ReCLAIM-2 Shows Potential of Elamipretide for Geographic Atrophy in Dry AMD

Results from the Phase 2 ReCLAIM-2 trial demonstrated the potential of elamipretide for photoreceptor protection and improved visual function in eyes with geographic atrophy (GA) associated with dry age-related macular degeneration (AMD).¹

Supplementing the Phase 1 findings, ReCLAIM-2 confirmed the connection between ellipsoid zone (EZ) health and visual function in dry AMD. These Phase 2 data pointed to elamipretide’s role in improving the bioenergetics and health of failing photoreceptors, leading to vision preservation and reducing further loss.

“I’m excited about the potential of having systemic treatments for dry AMD and GA,” Arshad Khanani, MD, director of clinical research at Sierra Eye Associates and clinical professor at the University of Nevada, Reno School of Medicine, told HCPLive. “Elamipretide’s mechanism of action, [based on] data from the ReCLAIM-1 and ReCLAIM-2 studies, is promising.”

Progressive mitochondrial dysfunction contributes to the pathophysiology of AMD, with retinal pigment epithelium (RPE) mitochondria experiencing pronounced degenerative changes in AMD.² These changes in retinal bioenergetics play a significant role in vision loss, with mitochondrial dysfunction in photoreceptors leading to EZ attenuation.

Elamipretide targets dysfunctional cardiolipin metabolism associated with mitochondrial disease and has been shown to protect RPE mitochondrial structure and function.³ In preclinical models, elamipretide protected RPE cells from oxidative stress, improved cell integrity, and restored structure-function relationships.

Notably, photoceptor loss can precede and predict the growth of GA in patients with dry AMD.⁴

The Phase 1 ReCLAIM trial focused on the photoreceptors, indicating a correlation between EZ health and visual function change in dry AMD.⁵ These Phase 1 data demonstrated an improvement in low-luminance best-corrected visual acuity (LLVA) from baseline in eyes with high-risk drusen (+5.6 letters; P = .006) and GA (+5.4 letters; P = .025).

ReCLAIM-2 randomized 176 patients with GA and ≥5-letter low luminance deficit to daily subcutaneous elamipretide 40 mg or placebo for 12 months.⁶ These Phase 2 data showed elamipretide reduced photoreceptor loss, achieving a 43% reduction in the progression of EZ total attenuation versus placebo at Week 48 (P = .003).

Importantly, elamipretide improved low-light visual function in ReCLAIM-2 data, becoming the only investigational product demonstrating the potential for improving visual function in dry AMD.¹

Elamipretide achieved a 47% reduction in the progression of partial EZ attenuation versus placebo at Week 48 (P = .004). Particularly, changes in LLVA were associated with changes in EZ total attenuation (P = .0001). Patients who experienced improved visual function (LLVA gainers) typically had healthier photoreceptors at baseline (P = .02).

Elamipretide’s safety remained in line with previous clinical reports, with 101 (86%) adverse events occurring in the elamipretide 40 mg arm, compared with 42 (71%) in the placebo arm. Mild-to-moderate injection site reactions were the most common, and the trial reported no ocular or serious adverse events related to the study drug.

The US Food and Drug Administration (FDA) has confirmed EZ attenuation as an approvable clinical trial endpoint in dry AMD, helping to move elamipretide into Phase 3 clinical trials.

“In a nutshell, it's all about structure, functional relationship, and targeting mitochondria structure and architecture, which is important to the function of photoreceptors,” Khanani told HCPLive. “It is a druggable target, in my opinion, and I'm looking forward to participating in the Phase 3 studies with elamipretide in patients with dry AMD.”

Elamipretide will continue to be studied in the identical, global, randomized, double-masked Phase 3 pivotal ReNEW and ReGAIN trials. In ReNEW and ReGAIN, 240 patients will be randomized to 40 mg daily subcutaneous elamipretide and 120 to subcutaneous placebo injection.

These trials’ primary endpoint will be the rate of change in the macular area of photoreceptor loss at Week 48. Secondary endpoints consist of the rate of change in the macular area of photoreceptor loss at Weeks 72 and 96, and categorical change 2- and 3-lines in LLVA at Week 48.

Stealth Biotherapeutics recently announced the first patient was enrolled in the Phase 3 ReNEW study, hitting a significant milestone for elamipretide.⁷

“It is an exciting time in our field for patients with dry AMD and GA, with multiple targets on goal,” Khanani added. “Elamipretide fits in nicely in treating this chronic disease in a systemic fashion to benefit our patients.”

References

1. _{Improving Bioenergetics for Retinal Health Slides. Stealth Biotherapeutics. 2023.}
2. _{Lenin RR, Koh YH, Zhang Z, et al. Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration. Int J Mol Sci. 2023;24(10):8763. Published 2023 May 15. doi:10.3390/ijms24108763}
3. _{Allen ME, Pennington ER, Perry JB, et al. The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats. Commun Biol. 2020;3(1):389. Published 2020 Jul 17. doi:10.1038/s42003-020-1101-3}
4. _{Gemenetzi M, Lotery AJ, Patel PJ. Risk of geographic atrophy in age-related macular degeneration patients treated with intravitreal anti-VEGF agents. Eye (Lond). 2017;31(1):1-9. doi:10.1038/eye.2016.208}
5. _{Allingham MJ, Mettu PS, Cousins SW. Phase 1 Clinical Trial of Elamipretide in Intermediate Age-Related Macular Degeneration and High-Risk Drusen: ReCLAIM High-Risk Drusen Study. Ophthalmol Sci. 2021;2(1):100095. Published 2021 Dec 22. doi:10.1016/j.xops.2021.100095}
6. _{Lally DR. Elamipretide-Mediated Visual Function Improvements Are Associated With Ellipsoid Zone Integrity in Patients With Geographic Atrophy. Presented at the ARVO 2023 meeting, April 23-27, New Orleans, LA.}
7. _{Stealth biotherapeutics announces first patient enrolled in Global Phase 3 clinical program for Elamipretide in patients with dry age-related macular degeneration. Stealth BioTherapeutics Inc. June 5, 2024. Accessed June 27, 2024. https://stealthbt.com/stealth-biotherapeutics-announces-first-patient-enrolled-in-global-phase-3-clinical-program-for-elamipretide-in-patients-with-dry-age-related-macular-degeneration/.}