In February 2023, the US Food and Drug Administration (FDA) approved a new drug for the treatment of age-related macular degeneration (ARMD). The drug, pegcetacoplan (commercial name Syfovre™), is produced by Appelis Pharmaceuticals. This is the first drug approved for treatment of dry macular degeneration. Among eyecare specialists, enthusiasm around this event has been mixed.
There is uncertainty about which patients should be treated with this new drug, and who will benefit. The context is analogous to a pair of drugs recently approved for Alzheimer’s disease. Aducanumab (Aduhelm) was FDA approved for treatment of Alzheimer’s disease. The clinical trials were initially ceased due to futility. Despite a “no” vote by a panel of experts the FDA granted approval based on post hoc analyses of a biomarker (reduction of amyloid beta plaque) without demonstrating a benefit in any clinical measure. The approval of this drug was controversial and discussed in more detail by Scott Gavura and Steven Novella.
Lecanumab (Leqembi) was also approved for Alzheimer’s disease. Compared to placebo, the drug slowed progression of dementia, but there were safety concerns and per Steven Novella, the slowing of the clinical course over the 18 months of the clinical trial were “modest.”
In terms of persuasiveness, the clinical trial data for pegcetacoplan for age-related macular degeneration fell somewhere between the 2 drugs for Alzheimer’s disease. Pegcetacoplan met its primary study endpoint and clearly modified the progression of ARMD, but like aducanumab, did not demonstrate a benefit in any measure of visual function. Like lecanumib, there are safety concerns.
About Macular Degeneration
In a previous SBM article I gave a background explanation of ARMD, with a focus on wet (or exudative) ARMD
Dry ARMD is the most common form, and patients with dry ARMD live in fear of developing the more rapidly progressive wet (or exudative) form. Wet AMRD is not the dismal relentlessly progressive disease it once was. I previously wrote about new treatments that have revolutionized and dramatically improved outcomes among patients with wet ARMD. These treatments are inconvenient because they require repeated injections of medication into the eye, but they are quite effective in stabilizing or improving vision. Since that article appeared on SBM two new drugs have been approved by the FDA for treatment of wet ARMD.
The vast majority of patients have dry ARMD. Dry ARMD tends to progress much more slowly than the wet variant, but is a threat to vision, nonetheless. There is a gradual deterioration of the structure and function of tissues in the macula. Among patients with dry ARMD those that develop a variant called geographic atrophy suffer the greatest loss of vision. In geographic atrophy, regions of the macula undergo profound loss of structure and function. These atrophic regions correspond to blind spots (scotomas) in vision. The zones of geographic atrophy enlarge over time. Because the blind spots are in or near the center, they are highly consequential in visual function.
Intravitreal injection
The route of drug delivery for the most effective treatment of wet ARMD is by intravitreal injection. This is a procedure performed in the office under local anesthesia. A small needle is inserted through the white part of the eye, into the vitreous. A small volume of drug is injected. It is tolerated surprising well by patients, and has a low rate of serious adverse effects. Pegcetacoplan for treatment of dry ARMD is delivered in the same way.
A video depicting intravitreal injection is linked here (not for the squeamish).
Pegcetacoplan: the good
Pegcetacoplan is a complement inhibitor. Complement is part of the immune system and the complement pathways are known to be involved in the pathophysiology of macular degeneration. The design of the pegcetacoplan clinical trials targeted geographic atrophy.
Patients entering the phase 3 trials had geographic atrophy at study entry. They were randomized to receive: pegcetacoplan every month, pegcetacoplan every other month, or sham treatment.
Through 24 months pegcetacoplan at both dosing frequencies decreased the growth of the geographic atrophy compared to sham treatment. This has rightly been hailed as a major victory…the first first drug definitively demonstrated to slow the progression of dry ARMD. The FDA looked favorably on these results and approved pegcetacoplan injection (commercial name Syfovre™) to be sold for treatment of geographic atrophy.
