Q&A: Christine Kay on the REMAIN trial results for patients with retinitis pigmentosa

At the Retina Society meeting held in Chicago, Illinois, Christine N. Kay, MD a vitreoretinal surgeon and IRD specialist from Gainesville, Florida, presented research on MCO-010, a novel optogenetic therapy for retinitis pigmentosa. This study explored a gene-agnostic treatment targeting bipolar cells through a single intravitreal injection. The RESTORE trial investigated the potential of this innovative approach to improve visual acuity in patients with severe vision loss, marking a significant advancement in retinal disease treatment.

Note: The following conversation has been lightly edited for clarity.

Modern Retina: Can you share some of the key highlights from your presentation on MCO-010 for the treatment of retinitis pigmentosa?

Christine Kay, MD: I'm a vitreoretinal surgeon and an IRD specialist located at Vitreo Retinal Associates in Gainesville, Florida. I presented here at Retina Society in Chicago the results from the REMAIN trial, a 152-week analysis from the MCO-010 optogenetic therapy for retinitis pigmentosa RESOTRE trial. Disclosure, I'm a consultant and advisor for Nanoscope.

MCO-010 is a novel optogenetic therapy delivering a high performing optin that targets bipolar cells to become sensitive to light. It's delivered by an AAV-2 in a single intravitreal injection, and it targets bipolar cells because if it's using an MG glue r6 promoter. In this RESTORE study that I presented, there were 27 patients or randomized 1 to 1 to 1 to 3 different arms. There was a low-dose arm, a high-dose arm, and a sham arm. Patients had advanced RP with severe vision loss, with a baseline visual acuity of worse than 1.9 logMAR, which is the equivalent of 20/1600 Snellen visual acuity. Patients at baseline had a single intravitreal injection at day 0. Patients receiving the ancient did receive an oral corticosteroid of prednisone approximately 3-week taper, but importantly, not in this trial, a topical steroid prophylaxis, taper. RESTORE met its primary endpoint in the change in BCVA, or best-corrected visual acuity, at week 2, and that's our primary result.

Approximately 40% of active treatment arms gained 0.3 logMar. For those of us that don't think in logMar, that's equivalent to 3 lines of visual acuity or 15 ETDRS letters, the mean BCVA improvement in both the high-dose and the low-dose groups was greater than 0.3 logMAR. These were statistically significant results compared to the sham arm. The key secondary endpoint was also met, and this was a BCVA at week 76 through 100 weeks in the RESTORE and up to 3 years in the REMAIN trial. The mean visual acuity improvement from baseline remained approximately 0.3 logMar after 2 and a half years the BCVA area under the curve profiles, which look at multiple points of visual acuity rather than just one point in time. These were 5 times greater in the treated groups versus the sham group at week 126. This was statistically significant as well. Regarding safety, which is always important to discuss with intravitreal, gene therapy, safety was a continue to be a pillar of the program. The most common adverse events were interior chamber cell and ocular hypertension, and these were primarily seen at either the time around the injection or at the time when the steroids were tapered. Importantly, recall that this was an oral steroid only regimen, and it was typically in the majority of patients, a topical durazole or Pred Forte that was restarted. This worked well, and patients were able to be tapered off these drops, all patients were off any steroid prophylaxis by 1 year, other than 1 patient of the patients who experienced an AE, again, it was typically treatable with topical steroids. In summary, the MCO-010 achieved its primary and key secondary endpoints and had an excellent safety profile and no SAEs or serious adverse events that clinically mean, meaningful, 0.3 logMar, which, again, is 3 lines or 15 ETDRS letters of vision improvements were durable out to 3 years. Based on these promising results and ongoing discussions with the FDA, Nanoscope hasn't initiated a rolling BLA submission.

MR: What questions did the meeting attendees have about these results?

Kay: One of the questions we got was regarding, you know, which patients respond and how they respond, and moderate responders versus high responders, that's something that I think is important to look at. I think the overarching theme of this gene-agnostic mutation, agnostic therapy, is that there's no specific target. As far as a gene target. The whole point of optogenetics is it's gene agnostic. So it doesn't matter which patients we do know they need to be severe vision loss patients. So and that qualifies to 20/200 or below visual acuity. In the trial, it was 20/1600 or below patients who were included. So we think of those as hand motion or below patients.

Now, if a patient was no light perception from birth, or had LCA or some congenital disease with no historic vision loss, those likely are not the best candidates. So there could be a floor effect with too low vision or no historic good precedent of vision. Again, this trial was targeting retinitis pigmentosa, not Leber congenital amaurosis or congenital blinding diseases. So there are certainly things that we've learned. We did collect genotype data during the trial, and there are super responders. There are patients who have had improvements into the 20/50 range, which is the theoretic, hypothetical ceiling of what a bipolar cell target could achieve. The bipolar cell matrix could allow for visual acuity, up to the 20/50 Snellen visual acuity.

So when I'm asked, "Is this clinically meaningful to patients? What does logMar visual acuity mean?" Because these are the types of patients I see in my IRD practice, I answer number one, these patients with this level of vision, they don't typically come in and have spontaneous improvement in vision. When they've lost this vision to this level, they tend to stay at that level or drop. So it is very clinically meaningful for them to have any improvement in visual acuity, to get from a hand motion to even see the 20/400 big E is a life changing improvement for those patients. For logMar, we know that from natural history studies of variability enter visit variability could be in the 0.15 range, so at anything in the 0.3 logMar is twice outside of visual of inter visit variability, and would be consistent with what the FDA considers to be approved for ETDRS vision, which, of course, is 0.3 logMar, 3 lines.

In essence, I do think it's clinically meaningful. I think it's visually significant to these patients, and I like the durability of the results as well as the safety with being able to reintroduce topical steroids if needed, and be able to get off those topical steroids. So I think this is very promising to my low vision patients with retinitis pigmentosa, who have very little, if no, other options for improvement. These are excellent results that are promising and exciting to be able to share today.