Stealth BioTherapeutics is investigating the potential of FORZINITY (elamipretide), a drug that has been shown to bind to the key mitochondrial inner membrane lipid cardiolipin, enhancing mitochondrial respiration and ATP production while protecting against reactive oxygen species (ROS). The company intends to use this drug as a treatment for multiple diseases in which mitochondrial dysfunction plays a key role. It was recently approved for Barth syndrome, a rare genetic disorder that afflicts roughly one in a million boys that is caused by mutations in the gene for Tafazzin (TAZ), an enzyme that catalyzes the final step in cardiolipin production. It is currently in a Phase III trial for age-related macular degeneration.

Age-related macular degeneration (ARMD) is the leading cause of blindness among people over the age of 65 in the developed world, afflicting more than 10 million persons in the United States alone. It is caused by damage to the macula — the oval-shaped pigmented area in the center of the retina at the back of the eye that is responsible for high-resolution central vision.

Maintenance cells called retinal pigment epithelium (RPE) cells are responsible for engulging and processing the damaged outer membranes of light-sensing cells (photoreceptors) in the macula; they are also responsible for recycling all-trans retinal into 11-cis retinal as part of the visual cycle, and retinal occasionally reacts to form the waste product A2E, which RPE cells are not competent to process. The failure of RPE to clear and process these wastes leads to the death of RPE cells, deposits of damaged material called drusen in the macula, and ongoing loss of photoreceptors.

In its advanced stages, ARMD can be divided into a “wet” form (in which blood vessels tunnel up into the retina frome choroid, leading to blood and fluid leakage into the retina) and a “dry” form, in which cellular debris called drusen accumulates on the macula and damages the photoreceptors There are therapies available for the “wet” form of ARMD, but it only acounts for about 10% of cases: the other 90% of advanced cases are of the “dry” form, for which no therapies exist.

Stealth BioTherapeutics argues that mitochondrial dysfunction is a critical driver of multiple ophthalmological conditions, including glaucoma, diabetic retinopathy, Fuchs dystrophy, and “dry” ARMD, for which it launched a clinical program.

The mitochondria of RPE cells in people with ARMD have approximately eight times more mutations than those from age-matched controls, and their mitochondria are enlarged and misshapen, with disruptions in their inner and outer mitochondrial membrane structures. The mitochondria from people with ARMD appear to trigger epigenetic changes and aberrant gene expression in RPE cells.

In mice whose RPE cells researchers specifically knocked out the mitochondrial antioxidant enzyme MnSOD, the RPE cells became abnormally large and may have died — an effect that elamipretide blocked. And elamipretide arrested further age-related loss of visual function in geriatric (24-month-old) or very aged mice (32-month-old), preventing further decline for several months.

In November 2016,  Stealth announced the initiation of ReCLAIM, an open-label twelve-week Phase I trial testing the safety and tolerability of elamipretide in people with intermediate ARMD and non-central geographic atrophy or high-risk drusen.

In December 2018, Stealth announced that FDA had granted it 0Fast Track designation for elamipretide for the treatment of dry ARMD with geographic atrophy.

In March 2019, Stealth announced that it had dosed its first patient in ReCLAIM-2, a randomized, double-blind, placebo-controlled Phase II trial of 40 mg of elamipretide (n = 117) versus placebo (n = 59) in subjects with advanced “dry” ARMD with geographic atrophy.

In April 2019, Stealth announced interim results of the ReCLAIM open-label Phase I trial. In the 15 people with non-central geographic atrophy, low-luminance visual acuity (i.e., sharpness of vision under low-light conditions) increased from a baseline of 43.9 ± 19.8 letters by a further 5.4 ± 7.9 letters on average; their best-corrected visual acuity (BVCA — their best distance vision while using their eyewear) rose from a baseline of 73.7 ± 9.5 letters by a further 4.6 ± 5.1 letters; and their low-luminance smallest line read correctly improved to a gain equivalent to five lines on an eye chart. Volunteers with non-central geographic atrophy also reported significant improvements in a standardized quality of life assessment.

Stealth also stated that all of these outcomes also improved in the nineteen volunteers with high-risk drusen, although the press release did not include numerical values for these patients. Notably, visual acuity also improved in control eyes afflicted by “wet” rather than “dry” ARMD. (A therapeutic effect in the “control” eye is plausible because elamipretide is delivered systemically, and not just to the target eye).

