ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation

Abstract

Objective: This study evaluated the safety and efficacy of elamipretide in dry age-related macular degeneration (AMD) with noncentral geographic atrophy (GA).

Design: ReCLAIM-2 was a prospective, phase II, randomized, placebo-controlled, double-masked, multicenter trial (NCT03891875).

Subjects: Patients aged ≥55 years with ≥1 eye with dry AMD with GA were enrolled.

Methods: Administration of daily subcutaneous elamipretide 40 mg was investigated in subjects for 48 weeks followed by a 4-week follow-up period.

Main outcome measures: The primary efficacy end points were the mean change from baseline (BL) in low-luminance best-corrected visual acuity (LL BCVA) and the change in square root (Sqrt) converted GA area from BL as measured by OCT. Additional predefined end points included ellipsoid zone (EZ) integrity preservation assessment and categorical changes in LL BCVA. The primary safety end point was the incidence and severity of adverse events.

Results: Of the 176 patients randomized, there were 117 and 59 patients in the elamipretide and placebo groups, respectively. Although elamipretide did not meet statistical significance for the primary end points (mean change in LL BCVA and mean change in Sqrt converted GA area), elamipretide produced a 43% reduction in the mean progression from BL in the macular percentage of total EZ attenuation/loss (i.e., complete loss of EZ band; nominal P = 0.0034) and 47% reduction in the mean progression of macular percentage of partial EZ attenuation/degradation (i.e., EZ-retinal pigment endothelium thickness of ≤20 microns; nominal P = 0.0040) versus placebo at week 48. Elamipretide treatment was also associated with significantly more patients experiencing a ≥10 letter gain in LL BCVA versus placebo (14.6% vs. 2.1%; nominal P = 0.0404). Adverse events were reported in 86% of those receiving elamipretide and 71% of the placebo group with the most common events being injection site reactions (e.g., pruritus, injection site pain, bruising, and erythema).

Conclusions: While the primary end points were not met in this phase II study, elamipretide treatment was associated with a slowing of progressive EZ degradation/loss, a surrogate for photoreceptor damage. These findings have important clinical relevance since EZ attenuation/photoreceptor loss precedes and predicts the progressive pathological changes associated with vision loss and AMD. The EZ attenuation/loss end point will serve as the regulatory approved primary end point in the elamipretide phase III clinical development program.

Financial disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Age-related macular degeneration; Elamipretide; Ellipsoid zone; Geographic atrophy; Visual acuity.

Figure 1

CONSORT study flow diagram. AE = adverse event; CONSORT = Consolidated Standards of Reporting Trials; QD = daily; SQ = subcutaneous.

Figure 2

Mean change in LL-BCVA (A) and GA progression (B) least square means estimated from a mixed-effects model for repeated measures. The mITT population was used for the analysis, for LLVA, placebo n = 52 and 48 for 24 and 48 weeks, respectively while elamipretide n = 93 and 82, respectively. From GA assessment, placebo n = 48 and 45, for 24 and 48 weeks, respectively while elamipretide n = 89 and 76, respectively. GA = geographic atrophy; LL-BCVA = low-luminance best-corrected visual acuity; LLVA = low-luminance visual acuity; LS = least square; mITT = modified intent-to-treat; SE = standard error; SQRT = square root.

Figure 3

Categorical improvement in LLVA∗. The mITT population was used for the analysis, placebo n = 48 and elamipretide n = 82. LLVA = low-luminance visual acuity; mITT = modified intent-to-treat. ∗P value significant for 2-line change only.

Figure 4

Total (A) and partial (B) EZ attenuation. Least square means estimated from a mixed-effects model for repeated measures. The mITT population was used for the analysis, for total attenuation, placebo n = 50 and 42 for 24 and 48 weeks, respectively while elamipretide n = 89 and 71, respectively. From partial attenuation, placebo n = 50 and 42, for 24 and 48 weeks, respectively while elamipretide n = 89 and 71, respectively. Statistical analysis showing nominal “P values.” Macular percent refers to the percent of the macular area included within the SD-OCT scan (target is 6 mm × 6 mm). EZ = ellipsoid zone; LS = least square; mITT = modified intent-to-treat; SD-OCT = spectral-domian OCT; SE = standard error.

Figure 5

Representative EZ integrity maps (i.e., EZ-RPE thickness map of the macular cube). Pink represents total attenuation and blue represents partial attenuation. Maps were matched for degree of baseline tEZ attenuation and growth from baseline to week 48 in exemplary patients of the placebo treatment, and elamipretide treatment arms are illustrated demonstrating increased EZ loss in the foveal group at week 48 (i.e., increased are of pink) compared with the elamipretide group. The fovea is centrally located in the image. EZ = ellipsoid zone; RPE = retinal pigment endothelium; tEZ = total ellipsoid zone.