Promising Results: SYFOVRE’s Impact on GA Lesions Shown in Compelling Clinical Data
Charles Wykoff, MD:
Yeah. Hi, great to be here with everyone. I’m Charles Wykoff, retina specialist from Houston, Texas, medical and surgical, and also heavily involved in clinical trials and drug development.
Can you please provide a quick overview of the phase three studies of Syfovre and highlight the key findings and how they contribute to our understanding of Syfovre’s efficacy and safety?
Charles Wykoff, MD:
The DERBY and OAKS phase three global randomized sham controlled trials were a pivotal, essentially identical trials from a treatment perspective that occurred globally to assess pegcetacoplan compared to sham for the treatment of geographic atrophy. There were 1,258 patients enrolled and there were essentially three arms. There was pegcetacoplan given monthly, pegcetacoplan given every other month and sham injection for a total of two years. The primary endpoint was the one-year endpoint, 12 months, but then they were full trial duration of 24 months. And that’s what we have just published in the Lancet that just came out very recently.
Could you elaborate on the significant improvements in visual acuity and discuss the clinical significance for patients?
Charles Wykoff, MD:
Yeah, great question. So there’s sort of two major ways that I think about these clinical trials. DERBY and OAKS were very large clinical trials, 24 months is a long period of time, and there were really efficacy outcomes that we were looking at and safety outcomes. So it’s important to think about those each of their own silo and package within this data set. So from an efficacy perspective, we saw that with pegcetacoplan given monthly or every month or every other month, there were significant reductions in the growth of geographic atrophy through 24 months. And those reductions were 22 and 18% with monthly and every other month dosing in OAKS and then 19 and 16% with every month and every other month dosing in DERBY. So we really saw consistent slowing of the progression of geographic atrophy as measured by fundus autofluorescence through two years in the combined and individual DERBY and OAKS data set.
That’s sort of the anatomic end point. That was the end point upon which the FDA approved pegcetacoplan to be used for the treatment of geographic atrophy earlier this year in 2023. And that was the end point that the trials were designed around. Now, all the other efficacy end points that were pre-specified from a functional perspective, and they included best corrected visual acuity, reading speed, NEI VFQ-25, mean sensitivity by microperimetry.
All of the other functional analyses did not show a significant benefit with treatment. And so there was a little bit of a disconnect when you look at the efficacy signal, right, you see this robust consistent anatomic benefit, but you’re not really seeing this functional benefit. And one of the key post-hoc analyses, but I think is helping us better understand that was a microperimetry analysis in which we looked at the junctional zone around the area of geographic atrophy. And when we do that and look over time, we do see a trend or a benefit with pegcetacoplan treatment where there were fewer points that were lost to scotomas and also more preservation of mean sensitivity in that junctional zone for the microperimetry analysis. Again, a post-hoc analysis. And the one other efficacy point that I would make is a critical component of the anatomic endpoint, which was there appeared to be an increasing treatment effect over time, especially if you looked at six-month intervals, zero to six, six to 12, 12 to 18 and 18 to 24, the treatment benefit for slowing geographic atrophy progression appeared to increase over time.
So we covered the efficacy phyllo, and then if you pivot and now look at the safety, every treatment across medicine and surgery has sort of a risk-benefit ratio. And so we just talked about the efficacy, important to consider safety as well. From a safety perspective, few key points. First of all, exudative AMD. So the development of wet AMD concurrent with treatment with pegcetacoplan appeared to be dose-dependent with between 11 to 13% of patients developing wet AMD in the study eye with monthly pegcetacoplan, 6 to 8% developing wet AMD with every other month dosing compared to 2 to 4% in the sham arm. Additionally, other safety events that were noted were ischemic optic neuropathy and intraocular inflammation. And finally, since being commercially available, there have been rare cases of vasculitis, which have not been observed in any of the prospective clinical trials with pegcetacoplan to date.
Were there any unexpected or particularly promising observations that emerged from these long-term studies?
Charles Wykoff, MD:
Yeah, I think the most interesting observation from these clinical trials was the increasing treatment effect side over time. This wasn’t something that I was predicting to see, where we see sort of a treatment effect in the first six months and then that grows in each subsequent six months. But by the end of the two-year period, in that last six-month interval, there was a 30% reduction with monthly dosing and 24% reduction with every other month dosing with pegcetacoplan treatment. I think that that’s fascinating. We don’t really understand the biology behind that yet. It could be that there are photoreceptors and RPE cells that are really predestined to atrophy when pegcetacoplan is being initiated. And as that sort of predetermined cell death zone occurs and transitions to atrophy, you have healthier tissue that’s left at the edge of atrophy over time. So you may be seeing an increase in treatment benefit the more preserved photoreceptors and RPE cells that we may be protecting over time.
