Can a Nutraceutical Slow GA Progression?

Two drugs have been FDA-approved in the United States for slowing progression of geographic atrophy (GA): pegcetocoplan injection (Syfovre, Apellis Pharmaceuticals) and avacincaptad pegol intravitreal solution 2 mg (Izervay, Astellas Pharma). The former blocks the complement-3 pathway, while the latter targets complement-5. Multiple studies have shown that overactivation of the complement system underlies retinal pigment epithelium and photoreceptor cell death that typifies advanced nonexudative age-related macular degeneration (AMD), specifically GA, which is responsible for one in five cases of legal blindness in the United States.^1,2

This article reviews the use of these new drugs in the treatment of GA, and considers the effect, if any, of adding a vitamin and/or nutritional supplement to the treatment regimen.

THE LITERATURE

In the phase 3 DERBY and OAKS trials, intravitreal monthly or bimonthly injection of pegcetocoplan reduced growth of GA by 19% to 22% compared with sham injection over 2 years, representing a statistically significant reduction in GA area growth with a greater effect from months 18 to 24.³ Treated patients experienced at least double the rate of new-onset exudative AMD compared with the sham group, however. Follow-up of OAKS/DERBY participants out to 36 months (GALE trial) has shown even greater reductions in GA lesion growth, lower risk of visual acuity loss, and preservation of visual fields.

The phase 2 GATHER-1 trial showed a 28% to 30% reduction in GA area growth over 18 months with avacincaptad pegol, with four- to five-times higher rates of macular neovascularization compared with the sham control, whereas the phase 3 GATHER-2 trial showed a 14% reduction in GA lesion growth over 12 months and a 75% increased rate of macular neovascularization with monthly injections.^4,5 Post-hoc analysis of GATHER-2 also showed a 56% lower risk of sustained vision loss, defined as a ≥ 15-letter loss over 12 months.⁶

In sum, these complement-blocking therapies appear to slow GA progression, increase rates of submacular neovascularization (albeit in a small minority of 5% to 10% of recipients), and potentially reduce the risk of further vision loss with frequent intravitreal injections.

THE RESPONSE

Patients

Talking about these new therapies with my patients with early to later-stage GA over the past year, all of them expressed concern about receiving ongoing injections and the overall treatment burden. Those with good vision asked why they needed treatment despite no current symptoms. The answer, of course, is that we are trying to prevent future vision loss and maximize visual function long-term.

Several patients agreed to a retina specialty consult for further consideration of treatment, but only one, a retired pharmacist, actually began therapy for bilateral GA in his better-seeing eye because he didn’t want his good eye to deteriorate.

Providers

In discussion with three local retina specialists, a consistent theme was uncertainty over how these new agents would fit into their practice.

A recent survey of ophthalmologists (both injecting and noninjecting) and community-based optometrists showed majority agreement that GA should be treated as early as possible, with referring optometrists expressing more concern over convincing patients with asymptomatic GA to receive treatment.⁷ Of note, only 15% of injecting ophthalmologists said they begin anti-complement therapy within 1 month of GA diagnosis.⁷ This suggests providers are waiting to see disease worsening first before deploying these newer therapies with their associated unknowns, burdens, and costs.⁸

REAL-WORLD EXAMPLE

A patient with GA OU and exudative AMD OS was dissuaded from receiving complement inhibition therapy by her treating retina specialist and who possibly benefited from use of a nutraceutical supplement intended for patients with diabetes.

The patient, now 87 years of age, has been receiving ongoing anti-VEGF therapy for exudative AMD OS every 4 to 8 weeks for the past 6 years (bevacizumab [Avastin, Genentech/Roche], then ranibizumab [Lucentis, Genentech/Roche], then 2 mg aflibercept [Eylea, Regeneron] the past year before seeing me for the first time). She was referred to me 2 years ago by her son, a patient with type 2 diabetes and mild nonproliferative diabetic retinopathy (DR) who had been using the Diabetes Visual Function Supplement Study (DiVFuSS) nutraceutical supplement for 5 years.

