Evaluation of Elamipretide Subcutaneous Injections in Patients with Dry Age-Related Macular Degeneration: A Phase 3 Randomized, Double-Masked, Placebo-Controlled Trial

The primary objective of this clinical trial is to evaluate the **efficacy** of once daily subcutaneous injections of elamipretide in subjects with **Dry Age-Related Macular Degeneration (Dry AMD)**. This is clinically relevant as Dry AMD is a leading cause of vision loss in older adults, and effective treatments are currently limited. Understanding the efficacy of elamipretide could potentially lead to a new therapeutic option for managing this condition.

Secondary objectives include: - Evaluating the **safety** and **tolerability** of once daily subcutaneous injections of elamipretide. - Assessing the **Pharmacokinetic (PK) profile** of elamipretide and its metabolites. These secondary objectives are crucial for determining the overall risk-benefit profile of the treatment and understanding its pharmacological behavior in the body.

The clinical trial involves a total of **265 participants** diagnosed with **Dry Age-Related Macular Degeneration (Dry AMD)**. The study population includes both male and female adults aged 55 years and older. Participants were selected based on the presence of at least one eye with dry AMD characterized by photoreceptor loss, as determined by the presence of extrafoveal geographic atrophy (GA) at the screening visit. The trial does not include a vulnerable population. Participants are required to be capable of administering the investigational medicinal product (IMP) and must be able to provide informed consent. They are also expected to comply with all site visits, examinations, daily IMP administrations, and other conditions outlined in the trial protocol. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, double-masked, placebo-controlled study to evaluate the efficacy, safety, and pharmacokinetics of subcutaneous injections of **Elamipretide** in subjects with **Dry Age-Related Macular Degeneration (Dry AMD)**. The trial will involve a total duration of approximately 96 weeks, with an estimated recruitment start date in August 2024 and an anticipated end date in December 2027. Participants will be randomly assigned to receive either the investigational drug, Elamipretide, or a placebo composed of excipients without the active drug substance. The primary objective is to assess the rate of change in the macular area of photoreceptor loss, specifically the Ellipsoid Zone - Retinal Pigment Epithelium (EZ-RPE) thickness, using spectral domain-optical coherence tomography (SD-OCT) and Ellipsoid Zone mapping at Week 48.

The study will commence with a screening visit to confirm eligibility, which includes criteria such as age (≥ 55 years), presence of dry AMD with photoreceptor loss, and the ability to comply with study requirements. Following successful screening, participants will undergo a series of study visits, including baseline assessments and regular follow-up visits at specified intervals to monitor efficacy and safety outcomes. Key follow-up visits are scheduled at Weeks 48, 72, and 96, where secondary endpoints such as changes in visual acuity and further assessments of photoreceptor loss will be evaluated. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any post-study care is arranged.

Participant involvement is expected to last for the entire duration of the trial, approximately 96 weeks, unless early termination is warranted. Conditions that may lead to early withdrawal include adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study period.

The clinical trial involves the administration of **Elamipretide**, an investigational drug, in the form of a **solution for injection**. The active substance in this medication is **elamipretide trihydrochloride**, a chemical compound. The pharmaceutical form is a liquid cartridge formulation, and the drug is administered via **subcutaneous injection**. The dosing regimen consists of once-daily injections, with a maximum daily dose of 40 mg/ml. The total maximum dose over the treatment period is 27,160 mg/ml, and the treatment duration is set for a maximum of 96 weeks. The investigational drug is developed by Stealth Biotherapeutics Inc. and is identified by the sponsor product code MTP-131. Participant compliance with the dosing schedule will be monitored throughout the trial.

The trial also includes a **placebo** group, which will receive a formulation composed of the excipients used in the investigational drug, but without the active drug substance. The placebo is designed to match the investigational drug in appearance and administration route, ensuring the study remains double-masked. The placebo is administered in the same manner as the investigational drug, via subcutaneous injection, to maintain consistency in the trial protocol. The use of a placebo allows for a controlled comparison to evaluate the efficacy and safety of Elamipretide in subjects with dry age-related macular degeneration (AMD).

The efficacy of Elamipretide in the treatment of **dry age-related macular degeneration (Dry AMD)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of change in the macular area of photoreceptor loss, defined as an Ellipsoid Zone – Retinal Pigment Epithelium (EZ-RPE) thickness of 0μm, which will be evaluated using spectral domain-optical coherence tomography (SD-OCT) and Ellipsoid Zone (EZ) mapping at Week 48. Secondary endpoints include the rate of change in the macular area of photoreceptor loss assessed by SD-OCT and EZ mapping at Weeks 72 and 96, as well as the proportion of subjects gaining ≥ 10 letters (2 lines) and ≥ 15 letters (3 lines) in Low Luminance Best-Corrected Visual Acuity (LL BCVA) from baseline at Week 48.