I think the other thing related to that anatomic endpoint, which is not in the Lancet paper, but it’s fascinating work out of a couple of OCT laboratories, is that there appears to be a greater impact on slowing photoreceptor loss with pegcetacoplan than is observed with the fundus autofluorescent changes when we’re looking at geographic atrophy on lesion side over time.
Could you provide some insights into the safety profile of Syfovre, especially in the context of a two-year study period?
Charles Wykoff, MD:
Yeah, great question. This is what we referred to before, so really important to always think about efficacy and then equally important to think about safety. And I would mention four things related to safety. And before we get into those details, it’s important when you’re communicating with patients about any intravitreal injection that there are risks with every intravitreal injection. And those risks that I think are constant across all injections are infection, so endophthalmitis, traumatic cataract, retinal tears, retinal detachments, et cetera. And then specifically related to pegcetacoplan in this series, I would put really four risks to think about.
One is the development of wet AMD in the study eye. We know this was dose dependent. We published this in the phase two data set and we saw a very similar trend in the phase three data set. And the baseline risk factors for that that are critical are a fellow eye history of wet AMD. In other words, if a patient has a history of wet AMD in one eye and they have geographic atrophy in the other eye and you’re treating the geographic atrophy eye with pegcetacoplan, be careful because that history of a fellow eye wet AMD is definitely a risk factor for the other eye to convert to wet AMD with or without pegcetacoplan treatment.
So be aware that wet AMD is a possible side effect of pegcetacoplan. And the reason that’s important clinically is to make sure that we are looking at OCT volume scan in these patients regularly. That said, if they do develop new exudative AMD, that we identify that at the earliest possible time that patients can be treated appropriately because there’s very good data going back many years that the earlier someone’s diagnosed with wet AMD and the earlier they’re treated, the better the long-term outcome. So critical to catch that sort of side effect early if and when it happens. And we know it is dose dependent. So we know 11 to 13% of patients with monthly dosing will develop [inaudible 00:08:46] over two years compared to 6 to 8% with every other month compared to 2 to 4% with sham. That’s the first.
The second one is intraocular inflammation. This was observed in patients in DERBY and OAKS as it was in the FILLY phase two trial. The majority of these were mild to moderate. And the majority of these patients, I think 77% of them, continued pegcetacoplan treatment even after developing intraocular inflammation. And these cases in the vast majority of cases were responsive to topical steroids without longterm sequelae. The third is ischemic optic neuropathy. This appears to be a more rare event. This has been seen more commonly with monthly dosing compared to every other month or sham dosing, and we don’t really understand the mechanism behind that at this stage. One thing to be aware of is that it appears that most of the patients that have developed ischemic optic neuropathy have what’s called a disc at risk, which is sort of a full optic nerve head. So it’s a risk factor to be aware of at baseline.
And again, just like the concept of looking at the volume scan for early transitions of wet AMD, make sure that you’re occasionally looking at the optic nerve head for any signs of swelling because if there are any signs of swelling, it’d be nice to catch that before it becomes clinically relevant or the patient loses vision due to ischemic optic neuropathy and the medicine could be discontinued if any optic nerve swelling is developing. And the final one, the fourth one was actually not seen in the clinical trials, but I think it’s important to mention it because it’s been reported in the commercial setting, which is rare cases of vasculitis and in some cases severe vision loss. And that is a possibility. The vast majority of these cases in the real world to date have occurred after the very first injection and it’s still a topic that’s actively being explored.
In terms of practical implications for healthcare providers, how might the results of these studies impact their approach to treating patients with GA?
Charles Wykoff, MD:
It’s an exciting but a challenging time for geographic atrophy management, I would say. We have now pegcetacoplan, we also have avacincaptad. So we have two FDA-approved agents for the management of geographic atrophy. And I think that it’s important that patients with geographic atrophy secondary to age-related macular degeneration are aware that these treatments exist. The phrasing I use with patients is that these are meaningful medications, I believe these are good medications, however I don’t think that these are great medications. I use that phrasing with patients and then I go on to describe why I feel that way.
I believe that they’re good because I think they do flow the progression of geographic atrophy in a meaningful way. Of course, I would like to see a larger efficacy size here. I’d like to see them reduce the progression of geographic atrophy by a larger percentage. But the data is what it is. And we have now treatment for this disease. But they’re not great medicines because, A, they don’t stop the progression and B, they don’t reverse it and bring patient’s vision back. And that’s what patients are really looking for in many cases.
