Mitochondrial stabilizers may play a role in treatment of dry AMD
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ROME — Two injectable drugs with mitochondrial-stabilizing properties, risuteganib and elamipretide, show promise in reversing vision loss in dry age-related macular degeneration.
“Both drugs have shown threshold OCT characteristics that predict BCVA response to treatment, and that’s the important message,” Baruch D. Kuppermann, MD, PhD, said at the FLORetina-ICOOR meeting.
In a phase 2a trial, 48% of the patients who received intravitreal injections of risuteganib (Allegro Ophthalmics) at baseline and week 16, with analysis at 28 weeks, achieved the primary endpoint of an eight-letter improvement, and 20% had a gain of 15 letters. OCT criteria at baseline correlated with best corrected visual acuity response, including enhanced ellipsoid integrity, greater outer retinal thickness and decreased geographic atrophy.
Further AI analysis performed separately by two reading centers, with responders defined as patients with at least an eight-letter gain, concluded that the more preserved the photoreceptors, the better response to risuteganib.
“If you have got at least a 30 µm photoreceptor layer, that will increase the responder rate by 40%,” Kuppermann said.
In the ReCLAIM-2 trial, 117 patients injected subcutaneously with elamipretide 40 mg (Stealth BioTherapeutics) on a daily basis were compared with 59 patients who received placebo.
The primary endpoint analysis was not successful. The mean change in low-luminance visual acuity and the mean change in geographic atrophy were not significant. However, there was a significant difference in the number of those who gained two and three lines of vision with the drug vs. placebo.
“Even more important, however, is that they showed a reduced ellipsoid zone (EZ) attenuation. This reduction was 43% of total EZ attenuation and 47% of partial ellipsoid zone attenuation,” Kuppermann said.
Of note, the FDA is willing to consider this as a surrogate endpoint in clinical trials.
These findings indicate that restoration of functional vision might be achievable in dry AMD patients with more anatomic integrity using mitochondrial-stabilizing drugs, suggesting that early treatment of dry AMD is warranted to reverse vision loss. They also suggest that it is important to establish thresholds, such as minimum EZ-retinal pigment epithelium thickness, to enrich the study population with potential responders to the study drug.
“Reduction of EZ attenuation may be an acceptable anatomic surrogate endpoint for clinical trials, which would facilitate the path of developing new drugs for this condition,” Kuppermann said.
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Kuppermann B. Neuroprotection and neuroenhancement for the treatment of retinal diseases. Presented at: FLORetina-ICOOR; Nov. 30-Dec. 3, 2023; Rome.
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