Mechanism of Action of Elamipretide for GA in Dry AMD

EP: 1.Establishing the Treatment Landscape in Geographic Atrophy

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EP: 2.Mechanism of Action of Elamipretide for GA in Dry AMD

EP: 3.Elamipretide in the Phase 2 ReCLAIM-2 Trial

EP: 4.Advancing Elamipretide into Phase 3 ReNEW and ReGAIN Trials

EP: 5.What Does Elamipretide Represent for GA in Dry AMD?

EP: 6.Concluding Thoughts on Elamipretide for GA in Dry AMD

In this HCPLive® Clinical Trial Spotlight, Arshad Khanani, MD breaks down the investigational product candidate, elamipretide, and the Phase 2 ReCLAIM-2 clinical trial, for the treatment of geographic atrophy (GA) in dry age-related macular degeneration (AMD).

Khanani is the director of clinical research at Sierra Eye Associates and a clinical professor of medicine at the University of Nevada, Reno School of Medicine. He serves as an investigator in the Elamipretide clinical trial program.

Each segment features Khanani breaking down the ophthalmic pipeline for GA, elamipretide’s mechanism of action, primary results from the ReCLAIM-2 clinical trial, what role it could play in treatment, and the recently announced Phase 3 clinical trial program.

Khanani: When looking at the mechanism of action to help patients with dry AMD, the approved treatments target the complement system, but another exciting potential pathway is to work on mitochondria. We know that progressive mitochondrial dysfunction contributes to AMD. Retinal pigment epithelium (RPE) mitochondria in AMD eyes undergo more pronounced degenerative changes and changes in retinal bioenergetics play a key role in vision loss. Mitochondrial dysfunction in photoreceptors can lead to ellipsoid zone (EZ) attenuation and vision loss. EZ is a mitochondrial-rich portion of photoreceptors visible on optical coherence tomography (OCT) and the mitochondria within the EZ support the high metabolic demands of photoreceptors.

In terms of these targets, I think retinal mitochondrial dysfunction is a druggable target, and that's why, if we can have a drug that can target mitochondria and avoid this dysfunction, we may be able to control the disease and have the sick mitochondria now functioning at a better level, leading to a slowing down of disease, or improvement in disease or improvement in vision outcomes.

One drug that comes to mind that works on mitochondria, and we have clinical data on, is elamipretide, which targets dysfunctional cardiolipin metabolism associated with mitochondrial disease. Cardiolipin is a mitochondrial-specific phospholipid that plays a critical role in mitochondrial structure and function, including oxidative phosphorylation. The idea is that mitochondrial targeting therapy can target the bioenergetic imbalance that is a major contributor to the progression of dry AMD.

Given its mechanism of action, elamipretide is a subcutaneous injection, and it's variable because we can treat both eyes of patients. We can treat the early macular degeneration patient population, and this decreases the treatment burden significantly. This can be done at home or by the caregiver because most patients are elderly. There's a big burden coming to the clinic. Many of them have walkers or they're in wheelchairs, and many of them don't have caregivers who can bring them every month or every other month to get treatments in the eye that are currently approved.

An important thing for systemic therapy is that we can treat both eyes without coming to a busy clinic like mine. As a field, we don't have any systemic treatments approved for retinal diseases because we also want to make sure that it's safe. And you know, the trial data on elamipretide to date, we have not seen any concerning systemic adverse events. It's very exciting to have this potential treatment option for our patients being studied in clinical trials.

This transcript has been edited for clarity.