The year 2023, with FDA approvals for both pegcetacoplan (Syfovre; Apellis Pharmaceuticals) and avacincaptad pegol (ACP; Izervay; Iveric Bio/Astellas), was a truly incredible year for retina specialists. At the 2023 annual meeting of the American Academy of Ophthalmology (AAO), 24-month data on GATHER 1/2 (ACP) and 3-year extension GALE data (pegcetacoplan) were presented. These data provide further evidence on the clinical efficacy of both drugs.
Given that there is no current clinical or imaging endpoint to know that the drug is “working” for each patient, long-term studies comparing treated and untreated patients are essential to provide guidance to retinal specialists. To be most adept at applying these data in the real world, it’s worthwhile to review the nuances of the extension studies and the conclusions. I have asked 2 incredible retina specialists, Vaidehi Dedania, MD, and Talia Kaden MD, to provide their interpretation of the data and share some thoughts on how they are starting patients on treatment.
Two-year Data on Avacincaptad Pegol
Vaidehi Dedania, MD
At the recent AAO annual meeting in San Francisco, the 24-month top-line results from the phase 3 GATHER2 clinical trial were presented.1 The results demonstrated that ACP met the primary objective of slowing geographic atrophy (GA) growth when compared to sham. When breaking down the 1-year and 2-year data, we first need to understand the statistical analyses performed for both groups.
If we start with 1-year data, it was slope analysis that the Food and Drug Administration (FDA) required. This was also used for the 2-year efficacy data endpoint for change in GA lesion growth. As this model assumes a constant rate of growth vs a nonlinear rate of growth, there was also a secondary piecewise analysis for the 2-year data. For the piecewise analysis the 24 months were split into 6-month segments. This means there was not a single slope from baseline to 24 months, but rather a slope for each 6-month segment as GA growth is not linear. As the segments were separated into 6 months, the numbers are slightly different from the year 1 data. For example, at 1 year there was a 17.7% GA growth reduction compared to 14% in the 2-year data. Looking at these data, it may seem that the treatment effect went down, but the piecewise analysis showed an increase in treatment effect over time instead of a constant rate.
These data remain promising, and as we continue to consider and use the therapy for our patients, counseling is crucial. I take a few factors into consideration when deciding which eye is the ideal eye and when counseling patients on the risks and benefits of treatment. Although the current indications for treatment include subfoveal, I have not treated anyone to date with subfoveal involvement. For a patient with bilateral GA, I start with the eye that has faster progression (based on previous images) and/or with the larger area of GA. After a series of 3 to 4 injections, the patient has a greater understanding of the experience, so I recommend proceeding with the fellow eye. I counsel patients with significant vision loss in 1 eye similarly to other patients because there are similar factors to consider, especially preservation of vision in the better-seeing eye.
When counseling patients on risks and benefits, I discuss the standard list as I would with any intravitreal injection. More recently, there has been focus on retinal vasculitis with and without occlusion, and while I discuss this with patients, I also direct them to the data, which has shown an overall very low rate of 0.01%. Finally, when counseling on the risk of choroidal neovascularization, at month 24, I discuss that the risk was 11.6% in the combined group (monthly and every other month [EOM]) and 9.0% in the sham group. Understanding the data and the effects of therapy are essential to our growth as a field in developing and implementing therapies to enhance the lives of our patients.
Three-year Data on Pegcetacoplan
Talia R. Kaden, MD
The last few months have been exciting, with the FDA approval of both pegcetacoplan and ACP. There have been readouts from GATHER2 and GALE, which provided 24-month ACP data and the 36-month pegcetacoplan extension data. When evaluating these, or any other trial data, it’s crucial not only to assess the top-line results, but also to try, as much as possible, to understand the details of the studies. To that end, these are some of the points to look at: what are the treatment arms and how are they defined (ie, when were patients treated, is the sham real or projected), and what are the final endpoints of the data?
In looking at the 24-month ACP data from GATHER2, it’s important to recognize the shift that occurred in the treatment groups at month 12. From month 0 to 12, there were only 2 groups — the patients who received treatment monthly and the patients who received sham monthly. At month 12, the ACP treatment group was split into 2: a group that continued with monthly treatment and a group that was converted to an EOM treatment with sham injections during the alternating months. This means that when evaluating the data at month 12 vs month 24, it is crucial to identify which treatment group you are considering. This also shifted the numbers in each group, effectively halving the number of patients in the monthly treatment.
GALE is the extension study for OAKS and DERBY and provided a look at 36 months of continuous treatment with pegcetacoplan. Again, there was a switch in group definition in this study. At the completion of the 24-month OAKS/DERBY trials, the sham groups (both monthly and EOM arms) were converted to paired treatment arms (ie, monthly sham became monthly treatment, EOM sham became EOM treatment). So, when looking at the sham group at 36 months, this is a projected sham based on data from months 0 to 24.2
In considering the GALE data, I was particularly interested in the relative advantage that monthly treatment demonstrated as compared to EOM treatment. In contrast to the year 2 data, where there was not a big difference between outcomes for monthly or EOM treatment when compared to sham (23% vs 22% reduction in GA lesion growth), at 36 months, there seemed to be a significant difference between the groups (35% vs 24%). Thus far, I have been treating my patients on an EOM basis, using the OAKS/DERBY data as a guide. If in fact this difference is borne out in both clinical trials and real-world data, I am likely to consider offering monthly treatment or potentially converting to monthly treatment after 2 years of initial therapy. For now, given the numbers in the study (around 100 patients in both the monthly and EOM groups), I am likely to maintain my practice patterns.
A treatment that would stop or reverse patients’ disease is not available right now, and that is exactly what I tell my patients. At best, these drugs can slow the rate of progression. This is admittedly not where we’d like to be as a field, but until we have that therapy, these drugs are our best option and to that end I try to be as informed as possible so I can best counsel and guide my patients in their decision-making.
Thus far, I am mostly treating patients who have already noticed a significant change in their vision because of their GA, either from notable nonsubfoveal scotomas in the treated eye or subfoveal scotomas in the fellow eye. These patients are often proactive in asking about the treatment because of their frustration over their noted change in vision.
If they are new to my practice, I will not treat them at the first visit, but rather suggest they discuss the treatment with their family or trusted friends prior to scheduling their first injection. Given the long-term nature of the disease and the expectation that we will be seeing each other regularly for some time, I want to be sure they are comfortable with the risks and potential benefits before initiating treatment. RP
Editor’s note: Listen to discussion of this article on the Retina Podcast at www.retinapodcast.com.
References
1. Iveric Bio announces positive 24-month topline results from phase 3 study of Izervay (avacincaptad pegol intravitreal solution) for geographic atrophy. News release. September 18, 2023. Accessed January 25, 2024. https://www.prnewswire.com/news-releases/iveric-bio-announces-positive-24-month-topline-results-from-phase-3-study-of-izervay-avacincaptad-pegol-intravitreal-solution-for-geographic-atrophy-301931191.html
2. Syfovre (pegcetacoplan injection) continued to demonstrate increasing treatment effects over 3 years in patients with geographic atrophy (GA). News release. November 4, 2023. Accessed January 26, 2024. https://investors.apellis.com/news-releases/news-release-details/syfovrer-pegcetacoplan-injection-continued-demonstrate-0
