Elamipretide Protects Photoreceptors from Thinning in Dry AMD

Elamipretide, a mitochondria-targeting therapy, preserved photoreceptor health after 48 weeks regardless of baseline burden of photoreceptor outer segment thinning in patients with dry age-related macular degeneration (AMD), based on a post-hoc analysis of the ReCLAIM-2 trial.1

Presented at the 43rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, by David Lally, MD, New England Retina Consultants, this study evaluated the association of baseline ellipsoid zone (EZ) integrity parameters on future photoreceptor loss, assessing the therapeutic impact of elamipretide on these predictive parameters.1

Recent trials have also posited elamipretide’s potential ability to treat traumatic optic neuropathy. When combined with subcutaneous etanercept, investigators in a 2021 trial found a significant increase in retinal ganglion cell survival rates compared to other common treatments. Additionally, elamipretide exhibited a substantial increase in retinal ganglion cell survival alone.2

Lally and colleagues examined panmacular spectral domain optical coherence tomography (SD-OCT) scans from the ReCLAIM-2 study, investigating eyes with EZ integrity measurements at baseline and week 48 of the trial. These were analyzed using an advanced segmentation platform with B-scan validation and manual correction by a certified expert grader.1

The team assessed photoreceptor health (EZ integrity parameters) by partial EZ attenuation (pEZa; EZ-retinal pigment epithelium [RPE] thickness ≤20µm), total EZ attenuation (tEZa; EZ-RPE thickness = 0µm), and photoreceptor thinning region (PTR; the difference between tEZa and pEZa), so that the region of outer segment thinning could be isolated. An analysis of covariance was also performed, assessing baseline PTR as a linear predictor of change in tEZa at week 48 to determine the relationship between PTR and tEZa change, and to evaluate the impact of elamipretide treatment on that association.1

Investigators first looked for heterogeneous slopes for the covariate, such as an interaction between baseline PTR and treatment group. Given the significance of the interaction (P = .0009), Lally and colleagues noted that a heterogeneous covariance slope model was fit, and relationships were estimated separately for each treatment group.1

A total of 41 eyes from ReCLAIM-2’s placebo group and 71 from the elamipretide group were included in this analysis. Investigators marked the mean baseline values for both groups as 7.74 mm2 versus 8.94 mm2 for pEZa, and 4.66 mm2 versus 5.31 mm2 for tEZa. This resulted in a PTR of 3.08 mm2 and 3.63 mm2, respectively.1

For placebo, the baseline PTR predicted significant changes in tEZa at week 48 (slope for regressor line of change in tEZa [slope] as predicted by PTR .38346 mm2; P <.0001). Lally and colleagues indicated that elamipretide treatment weakened this association in the placebo group so significantly that baseline PTR was no longer predictive of tEZa change by week 48 (slope as predicted by PTR .00715 mm2; P = .9022).1

This model demonstrated a treatment difference when assessing the least square (LS) mean for a change in tEZa at week 48 by treatment (elamipretide 1.369 mm2; placebo 2.374 mm2), where the LS mean difference between treatment groups (1.0056 mm2) was statistically significant (P = .0026).1

Ultimately, investigators determined that elamipretide treatment preserved photoreceptor health compared to placebo, as well as disrupting the association noted with placebo, which means the treatment may be modifying the rate of photoreceptor loss in dry AMD.1

“Mitochondrial dysfunction is associated with the progression of dry AMD, contributing to outer segment thinning and subsequent photoreceptor loss,” Lally and colleagues wrote. “This clinically relevant finding suggests photoreceptor outer segment thinning not only precedes but also predicts the pathological changes linked to vision loss and advanced stages of dry AMD.”

Elamipretide is actively being investigated in 2 ongoing, pivotal phase 3 trials, titled ReNEW and ReGAIN.1

References

1. Lally D. Elamipretide Protection Against Photoreceptor Loss in Dry AMD: Predictive Baseline Quantitative Ellipsoid Zone Integrity Parameters in ReCLAIM-2. Abstract presented at the 43rd Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, July 30-August 2, 2025.

2. Tse BC, Dvoriantchikova G, Tao W, et al. Mitochondrial targeted therapy with elamipretide (MTP-131) as an adjunct to tumor necrosis factor inhibition for traumatic optic neuropathy in the acute setting. Exp Eye Res. 2020;199:108178. doi:10.1016/j.exer.2020.108178