ASRS 2024: Fas inhibition with ONL-1204 for GA

Durga Borkar, MD, sat down with Sydney M. Crago, Assistant Managing Editor of Ophthalmology Times and Modern Retina, to discuss Fas inhibition with ONL-1204 for the treatment of geographic atrophy: First-time results from a phase 1b study, which she is presenting at the American Society of Retina Specialists (ASRS) meeting held in Stockholm, Sweden.

Video Transcript:

Editor's note: The below transcript has been lightly edited for clarity.

Sydney M. Crago:

I'm Sydney Crago with Modern Retina, and I'm here today with Dr. Durga Borkar to talk a little bit about her presentation at the ASRS meeting in Stockholm, Sweden. Dr. Borkar, can you share a brief summary of the setup of this phase 1b city for ONL-1204.

Durga Borkar, MD:

Of course, as you know, ONL Therapeutics is developing ONL-1204 ophthalmic solution as a novel first-in-class neuroprotective agent to preserve retinal cell health during disease. At the time, this phase 1 study in geographic atrophy was initiated ONL-1204 had only really been tested in a phase 1 study as an adjunct to surgery in patients with rhegmatogenous retinal detachment. The phase 1 study I'm presenting here at the ASRS meeting was testing ONL-1204 as a method to treat patients with geographic atrophy secondary to age-related macular degeneration. And the study had 2 components. The first component was an open-label dose escalation study where patients with geographic atrophy received a single intravitreal injection of ONL-1204. The purpose of this portion of the study was to ensure that it was okay to inject ONL-1204 and not have it removed by vitrectomy as it was in the retinal detachment study. The second component of this study was called the natural history treatment portion. Here patients with geographic atrophy were monitored for 6 months to assess the growth, rate of growth of their lesions. They were then randomized to receive either a low dose 50 micrograms of ONL-1204, a high dose 200 micrograms ONL-1204, or sham injection. Patients received a total of 2 injections, and they were spaced 3 months apart. Patients were then monitored for a total of 6 months.

SM: How does ONL-1204 differ from current geographic atrophy treatments?

DB: That's a great question. ONL-1204. is really a novel first-class agent designed to inhibit the activation of the Fas receptor. Fas is a member of the TNF family of receptors and is a critical regulator of cell death and inflammation; it actually acts upstream of the complement pathway that many are familiar with. ONL-1204 has been shown in numerous preclinical models of age-related macular degeneration to preserve retinal cells and reduce activation of the inflammatory cascade.

SC: Since this is a first-in-class inhibitor for Fas, What can you tell us about Fas inhibition?

DB: Fas receptor, which sits on the surface of cells, becomes upregulated and activated during disease. The activated Fas receptor then turns on both cell death pathways as as well as up regulates pro-inflammatory pathways. ONL-1204. prevents the activation of Fas, and by doing so, it prevents the cell death pathways from turning on, as well as prevents the release of the inflammatory factors that serve to potentiate and accelerate disease. ONL-1204 acts at the apex of the cell death and inflammatory cascades preventing shunting of these processes to other pathways. ONL-1204, our evidence suggests, acts more upstream from the currently available treatment modalities for geographic atrophy.

SC: And then, what were the results of this phase 1b study?

DB: This phase 1 study has some really exciting and encouraging results. In the first component of the study, the open-label dose escalation component, a single injection of ONL-1204 was able to reduce the rate of GA lesion growth by 42% as compared to the rate of GA lesion growth in the fellow untreated eye. And in the second portion of this study, the natural history treatment component, 2 injections of ONL-1204 given 3 months apart, we're able to reduce the rate of lesion growth by approximately 50% and the higher dose arm by 6 months. And you know, when you think about the currently available drugs that we have, they don't show a treatment effect this early on and with this few injections.

SC: And then, what are the next steps for ONL-1204?

DB: ONL Therapeutics is currently beginning the site initiation and activation process for global phase 2 trial testing 2 doses of ONL-1204, as well as to dosing frequencies: once every 3 months and once every 6 months. This study will then lay the groundwork for the eventual pivotal phase 3 programs that we hope will help transform the landscape of geographic atrophy treatment.