Drugs to treat GA: Yes, please!

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One of the most significant conversations in ophthalmology today concerns geographic atrophy (GA) drugs for the treatment of the end stage of age-related macular degeneration (AMD). The advantages of these drugs may outweigh the disadvantages, according to Eleonora Lad, MD, PhD, a retina specialist and vice chair of ophthalmology clinical research at Duke University School of Medicine in Durham, North Carolina.

Lad explained that she is a proponent of complement inhibition in GA because strong evidence exists for the overactivation of the complement system in GA. Genetic polymorphisms in the complement proteins have been identified in patients, leading to increased complement activation and impaired complement regulation. In addition, there are complement products in drusen, the hallmark of dry AMD, the retinal pigment epithelium, and choriocapillaris that are involved in the progression of GA.

Good evidence also exists that shows that the polymorphisms in the complement system are associated with a 2- to 6-fold increase in the risk of developing AMD.^1,2

Clinical trials

The FDA has approved 2 drugs to treat GA: pegcetacoplan (Syfovre; Apellis Pharmaceuticals, Inc) and avacincaptad pegol (Izervay; Astellas Pharma US, Inc), based on the results of the phase 3 OAKS (NCT03525613), DERBY (NCT03525600),³ and GATHER2 (NCT04435366)⁴ trials.

These primary clinical trials showed that the treatments slowed the progression of GA. Because late-stage AMD lesions cause irreversible vision loss, visual acuity was not expected to increase in the absence of regenerative treatments such as cell transplantation. The primary analyses of the clinical trials did not show a benefit to visual function.

Lad pointed out that these trials were not designed to pick up a functional benefit. “The type of lesions enrolled would not have deteriorated functionally very much over time. Different patients would have to be enrolled to show primarily a functional benefit. The current clinical trials are addressing this and enrolling patients with smaller lesions and those that are more likely to change functionally in order to demonstrate a functional benefit,” she explained.

However, post hoc analyses in the primary studies showed that both drugs slow visual impairment. The time to severe visual impairment was increased, thus allowing patients to retain vision over time.

Data from the GALE 3-year extension trial (NCT04770545)⁵ of OAKS and DERBY demonstrated a benefit in visual function on the prespecified end point of microperimetry.

“In GALE, there was evidence from prespecified microperimetry analyses that pegcetacoplan resulted in clinically meaningful benefit on visual function in treated patients,” Lad said.

She also acknowledged that although the safety profiles seen in the clinical trials were considered good, the most significant adverse effect was the increased incidence of conversion to the wet form of the disease. Other risks included infection associated with the frequent intravitreal injections and the rare development of intraocular inflammation and occlusive retinal vasculitis in patients treated with pegcetacoplan, which resulted in vision loss.

Explaining GA treatments to patients

Considering these factors, Lad outlined her main argument for using GA drugs—to slow GA progression. Her approach is to explain to patients with GA that the 2 available treatments were seen in clinical trials to reduce the growth of GA lesions in a clinically meaningful way 12 months after treatment onset.

Microperimetry documented that the worsening of scotomatous points in the retina with GA slowed down because of treatment, indicating that patients can maintain their functional retina vision longer than without treatment.

When patients opt to pursue treatment for GA, Lad does a trial run and treats the worse-seeing eye, which she then follows for 4 to 6 weeks. In the absence of an adverse effect, she can then treat the fellow eye or both eyes based on the patient’s decision.

“Currently, the only FDA-approved treatments to slow GA progression are complement inhibitors. That is my main argument for offering this treatment option to my patients,” she said.

Many patients with GA wish to improve their daily functioning. These patients are referred to the low vision clinic for rehabilitation devices and training. They also often ask about regenerative or vision-improving therapies. Clinical trials on cell transplantation and retinal prostheses are ongoing, and others on optogenetics are in the planning phases.

Slowing GA with the Mediterranean diet

A nonmedical approach may benefit patients with GA. Study data have shown that adhering to a Mediterranean diet is associated with a slower progression of GA. Key components of the diet that contribute to this effect include high consumption of whole fruits, low red meat intake, moderate alcohol consumption, and a high ratio of monounsaturated to saturated fatty acids, according to findings from a recent study.⁶

“As retina specialists, it is our ethical responsibility to inform patients about all treatments that have been approved and to discuss the specific benefits and risks of available therapies with them. The decision regarding the best therapeutic regimen for each patient should be a result of a team discussion involving the patient, caregivers, and medical professionals,” Lad summarized.•

Eleonora Lad, MD, PhD

Lad is a retina specialist and vice chair of ophthalmology clinical research at Duke University, Durham, NC. She serves as a scientific advisor for Apellis Pharmaceuticals, Alexion, Annexon Biosciences, Astellas Pharma US, Complement Therapeutics, and Janssen.

nora.lad@duke.edu

References

1. Carrera W, Heier JS. Complement inhibition in geographic atrophy. Retinal Physician. 2023;20:9-14.

2. Bakri SJ, Bektas M, Sharp D, Luo R, Sarda SP, Khan S. Geography atrophy: mechanism of disease, pathophysiology, and role of the complement system. J Manag Care Spec Pharm. 2023;29(suppl 5-a):S2-S11. doi:10.18553/jmcp.2023.29.5-a.s2

3. Heier JS, Lad EM, Holz FG, et al; OAKS and DERBY study investigators. 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. Lancet. 2023;402(10411):1434-1448. doi:10.1016/S0140-6736(23)01520-9

4. Khanani AM, Patel SS, Staurenghi G, et al; GATHER2 trial investigators. 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. doi:10.1016/S0140-6736(23)01583-0

5. Abbey AM, Wykoff CC, Heier JS, et al. Long-term efficacy and safety of pegcetacoplan over 36 months including 12-month results of the GALE open-label extension study. Invest Ophthalmol Vis Sci. 2024;65(7):380.

6. Agron E, Mares J, Chew EY, Keenan TDL; AREDS2 Research Group. Adherence to a Mediterranean diet and geographic atrophy enlargement rate: Age-Related Eye Disease Study 2 Report 29. Ophthalmol Retina. 2022;6(9):762-770. doi:10.1016/j.oret.2022.03.022