Photoreceptor viability may be a more promising target than GA in AMD

The greatest benefit of elamipretide on visual function occurred in subjects with less advanced disease at baseline. (Adobe Stock image)

Elamipretide (Stealth BioTherapeutics Inc.)may have a positive effect on photoreceptors and visual function in age-related macular
degeneration (AMD). But its degree of effect may depend on how attenuated the ellipsoid zone (EZ)is in the fovea, according to Mark Barakat, MD, who presented data at the virtual Angiogenesis, Exudation, and Degeneration 2023 meeting.

The focus has shifted to the EZ that is rich in mitochondria. A marker of photoreceptor health, the EZ suffers progressive damage that precedes vision loss and geographic atrophy (GA) in dry AMD, explained Barakat, a retinal specialist at Retinal Consultants of Arizona.

The rationale for using the peptide elamipretide is that it penetrates cell membranes and targets the inner mitochondrial membrane. In a preclinical study, elamipretide was seen to protect the mitochondria in a diabetic mouse model, the mitochondria retained normal architecture, and the inner mitochondrial membrane structure was stabilized.¹

ReCLAIM-2 Trial

In this randomized, double-masked, placebo-controlled ReCLAIM-2 study (NCT03891875), the safety, efficacy, and pharmacokinetics of elamipretide were evaluated in subjects with AMD and noncenter GA; 117 participants were randomly assigned to elamipretide and 59 with placebo. The patients’ GA lesions ranged in area between 0.05 mm2 and < 10.16 mm2 and were 150 µm or more from the foveal center; the best corrected visual acuity (BCVA) was 55 or more letters and the low luminance visual acuity (LLVA) was 10 letters or more, with a 5-letter or more low-luminance deficit.

The primary end points were the mean change in the LLVA and change in the GA area as seen in optical coherence tomography (OCT) images. The secondary end points were categorical change in the LLVA, EZ attenuation, and associated biomarkers of retinal and mitochondrial health, Barakat said.

He added that unlike virtually all other pipeline candidates, elamipretide is a mitochondrial stabilizing agent, the only class to have demonstrated a potential to improve LLVA in dry AMD. Although the primary end point of mean change in LLVA was not met, a significantly greater proportion of patients randomly assigned to elamipretide gained 2 or more lines of LL-BCVA compared with placebo (P = .04). Sixteen patients randomly assigned to elamipretide had a 1-line gain in LL-BCVA,
12 a 2-line gain, and 5 a 3-line gain.

Barakat also reported that elamipretide protected against both progressive EZ total attenuation (defined as EZ:retinal pigment epithelium [RPE] thickness of 0 µm) and partial EZ attenuation (defined as EZ:RPE thickness of < 20 µm). Patients randomly assigned to elamipretide had a 43% lower rate of total and a 47% lower rate of partial EZ attenuation (P = .003) compared with placebo (P = .004). Total attenuation is considered a marker of photoreceptor loss.

The baseline characteristics of patients who achieved a 2-line or greater increase in the LL-BCVA were less extensive GA and EZ attenuation throughout the entire OCT scan and in the central 1 mm. Those patients who had a 2-line or greater gain in LL-BCVA had a total macular GA area of approximately 2 mm2 at a distance of approximately 0.75 mm from the foveal center.

The baseline degree of macular attenuation of the EZ (ie, total or
partial) by elamipretide were approximately 12% and 20%, respectively, in patients with the most line gains in LL-BCVA.

Patients with the most line gains in LL-BCVA had an EZ-RPE thickness of approximately 24 µm and a zero µm RPE-basement membrane thickness of approximately 10%, ie, the GA area.

Baseline EZ attenuation of the central 1-mm map area indicated that the total and partial attenuation rates were approximately 25% and 40%, respectively.

The study’s take-home points were as follows:

• Elamipretide may have a positive effect on photoreceptor health (EZ total and partial attenuation) and visual function (LL-BCVA).
• The foveal encroachment of partial and total EZ attenuation may have blunted the elamipretide effect on visual function.
• The greatest benefit of elamipretide on visual function occurred in subjects with less advanced disease at baseline
  (ie, more viable photo-receptor EZ mitochondria).
• Enrichment strategies based on photoreceptor viability rather than GA are likely to be more relevant to the mechanism of action of elamipretide. •

Reference

Szeto HH, Liu S. Cardiolipin-targeted peptides rejuvenate mitochondrial function, remodel mitochondria, and promote tissue regeneration during aging. Arch Biochem Biophys. 2018;660:137-148. doi:10.1016/j.abb.2018.10.013