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Mitochondrial Stabilizing Drugs Have Potential to Reverse Vision Loss in Dry AMD


A review of data on 2 mitochondrial membrane stabilizers—risuteganib and elamipretide—has highlighted the potential to not just slow disease progression but actually reverse vision loss in patients with intermediate dry age-related macular degeneration (AMD).

Although the dry form of age-related macular degeneration (AMD) is common, affecting approximately 80% of people with AMD,1 there is a huge unmet need for treatment for these patients, explained Baruch D. Kupperman, MD, PhD, during his presentation at the Angiogenesis, Exudation, and Degeneration 2023 meeting, held virtually February 10-11, 2023. When dry AMD progresses, it turns into wet AMD, which does have treatment options available.

Kuppermann is the Steinert Endowed Professor and chair of the Department of Ophthalmology, as well as the director of the Gavin Herbert Eye Institute at the University of California, Irvine.

There are treatments focusing on geographic atrophy, which is an advanced form of dry AMD, but all of these products focus on slowing the progression of the disease and not on improving vision. Approximately 10% of patients with dry AMD have GA compared with 42% who have intermediate dry AMD.2 Between 32% and 41% of eyes with early or intermediate dry AMD have a visual acuity of 20/40 worse and require intervention.

Kupperman discussed 2 mitochondrial membrane stabilizers that have shown promising results in reversing vision loss in patients with dry AMD. However, it’s important to identify which patients may experience the greatest benefit.

Macular degeneration is characterized by marked mitochondrial defects, he explained. Past research has shown the elamipretide, previously studied in Duchenne muscular dystrophy, has been shown to be a mitochondrial membrane stabilizer, and now risuteganib has been show to “preserve mitochondrial structure in RPE [retinal pigment epithelium] cells under stress.”

Research on risuteganib has shown the therapy improves mitochondrial structure and restores energy product in cell cultures.3 A phase 2a study looked at the drug in dry AMD, trying to exclude patients with GA. In one arm of the study, 15 patients received a sham injection before crossing over to receive risuteganib at week 16. In the other arm, patients received 1 mg risuteganib intravitreally at baseline and then again at week 16. The end point analysis was at 28 weeks for the patients receiving risuteganib initially at baseline.

“It was meant to be an asymmetric analysis where—since this is an inexorably progressive disease, people don't tend to get better spontaneously—the goal was to look at a longer time point in the eye that was treated and a shorter time point in the sham group,” Kupperman said.

The study found that 48%, 32%, and 20% of patients in the risuteganib 28-week arm had vision improvements of ≥ 8, ≥ 10, and ≥ 15, respectively, letter improvements from baseline. In comparison, only 7.1% of patients in the sham injection arm had improvements of ≥ 8 or ≥ 10 letter and none had ≥ 15 letter improvements from baseline.

The study showed improvements in vision, which is something that was thought to be impossible, Kupperman said.

Considering potential predictors of response for risuteganib and other potentially therapeutic pathways, he noted that age, gender, race, and genotype did not correlate with either a response or no response.

However, optical coherence tomography (OCT) criteria at baseline did correlate with Best Corrected Visual Acuity (BCVA) response to risuteganib. Predictors to response, which was an improvement in vision, were enhanced ellipsoid integrity, greater outer retinal thickness, and decreased areas of geographic atrophy.

Kupperman also briefly reviewed predictors of response to elamipretide for high-risk drusen. While drusen do not cause AMD, having drusen increases the risk of developing AMD and maybe a sign of AMD.4 A post-hoc analysis of the phase 1 ReCLAIM study found mean central macular retinal thickness positively correlated with an improvement in low luminance BCVA.5 Eyes with greater baseline preservation of the central macular outer retina gained 2 lines or more of vision.

Overall, this research has shown that restoring functional vision is achievable in patients with dry AMD through the use of these mitochondrial stabilizing drugs, “suggesting the early treatment of dry AMD is warranted to reverse vision loss,” Kupperman concluded.


1. Boyd K. What is macular degeneration? American Academy of Ophthalmology. February 10, 2022. Accessed February 10, 2023. https://www.aao.org/eye-health/diseases/amd-macular-degeneration

2. Rafaelof M, Moshfeghi AA, Bouckaert L, Boucher N, Saroj N, et al. Assessment of eyes with non-exudative age-related macular degeneration in US retina practices. Invest Ophthalmol Vis Sci. 2020;61(7):4175.

3. Yang P, Shao Z, Besley NA, et al. Risuteganib protects against hydroquinone-induced injury in human RPE cells. Invest Ophthalmol Vis Sci. 2020;61(10):35. doi:10.1167/iovs.61.10.35

4. Porter D. What are drusen? American Academy of Ophthalmology. March 8, 2022. Accessed February 10, 2023. https://www.aao.org/eye-health/diseases/what-are-drusen

5. Ehlers JP, Cetin H, Hanumanthu A, et al. Association of ellipsoid zone integrity and treatment response in subjects with non-neovascular AMD treated with subcutaneous elamipretide: post hoc analysis of the phase 1 ReCLAIM study. Invest Ophthalmol Vis Sci. 2021;62(8):1942.

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