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

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

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

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

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

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%

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

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

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 22, TBUT improved from ~9sec to ~15sec (~65% increase) in At day 22, Lipid quality improved by ~35% (3.27 to 2.12) in the the treatment group with no change in the control group (p=0.0008) treatment group with no change in the control group (p=0.002)

8 Outcomes: 7 Treatments period Stopped Treatment 6 At day 22 study group 5 TBUT improved from ~9sec 4 to ~15sec (~65% increase)

SEM) 3 ± 2 No change was observed 1 in the control

Seconds ( Seconds group (p=0.0008) 0 -1 Following treatment -2

baseline cessation treatment group -3 returned to baseline levels day 1 day 3 day 11 day 22 day 44 day 62 day 105 evaluation visits (days)

Treated Control

50% Outcomes: Treatments period Stopped Treatment 40% At day 22 the study group

30% improved Meibum quality by ~35% (3.27 to 2.12 )

20% SEM) ± No change was observed 10% in the control

Seconds ( Seconds 0% group (p=0.002)

-10% Following treatment

baseline cessation treatment group 20% returned to baseline levels day 1 day 3 day 11 day 22 day 44 day 62 day 105 evaluation visits (days)

Treated Control

Stabilisation Optimal melting

• SeS2 stabilised by anhydrous • Specific composition with semi-solid composition that optimal melting point and prevents formation of viscosity range suitable for particle aggregates softening and fluidisation of meibum lipids Surfactant-free • Ocular formulation with Applicator homogeneous dispersion • Combination of

of SeS2 particles formulation and applicator in single, ready-to-use Adhesion ocular product • Good spread ability and adhesiveness on eyelid

Cohort 1 (Group 1-4) Expansion cohort Study adapts to: Screening Baseline (D-14) (D 0) D 14 M 1 M 1.5 M 3 M 1 M 3 Dose concentration SeS 0.1%: Bi-weekly, SeS 0.1%: Bi-weekly, • 0.1%, 0.5%, 2 2 SeS High* dose (N=32) N=8 N=4; QPM, N=4 2 Group 1 1.0% & 2.5% Vehicle: Bi-weekly, N=1; Vehicle: Bi-weekly, N=2 SeS2 Low* dose (N=32) QPM, N=1 Dose Vehicle (N=32) frequency SeS2 0.5%: Bi-weekly, SeS2 0.5: Bi-weekly, N=4; N=8 QPM, N=4 • Twice weekly Group 2 Vehicle: Bi-weekly, N=1; or daily Vehicle: Bi-weekly, N=2 QPM, N=1

DRC, safety/tolerability to select/inform dose range for expansion SeS2 X%*: Bi-weekly or PI decision: Escalation, de-escalation or stop (evaluation conducted by QPM, N=16 patient/PI can consult DRC medical team for masked advice) Group 3&4* Vehicle: Bi-weekly or *Replicate Groups 1 & 2 Primary efficacy endpoint QPM, N=4 * Informed by the DRC (available doses: 0.1%, 0.5%, 1.0% or 2.5%)

Marc Gleeson

[email protected] +61 422 956 128