ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation
Ehlers JP, Hu A, Boyer D, Heier JS, Wykoff CC, Iyer S, Hill L
Ophthalmology Science (2024) · n=176
Across 176 patients with dry age-related macular degeneration and geographic atrophy, ReCLAIM-2 missed both prespecified primary endpoints — low-luminance visual acuity and GA area progression — but produced statistically significant secondary signals on ellipsoid zone preservation (43% reduction in total EZ attenuation, p = 0.0034) that Stealth has cited as proof-of-mechanism for future development.
This 2024 Ophthalmology Science paper reports the Phase 2 ReCLAIM-2 trial of subcutaneous elamipretide in dry age-related macular degeneration with geographic atrophy. The trial randomized 176 patients aged ≥55 with at least one eye affected by dry AMD with GA to 40 mg/day subcutaneous elamipretide (n=117) or placebo (n=59) for 48 weeks plus a 4-week follow-up period. The prespecified primary endpoints were the mean change from baseline in low-luminance best-corrected visual acuity (LL BCVA) and the change in square-root-converted geographic atrophy area as measured by OCT. Neither primary endpoint was met: LL BCVA change was −3.0 letters on elamipretide vs −4.4 letters on placebo (p = 0.49), and GA area progression was 0.312 mm vs 0.275 mm (p = 0.34). Secondary endpoints around ellipsoid zone (EZ) integrity — a structural biomarker of photoreceptor health — separated more cleanly: elamipretide produced a 43% reduction in mean progression of macular percentage of total EZ attenuation (3.69% vs 6.47%, p = 0.0034) and a 47% reduction in partial EZ attenuation (4.10% vs 7.68%, p = 0.0040). A categorical secondary signal also favored elamipretide: 14.6% of treated patients gained ≥10 letters of LL BCVA versus 2.1% of placebo (p = 0.0404). Adverse events occurred in 86% of elamipretide patients versus 71% of placebo, dominated by injection-site reactions (60% vs 27%) that were predominantly mild-to-moderate.
The two prespecified primary endpoints both failed to separate elamipretide from placebo. This is the load-bearing fact. The trial design's use of LL BCVA and square-root-converted GA area as primaries reflects the field's consensus on what constitutes clinically meaningful change in dry AMD — both were chosen prospectively, not retrofit from data. The secondary EZ findings are mechanistically interpretable and statistically significant within the trial, but they are not the endpoints the trial was powered to test, and the relationship between EZ integrity changes and downstream visual function preservation requires further longitudinal data to validate. The categorical ≥10-letter LL BCVA gain favoring elamipretide is intriguing as a responder-analysis signal but again is secondary and post-hoc-adjacent in spirit. The conventional reading of ReCLAIM-2 is "negative trial with mechanistic signal worth following up" rather than "positive trial." Stealth BioTherapeutics has framed the trial as a mechanism-validation result that justifies further AMD development; the FDA-regulatory framing treats prespecified primary endpoints as load-bearing, and on that framing this trial is a primary-endpoint miss.
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