Gildeuretinol Shows Promise in Slowing Geographic Atrophy Progression

Compelling results from the SAGA trial, a two-year randomized, double-masked, placebo-controlled study, found oral gildeuretinol (ALK-001) notably reduced the progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD), compared with placebo.

These data, presented at the 128th Annual American Academy of Ophthalmology (AAO) Meeting, showed the investigational agent designed to mimic vitamin A achieved a trend toward slower GA lesion growth rate from baseline to 24 months, and a statistically significant visual function benefit in low-luminance visual acuity (LLVA).

“Decreasing vitamin A dimerization is a potential mechanism of action to treat GA compared to placebo, and we see that there is a trend toward slow GA lesion growth from baseline to Month 24 and a statistically significant functional vision benefit on LLVA, the first investigational oral agent to demonstrate this,” said presenting investigator Alex Melamud, MD, The Retina Group of Washington.

By mimicking vitamin A, oral gildeuretinol is designed to reduce the dimerization of vitamin A, a process implicated in the progression of GA related to AMD. By slowing this dimerization, Gildeuretinol aims to decrease the lesion growth rate and preserve visual function in affected patients. It is also being evaluated in Stargardt disease, which shares a common pathophysiology with GA.

SAGA is a 2-year trial that enrolled patients aged 60 or older with ≥1 well-demarcated GA lesion. Participants were randomized in a 2:1 ratio to receive either gildeuretinol or placebo, with follow-up visits every six months. The study’s primary endpoint was the rate of lesion growth from baseline to month 24, measured by fundus autofluorescence (FAF) and confirmed by optical coherence tomography (OCT). Key secondary endpoints included LLVA and best-corrected visual acuity (BCVA).

Overall, SAGA retained 70% of participants, with demographics revealing a mean age of 78, predominantly female and Caucasian. Most subjects had subfoveal lesions, with the majority presenting multifocal GA lesions.

Upon analysis, SAGA did not show a statistically significant difference in lesion growth rates between the Gildeuretinol and placebo groups (P = 0.075). However, these data revealed a notable trend, indicating a 13.4% reduction in lesion growth rate at the final follow-up.

Given that pharmacokinetic studies suggest a lag in achieving therapeutic levels of deuterated vitamin A, a pre-specified sensitivity analysis from months 6 to 24 demonstrated a statistically significant 15.3% reduction in GA lesion growth with gildeuretinol compared with placebo.

LLVA was a key secondary endpoint and found significant benefits with gildeuretinol. These patients experienced a lower loss in visual acuity than those receiving placebo. Melamud indicated this finding is particularly noteworthy as it marks the first oral therapy to demonstrate improvements or stabilization in LLVA.

There were no statistically significant benefits noted in BCVA over the study, but patients treated with gildeuretinol preserved 3.3 letters on visual acuity testing more than placebo at the end of the study.

Safety analysis indicated that most treatment-emergent adverse events (TEAEs) were mild to moderate and no deaths were attributed to gildeuretinol. A lower rate of choroidal neovascularization (CNV)-related adverse events were observed among at-risk patients.

Overall, these SAGA data indicated the potential of gildeuretinol as a novel therapeutic option for slowing the progression of GA. Particularly with a favorable safety profile, and its unique mechanism of action, gildeuretinol could emerge as the first oral therapy in this therapeutic category, warranting further investigation into its use in treatment regimens for patients with GA secondary to AMD.

“Gildeuretinol was well-tolerated and exhibited a favorable safety profile, consistent with other studies in the gildeuretinol Stargardt program,” Melamud added.

References

_{Melamud A. Gildeuretinol in Geographic Atrophy: Results from SAGA, a 2-year, Randomized, Double-masked, Placebo-controlled Study. Presented at the American Academy of Ophthalmology (AAO) 2024 Meeting. Chicago, Illinois. October 18-21, 2024.}