Safety and tolerability of intravitreal ONL1204 in patients with macula-off rhegmatogenous retinal detachment

Abstract

Purpose : The Fas receptor is a primary mediator of photoreceptor (PR) cell death and retinal inflammation in rhegmatogenous retinal detachment (RRD). Targeting the Fas receptor is a potential method to reduce PR death and improve visual function after reattachment. ONL1204, a 12 amino-acid peptide, is a first-in-class inhibitor of the Fas receptor.

Methods : This was a prospective, ethics-committee-approved, open-label, dose-escalation study conducted across four sites in Australia (NCT03780972). Adult patients with macula-off RRD of between 7 to 28-day duration were recruited. After ophthalmic evaluation, patients received a single intravitreal injection of ONL1204 in 4 escalating dose cohorts (25, 50, 100 and 200 mg). Retinal reattachment surgery with vitrectomy (with or without scleral buckle) was performed per standard of care. Patients were followed for 6 months post-operatively, with repeat ophthalmic evaluations and retinal imaging. Vitreous samples taken prior to injection of ONL1204 - and again at the time of vitrectomy - underwent a cytokine panel analysis.

Results : A total of 14 patients were enrolled across the dose cohorts. Presenting visual acuity was between 20/100 and Hand Motion. The average time of macula-off status was 16.9 days (range 11-24 days). No dose-limiting toxicities were observed at any of the concentrations tested. Most adverse events were procedure- or surgery-related and mild to moderate. There were seven serious adverse events (SAEs), including six re-detachments in four patients. One patient had post-operative inflammation that was treated as presumptive endophthalmitis. None of the SAEs were study drug-related. All retinas were reattached at the end of the study, with mean final visual acuity improved compared to presentation. Levels of several Fas-regulated cytokines were reduced after ONL1204 treatment, consistent with the proposed mechanism of action of ONL1204.

Conclusions : ONL1204 is safe and well-tolerated in patients with macula-off RRD. In addition, cytokine profile reductions suggest that it has the potential to reduce PR cell death and disease-associated inflammation, which may improve patients’ visual outcomes. Phase 2 studies of this investigational agent are currently being initiated.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.