Oral gildeuretinol acetate may not significantly slow geographic atrophy progression compared with placebo in patients with age-related macular degeneration, missing the trial's primary endpoint despite favorable findings across several exploratory structural, functional, and patient-reported outcomes.
In the phase 2/3 SAGA randomized clinical trial, researchers randomly assigned 198 patients aged 60 years or older with geographic atrophy secondary to age-related macular degeneration at 24 US centers 2:1 to receive oral gildeuretinol acetate 14 mg once daily or placebo for 24 months. The primary endpoint was geographic atrophy lesion growth measured by fundus autofluorescence. Prespecified secondary outcomes included low-luminance visual acuity (LLVA), best-corrected visual acuity (BCVA), the National Eye Institute Visual Function Questionnaire-25 (VFQ-25), and the Functional Reading Independence (FRI) Index.
After follow-up, geographic atrophy lesion growth was reduced by 13% with gildeuretinol compared with placebo, but the difference was not statistically significant. In a prespecified sensitivity analysis that accounted for a 6-month delay in treatment effect, lesion growth was reduced by 15% with gildeuretinol. Because the primary endpoint was not met, the researchers considered the sensitivity analysis exploratory.
Exploratory functional outcomes also favored gildeuretinol. The patients receiving active treatment experienced less decline in LLVA compared with those receiving placebo, whereas differences in BCVA did not reach statistical significance. Those treated with gildeuretinol also had less deterioration in vision-related quality of life, as measured by the VFQ-25, and maintained greater reading independence based on FRI scores. The researchers emphasized that these secondary findings should be interpreted as exploratory because hierarchical testing did not proceed after the primary endpoint was not achieved.
Safety findings were generally similar between the treatment groups, and no new safety signals were identified. Treatment-emergent adverse events occurred in 72% of patients receiving gildeuretinol and 83% receiving placebo. Ocular adverse events were uncommon, and investigators reported fewer cases of neovascular age-related macular degeneration and choroidal neovascularization in the gildeuretinol group than in the placebo group. One serious adverse event was considered related to the study drug, and all mortalities were judged unrelated to treatment.
The researchers noted several limitations. Enrollment was curtailed at 198 participants instead of the planned 300 because of the COVID-19 pandemic, reducing statistical power. Approximately 70% of eyes contributed primary outcome data at 24 months, and the analyses assumed missing data occurred at random. The researchers also cautioned that the favorable findings from the prespecified sensitivity analysis and secondary endpoints are hypothesis-generating rather than confirmatory because the primary endpoint was not met.
Overall, the findings suggested that although oral gildeuretinol acetate did not demonstrate a statistically significant benefit for the primary efficacy endpoint, its favorable exploratory effects on structural, functional, and patient-reported outcomes support further evaluation in larger, adequately powered clinical trials.
"The primary analysis did not reach statistical significance, but exploratory analyses generally favored gildeuretinol acetate across structural, functional, and patient-reported outcomes, with greater separation observed in prespecified sensitivity analyses. Larger, adequately powered studies are warranted to confirm these findings," wrote lead study author David S. Boyer, MD, of Retina Vitreous Associates Medical Group, and colleagues.
The study was funded by the National Eye Institute and sponsored by Alkeus Pharmaceuticals. Full disclosures of the study authors can be found in the study.
Source: Ophthalmology Retina
