New eye drops found safe and effective in diabetic retinopathy and diabetic macular edema in New trial
New eye drop treatment has been found to be safe and tolerable with 100% participants completing the study for diabetic retinopathy and diabetic macular edema, according to data recently released for the phase 1b/2a trial.
These data demonstrate the safety and tolerability of EXN407, as well as clear indications of biological activity, positioning it well for further development as the first topical treatment for retinal vascular diseases such as diabetic retinopathy and diabetic macular oedema. Exonate is now planning to progress EXN407 to the CLEAR-DM (Clinical Evaluation of a New Eyedrop for Alleviating Retinopathy in Diabetic Macular Oedema) Phase IIb clinical trial.
EXN407 is a twice-daily formulation, comprised of a small molecule SRPK1 inhibitor. The eye drop formula exploits SRPK1 involvement in the alternative splicing of vascular endothelial growth factor (VEGF), a protein heavily involved in the regulation of blood vessel growth. Through inhibition of SRPK1, EXN407 can selectively target pro-angiogenic isoforms of VEGF that lead to vascular retinal disease progression via aberrant growth of leaky blood vessels within the eye.
The mild NPDR/DME (NCT04565756) clinical study assessed the safety, tolerability and signals of biological response to EXN407 monotherapy in a double-masked, placebo-controlled Phase Ib/IIa dose-ranging clinical trial in treatment-naïve patients with mild/moderate non-proliferative diabetic retinopathy (NPDR) and mild diabetic macular oedema. The independent Dose Escalation Committee characterised EXN407 as safe and well-tolerated, with 100% of patients completing the study without requiring anti-VEGF rescue, and no major or serious adverse events reported relating to EXN407. Moreover, EXN407 exhibited high levels of tolerability, with drop comfort scores similar to placebo and artificial tears.
In addition to the primary safety and tolerability endpoints, the study concluded that there were promising signals of biological response from EXN407, demonstrating sustained decreases in macular thickness, relative to the placebo group and comparable to previously reported anti-VEGF injections. The trial further noted that EXN407 treatment led to a significant decrease in vascular leakage (60% of EXN407-treated patients relative to 20% placebo) and that EXN407 inhibited further increases to vascular leakage (10% of EXN407-treated patients relative to 50% placebo).
“The Phase Ib/IIa data demonstrate the clear potential of EXN407 as a non-invasive treatment for these devastating, sight-threatening conditions, and the favourable safety profile and biological activity of EXN407 support its continued clinical development in retinal vascular diseases,” said Catherine Beech, chief executive officer of Exonate: “The results suggest that topical ocular EXN407 may provide clinical benefit and substantially reduce the injection burden for patients with diabetic eye disease. We look forward to engaging with strategic partners to support the CLEAR-DM phase IIb trial, which has been designed to fully demonstrate the clinical benefits of EXN407 in NPDR/DME.”
Full results of the Phase Ib/IIa will be presented at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in May 2024.
About the EXN407 Phase Ib/IIa mild NPDR/DME Trial (NCT04565756)
The double-masked, placebo-controlled dose-ranging Phase Ib/IIa trial randomised 13 treatment-naïve mild diabetic molecular oedema (DMO/DME) patients (defined as Best Corrected Visual Acuity (BCVA) > 69 ETDRS letters and Central Macular Thickness (CMT) between 280 and 420 microns) to one of three twice-daily doses of EXN407 monotherapy, or placebo: 0.5 mg/mL (3 active/2 placebo), 1 mg/mL or 1.5 mg/ml (3 active/1 placebo for each cohort), for eight days. Following the conclusion of the dose escalation phase, 35 treatment-naïve mild DME patients were randomised to EXN407 monotherapy 1.5 mg/ml (23 active/12 placebo) for 85 days. Participants were all followed for one month (to day 113) after discontinuation of EXN407. Rescue medication (standard of care, ranibizumab or aflibercept) was made available.
The primary endpoint was safety/tolerability, and the secondary endpoint was systemic exposure. Exploratory endpoints were effects of EXN407 monotherapy on CMT and vascular leakage. The independent Dose Escalation Committee characterised EXN407 as safe and well-tolerated, with no major or serious drug-related safety concerns. EXN407 also exhibited improved tolerability, with drop comfort scores similar to placebo and artificial tears. Key safety results are summarised below:
• There were a total of four Treatment Emergent Adverse Events (TEAEs) that were considered as probably related (two related to EXN407 and two related to the placebo). There was one additional event considered as definitely related to EXN407. All of these events were ocular TEAEs, were considered mild in severity, did not lead to study discontinuation, and were resolved without treatment.
• None of the patients discontinued eye drop therapy during the course of the trial.
• Reported non-ocular events were consistent with those observed in diabetic populations.
• Exposure of EXN407 into the vascular compartment was low, achieving maximal concentrations by 30 minutes post administration, and blood concentration values returned to BLOQ by approximately four hours, indicating minimal risk of adverse drug reactions in non-ocular tissues. Further, the data indicated that there is little or no risk of accumulation of EXN407.
