keratin 1-Keratin 10 Helix 2B Heterodimer | Reveals Molecular Surface Properties and Biochemical Insights into Human Skin Disease | Istrate et al. Macromol. Biosci. 2009, 9, 805–812: Non-Isothermal Kinetics of Hard a-Keratin Thermal Denaturation Copyright© Azura Ophthalmics | Confidential UNIQUE MECHANISM OF ACTION IN MGD Keratostatic: Lipogenesis Slows down both the rate of keratinocyte Stimulates lipogenesis to increase the quantity proliferation and keratin production1 of lipids produced by the Meibomian glands2 Keratolytic: Control of Demodex Softens keratin plug by breaking down Demodex mites on eyelash follicles can disulfide (S-S) bonds, thereby alleviating contribute to MGD and blepharitis3,4 hyperkeratinization that leads to blockage Active ingredient in AZR-MD-001 is effective 1 of Meibomian glands in treating Demodex folliculitis5,6 AZR-MD-001 is the only known molecule that can target the full scope of dysfunctional Meibomian glands: Hyperkeratosis and Reduced Lipid Production 1 Data on file, Azura Ophthalmics. Study Report AZRPC003. | 2 Data on file, Azura Ophthalmics. Study Reports AZRPC004, AZRPC005 | 3 Zhang et al. Int J Ophthalmol. 2018 4 Gonzalez-Hinojosa et al. Indian J Ophthalmol. 2018 | 5 Luo et al. Medicine. 2016 | 6 Sanfilippo et al. Cutis. 2005. Copyright© Azura Ophthalmics | Confidential IN VITRO/EX VIVO Keratinocytes (HaCat Cells) Human Skin In Vitro Ex Vivo 150 Cell proliferation | BrdU, % of control 150 Cell proliferation | BrdU, % of control BrdU – Incorporated into 125 125 synthesized DNA of replicating cells 100 100 Reduction in BrdU = reduction 75 75 in cell growth/proliferation 50 50 SeS2 reduces growth/proliferation 25 25 of keratinocytes 0 0 vehicle 500µM 1mM 5mM control 100µM 1mM 10mM Copyright© Azura Ophthalmics | Confidential HUMAN SKIN EX VIVO A. 2-h incubation B. Overnight incubation AZR-MD-001 AZR-MD-001 Examined the ability of SeS2 to break disulfide bonds in 500 Free thiol moieties | % of control 500 Free thiol moieties | % of control S human keratin S 400 400 Breakage (chemical reduction) Disulfide bond Reduction Oxidation (S-S) of disulfide bonds generates 300 300 free thiols = keratolytic/skin softening effect 200 200 SH SeS has a keratolytic effect Free thiols 2 SH (S-H) 100 100 at high concentration (1% and 2.5% – 2.5-fold and 3.5 fold > free thiol formation vs. control) 0 0 0 1% 2.5% 0 1% 2.5% Copyright© Azura Ophthalmics | Confidential INCREASES LIPID PRODUCTION Lipid production 3D model culture Histological staining 400% of Sebocytes with Oil-Red-O 350% SeS2 or vehicle treatment Automated quantification 300% for 14 days of surface area 250% 200% 150% 100% 50% * Arrows point to Control 0.01µM 0.10µM 0% lipid staining Control SeS2 0.01 µM SeS2 0.1 µM Copyright© Azura Ophthalmics | Confidential PROOF OF PRINCIPAL CLINICAL ACTIVITY Objective • Does MGT001C1 improve meibomian gland function in patients with MGD? Remove the blockage in the Meibomian Glands Study design • Controlled contra-lateral eye comparison Human Restore and proof of • Outcome measure: Lipid Quality and Tear Film enhance lipid concept Stability (Tear Break-Up Time - TBUT) production of study the Glands Methods • MGT001C1 treatment for 3-4 weeks (2x a week) Prevent the • One eye treated and fellow eye control process from • Main outcome measures: Mean change recurring from baseline Copyright© Azura Ophthalmics | Confidential NON OPHTHALMIC FORMULATION 7 Tear stability (n=14) 40% Lipid quality (n=14) 6 30% 5 4 20% 3 SEM (%) SEM 10% 2 ± SEM TBUT (seconds) TBUT SEM 1 0% ± 0 Mean -10% -1 Mean Mean -2 -20% 1 3 11 22 1 3 11 22 Evaluation visits (days) Evaluation visits (days) Treated Control Treated Control At day
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