SRPK family

OcuTerra Therapeutics on Thursday announced that its topical diabetic retinopathy candidate nesvategrast – the only asset in its pipeline – failed to meet the primary and key secondary efficacy endpoints of a Phase II study. “We are disappointed that the top-line data…did not demonstrate a statistically significant impact on severity or progression of diabetic retinopathy,” remarked OcuTerra CEO Kerrie Brady. She added that the company would review the trial’s complete dataset to decide on the next steps for the small-molecule RGD integrin inhibitor, also known as OTT166, and explore strategic alternatives.The DR:EAM study investigated daily nesvategrast across two dose levels against placebo in 225 patients with diabetic retinopathy. While the top-line data demonstrated favourable safety and tolerability for nesvategrast, it failed to show a significant improvement on the Diabetic Retinopathy Severity Scale (DRSS) versus placebo, which was the primary efficacy endpoint. The drug also fell short on the secondary goal of disease progression, but managed to meet the other secondary endpoint of preventing vision threatening events by week 24 in patients with baseline DRSS levels between 47 and 53.Another topical small molecule vying for a spot in the diabetic retinal diseases space is Exonate’s SRPK1 inhibitor EXN-407, which recently showed favourable safety, tolerability and biological activity in a Phase Ib/IIa trial, making its way to the Phase IIb CLEAR-DM study.

EXN407 is the first topical SRPK1 inhibitor to demonstrate both safety and signals of biological response as monotherapy for these indications Data generated fully support continued clinical development of EXN407 into the CLEAR-DM Phase IIb study Full Phase Ib/IIa data selected for presentation at ARVO 2024 CAMBRIDGE, England & NOTTINGHAM, England--(BUSINESS WIRE)-- Exonate Ltd., a biotechnology company developing novel, non-invasive, small-molecule therapeutics for patients with retinal vascular diseases, today announced the data from a successful Phase Ib/IIa trial for lead candidate EXN407. 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 pro 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: To find out more information about Exonate’s therapeutic pipeline for diabetic complications and other indications, as well as our clinical programmes, please visit: View source version on businesswire.com: Contacts Katie Odgaard Tel: +44 (0)7787 502 947 Email: katie.odgaard@zymecommunications.com Source: Exonate View this news release online at:

During the trial, EXN407 met all endpoints and displayed ‘encouraging’ biological activity in diabetic patients with retinal eye disease. Dr Catherine Beech, CEO of Exonate, said: “The results from the EXN407 trial are very encouraging, with the data validating the hypothesis that modulating VEGF splicing can lead to clinical benefits." Diabetic macular oedema is a condition affecting many diabetes patients worldwide, where leaking blood vessels in the eye cause a thickening of the macula region of the retina, leading to vision loss. Current treatments for the condition involve monthly injections directly into the patient’s eye that prevent aberrant blood vessel growth. However, the invasive treatments place long-term burdens on patients If successful, EXN407 will be the first topical eye drop available for the treatment of retinal vascular diseases, including diabetic retinopathy and diabetic macular oedema. EXN407, is a small molecule inhibitor of splice factor kinase SRPK1. Patients in the trial, carried out in collaboration with Janssen Pharmaceuticals, were treated twice a day for three months, with either EXN407 or placebo. In addition, the company has now regained full rights to its complete portfolio of ophthalmology assets from Janssen Pharmaceuticals. Moving forward, Exonate will now progress EXN407 to a phase 2 clinical study in 2024. "We are excited to progress to the phase II trial next year and welcome enquiries by potential partners for the programme," Beech added. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Exonate’s small-molecule drugs are addressing the need for effective, non-invasive treatment of retinal diseases. The treatments offer high ocular permeability that allows targeted therapeutic delivery to the retina with topical eye drops, removing the need for unpleasant intravitreal injections, the company said.