Eighteen years ago the Food and Drug Administration (FDA) approved the first anti-VEGF drug for wet Age Related Macular Degeneration (ARMD); a treatment that transformed wet ARMD from a relentlessly progressive, disabling condition to a manageable one. A major limitation of anti-VEGF medications is that they are relevant for a minority of patients with ARMD. Only about 15% of patients with ARMD develop the wet (or exudative) form. A safe and effective treatment for the more common dry form of ARMD remained an unmet medical need. Last year the FDA approved pegcetacoplan (Syfovre™), Apellis Pharmaceuticals), the first treatment for dry ARMD. Specifically, pegcetacoplan was approved for geographic atrophy, the most destructive variant of dry ARMD. Like the available treatments for exudative macular degeneration, pegcetacoplan is delivered by intravitreal injection. In this article I hope to address the question of whether or not this new treatment satisfies an unmet medical need.
Apellis, the company behind pegcetacoplan, has launched a low-key advertising campaign. You may have seen the ads — the PSA-style TV commercials themed “GA won’t wait” featuring spokesperson Henry Winkler. It is a “raising awareness” infomercial that introduces the abbreviation “GA” as an abbreviation for geographic atrophy. The name of the drug is never mentioned, but viewers are advised to see a doctor if they experience certain symptoms. The address to an informational website is given.
I wrote a previous SBM article entitled: A new treatment for macular degeneration: The Good, The Bad, and The Disappointing. In that article I explained that preliminary reports disclosed an anatomic advantage, but no functional benefit for treated eyes. Treated eyes were also more likely to progress from dry to wet macular degeneration. At that point there was no published report of the phase 3 clinical trials. Since then there have been some emerging safety concerns, as well as publication of the phase 3 data.
The phase 3 studies
The FDA approval of pegcetacoplan was based on a pair of nearly-identical phase 3 clinical trials called OAKS and DERBY. A published report appeared in The Lancet, October 2023, linked here. (Probably behind a paywall for most of you).
In both studies, eyes were randomized to receive intravitreal pegcetacoplan every month, intravitreal pegcetacoplan every other month, or control (sham injection). The success of pegcetacoplan was based on the measurement of geographic atrophy (GA) from specialized retinal photographs. The primary endpoint was the growth rate of GA in the treated eyes compared to sham-treated for 12 months.
In the OAKS study, both monthly and every-other monthly doses demonstrated statistically-significant benefit for the predefined 12-month endpoint of GA growth. In the DERBY study, neither dosing regimen achieved a statistically significant benefit vs sham for the same endpoint, but did achieve statistical significance at 24 months (a secondary endpoint). Failure for one of two pivotal trials to achieve a primary endpoint could spell trouble for regulatory approval of a new drug, but the FDA approved pegcetacoplan for GA in February 2023.
Further Details
The drug did not (and was not expected to) reverse the damage from geographic atrophy. All groups progressed, but based on specialized photographs, treated eyes progressed more slowly. After one year a reduced growth rate of GA (the primary outcome measure) was demonstrated in one of the two phase 3 studies and after two years in both studies. This anatomic endpoint can demonstrate that the drug is having a biologic effect on relevant tissues, but it does not prove that patients are benefiting in any meaningful way. Patients care about functional endpoints: Will treatment result in better vision compared to no treatment?
In order to test the hypothesis that pegcetacoplan confers a visual advantage, the designers of these clinical trials included multiple functional measures as secondary endpoints. There were five prespecified secondary outcomes intended to measure and compare visual function for treated vs sham eyes. These outcomes were reported for the combined data of the OAKS and DERBY studies. Because there were 5 functional endpoints, each tested for 2 dosing regimens, there were 10 comparisons. None of these revealed a statistically-significant functional advantage for eyes treated with pegcetacoplan. With the power of the combined data from two phase 3 clinical trials and 10 comparisons with sham control, they failed to demonstrate any functional benefit for eyes receiving the experimental treatment. Not a strong endorsement for a meaningful benefit to patients.
