An investigational Fas inhibitor demonstrated encouraging results in patients with geographic atrophy (GA) in a phase 1b clinical trial. In the study, eyes treated with ONL1204 (ONL Therapeutics) showed reductions in GA lesion growth at 6 months of up to 50% compared to sham-treated eyes after 2 injections spaced 3 months apart, and a 42% reduction in lesion growth compared to fellow untreated eyes after a single injection.
“These numbers are impressive given the current options that are available for GA,” observed Durga Borkar, MD, a vitreoretinal surgeon at the Duke University Eye Center in Durham, North Carolina, who presented the data at the Retinal World Congress meeting in Fort Lauderdale, Florida. “Overall, we found that ONL1204 appears to be safe and well tolerated and has a very strong efficacy signal with just 1 or 2 injections as early as 6 months after initiating treatment.”
Fas receptors are members of the tumor necrosis factor (TNF) receptor superfamily and play a key role in apoptosis signaling. When Fas is activated, it can initiate signaling pathways that lead to the death of photoreceptor cells and inflammatory damage within the retina. ONL1204, a 12 amino acid peptide developed to inhibit Fas activation, has demonstrated the ability to preserve photoreceptors in multiple preclinical models. Its ability to interfere with Fas signaling suggests that it may provide neuroprotection across a range of retinal diseases, Dr. Borkar explained.
The phase 1b study of ONL1204 had 2 components. In the first, 6 patients with GA secondary to AMD received a single intravitreal injection of ONL1204 and were followed for 6 months. The second component involved 17 patients who completed a natural history period and 16 patients then were randomized to receive either low-dose ONL1204 (50 µg), high-dose ONL1204 (200 µg), or a sham injection. In this arm, patients received 2 injections spaced 3 months apart, followed by an additional 3-month observation period. The primary endpoints were safety and tolerability, with secondary endpoints examining the rate of GA lesion growth. Exploratory endpoints included changes in best-corrected visual acuity (BCVA) and low-luminance BCVA.
“ONL1204 was very safe and well tolerated,” Dr. Borkar said. “There were very few treatment-emergent adverse events.” She noted one transient case of increased intraocular pressure and one case of mild vitreous floaters, both in the high-dose arm. Importantly, no cases of choroidal neovascularization or intraocular inflammation were observed.
In the dose-escalation arm, a single injection of ONL1204 led to a 42% average reduction in lesion growth in the treated eye compared to the untreated fellow eye at 6 months. “In terms of the magnitude of the treatment effect with a single intravitreal injection, that’s very impressive,” Dr. Borkar commented. In the randomized component, patients in the low-dose group exhibited a 24% reduction in the rate of GA lesion growth compared to sham, whereas those in the high-dose group demonstrated a 50% reduction. Mean slope rates were measured in mm2 per year. “These numbers are fairly impressive given the current options that are available for GA,” Dr. Borkar said.
Beyond the clinical results, Dr. Borkar also presented data from exploratory analyses using artificial intelligence (AI) tools to assess optical coherence tomography (OCT) biomarkers. The AI analysis examined ellipsoid zone attenuation and the area of retinal pigment epithelium (RPE) at risk. “The biomarker findings actually correlate really well with some of the structural and functional improvements that we observed,” she said. According to Dr. Borkar, eyes treated with ONL1204 exhibited less ellipsoid zone attenuation compared to fellow eyes, whereas sham-treated eyes showed a higher growth of RPE area at risk. Additionally, ONL1204-treated eyes demonstrated an increase in thickness near the lesion over time compared to sham.
Although the phase 1b study was small and exploratory, the results suggest that ONL1204’s neuroprotective mechanism could have broader applications beyond GA. “This mechanism of action is hopefully going to be beneficial in multiple ophthalmic diseases,” Dr. Borkar said. A phase 2 study of ONL1204 in GA is preparing to enroll more than 300 patients, with the first patient visit anticipated later this year.
In addition to GA, ONL1204 has been studied in other ophthalmic indications. ONL Therapeutics has completed phase 1 and phase 2 clinical trials evaluating ONL1204 as an adjunct to surgical repair for rhegmatogenous retinal detachment. Data released to date show that the agent was well tolerated and suggested a potential to reduce photoreceptor cell loss after detachment. The company has also completed a phase 1b study examining ONL1204 in patients with open-angle glaucoma, where Fas activation is thought to contribute to retinal ganglion cell death. “These early studies highlight that Fas inhibition may have utility in a range of diseases characterized by cell death and neurodegeneration in the retina,” Dr. Borkar said. RP