Phase 1 Clinical Trial of Elamipretide in Dry Age-Related Macular Degeneration and Noncentral Geographic Atrophy: ReCLAIM NCGA Study

Abstract

Purpose: Assess the safety, tolerability, and feasibility of subcutaneous administration of the mitochondrial-targeted drug elamipretide in patients with dry age-related macular degeneration (AMD) and noncentral geographic atrophy (NCGA) and to perform exploratory analyses of change in visual function.

Design: Phase 1, single-center, open-label, 24-week clinical trial with preplanned NCGA cohort.

Participants: Adults ≥ 55 years of age with dry AMD and NCGA.

Methods: Participants received subcutaneous elamipretide 40-mg daily; safety and tolerability assessed throughout. Ocular assessments included normal-luminance best-corrected visual acuity (BCVA), low-luminance BCVA (LLBCVA), normal-luminance binocular reading acuity (NLBRA), low-luminance binocular reading acuity (LLBRA), spectral-domain OCT, fundus autofluorescence (FAF), and patient self-reported function by low-luminance questionnaire (LLQ).

Main outcome measures: Primary end point was safety and tolerability. Prespecified exploratory end-points included changes in BCVA, LLBCVA, NLBRA, LLBRA, geographic atrophy (GA) area, and LLQ.

Results: Subcutaneous elamipretide was highly feasible. All participants (n = 19) experienced 1 or more nonocular adverse events (AEs), but all AEs were either mild (73.7%) or moderate (26.3%); no serious AEs were noted. Two participants exited the study because of AEs (conversion to neovascular AMD, n = 1; intolerable injection site reaction, n = 1), 1 participant discontinued because of self-perceived lack of efficacy, and 1 participant chose not to continue with study visits. Among participants completing the study (n = 15), mean ± standard deviation (SD) change in BCVA from baseline to week 24 was +4.6 (5.1) letters (P = 0.0032), while mean change (SD) in LLBCVA was +5.4 ± 7.9 letters (P = 0.0245). Although minimal change in NLBRA occurred, mean ± SD change in LLBCVA was -0.52 ± 0.75 logarithm of the minimum angle of resolution units (P = 0.005). Mean ± SD change in GA area (square root transformation) from baseline to week 24 was 0.14 ± 0.08 mm by FAF and 0.13 ± 0.14 mm by OCT. Improvement was observed in LLQ for dim light reading and general dim light vision.

Conclusions: Elamipretide seems to be well tolerated without serious AEs in patients with dry AMD and NCGA. Exploratory analyses demonstrated possible positive effect on visual function, particularly under low luminance. A Phase 2b trial is underway to evaluate elamipretide further in dry AMD and NCGA.

Keywords: AE, adverse event; AMD, age-related macular degeneration; BCVA, best-corrected visual acuity; Dry age-related macular degeneration; ETDRS, Early Treatment Diabetic Retinopathy Study; Elamipretide; FAF, fundus autofluorescence; GA, geographic atrophy; Geographic atrophy; LLBCVA, low-luminance best-corrected visual acuity; LLBRA, low-luminance binocular reading acuity; LLQ, low-luminance questionnaire; Mitochondrial dysfunction; NCGA, noncentral geographic atrophy; NLBRA, normal-luminance binocular reading acuity; Phase 1 clinical trial; RPE, retinal pigment epithelium; SD, standard deviation; logMAR, logarithm of the minimum angle of resolution.

Figure 1

Effects of elamipretide on best-corrected visual acuity (BCVA). A, Line graph showing the mean change in BCVA (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) from baseline (day 0) over the 24-week active study period. Bars indicate standard deviation (SD). ∗∗P = 0.0032 for mean change value at week 24 vs. baseline; P < 0.0125, Holm method threshold for statistical significance. B, Scatterplot showing the change in BCVA (ETDRS letters) from baseline at week 24. Horizontal solid line = mean value; vertical dashed line = SD. C, Bar graph showing the percentage of study participants by categorical change in BCVA (ETDRS letters) from baseline at week 24.

Figure 2

Effects of elamipretide on low-luminance best-corrected visual acuity (LLBCVA). A, Line graph showing the mean change in LLBCVA (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) from baseline (day 0) over the 24-week active study period. Bars indicate standard deviation (SD). ∗∗P = 0.0245 for mean change value at week 24 vs. baseline; P < 0.025, Holm method threshold for statistical significance. B, Scatterplot showing the change in LLBCVA (ETDRS letters) from baseline at week 24. Horizontal solid line = mean value; vertical dashed line = SD. C, Bar graph showing the percentage of study participants by categorical change in LLBCVA (ETDRS letters) from baseline at week 24.

Figure 3

Line graph showing the effects of elamipretide on low-luminance binocular reading acuity (LLBRA). Mean change in LLBRA (in logarithm of the minimum angle of resolution units) from baseline (day 0) over the 24-week active study period. Bars indicate standard deviation. ∗∗P = 0.005 for mean change value at week 24 vs. baseline; P < 0.0167, Holm method threshold for statistical significance.