Industry leaders view pegcetacoplan as most important retinal technology in 10 years.
Retina specialists now have another tool to take on geographic atrophy (GA), with the FDA’s approval of intravitreal pegcetacoplan (Syfovre; Apellis Pharmaceuticals, Inc) injection as the first and only approved treatment for GA secondary to age-related macular degeneration (AMD). The FDA announced its approval on February 17, based on the results of the 24-month phase 3 data submitted in its new drug application in November 2022.
In a statement, Apellis noted that the top-line findings show that pegcetacoplan slows GA progression, with increasing effects over time; is approved for all patients with GA, with dosing flexibility every 25 to 60 days; and has a well-demonstrated safety profile following approximately 12,000 injections over 24 months.
Physicians are expressing enthusiasm about the availability of this drug in the retinal armamentarium. “The studies with complement inhibitors provide proof of principle that complement is indeed involved in GA and that inhibition slows the process. It is an important first step and provides hope for our patients with advanced atrophic AMD. The decision about treatment will be individual between the physician and each patient regarding the need for injections and whether the anticipated benefit will be appreciated as improved quality of life by the patient,” said Mary Elizabeth Hartnett, MD, FACS, FARVO, FASRS, the Michael F. Marmor, MD, Professor in Retinal Science and Disease, professor in ophthalmology and visual science, and director of pediatric retina at Byers Eye Institute at Stanford University in Palo Alto, California.
Peter J. McDonnell, MD, director of the Wilmer Eye Institute in Baltimore, Maryland, and chief medical editor of Ophthalmology Times®, pointed out that it was a major advance to have a therapy for neovascular AMD and now, considering the much larger number of patients with atrophic AMD, this represents an even greater achievement in terms of addressing an unmet need. “The availability of this new therapy will have major implications in terms of the ability of ophthalmologists to treat this extremely large number of patients and for payors, [especially Medicare], to absorb this additional cost,” McDonnell said.
Rishi P. Singh, MD, president of Cleveland Clinic Martin North and South Hospitals in Stuart, Florida, noted that pegcetacoplan offers a new option for ophthalmologists to consider when treatment patients with these diseases.
“It is a value to patients and providers of care, with regards to what it can do to slow the progression of this disease state over time,” he said. “It will be taken and monitored with its efficacy and safety together as the real-world analyses are started. We are going learn a lot in the first year of treatment as to what this drug holds for our patients and for their potential progression of [GA] over time.”
Eleonora Lad, MD, PhD, lead investigator for the OAKS study, director of ophthalmology clinical research, and associate professor of ophthalmology at the Duke University Medical Center in Durham, North Carolina, said, “Until now, there have been no approved therapies to offer [patients] living with GA as their vision relentlessly declined. With Syfovre, we finally have a safe and effective GA treatment for this devastating disease, with increasing effects over time.”
“This is the most important advance in more than a decade. It represents our most important advance since anti-[VEGF] injections were introduced,” Charles C. Wykoff, MD, PhD, said.
Wykoff, a principal investigator in the phase 3 trial of pegcetacoplan, explained that
the factor most important to him was the demonstration of the increasing efficacy of the drug over the 2-year course of the DERBY (NCT03525600) and OAKS (NCT03525613) studies.
“This increasing efficacy over time is critical. The most important point to emphasize to doctors and providers is that the benefit that the drug provides in preserving retinal tissue increases over time,” he said. “The longer the patient is treated, the more benefit will be achieved.”
This increased benefit was observed in the data from the 6-month intervals extending from baseline to 24 months. The combined data from the DERBY and OAKS trials, which included 621 and 637 patients, respectively, from baseline to the 2-year time point showed that the percentages of GA growth decreased by 21% and 17%. The key is that with pegcetacoplan treatment, GA progression does not worsen as rapidly as it would have, had the patients not been treated.
A look at the first 6-month segment showed a reduction in GA progression of approximately 12% to 13%. However, Wykoff noted that the reductions in growth ranged from 24% to 30% during the last 6-month period. “This was a substantial increase in the efficacy over time,” he said.
Regarding safety, there is an increased risk of wet AMD development with treatment; the data showed 12%, 7%, and 3% of patients developed wet AMD in the monthly, ev- ery-other-month, and sham arms. In addition, intraocular inflammation developed in some patients, the cases of which were largely mild; most patients continued with pegcetacoplan following resolution of the inflammation. Other adverse reactions (≥ 5%) reported were ocular discomfort, vitreous floaters, and conjunctival hemorrhage.
Another important point that should be explained to patients is that although GA growth is slowed meaningfully, the data did not show improvement in visual function.
In the studies on which the FDA approval was based, the study eyes treated with pegcetacoplan had advanced dry AMD (ie, GA and not neovascular AMD) at baseline and had never been treated in that eye with anti-VEGF therapy. As mentioned, some patients developed wet AMD during the trial and received both anti-VEGF therapy and pegcetacoplan injections on the same day to address both the wet AMD and GA.
This is an important point regarding clini- cal application, according to Wykoff, because the patients with wet AMD are a large population in retina practices, they are receiving anti-VEGF injections, and they have progressively worsening GA. Physicians will have to explain that although the retinal bleeding from the neovascular AMD is controlled, the GA is worsening and vision is decreasing as a result, and more treatment is needed to slow the GA. This will represent substantially more treatment, but in this group, something to which they are accustomed.
In patients with only GA, physicians will be faced with a discussion with each patient of when therapy should start. “Some will embrace early therapy to prevent GA from involving the central vision and attempt to preserve it over the long term with many years of treatment, [whereas] other patients may decide to wait until they become symptomatic before starting treatment. There will be a balance between discussing the need for repeated treatments, the strength of the efficacy, and the safety signal with patients so they can make individual decisions about what is appropriate for them,” he said.
Pegcetacoplan became available for use in clinical practice at the beginning of March through specialty distributors and specialty pharmacies nationwide.
Pegcetacoplan is an investigational, targeted C3 therapy designed to regulate excessive activation of the complement cascade, part of the body’s immune system, which can lead to the onset and progression of many serious diseases.
The 24-month efficacy data obtained from the phase 3 DERBY and OAKS studies were the basis for the FDA approval. “These data showed robust and consistent effects with monthly and every-other-month pegcetacoplan treatment in both studies,” according to a statement from Apellis.
OAKS and DERBY are phase 3, multicenter, randomized, double-masked, sham-controlled studies conducted to compare the efficacy and safety of pegcetacoplan with sham injections across a broad and representative population of patients with GA secondary to AMD. The primary objectives of the studies were to evaluate the efficacy of monthly and every-other-month pegcetacoplan in patients with GA, assessed by change in the total area of GA lesions from baseline as measured by fundus autofluorescence at 12 months. Patients continued to receive masked treatment for 24 months.