Arshad Khanani, MD, Sierra Eye Associates/University of Nevada Reno School of Medicine

Arshad Khanani, MD shares his excitement about the potential of elamipretide joining the treatment armamentarium in GA and his final thoughts on the topic.

Concluding Thoughts on Elamipretide for Geographic Atrophy 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 

 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.

: As a busy clinician, I'm excited to use the currently available treatment options for our patients with GA, because we haven't had any treatments. But, we know that the current treatments have modest efficacy. We have not seen a functional benefit, and there is a significant treatment burden associated with intravital injections given for GA every month or every other month.

As we know this is a bilateral disease in most cases, many of these patients who drive themselves to our clinic, have to come in and get one injection and then come back for another injection, or get both injections at the same time. This is a significant burden on patients as well as their caregivers.

I'm excited at the potential of having systemic treatment for dry age-related macular degeneration (AMD) and GA. Elamipretide’s mechanism of action, [based on] data from the ReCLAIM-1 and ReCLAIM-2 studies, is promising.

I’m excited that the Phase 3 ReNEW and ReCLAIN studies have started and I’m looking forward to participating in the Phase 3 program. Hopefully, we can have a systemic treatment available for our patients in the near future that can address disease early, help treat both eyes and have some vision function benefit for our patients.

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

This transcript has been edited for clarity.

Disclosures: Dr. Khanani serves as a consultant to Stealth BioTherapeutics. Stealth had no input into or control over the content of this series. The content was chosen and prepared independently by HCPLive.

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Concluding Thoughts on Elamipretide in Dry AMD Patients with GA

Arshad Khanani, MD points to the viability of the mechanism of action of elamipretide for GA in dry AMD, and what it could represent for patient outcomes.

Viability of Elamipretide for GA in Dry AMD

Khanani: In summary, mitochondrial-targeted therapy, targeting the bioenergetic imbalance that is a major contribution to the progression of dry AMD, is very exciting. Given the mechanism of action of elamipretide and the route of administration, which is subcutaneous, it would be a viable therapy for patients, including the early dry AMD patient population. This therapy can be given at home by the patient or the caregiver.

As we know, dry AMD is bilateral disease in most cases, and a systemic treatment will help these patients benefit in both eyes, while avoiding the treatment burden that is a main concern with the currently approved treatments. We want therapy to be safe, and based on the data that we have seen, elamipretide has no drug-related systemic adverse events, except for injection area irritation that can be addressed with topical steroids or oral antihistamines.

In terms of trial design, learning from Phase 2 informed the selection of a proper endpoint based on the mechanism of action, which is the ellipsoid zone (EZ) to retinal pigment epithelium (RPE) thickness over time, compared to the GA growth endpoint that we have seen. This EZ attenuation endpoint has been validated by the US Food and Drug Administration (FDA) and the Phase 3 programs, ReNEW and ReGAIN studies are ongoing. 

The goal is to preserve photoreceptor function and hopefully have some functional benefit for our patients suffering from this disease. Sick mitochondria can hopefully get back to normal or improve in function with this drug, and the Phase 3 trials are looking at patients with early GA.

We can treat these patients and preserve their function. In a nutshell, it's all about structure, functional relationship, and targeting mitochondria structure and architecture, which is important to the function of photoreceptors. 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.

Arshad Khanani, MD points to the viability of the mechanism of action of elamipretide for geographic atrophy in dry AMD, and what it could represent for patient outcomes.

What Does Elamipretide Represent in Dry AMD Patients with GA?

Arshad Khanani, MD provides insight into the pivotal Phase 3 clinical trials investigating elamipretide for geographic atrophy in dry AMD. 

Advancing Elamipretide into Phase 3 ReNEW and ReGAIN Trials

 Elamipretide is now in Phase 3 pivotal clinical trials, the ReNEW and ReGAIN studies. When these trials were designed, we took the learnings from Phase 2 and that informed the selection of a proper endpoint for the mechanism of action, which is measuring ellipsoid zone (EZ) to retinal pigment epithelium (RPE) thickness, or that of a typical GA growth endpoint.

These programs, ReNEW and ReGAIN, are global programs looking at photoreceptor preservation and vision function as the endpoint of interest. Inclusion criteria in ReNEW and ReGAIN will enable patients with less severe disease to participate in clinical trials, unlike most dry AMD trials, where we are intervening with large GA lesions.

When you look at the clinical trial design, patients will receive elamipretide 40 mg subcutaneously, or placebo injection subcutaneously. Patients can have very small GA lesion areas to be included in these trials. The key criteria are non-central GA lesions ≥0.50 mm2 or ≤10.16 mm2, and ≥150 µm from the foveal center, a best-corrected visual acuity (BCVA) score of ≥55 ETDRS letters, and low-luminance visual acuity (LLVA) of ≥10 letters, with an LLVA deficit of >5 ETDRS letters that we used in the phase 2 trial.

The primary endpoint will be the slope of change in EZ total attenuation. Secondary and exploratory endpoints will include the change in EZ total attenuation, as well as the categorical change in LLVA. As you recall, in the Phase 2 study, we saw a significant benefit when you're looking at the change in EZ attenuation, as well as the benefit of improving LLVA. This treatment protects against mitochondrial dysfunction. We hope that we will be able to get those sick mitochondria back to functioning again. The program has hit a significant milestone with the first patient recently enrolled in the ReNEW study.

Arshad Khanani, MD provides insight into the pivotal Phase 3 clinical trials investigating elamipretide for geographic atrophy in dry AMD.

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

Elamipretide in ReCLAIM-2 Trial

: 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.

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

Arshad Khanani, MD, Sierra Eye Associates/University of Nevada Reno School of Medicine

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