The European Medicines Agency (EMA) confirmed its decision to refuse market authorization for Apellis Pharmaceuticals’ (Waltham, Massachusetts, United States) SyfovreⓇ (pegcetacoplan injection), a drug designed to treat geographic atrophy (GA) caused by dry age-related macular degeneration (AMD).
The EMA’s September 19, 2024 ruling follows a re-examination requested by Apellis after an initial rejection in June 2024. Despite the company’s efforts to address concerns raised by the Committee for Medicinal Products for Human Use (CHMP), the EMA maintained its stance, citing insufficient “clinically meaningful benefits” and safety concerns over the intravitreal injections required for the drug’s administration.
Apellis’ CEO and co-founder, Dr. Cedric Francois, expressed deep disappointment in a news release, stating, “We are deeply disappointed by this outcome, which leaves millions of Europeans with GA without a treatment for this irreversible form of blindness.” The compay also noted that the decision was particularly frustrating, given what they perceive as the broad support Syfovre had garnered from the European retina community, as well as multiple dissenting votes within the CHMP itself.
A controversial balance of risk and reward
Syfovre was developed to inhibit the C3 protein, a key part of the immune system’s complement pathway responsible for the excessive inflammation and cell death seen in GA. The drug’s objective was to slow the progression of geographic atrophy, a condition that affects over five million people worldwide.
In clinical trials, Syfovre demonstrated ability to slow the growth of GA lesions after one year of treatment. However, this reduction seemingly did not translate into significant improvements in patients’ daily functioning or visual acuity, leading the EMA to conclude that the drug’s benefits did not outweigh the risks.1,2
One major concern was the risk of complications from the regular eye injections required for Syfovre. Adverse events reported during the trials included inflammation and the development of wet AMD—a more severe form of macular degeneration.2
Impact on patients in Europe
Currently, there are no approved GA therapies in Europe to address this debilitating condition. Although early-stage AMD can be managed with vitamins such as AREDS2, there are no options for advanced GA, leaving many patients with an unmet medical need.
Prof. Dr. med. Frank G. Holz (Germany), a prominent retina specialist involved in Syfovre’s clinical trials, lamented the lost opportunity to bring the drug to European patients. “As an ophthalmologist and retina specialist, I have seen how patients with GA lose their ability to read, drive, and even see faces,” he said. “The Phase 3 data for pegcetacoplan are clinically meaningful and showed the potential to make a difference for EU patients.”
Business impact
For Apellis, the EMA’s decision poses serious challenges to the future of Syfovre in Europe. While the company remains focused on expanding access to the drug in the United States—where it received FDA approval in 2023—the European market now seems out of reach for the foreseeable future. Apellis has not announced whether it will pursue further appeals or adjust its clinical strategy to meet European regulatory standards.
Following the EMA’s announcement, Apellis’ stock (NASDAQ: APLS) plunged by nearly over 10%, with trading volumes spiking to over 500% of the 10-day average, reflecting deep investor concerns over the drug’s future prospects.
Industry impact
The EMA’s decision also casts a shadow over the broader pharmaceutical’s efforts to address GA. Izervay™ (avacincaptad pegol) by Astellas Pharma (Tokyo, Japan) is currently under review by the EMA’s CHMP. Both drugs work by targeting the complement system, and both have face questions over safety risks and modest clinical benefits. The EMA’s strict standards could mean Izervay’s approval faces similar hurdles.3
As the retina community looks to the future, all eyes will be on the results of ongoing clinical trials and the possibility of new, more effective treatments emerging on the horizon. Until then, Syfovre’s rejection serves as a stark reminder of the challenges facing the pharmaceutical industry in the race to combat blindness.
References
- Heier JS, Lad EM, Holz FG, et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. The Lancet. 2023;402(10411):1434-1448.
- European Medicines Agency. Refusal of the marketing authorisation for Syfovre (pegcetacoplan):Re-examination confirms refusal. 19 September 2024. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/syfovre. Accessed on 21 September 2024.
- Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023;402(10411):1449-1458.