We can add 2 additional analyses to the 10 described above. The Lancet paper also reported a pair of post hoc analyses. Post hoc means that an analysis was not planned at the design stage, but created after the data were seen. There may be legitimate reasons for performing post hoc analyses, but the results must be interpreted in context and viewed with appropriate skepticism. Post hoc analyses are ripe fruit for p-hacking. In these analyses, they compared the number of blind spots near the edge of the geographic atrophy at baseline and after 24 months. This analysis was statistically significant for the every-other month dosing, but not for the monthly dosing regimen.
Including the planned and post hoc functional outcomes, there were 12 statistical analyses, and only 1 result meeting the traditional threshold for statistical significance. With 12 analyses, the likelihood of finding at least one false positive would be about 46%, even if the treatment was completely ineffective. Considering that the one positive result was for a post hoc analysis makes it even less persuasive.
Bad news
Eyes receiving the drug experienced some disadvantages. They were 2 to 4 times more likely than sham-treated eyes to progress to wet (exudative) macular degeneration. Wet macular degeneration is the rarer but more rapidly progressive form of ARMD making this a decidedly undesirable side-effect. There were other adverse events over-represented in the treated eyes and patients, including a higher mortality rate.
More bad news
Shortly after the approval of pegcetacoplan The American Society of Retina Specialists began to collect reports of patients whose eyes developed inflammation and retinal vasculitis after pegcetacoplan injection. By mid-July they had received a half dozen reports. By the end of July the number had increased to 21, with some patients suffering severe vision loss in the affected eye.
Known-knowns
Here are things we know: In a pair of large phase 3 clinical trials, eyes treated with pegcetacoplan did not experience any demonstrable functional benefit. The hope is that, given enough time, functional outcomes will catch up with the photographic evidence of efficacy, but this remains speculative.
We also know that in those trials eyes treated with pegcetacoplan were 2 to 4 times more likely to transition to the more rapidly progressive wet ARMD. There were some other less frequent, but equally troubling excess adverse events in the treated subjects. Since the drug was approved, some patients have experienced complications resulting in severe vision loss.
Known-unknowns
For pegcetacoplan there are important unknowns: Will functional benefits be demonstrated in future studies? Why weren’t cases of vasculitis and severe vision loss seen in the clinical trials? How common are these complications in the real world? How likely is random patient to suffer severe vision loss after treatment?
Is pegcetacoplan “safe and effective” for treatment of geographic atrophy
In the judgement of the FDA, pegcetacoplan favorably modifies the progression of geographic atrophy with an acceptable safety profile. This, in turn, allows Apellis to sell the drug for use in patients.
A balance between hypothetical benefits and real risk creates a problematic risk/benefit ratio. The lack of functional benefit and excess adverse events led some colleagues to voice aversion to this new treatment. This point/counterpoint article summarizes the pro and con arguments voiced after the approval of pegcetacoplan. The “con” side of the argument bears the provocative title: “An Exciting Game Changer for Everyone Except the Patient.”
As a clinician, my role is to provide case-by-case advice about the relative safety and efficacy of options available to my patients. For pegcetacoplan, the available data have not provided convincing evidence of a benefit that is meaningful to most patients. On the flip-side, there are harms that are real, but not fully quantified.
In addition to arguments of safety and efficacy are assessments of “value.” The cost of each dose is $2,316 (accessed 12/18/2023) repeated every month or every-other month. Add to this the procedure-related expenses and inconveniences.
Not all regulatory agencies are following the example of the FDA. European regulators are predicted to deny approval of the drug.
There is not a medical need for a treatment that results in better-looking retinal photographs. There is a medical need for a treatments that benefit patients’ vision and quality of life. Until confronted with more-persuasive evidence, I maintain that a treatment with demonstrable safety and efficacy for treatment of dry age-related macular degeneration remains an unmet medical need.