For the first time, an investigational oral agent has shown a statistically significant visual function benefit in low-luminance visual acuity (LLVA), Alex Melamud, MD, reported at Retina Subspecialty Day at the 2024 American Academy of Ophthalmology meeting in Chicago. During the late-breaking news session, Dr. Melamud presented data from the phase 2/3 SAGA study evaluating the effects of gildeuretinol acetate (ALK-001; Alkeus Pharmaceuticals) in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
Gildeuretinol is an investigational oral agent, taken once a day, that is designed to replace vitamin A in the visual cycle, said Dr. Melamud. Vitamin A dimerization has been implicated in photoreceptor degeneration, as well as complement activation and dysregulation, so investigators believe gildeuretinol could reduce disease progression in GA as well as wet and dry AMD and Stargardt disease, he said.
SAGA was a double-masked, randomized, placebo-controlled trial to investigate the safety, pharmacokinetics, tolerability, and efficacy of ALK-001 in 198 enrolled patients with GA secondary to AMD. The primary efficacy endpoint was the growth rate of GA lesions from baseline to 24 months as assessed by fundus autofluorescence (FAF). Key secondary efficacy endpoints were LLVA and best-corrected visual acuity (BCVA). Patients were randomized 2 to 1 in gildeuretinol or placebo group. Almost 70% of patients in each arm completed the study, said Dr. Melamud.
The primary efficacy endpoint was the rate of lesion growth from baseline to 24 months. The gildeuretinol group demonstrated 13.4% lower growth rate than the placebo group, but this was not statistically significant (P=.075), he said. However, researchers noted a greater reduction after month 6 (Figure 1). “Pharmacokinetic studies have demonstrated that it takes several months with oral gildeuretinol supplementation to achieve an 80% turnover of deuterated vitamin A in the body,” Dr. Melamud explained. “Therefore, a prespecified sensitivity analysis was planned to look at the rate of lesion growth from 6 to 24 months. This did reach statistical significance, demonstrating a 15.3% growth rate reduction at month 24 in the gildeuretinol group as compared to placebo.”
Figure 1. Gildeuretinol acetate (ALK-001; Alkeus Pharmaceuticals) showed a statistically significant visual function benefit in low-luminance visual acuity (LLVA), according to data presented at the 2024 American Academy of Ophthalmology meeting in Chicago. (Image courtesy Alex Melamud, MD.)
No statistically significant benefit for BCVA was noted over the course of the study. In final follow-up, patients treated with gildeuretinol preserved 3.3 EDTRS letters compared to patients in the placebo group, said Dr. Melamud (Figure 2). Most treatment-emergent adverse events (TEAEs) were mild or moderate, with 1 serious TEAE related to the study drug. “Interestingly, there was a lower rate of choroidal neovascularization–related adverse events in at-risk patients in the gildeuretinol study group,” Dr. Melamud noted.
Figure 2. Patients treated with gildeuretinol preserved 3.3 EDTRS letters compared to placebo, according to data from the SAGA trial. (Image courtesy Alex Melamud, MD.)
“In summary, decreasing vitamin A dimerization is a potential mechanism of action to treat geographic atrophy,” he continued. “Compared to placebo, we see that there is a trend toward slower GA lesion growth from baseline to month 24, a statistically significant slower GA lesion growth rate from 6 to 24 months, and statistically significant functional vision benefit on low-luminance visual acuity and this is the first investigational oral agent to demonstrate this.” RP