Stealth-affiliated scientists published the final results from the ReCLAIM trial in 2022 in two separate publications. The main results were very similar to what they had announced in the press release. In the non-central geographic atrophy publication, the investigators clarified that there were originally 19 volunteers in the non-central geographic atrophy group, but four dropped out for a variety of benign reasons. They additionally reported that geographic atrophy had progressed, but somewhat more slowly than historical comparators.

In the publication of data from subjects with high-risk drusen in ReCLAIM, full data were also largely consistent with the press release. Of 21 subjects recruited, 18 completed the trial, with no major safety signal. In a completer analysis, BCVA improved from baseline to 24 weeks by 3.6 letters (P = 0.014) and BVCA under low luminance by 5.6 letters (P = 0.004). Compared with baseline, mean normal-luminance binocular reading acuity (NLRA) improved by –0.11 logarithm of the minimum angle of resolution (logMAR) units (range in values of 1.9 logMAR, with lower values indicating sharper reading) and low-luminance binocular reading acuity by −0.28 logMAR units (range of values 1.8 logMAR).

Subjects also reported significant improvements in vision-related quality of life. There were no significant changes in RPE-drusen complex volume, fundus autofluorescence or development of new hypoautofluorescence (a measure of geographic atrophy), mesopic microperimetry (which spatially maps retinal sensitivity and correlates results with visual function), or dark adaptation.

In May 2022, Stealth announced the topline data from the Phase II ReCLAIM-2 trial. Elamipretide failed to meet its primary endpoints (mean changes in LLVA and geographic atrophy). However, more than 15% of elamipretide-treated subjects gained at least two lines of vision at Week 48, a key secondary endpoint. Moreover, elamipretide slowed the progression of ellipsoid zone (EZ) attenuation relative to placebo. (The EZ is one of four reflective bands in the outer retina that are detected by spectral domain optical coherence tomography (SP-OCT); it reliably predicts long-term geographic atrophy in numerous diseases of the macula, including ARMD). Based on these results, Stealth declared its intent “to progress development initiatives intended to better position this indication for potential partnering consistent with previous guidance.”

In June 2023, Cleveland Clinic Cole Eye Institute researchers presented the results of the Phase II ReCLAIM-2 trial at the 2023 ARVO Annual Meeting. Over the 48 weeks of the trial, elamipretide slowed the progression of EZ ttenuation relative to placebo (15% partial attenuation in elamipretide vs 34% in subjects receiving placebo, and 26% total EZ attenuation in elamipretide vs 48% in placebo).

Additionally, more subjects in the elamipretide group gained at least two lines on the low-light BCVA (14.6% vs 2.1%). These two outcomes were modestly correlated with each other (r = 0.26, P = 0.02). Adverse events were common, but were experienced in both groups and were largely injection-site reactions. ReCLAIM-2 was published in January-February of 2025.

Later that month, Stealth announced a positive end-of-phase-II meeting with FDA for elamipretide in ARMD, establishing its elamipretide development plan. Based on the correlation between total EZ attenuation and low light-BVCA, Stealth argued that EZ attenuation would be a useful surrogate marker for disease progression, and FDA’s minutes confirmed that EZ attenuation would be an approvable endpoint in “dry” ARMD trials.

In November 2023, Stealth CEO Reenie McCarthy announced their intention to launch Phase III trials of elamipretide for photoreceptor dysfunction associated with “dry” ARMD. The announcement stated that they would run the Phase III ReNEW trial and confirmatory ReGAIN trial in parallel. Subjects “will be randomized 2:1 to either elamipretide or placebo for 96 weeks, with the option … to enroll in the open-label extension trial, ReTAIN.”

Stealth revealed further details in a subsequent interview, and the company established a trial website. The primary endpoints are the rate of change in the macular area of photoreceptor loss assessed by spectral domain-optical coherence tomography (SD-OCT) and EZ mapping at week 48. (The EZ is one of four reflective bands that are visualized on SD-OCT and has good prognostic value in ARMD and other macular diseases).

Stealth enrolled the first subject in the ReNEW trial (NCT06373731) in June 2024. At that time, Stealth was still communicating its intent to run ReGAIN. However, as of September 2025, neither Clinicaltrials.gov nor the website appear to list the ReGAIN trial.

In March 2025, Stealth announced that it had enrolled half of the eventual 360 subjects in its global Phase III ReNEW trial of elamipretide in subjects with “dry” ARMD.