Dr. Nadia K. Waheed reviews the latest updates on the FOCUS trial, evaluating AAV-based viral vector GT005 for the treatment of geographic atrophy.
At the Angiogenesis, Exudation and Degeneration meeting, Nadia K. Waheed, MD, MPH, presented her talk entitled, “CFI Supplementing Gene Therapy in GA Clinical Trial Update.” She discussed the Phase I/II study for the AAV-based viral vector, GT005, from Gyroscope Therapeutics.
Sheryl Stevenson: Dr. Waheed, thank you so much for joining us at this year's Angiogenesis meeting, and we look forward to learning more about your presentation. Could you tell us more about your talk regarding CFI supplementing gene therapy in geographic atrophy?
Dr. Waheed: Absolutely. Sheryl, thank you so much for having me and just really enjoying the talks at Angiogenesis this year. I presented on a complement factor I supplementation in patients with geographic atrophy using a gene therapy approach. So these are some of the preliminary results from the focus study.
And the focus study is a Phase 1/2 study using Gyroscope Therapeutics GT005, which is an AV2-based viral vector that is injected subretinally in the subretinal space, and produces complement factor I. Now complement factor I, as you know, is a natural factor produced, and it's one of the only inhibitory enzymes within the complement system. So the goal of complement factor I is actually to slow down the over-activation of the complement and to push back the hyperactivity of the complement system that takes place.
So in this study, it consists of two parts. It's a first inhuman Phase 1/2a study, and there's a dose escalation phase with GT005 using three different doses, and then there's a dose expansion phase using the standard transvitreal subretinal surgical approach.
Now additionally, in part 2 of the study, we use a different surgical approach and the surgical approach uses the orbit subretinal delivery system, which is a specific specialized system that delivers gene therapy into the subretinal space, truly into the subretinal space, without doing a transvitreal surgery and thereby avoiding the risks of the of the tranvitreal surgery.
So the results that I presented were primarily of the transvitreal surgery with a little bit on the ongoing subretinal delivery system or subretinal delivery system surgeries as well, are mostly just the safety data from there. And, you know, what we saw was that subretinal gene therapy with GT005 appear to be a well-tolerated.
Additionally, you know, one of the things that's unique about this study is that it has a very robust sampling and biomarker measurement profile. So we do something in the vitreous space and look for a complement factor I levels before and after administration of the gene therapy. And what we saw was that there was a significant sustained increase in complement factor I levels that persisted out to a year and for some patients, we have two-year data, and we see that there's still elevation of these complement factor I levels at the two-year time point.
Additionally, what was really interesting, you know, if complement factory I actually does what it's supposed to do, which is it down regulates the complement system, then you would expect to see some of the byproducts of the complement system, as well as the byproducts of the amplification loop of the complement system to go down, right? And so what we did see was that, you know, that the byproducts of inhibiting with CFI, you know, the byproducts of C3 breakdown products actually did go down in our patients, they went down in a very significant and sustained way, and continued to be reduced all the way to the to the one-year sampling time point. And in the small number of patients that we have followed out two years, we also saw that BA, which is a measure of the amplification loop of the complement system, was also downregulated. So a significant sustained reduction in BA levels at a level at which we expect it to be if we were truly inhibiting the complement system in a clinically meaningful way.
And then additionally, you know, if it is inhibited, then you would expect chronic inflammation to go down. And as a result of chronic inflammation going down, you would expect C3, which is input into the complement system to go down as well. What was really interesting—and I do think this is the first time that it's ever been seen—is that not only do the downstream products go down, but the entry product, which is C3, also was reduced in these patients when we looked at them at the one-year time point. And this seems to correlate with a reduction in chronic inflammation in these patients.
So really, really interesting results from my perspective, just looking at, you know, the biomarker data from here and of course, the study is ongoing. It's looking also at geographic atrophy lesion size. And additionally there are two Phase 2 studies, the HORIZON and EXPLORE studies, that are ongoing using, you know, the same GT005 gene therapy product with CFI supplementation that are currently enrolling and hopefully will give us a better answer in terms of the clinical endpoints for these patients.
Sheryl Stevenson: Excellent, very interesting results. Dr. Waheed, thank you so much for your valued insights.
Dr. Waheed: Thank you so much, Sheryl. Thank you for having me.
Note: This transcript has been lightly edited for clarity.