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

Abstract

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.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.