Apellis Pharmaceuticals’ Syfovre (pegcetacoplan) is the first and only FDA-approved treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). More than 1 million people in the United States have GA.

“We’ve had long-lasting effective therapies for neovascular AMD for the past 20 years, but nothing was available for half of the patients that were going blind from advanced macular degeneration who have GA,” says Rishi P. Singh, MD, FASRS, staff surgeon and president at Cleveland Clinical Martin Hospitals in Stuart, Florida, and professor of ophthalmology at Cleveland Clinic Lerner College of Medicine, who was a clinical trial investigator for Syfovre. “These patients have lost vision and have significant disability and impairment.”

HOW IT WORKS

Syfovre targets C3 and C3b in the complement cascade, which is part of the body’s immune system. When the complement system is overactivated, it can attack and destroy healthy retinal cells and tissue, which can drive the growth of GA lesions, explains Caroline Baumal, MD, chief medical officer at Apellis. C3 plays a central role in driving the downstream damaging effects of complement overactivation in the progression of GA, including uncontrolled inflammation, opsonization, and retinal cell death.

Syfovre acts centrally by regulating C3, and exerting broad control of the complement system’s overactivation and of the complement effectors that are involved in the pathogenesis of GA. By targeting C3, Syfovre slows disease progression by reducing the rate of GA lesion growth and preserving retinal tissue, Dr. Baumal says.

ADDITIONAL BENEFITS

Syfovre is approved for all patients with GA secondary to AMD. This includes patients with subfoveal and nonsubfoveal lesions. Retina specialists may initially want to prioritize Syfovre treatment for patients who have impending foveal involvement with GA, especially if the fellow eye has experienced vision loss from either wet AMD or GA, Dr. Baumal says. As physicians gain clinical experience, they might want to broaden the patient types that they treat.

Syfovre’s effects increase over time. “In clinical trials,¹ the longer a patient was treated, the greater the impact the medicine had on the degenerative process as noted in 24-month results,” Dr. Baumal says.

Dr. Singh sees the medication as a patient’s investment in their vision. “The compounding of the reduction of lesion growth rates helps to ensure that there is less progression of the loss of important retinal tissue over time,” he says.

The label offers flexible dosing every 25 to 60 days, giving physicians options in treatment intervals based on individual patient needs. Syfovre can be used for all patients with GA, regardless of lesion location. This is a reflection of the broad and representative population of patients enrolled in phase 3 trials,¹ Dr. Baumal says.

Syfovre’s safety was well demonstrated² following nearly 12,000 injections over 24 months in phase 3 trials. The most common adverse reactions (≥5%) were ocular discomfort, neovascular AMD, vitreous floaters, and conjunctival hemorrhage.³

ADMINISTRATION

Syfovre’s frequency is determined based on individual patients and their disease characteristics and prognosis. For example, earlier in their disease a patient and their physician may decide that less-frequent dosing is the best treatment plan, Dr. Baumal says. There are clinical efficacy and safety data³ from Syfovre’s every-other-month and monthly treatment regimens in the label that can help to guide these decisions.

“I plan to initiate treatment every other month to balance the burden of treatment benefits and risk profile for most patients,” says Jordana G. Fein, MD, MS, a partner physician at Retina Group of Washington, and assistant professor of ophthalmology at Georgetown University School of Medicine, both in Washington DC, who participated in clinical trials and treats patients with Syfovre. “If we can slow down the disease’s progression by decreasing the rate of growth of atrophy, then patients are more likely to maintain visual functioning for longer.”

DRUG DEVELOPMENT CHALLENGES

The etiology of GA is complex and multifactorial, involving multiple genetic and environmental factors. “There are several complement genes involved in the pathogenesis of GA, which may account for the heterogeneity of GA in lesion presentation and characteristics of lesion growth,” Dr. Baumal explains. Age also plays a key role in the pathogenesis of GA and adds further complexity for clinical studies of GA in elderly populations with coexisting systemic health issues.

“Many pharmaceutical and biotech companies have tried to develop therapies for GA,” Dr. Baumal says. “Prior investigational agents targeted other parts of the complement cascade. One of the reasons why we believe Syfovre was successful is because it acts centrally by targeting C3, thus inhibiting downstream actions in the complement cascade.”

It has been difficult to find a treatment for GA because its pathophysiology is still not completely understood. “Trying to figure out the right target within the complement cascade has been challenging,” Dr. Fein says.

The treatment became available in March. A 3-year clinical extension study will continue to monitor patients for side effects, efficacy, and outcomes. RP

REFERENCES

1. Apellis Pharmaceuticals. Efficacy of intravitreal pegcetacoplan in geographic atrophy: 24-month results from the phase 3 OAKS and DERBY trials. Presented at: the Annual Scientific Meeting of the Retina Society. November 2022; Pasadena, CA.
2. Apellis Pharmaceuticals. Safety of intravitreal pegcetacoplan in geographic atrophy: 24-month results from the OAKS and DERBY phase 3 trials. Presented at: the Annual Scientific Meeting of the Retina Society. November 2022; Pasadena, CA.
3. Apellis Pharmaceuticals, Inc. Highlights of prescribing information. 2023. Accessed March 31, 2023. https://pi.apellis.com/files/PI_SYFOVRE.pdf
4. Apellis Pharmaceuticals. An extension study to evaluate the long-term safety and efficacy of pegcetacoplan (APL-2) in subjects with geographic atrophy secondary to AMD (GALE). ClinicalTrials.gov Identifier: NCT04770545. Updated March 30, 2023. Accessed March 31, 2023. https://clinicaltrials.gov/ct2/show/NCT04770545