Her systemic history included hyperlipidemia and hypertension, for which she was taking atorvastatin and losartan. She was also taking PreserVision AREDS2 Eye Vitamin and Mineral Supplement (Bausch + Lomb) twice daily. Her BCVA was 20/30- OD and 20/100 OS, and she complained of blurred vision and difficulty reading. She is pseudophakic with clear capsules. Dilated examination showed GA OU, left > right, as well as macular hemorrhage OS, 6 weeks after her last anti-VEGF injection. Retinal imaging was performed (Figure, A), and spectral-domain OCT confirmed extra-foveal GA OD and subretinal fluid OS. We discussed lifestyle strategies to reduce the risk of worsening AMD, including a low glycemic index Mediterranean diet.

The patient was referred back to her retina specialist and returned to me 12 months later, in the fall of 2022, with significantly larger GA area OU (Figure, B) and BCVA of 20/50 OD and 20/200 OS. We discussed pegcetocoplan injection (Syfovre, Apellis), which was recently approved for the treatment of GA secondary to AMD, and she asked that I send a note to her retina specialist. She returned to me 1 month later, concerned because he had dissuaded her from the newly approved treatment for GA. He had told her they should wait for more evidence before initiating a new drug and that she may not be a good candidate, given the increased risk of wet AMD in her better-seeing eye. Her son asked if there was anything they could do to preserve his mother’s vision and specifically inquired about the DiVFuSS formula. We discussed the fact that this formula has no evidence of benefit in AMD and the importance of ongoing retina specialty follow-up for exudative disease OS and careful monitoring OD. We agreed she should continue the AREDS2 formula once daily and begin taking the DiVFuSS formula, two gel caps twice daily.

The patient returned 14 months later in January 2024 (14 months since her previous visit) having received eight additional aflibercept injections in her left eye and none in the right, per the report from her retina specialist. Her BCVA was 20/40 OD and 20/400 OS. Examination showed a minimally enlarged macular GA lesion OD without evidence of sub- or intraretinal fluid on OCT (Figure, C). The left eye’s macular GA appeared unchanged, and OCT showed minimal fluid 3 weeks after the last aflibercept injection. The patient and her son reported strict adherence to use of the AREDS2 and DiVFuSS formulas, and she reported improved reading ability.

DISCUSSION

This patient had demonstrable and significant GA lesion growth over 1 year, but far less change over the next 14 months with the addition of a nutraceutical specifically designed for DR. Visual acuity often varies from visit to visit in patients with AMD, but correlates well with GA lesion growth. It is encouraging that this patient noticed improved reading ability with stable visual acuity.

AMD and DR share many common pathophysiological processes, including mitochondrial over-production of reactive oxygen species (ROS) and disease worsening with higher intake of refined carbohydrates.^9,10 The DiVFuSS formula contains multiple components, including higher levels of zeaxanthin, than the AREDS2 formula (8 vs 2 mg), and there is evidence that zeaxanthin ingestion prevents retinal pigment epithelium atrophy in a mouse model of oxidative stress.¹⁰ Moreover, recent evidence suggests zeaxanthin/meso-zeaxanthin are the primary central foveal carotenoids and provide superior singlet oxygen quenching capacity compared with lutein, which might help explain foveal sparing in GA.¹¹

The DiVFuSS formula also improved multiple measures of visual function (contrast sensitivity, color perception, and visual field sensitivity) in a placebo-controlled trial of patients with diabetes and early DR and normalized mitochondrial ROS, VEGF production, and apoptosis in a murine model of DR.^12,13

I did not obtain fundus autofluorescence images of this patient’s GA lesion size or perform more sophisticated measures of visual function over time, as they were not available to me. Additionally, foveal sparing in GA occurs in about 20% of patients, so it is possible that slowed growth of macular GA lesion area in this patient was due to factors other than the addition of a different nutraceutical supplement.¹⁴ However, the AREDS trials demonstrated that although the derived formula conferred benefit against development of exudative AMD in patients with moderate nonexudative AMD, particularly those with low dietary intake of lutein and zeaxanthin, the formula was less effective against GA.¹⁵ This case raises the possibility that a different nutraceutical strategy might have benefit in advanced dry AMD, especially as the evidence for and clinical uptake of anti-complement therapies for GA emerge more clearly over the coming years.