Exonate Ltd. reported positive data from its phase 1b/2a study evaluating the safety and biological activity of its lead ophthalmic candidate EXN407, intended to treat diabetic retinopathy (DR) and diabetic macular oedema (DMO)—also known as diabetic macular edema (DME).
Talk about this company.
Spun out of the University of Nottingham in 2014, the United Kingdom-based biotechnology company is developing novel, non-invasive, small-molecule therapeutics that prevents the production of proangiogenic vascular endothelial growth factor (VEGF) via selective inhibition of serine arginine protein kinase (SRPK1)-mediated VEGF splicing. While that’s quite a mouthful, what you really need to know is its target: treating retinal vascular diseases (RVDs) that could potentially lead to vision loss.
And how were these developed?
The mRNA company originally collaborated with Janssen Pharmaceuticals, Inc. in 2020 to develop a new eye drop for RVDs, with the program facilitated by Johnson & Johnson Innovation.
Since then, Exonate has regained complete control over its ophthalmology portfolio to progress it through clinical trials.
Gotcha. Now explain EXN407.
EXN407 is formulated as a topical, twice-daily, small-molecule inhibitor of SRPK1.
Per Exonate, the eye drop “exploits SRPK1 involvement in the alternate splicing of (VEGF),” which is heavily involved in blood vessel growth regulation.
How does it work?
By inhibiting SRPK1, EXN407 is able to selectively target “pro-angiogenic isoforms of VEGF that lead to vascular retinal disease progression via aberrant growth of leaky blood vessels within the eye.”
Translation: the eye drop operates as a non-invasive alternative treatment to treat RVDs.
Gotcha. So tell me about this trial.
The first-in-human (FIH), phase 1b/2a study (NCT04565756) was a randomized, double-masked, vehicle-controlled, multiple dose, dose-escalating trial that evaluated the safety and tolerability of EXN407 in treatment-naïve patients with:
- mild/moderate nonproliferative DR (NPDR)
- Mild DMO
Participant criteria?
A total of 48 patients (aged 18+) were enrolled, with all required to have a center-subfield macular thickness (CMT) between 280-420 µm, according to Clinical Trials.
Other eligibility criteria include a best-corrected visual acuity (BCVA) better than or equal to 69 Early Treatment Diabetic Retinopathy Score (ETDRS)—an estimated Snellen equivalent 20/40 (6/12 letters) in the study eye.
See here for the complete criteria.
How were patients evaluated?
Participants were randomized into three dose escalation cohorts and one dose expansion cohort, with patients receiving either EXN407 or a placebo as a single 30 μL drop, twice a day, via unilateral administration into the study eye:
- Cohort 1
- Low-dose: 0.5 mg/mL (0.05%)
- Twice a day; 14 doses over 7 days
- Cohort 2
- Mid-dose: 1 mg/mL (0.1%)
- Twice a day; 14 doses over 7 days
- Cohort 3
- High-dose: 1.5 mg/mL (0.15%)
- Twice a day; 14 doses over 7 days
- Dose expansion cohort
- Highest well-tolerated dose of EXN407
- Twice a day; up to 84 days (168 days in total)
And what was measured?
The primary outcomes included ocular safety and tolerability of EXN407 in both dose escalation (day 1 to day 36) and dose expansion (day 1 to day 113) phases.
See here for secondary outcomes.
Now the findings.
Per Exonate, the data demonstrated EXN407’s safety and tolerability, as well as “clear indications of biological activity.”
Meaning: This biological response indicated sustained decrease in macular thickness that was relative to the placebo group plus comparable to previously reported anti-VEGF injections.
Any adverse events?
All participants completed the study without requiring anti-VEGF rescue; further, no major or serious adverse events (AEs) were reported in connection to the eye drop, Exonate reported.
How did EXN407 impact vascular leakage?
A significant decrease in vascular leakage was noted in EXN407-treated patients (60%) vs placebo-treated patients (20%).
Further, the eye drop also prevented additional increases in vascular leakage compared to placebo (10% vs 50%, respectively).
What did the company have to say?
Exonate CEO Catherine Beech noted that the data suggests EXN407 may provide clinical benefit and substantially reduce the injection burden for diabetic eye disease patients.“We look forward to engaging with strategic partners to support the CLEAR-DM phase 2b trial, which has been designed to fully demonstrate the clinical benefits of EXN407 in NPDR/DME,” she stated.
And what’s this CLEAR-DM trial?
The next phase 2 clinical step for EXN407, which will continue to be evaluated for its safety and tolerability in treating diabetic eye disease.
Gotcha. What else to know?
Exonate will be presenting the complete phase 1b/2a data during the Association for Research in Vision and Ophthalmology (ARVO) annual meeting in Seattle, Washington, May 5-9, 2024.