A double-masked, Placebo-Controlled, Phase 1b/2a Study of EXN407 Eye Drops in Patients with Mild Center Involving Diabetic Macular Edema (DME)

Posterboard#: B0158

Abstract Number: 6248 - B0158

AuthorBlock: loic Cm lhuillier¹, Hemal Mehta², Jagjit Gilhotra³, Fred Chen^4,5, Sanjeewa Wickremasinghe⁵, Wilson Heriot⁶, Peter Davies⁷, Lily Ooi⁸, Jennifer Arnold⁹, Rohan Merani¹⁰, Mike Taylor¹, David O. Bates^11,1, Samantha Fraser-Bell¹², Mark C. Gillies¹², Mario G. Fsadni^1,13, Andrew Chang^14
1Exonate ltd, , United Kingdom; ²Strathfield Retina Clinic, Sydney, New South Wales, Australia; ³Royal Adelaide Hospital, Adelaide, South Australia, Australia; ⁴Lions Eye Institute, Nedlands, Western Australia, Australia; ⁵Centre for Eye Research Australia Ltd, East Melbourne, Victoria, Australia; ⁶Retinology Institute, Glen Iris, Victoria, Australia; ⁷Newcastle Eye Hospital, Waratah, New South Wales, Australia; ⁸Princess Alexandra Hospital, Woolloongabba, Queensland, Australia; ⁹Marsden Eye Specialists Laser LASIK Eye Cataract Glaucoma Eyelid & Oculoplastic, Parramatta, New South Wales, Australia; ¹⁰Macquarie University, Sydney, New South Wales, Australia; ¹¹University of Nottingham, Nottingham, United Kingdom; ¹²The University of Sydney Save Sight Institute, Sydney, New South Wales, Australia; ¹³International Pharm-Med, Bramhall, United Kingdom; ¹⁴Sydney Retina Clinic, Sydney, New South Wales, Australia;

DisclosureBlock: loic Cm lhuillier, Code E (Employment) Exonate, Code I (Personal Financial Interest) Exonate, Hemal Mehta, None; Jagjit Gilhotra, None; Fred Chen, None; Sanjeewa Wickremasinghe, None; Wilson Heriot, None; Peter Davies, None; Lily Ooi, None; Jennifer Arnold, None; Rohan Merani, None; Mike Taylor, Code C (Consultant/Contractor) Exonate ltd, David O. Bates, Code C (Consultant/Contractor) Exonate, Code I (Personal Financial Interest) Exonate, Samantha Fraser-Bell, None; Mark C. Gillies, None; Mario G. Fsadni, Code C (Consultant/Contractor) Exonate, Andrew Chang, Code C (Consultant/Contractor) Bayer, Roche, Apellis, Zeiss, Alcon Novartis, Code F (Financial Support) Bayer, Roche

Purpose
Intravitreal anti-VEGF injections have become the mainstay of DME treatment. The SRPK1 kinase regulates alternative splicing of VEGFA to form pro-angiogenic (VEGF-A₁₆₅a) isoforms. EXN407 is a potent and selective SRPK1 inhibitor that reduces the production of VEGF-A₁₆₅a by retinal cells and, as eye-drops, reduces retinal neovascularization and vascular permeability in vivo, reaching high retinal levels in rabbits and non-human primates >10x that required for in vivo efficacy, with low systemic exposure. Therefore, we set out to assess safety, tolerability, plasma pharmacokinetics (PK) and biological activity of EXN407 eye drops in people with mild DME.

Methods
48 subjects were recruited with mild DME and central macular thickness (CMT) 280-420 µm in the study eye and randomized to placebo or EXN407 eye drops. BID administration to the study eye only of EXN407 at 0.5, 1.0, 1.5 mg/mL or placebo was undertaken by 3 patients per dose for 7 days. 23 subjects received BID EXN407 (1.5 mg/mL) and 12 placebo for 85 days. Subjects were monitored at screening, 7, 29, 57, 85 and 113 days for visual acuity (BCVA), CMT (measured by SD-OCT), and at screening, 7 and 85 days by fundus fluorescein angiography. Blood samples were taken at 15, 30, 60, 120, 180 and 240 mins after the first eye drop at Day 3 and Day 8, and EXN407 measured by mass spectrometry.

Results
EXN407 was well tolerated in all 32 treated subjects in both cohorts. No ocular AEs were severe, serious, or led to treatment discontinuation. Systemic exposure was low. CMT significantly decreased (7µm, p<0.05) in EXN407-treated patients after 85 days, similar to previously reported anti-VEGF injections in a similar population[1]. There was no significant change in CMT in placebo group, or non-study eye. Changes in vascular leakage were assessed by two masked graders who independently compared fluorescein leak on Baseline, day 8 and day 85 fundus angiograms. There was a significant decrease in vascular leakage in eyes treated with EXN407 (50% of patients) versus placebo (10% of patients, odds ratio 7.4, 95%CI 1.4-49.5, p=0.0252) between baseline and day 84, as well as between day 8 and day 84.
[1] Sohelian 2011.

Conclusions
Topical EXN407, BID (1.5mg/mL) was safe and well tolerated in subjects with mild, centrally-involved DME. The potential therapeutic effects of EXN407 warrant further investigation.