Article

The ReCLAIM Phase 1 Clinical Trial of Elamipretide for Dry AMD

A novel drug with potential to improve vision in patients with dry AMD.

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Patients with advanced dry age-related macular degeneration (AMD) and central geographic atrophy, or loss of retinal pigment epithelium (RPE) and photoreceptors at the fovea, experience profound central vision loss. However, patients with intermediate dry AMD (high-risk drusen) and patients with dry AMD and noncentral geographic atrophy (NCGA) typically retain preserved best-corrected visual acuity (BCVA).1-3 Despite this BCVA preservation, increasing evidence indicates that dry AMD patients experience significant loss of other types of visual function, especially dim-light vision and diminished dark-vision activities of daily living (ADLs).4-6 This includes impaired low-luminance visual acuity (LLVA), loss of low-luminance reading accuracy, and impaired light transition tolerance (ie, difficulty adjusting from bright to dim light conditions). Loss of dark vision includes impaired dark adaptation, which increases safety risk (ie, falls and fractures) as well as loss of night-time social activity. Currently, no effective treatment options are available for dry AMD. Moreover, pharmaceutical companies have largely centered their efforts on novel therapies to slow disease progression. Very few research programs have focused on understanding mechanisms of action and developing therapies to reverse vision loss and boost visual acuity. Thus, drugs to improve vision in dry AMD are a tremendous unmet clinical need.

Priyatham (Prithu) Mettu, MD, is an assistant professor of ophthalmology at Duke University School of Medicine in Durham, North Carolina. Scott Cousins, MD, serves as the Robert Machemer, MD, Professor of Ophthalmology and Immunology at Duke University School of Medicine as well as director of the Duke Center for Macular Diseases and vice chair of research at the Duke Eye Center in Durham, North Carolina. The ReCLAIM study was supported by a sponsored research agreement from Stealth BioTherapeutics to Duke University. Dr. Cousins received salary support as principal investigator and Dr. Mettu received salary support as investigator; both report consultancy to Stealth BioTherapeutics. Reach Dr. Mettu at priyatham.mettu@duke.edu.

ELAMIPRETIDE: MECHANISM OF ACTION AND PRECLINICAL PROOF OF CONCEPT

Elamipretide (Stealth BioTherapeutics) is a novel tetrapeptide drug7-9 currently in development for both common and orphan diseases that involve dysfunction of the mitochondria, the cellular organelles that generates chemical energy in the form of adenosine triphosphate (ATP). At the cellular level, mitochondrial dysfunction causes loss of ATP production, increased levels of reactive oxygen species (eg, superoxide), calcium dysregulation, and, if prolonged, cell death. Elamipretide, given as systemic injection, penetrates tissues and cells and enters the mitochondria, where it reverses mitochondrial dysfunction (improved ATP production, restored mitochondrial membrane potential, normal calcium flux, and reduced superoxide generation).

Considerable evidence has been generated to demonstrate a role for mitochondrial dysfunction as a key mediator of disease pathobiology in AMD.10 Thus, the mechanism of action for elamipretide is particularly compelling. The potential benefit of elamipretide has been demonstrated in preclinical models of AMD. Intriguingly, in the high-fat-diet-fed APOE4 mouse model of dry AMD, subcutaneous elamipretide reversed established vision loss (as evident by reversal of electroretinographic deficits) and promoted clearance of sub-RPE deposits, as compared to control-treated mice.11 Collectively, these data provided strong rationale and preclinical proof-of-concept efficacy to support clinical trial development of elamipretide for dry AMD.

RECLAIM STUDY

The ReCLAIM study (NCT02848313, Duke Health IRB Pro00074019) was a phase 1, single-site, open-label clinical trial to evaluate the safety and tolerability of subcutaneous elamipretide in subjects with dry AMD. Patients with dry AMD were enrolled into 1 of 2 prespecified disease subgroups: (1) noncentral geographic atrophy (NCGA); or (2) high-risk drusen without geographic atrophy (HRD). One eye of each participant ≥55 years of age was eligible if BCVA was ≥55 ETDRS letters (Snellen equivalent ≥20/70) with low-luminance visual acuity (LLVA) deficit >5 letters, where LLVA deficit was defined as the difference between BCVA and LLVA measures, and LLVA was measured as BCVA through a log 2 neutral density filter. In addition, patients were administered a Low-Luminance Questionnaire (LLQ) and had to have ≥2 abnormal LLQ subscales, where at least 1 subscale was either general dim light vision or dim light reading. In the HRD subgroup, high-risk drusen was defined as presence of either at least 1 large (≥125 μm) druse or multiple medium-size (63-124 μm) drusen, while in the NCGA subgroup, noncentral GA was defined as area >1.27 mm2 (approximately >0.5 DA) and <10.16 mm2 (approximately <4 DA) by fundus autofluorescence with sparing of the fovea (RPE and outer retina intact at foveal center) by spectral-domain OCT. All participants received daily subcutaneous elamipretide (40 mg), with outcomes assessed at week 24.

Subcutaneous elamipretide was generally safe and well tolerated with no treatment-related serious adverse events. Adverse events were mostly limited to injection-site reactions.

NCGA SUBGROUP

In the NCGA subgroup (n=19, mean age 76.0, 57.9% female), mean BCVA at baseline was 73.7±9.5 letters and mean baseline LLVA was 44.0±19.8 letters. At week 24, there was a mean increase in BCVA of 4.6±5.1 letters from baseline (P=.003), with a mean increase in LLVA of 5.4±7.9 letters from baseline (P=.025). While there was no significant change in the mean best-corrected reading acuity (BCRA) under standard lighting conditions at 24 weeks (logMAR -0.02±0.13, P=.55), there was a substantial mean increase in low-luminance reading acuity (LLRA) of logMAR -0.52±0.75 (P<.017), approximately 5-line gain in LLRA from baseline. In this subgroup, the mean change in NCGA square root area was 0.13±0.14 mm by OCT, a rate of growth that was less than the than 24-week rate of growth observed in recently completed natural history studies and placebo control arms of clinical trials.

HRD SUBGROUP

In the HRD subgroup (n=21, age 70.9, 61.9% female), mean BCVA at baseline was 79.4±7.4 letters, and mean baseline LLVA was 63.7±10.0 letters. At week 24, there was a mean increase in BCVA of 3.6±6.4 letters from baseline (P=.025), with a mean increase in LLVA of 5.6±7.8 letters from baseline (P=.006). At week 24, there was a modest but significant mean increase in BCRA of logMAR -0.11±0.15 (P=.005), approximately 1-line gain in BCRA from baseline, with a significant mean increase in LLRA of logMAR -0.28±0.17 (P=.0001), approximately 3-line gain in LLRA from baseline.

CONCLUSIONS

The ReCLAIM study demonstrated that elamipretide is safe and generally well tolerated in patients with dry AMD, both for NCGA and HRD (intermediate AMD). To our knowledge, this clinical trial of elamipretide is the first to demonstrate the potential of a novel drug to improve visual function in dry AMD. Available data from the NCGA subgroup also suggest the possibility that elamipretide may slow GA progression. Collectively, these findings support the hypothesis that mitochondrial dysfunction is a major contributor to AMD pathobiology and provide a strong rationale for mitochondrial-targeted drugs to reverse ongoing visual dysfunction, especially low-luminance vision loss, in patients with dry AMD. A randomized, multicenter, Phase 2b, placebo-controlled clinical trial of daily subcutaneous elamipretide in patients with dry AMD and NCGA (ReCLAIM-2; NCT03891875) is under way in sites across the United States. RP

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