Pegcetacoplan: the bad
Wet macular degeneration is the rare, but most feared form of AMRD. Anti-VEGF drugs, delivered by intravitreal injection have revolutionized treatment of wet ARMD, but these treatments are inconvenient, uncomfortable, and expensive. Compared to sham-treatment, eyes treated with pegcetacoplan every other month were roughly twice as likely to develop wet ARMD. Eyes treated monthly were roughly four times more likely to convert. This is a serious disadvantage. Prior to the availability of effective treatment for wet ARMD this would have been an intolerable adverse effect. It is still highly undesirable. We are trading the hope of decreasing the risk of vision loss from geographic atrophy with increasing the risk of another vision threatening form of macular degeneration, wet ARMD.
If a patient develops wet ARMD while treated with pegcetacoplan, they can continue intravitreal injections with pegcetacoplan every 1-2 months, but they must also begin treatment with an intravitreal anti-VEGF drug, usually initiated with monthly intravitreal injections, and sometimes requiring monthly treatment for life.
Pegcetacoplan: the unfortunate
The results of the phase 3 clinical trials leading to FDA approval of pegcetacoplan for macular degeneration are not yet available in a peer-reviewed article. It is always uncomfortable to advise patients on a new treatment with incomplete information. Information is limited that which has been presented at meetings, and in press releases. In addition to the increased risk of exudative ARMD there are more disappointing features.
In a large clinical trial like this, the sponsor identifies a primary endpoint. This is the measurement on which success or failure is defined. The endpoint for pegcetacoplan clinical trials was an anatomic one: change in size of geographic atrophy (GA). From a study design perspective, GA size is a nice variable. GA is easy to measure using standardized imaging techniques. Changes are relatively easy to quantify. Measurements can easily be blinded to patient treatment assignment and managed at a centralized reading center. Pegcetacoplan at both dosing intervals decreased the rate of growth of GA compared to sham treatment.
Patients are less interested in anatomic endpoints and more interested in outcomes reflecting visual function: how will this treatment affect/protect my vision? Measures of visual function would be things like visual acuity, field of vision, contrast sensitivity, reading speed, etc.
None of the visual functional endpoints reported by the sponsor, so far, have shown a significant benefit for the drug vs sham treatment. In addition there are always secondary endpoints in the analysis plan. It is safe to infer that no secondary endpoints measuring a functional visual outcome achieved statistical significance. If they had, those particular result would have been highlighted in the current reports. Given a clinical trial of this size (over 1258 patients) and duration (2 years) the inability to demonstrate a tangible benefit to patients is disappointing.
The Buzz
I understand why the FDA approved this drug. It achieved its primary efficacy endpoint. It is the first entry addressing a major unmet medical need.
The press reports accompanying the approval of this drug has included many breathless endorsements declaring a “breakthrough” and providing “hope” to patients.
Despite the enthusiastic hype there have been some skeptical voices. These have mostly been confined to peer-to-peer conversations and QA sessions at meetings, but few have made their way into print.
Demetrios Vavvas, MD, PhD Professor of Ophthalmology at the Harvard School of Medicine stated he will not be offering the drug to any patient:
“So if a patient comes in and asks you, ‘Will I see any benefit?’ the answer is no. There is no improvement in any symptoms or quality of life or any functional index that was tested.”
The Bottom Line
This was an important and path-breaking study. It provided proof of principle that pharmacologic intervention could influence the progression of a blinding form of dry macular degeneration, It validated the complement pathway as a target for intervention. There are numerous other drugs in the pipeline.
But, does this particular drug, as administered in these clinical trials, provide sufficient benefit to justify the cost, inconvenience, and risk? In my opinion, the available evidence has not answered this most-critical question.
I expect this drug to be heavily marketed to physicians and to potential patients.
Faced with ambiguous data like these, educating patients and providing informed consent is a true challenge. How do I, in the limited time allowed in a clinical encounter, explain a treatment that attenuated the progression of the disease, but did not result in a functional benefit, and…by the way…doubled to quadrupled the risk transformation to a more aggressive (but treatable) form of the disease.
The way I have explained this to patients goes something like this: “…Some of the people received eye injections with the drug and some did not. After 2 years, the pictures looked better in the patients that received the drug, but they did not see any better. They were also more likely to develop an aggressive form of macular degeneration that requires more eye injections“
There are undoubtedly patients who will choose to proceed. For example, if I was a patient that had experienced loss of vision in one eye due to geographic atrophy, I might roll the dice and begin treatment in the other eye.