And so it’s really important to me that patients understand their shortcomings, they also understand the risk of injections and the risk of the specific medications. But in that context, I’ve found that many patients are interested in receiving anti-compliment therapy to try to slow their progressive irreversible disease. So important that patients are aware these medications exist, important that they’re informed as to what to expect from an efficacy and treatment perspective and also what the potential risks are.
Looking forward, what are the next steps in the development and research of Syfovre, and what can the medical community and patients anticipate in terms of future advancements or studies?
Charles Wykoff, MD:
Yeah, great question. I think the Syfovre or pegcetacoplan phase three trials were large, very large studies, over 1,200 patients treated over two years, and they’re randomized on very impressive global trials. And what’s even more impressive to me are the long-term extension study results. So OAKS and DERBY transitioned into GALE, G-A-L-E, which is an open-label extension study. And remarkably, 83% of patients that completed OAKS and DERBY decided to continue on with therapy into GALE. And what happened there was that patients that were receiving monthly or every other month pegcetacoplan continued on their initial randomized arm. And then patients initially in sham, transitioned over to active treatment with pegcetacoplan either monthly or every other month. Because originally the sham patients were randomized into monthly or every other month also.
And so we now have a wealth of data through the extension study. It’s actually a three-year extension studies. Ultimately, we’ll have five years worth of data of treatment for these patients, which is a tremendous treasure trove of data that we will be able to use to better understand this disease itself and also the effects of pegcetacoplan. And so far, we have 36-month data, so one-year data with GALE plus the two years of data from OAKS and DERBY. And we’re seeing the same trend, most importantly in my perspective, in an increasing efficacy signal through one year within GALE. So we’re seeing, again, that increasing treatment effect over time with both monthly and every other month dosing. And we’ll be showing that data for the first time this year at the AAO meeting.
Are there any other key takeaways or insights you’d like to share with fellow healthcare professionals based on these phase three results?
Charles Wykoff, MD:
The last 20 years have seen a tremendous evolution in the ability to treat wet age-related macular degeneration. Our anti-VEGF therapeutics have proven remarkably effective at reversing vision loss, improving vision, stabilizing vision in many, many patients globally with wet AMD. It’s been a huge breakthrough for the field that we are still utilizing tremendously across the globe today for wet AMD. And when I look at dry AMD, I’m hopeful that over the next 20 years we’ll be able to have similar strides in managing dry AMD.
And when I look at pegcetacoplan, I see this as a first step. A meaningful, important, critical first step, but it won’t be the last step. And I do think pegcetacoplan is a meaningful introduction to the space for patients that are interested in receiving it to slow the progression of their anatomic disease. And I do believe that with longer-term therapy and higher-resolution functional imaging around the areas of geographic atrophy, we’ll be able to more definitively demonstrate a functional benefit for patients being managed with pegcetacoplan over time in geographic atrophy. Although, a lot of that data has yet come and many other analyses are ongoing to try to better understand that.
So it’s an important step forward, but again, there are challenges to these medications. It’s a lot of injections over time, either monthly or every other month dosing. And there are risks that patients need to be aware of before initiating therapy. And then it’s also important to communicate with patients that these are long-term options. An injection or two and then stopping is not going to help the patient. So it’s really a long-term commitment on the patient’s part to receive pegcetacoplan therapy in attempt to slow the progression of their disease. And there are many other therapeutics in development that I am hopeful over time will lead to even better efficacy and improved safety and improved durability for our patients long-term.
Lastly, could you summarize the broader impact that Syfovre could have on the field of ophthalmology and the lives of patients affected by GA?
Charles Wykoff, MD:
Yeah. Geographic atrophy is a progressive blinding, irreversible disease, and this has remained, in my opinion, one of the largest unmet needs in all of eye care in the United States and many countries around the world. And so I do think it’s quite meaningful for ophthalmology in general that we now have a treatment for geographic atrophy in pegcetacoplan. And we have two FDA-approved therapies with pegcetacoplan and avacincaptad, and that is quite exciting and quite meaningful for the field. Again, these medications are effective, I believe they’re clinically relevant, but their effect size is relatively modest.
And so I think we’re going to learn a lot more over time about the potential functional benefits of long-term therapy through, again, the ongoing GALE, long-term extension studies, which will have five-year data. Additionally, many other analyses from real-world data sets, looking at both anatomic and functional outcomes with these anti-compliment therapeutics, I think are going to be quite useful in directing us towards who are the patients that would most benefit from therapy. And then I think looking over the horizon, I think that the introduction of these medications into clinical practice is exciting because I hope that they are just the first among many therapeutics to help patients with AMD, both earlier stages eventually and geographic atrophy, to slow the progression of their disease over time.
This content is independent editorial sponsored by Astellas. Astellas had no input in the development of this content.