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, et al. · Ophthalmology Science

Both primary endpoints were missed at a family-wise alpha of 0.10: low-luminance acuity fell 3.0 letters on elamipretide against 4.4 on placebo (P=0.49), and square-root-transformed geographic-atrophy area grew 0.312 mm against 0.275 (P=0.34). Every continuous secondary endpoint was null too, with reading acuity, best-corrected acuity (-3.3 against -2.6, P=0.5642) and atrophy area on autofluorescence (1.099 against 0.958, P=0.2672) all numerically level or worse on drug. The positive results are the prespecified exploratory ellipsoid-zone measures, which the paper says were not adjusted for multiplicity and carry nominal P values only: 43% less complete attenuation (P=0.0034) and 47% less partial attenuation (P=0.0040), alongside a categorical analysis in which more patients gained 10 letters or more of low-luminance acuity (14.6% against 2.1%, P=0.0404). Adverse events were reported in 86% on drug against 71% on placebo, injection-site reactions in 60% against 27%.

Population

176 adults with dry AMD and noncentral geographic atrophy

Intervention

Elamipretide 40 mg subcutaneous daily for 48 weeks

Comparator

Placebo (2:1 randomization)

Limitations

Dropout was uneven — 29% of the elamipretide arm left the study early against 14% of placebo, and 24.8% against 15.2% stopped treatment for adverse events, most often injection-site reactions. Randomisation left the elamipretide arm with the greater disease burden at baseline, including 5.4 letters less low-luminance acuity and more ellipsoid-zone attenuation, which is the direction that leaves the most room to gain on a responder analysis. Twenty-seven patients with central atrophy were enrolled before a protocol amendment restricted entry to noncentral disease. Funded by Stealth BioTherapeutics, which reviewed the manuscript, with the sponsor named in most authors' disclosures; the exploratory endpoint is the one the phase 3 programme adopts as its primary.