Elamipretide in the Phase 2 ReCLAIM-2 Trial

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Arshad Khanani, MD discusses the key findings on elamipretide from the Phase 2 ReCLAIM-2 clinical trial.

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: The data currently available for elamipretide in patients with dry AMD, the ReCLAIM Phase 1 trial, informed us to focus on the photoreceptors, and it showed us the relationship between ellipsoid zone (EZ) health and vision function change.

In the Phase 1 ReCLAIM, study, 40 dry AMD patients, including 19 with GA and 21 with high-risk drusen received elamipretide 40 mg subcutaneously every day for 6 months. This was a Phase 1, open-label, mainly a safety study, but we still wanted to study the efficacy biomarkers.

When you look at the data, the low luminance best corrected visual acuity (LLVA) from baseline improved to a mean of 5.6 letters in high-risk drusen patients and 5.4 letters in patients with GA. Since this was a safety study, we wanted to look at safety closely. There were no serious ocular adverse events and no ocular AEs deemed related to the drug. The most commonly reported adverse event was an injection site reaction in that trial.

That trial led to the design of the ReCLAIM-2 study, which demonstrated photoreceptor protection. In the Phase 2 trial, we confirmed the relationship between EZ and visual function and the potential to improve visual function. This Phase 2 study included 176 patients with GA who were randomized at ≥5 letter LLVA deficit to elamipretide 40 mg subcutaneously, or placebo subcutaneously, once a day for 12 months.

As you are aware, the primary endpoint at that time was GA. That was used as a primary endpoint for this study because that was a regulatory endpoint at the time when the study was initiated. It was not met, but we saw a significant benefit of elamipretide, especially in reducing progressive photoreceptor loss by >40%.

The baseline photoreceptor loss was 2x greater than the baseline GA area. That's why I think it's exciting that Phase 2, which is a learning opportunity for us to figure out the efficacy and safety of drugs, showed us that we have to focus on patients' EZ, more than just the GA growth. Again, GA growth was used as an endpoint because that was the regulatory pathway for drugs that were in development.

When you look at the data from the ReCLAIM-2 study, elamipretide reduced photoreceptor loss and pre-specified analysis provides proof of mechanism and elamipretide target engagement. For us as clinicians, photoreceptor loss is seen as EZ total attenuation. The FDA confirmed that EZ attenuation is now an approvable clinical trial endpoint for patients with dry AMD.

When we look at the data from the ReCLAIM-2 study, we saw a 43% reduction in progression of EZ total attenuation in patients treated with elamipretide, compared to patients treated with placebo. I think that is an important endpoint, and now an approvable endpoint. Looking at the ReCLAIM-2 data, we saw a benefit of systemic treatment with elamipretide in that endpoint.

I think, going forward, since it's now a regulatory-approved endpoint, the future Phase 3 trials are designed to look at that as a primary endpoint. But, also looking at the functional benefit of elamipretide in ReCLAIM-2, we saw it improved low light vision function. To date, it is the only drug to demonstrate potential to improve vision function in patients with dry AMD in a Phase 2 setting.

I think vision changes are associated with the health of the photoreceptors. You have these sick mitochondria, and if we can improve their bioenergetics, then hopefully we can get them to work better and then, maybe we are able to improve vision.

When you look at the change in LLVA in the ReCLAIM-2 study, it correlated with a change in EZ total attenuation. Visual function gainers, LLVA gainers, were the patients with healthier photoreceptors at baseline. This was measured using EZ to RPE thickness in the central 1mm, and we had seen that there's a relationship.

I think the bottom line is that the ReCLAIM-2 study established that we need to look at photoreceptors because that's where the mitochondria are and if you are improving the bioenergetics of the mitochondria, we can hopefully improve function for these patients in addition to decreasing or slowing down the EZ attenuation.

Safety is important, again, for any new drug, especially a systemic drug, and there were no serious adverse events that were related to the drug in this trial. I think the injection site irritation is something that was seen in the trials before, in ReCLAIM-1 and now also in ReCLAIM-2, but this can be mitigated with steroid cream or antihistamines, so I don't think that's a big issue. I'm excited that this program has moved forward and is now in Phase 3 clinical trials.

This transcript has been edited for clarity.

Disclosures: Dr. Khanani serves as a consultant to Stealth BioTherapeutics, the sponsor of this content.

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