Ocunexus Therapeuticsf Brian Levy OD, MSc. CEO

Xiflam (oral small molecule) Stage: Phase 2B

Upstream Regulation of the Inflammasome (NLRP3) Pathway of Inflammation in Retinal Disease

Who are we and What do We have that is Completely Different?

• We are clinical stage with transformational upstream MOA controlling the inflammasome

• High potential for modifying the course and treatment of GA in AMD and DR (DME)

• Orally administered QD drug (Xiflam) which is a Connexin43 Hemichannel Inhibitor

• Multiple Phase 2B Clinicals provide robust Human Safety Database showing good tolerability with no safety concerns

• Ready to file IND in Q4/19 and have Xiflam in the Clinic for GA and DR by Q2/20

• Extensive/strong patent portfolio (2040) Ocunexus Drug Target: Connexin43 Hemichannel

• Connexin43 Hemichannels are continuously forming in the cell membrane

• Hemichannels remain closed until they dock with another hemichannel on an adjoining cell to create a gap junction

• In disease states Cx43 overexpressed and prematurely open in the cell membrane

• Open Undocked Hemichannels are pathological allowing intracellular ATP to enter the extracellular space

• ATP signals the assembly and recycling of the inflammasome Xiflam blocks the open hemichannels, prevents ATP release, inhibits the cycle of inflammation

DISEASE Inflammasome Signal 1 – PRIMING

Xiflam Intervention • Connexin hemichannels open Inflammasome Signal 2 – ACTIVATION • ATP released

Inflammasome (NLRP3) Complex Assembly

Multiple pro-Inflammatory Cytokine Release Connexin hemichannels open Further ATP Release - INFLAMMATION PERPETUATING RECYCLING VESSEL LEAK OF NLRP3 INFLAMMASOME EDEMA ISCHEMIA

FIBROSIS Connexin43 Hemichannel Block Inhibits ATP Release to Prevent Assembly of the Inflammasome (NLRP3) Complex

Methods: RPE Cells challenged with 10 ng/mL TNF-α + 10 ng/mL IL-1β and high glucose(HG)

Result = Extracellular ATP Release • NLRP3 activated - small red dots – white arrows Panel A • Connexin43 hemichannel block prevents ATP release and inflammasome assembly • Exogenously added ATP retriggers assembly, proving the

(Mugisho et al. Biochim Biophys Acta. 2018; 1862:385-393) mechanism of action Connexin43 is Overexpressed in Diabetic Retinopathy and Macular Degeneration (Human Donor Retinas) Normal Diabetic Retinopathy Macular Degeneration

Grey regions = amacrine cells Regions of Neovascularization show high Cx43 levels (green)

Source: Immunohistochemical Characterization of Connexin43 Expression in a Mouse Model of Diabetic Retinopathy and in Human Donor Retinas. Int J Mol Sci. Nov 29, 2017 17 Xiflam in Acute Bright Light Model of GA

Methodology

• 2700 Lux, 30 cm above cage • 24 hours exposure • Oral Xiflam vs Placebo (vehicle) treatment 2h into the light exposure period • Retinal Thickness Measured by OCT • Visual Function Measured by ERG • Follow-up Measurements 2 weeks and 3 months Orally Xiflam Preserves Retinal Structure (OCT) and Function (ERG) in Bright Light Model of Geographic Atrophy

Xiflam Treated at 3m Placebo Treated at 3m

Retinal Thickness

Retinal OCT

Electroretinogram (ERG) LD = Light Damage Novel Chronic Diabetes with Phenotypical Diabetic Retinopathy Serendipitously Discovered by Prof. Green’s Lab in NZ

Methodology: • An isolated strain of Sprague Dawley (SD) rats which develop diabetes within 4 weeks of birth (termed MSD rats) • Glucose levels 14 – 21 mmol/L compared to 5.6 – 5.8 mmol/L in normal SD rats • MSD rats show clinical signs of diabetic retinopathy within 4 weeks of birth • OCT imaging shows micro- and macroaneurysms OCT Imaging of Spontaneously Diabetic Rats at 4 weeks of age

Micro aneurysms and macro aneurysms were specifically in the INL and ONL Normal SD

Micro aneurysms - 20-30 µm diameter Macro aneurysms - 140-160 µm diameter Diabetic MSD – arrows indicate microaneurysms

OCT approximately 5-8 abnormalities per eye (based upon 7 scan lines – will be an underestimate) Diabetic MSD – arrow indicates macroaneurysm Genotyping underway Xiflam Treated MSD rats with Diabetic Retinopathy have Fewer and Smaller Aneurysms and Significantly Improved Visual Function by ERG (Week 8)

Retinal OCT Imaging showing resolution of macro and microaneurysms

MSD** MSD** Xilfam MSD* SD*

Xilfam MSD* SD* MSD** MSD**

• ERG in Normal SD* • ERG regains function in Xiflam Treated MSD* (8 weeks) • Impaired ERG in MSD** (5 weeks) • ERG remains impaired in Placebo Treated MSD** Proposed Xiflam Phase 2B Geographic Atrophy Clinical Trial

Objective: • Adaptive trial to assess safety, efficacy and tolerability of Xiflam over 12 months

• Indication dry AMD with patients exhibiting signs of Geographic Atrophy (GA)

• Primary Endpoint stop progression/show regression of GA lesions

Patients Meet Reading Center Entry Criteria for GA N=180 Randomized 1:1:1

Dose Concentration #1 Dose Concentration #2 Placebo (QD) (QD) (QD)

Followup: Monthly for 1st 6M with interim analysis by DSMC at 6M Quarterly for next 6M with analysis and DSMC input at 12M Proposed Xiflam Phase 2B DME Clinical Trial

Objective: • Adaptive trial designed to assess safety, efficacy and tolerability of Xiflam over 12m • Indication is treatment of patients with OCT diagnosis of Diabetic Macular Edema (DME) at baseline • Kidney Function will be evaluated from baseline

All Patients Meet Reading Center Entry Criteria for DME N=180 Randomized 1:1:1

Dose Concentration #1 Dose Concentration #2 Placebo (QD) (QD)

Followup: Monthly for 1st 6M with interim analysis by DSMC at 6M Next visit and analysis by DSMC at 6M Quarterly for next 6M with analysis and DSMC input at 12M Xiflam Value Proposition – Phase 2B ready Disruptive potential for disease modification preventing the recycling of the inflammasome and pro-inflammatory cytokines vs Current Tx paradigm of IVT injections for recycling flare ups of the disease from monthly to PRN for life

• Orally administered small molecule Cx43 inhibitor • Robust phenotypical data in DR and GA • Clinical safety database >1000 pts shows drug to be well tolerated with no safety concerns • Crosses the blood brain/retinal barrier • Target (Cx43) present in human cadaver retinas with DR(DME) and AMD(GA) • In Clinic by Q2/20 • Long Patent Life (out to 2040) • Looking to close the round Medical Advisors

Philip Rosenfeld MD PhD David Boyer MD Jeffrey Heier MD Peter Kaiser MD David Brown MD Barry Kupperman MD PhD Leading the Pack

Brian Levy African Wildlife Photography