Stealth BioTherapeutics‘ lead investigational product candidate elamipretide (approved and marketed as FORZINITY™ for Barth syndrome) has been the subject of several trials testing its therapeutic potential in mitochondrial myopathies due to aging or congenital mutations.
Age-Related Muscular Mitochondrial Dysfunction
Stealth initially registered the MOTION Trial (NCT02245620) in 2014. MOTION was a randomized, double-blind, placebo-controlled Phase II trial that tested elamipretide’s effects on muscle function in 40 elderly subjects (ages 60-85 years) with reduced mitochondrial function. Mitochondrial function was measured in vivo via (31P)Magnetic Resonance Spectroscopy (MRS) and maximum ATP synthetic rate measured on Optical Spectra Scan (OPS); maximum ATP synthetic rate was the primary outcome.
In September 2016, Stealth announced the results of MOTION. Elamipretide-treated subjects’ maximal mitochondrial energy production increased by 30% from baseline, as compared to 10% in the placebo group, though the difference did not reach statistical significance (p=0.055). If real, Steath asserted that an increase in mitochondrial bioenergetics this large would be equivalent to a regimen of endurance exercise three times a week for six months. The apparent improvement in bioenergetics was associated with an increase in the ability to produce sustained muscular force (p=0.004). Elamipretide was well-tolerated, with no treatment-emergent adverse events.
The MOTION results were presented at the Late Breaker Poster Session of the Heart Failure Society of America’s Annual Scientific Meeting in Orlando, Florida on September 17, 2016. The results were formally published in July 2021. The increase in mitochondrial energy production relative to placebo was revealed to be only immediately after the 2-hour drug infusion: there was no difference on day 7 after treatment, as in the study design. The authors noted that this result was after a single infusion, and the lack of effect at day 7 likely reflected elamipretide’s 16 hour half-llife. There was no significant change in resting muscle mitochondrial coupling or fatigue resistance in the tested first dorsal interosseous muscles.
Primary Mitochondrial Myopathies
Primary mitochondrial myopathies (PMMs) are a heterogeneous grouping of genetic disorders that impair mitochondrial OXPHOS, primarily in skeletal muscle. The underlying mutations can be in genes of the mitochondrial or nuclear genome and can encode proteins in the energy-generating mitochondrial electron transport chain or in other mitochondrial genes, such as the mitochondrial DNA polymerase POLG. With some variability, patients suffer muscle weakness and atrophy and have limited exercise capacity, often combined with fatigue and pain. Over time, patients’ exercise capacity progressively diminishes, ultimately to the point that it impairs their ability to perform activities of daily living (ADL).
In February 2015, Stealth launched MMPOWER, a Phase I/II, multi-center, randomized, double-blind, placebo-controlled trial of multiple ascending doses of elamipretide in subjects with PMM (NCT02367014). The goal was to evaluate its safety, tolerability, pharmacokinetics, and six-minute walk test (6MWT) after 5 days of treatment as a primary preliminary efficacy endpoint. Three groups of nine subjects were administered one of three doses of the drug, with three additional patients as placebo controls for each dose cohort.
In February 2016, FDA granted elamipretide Fast Track designation for the treatment of primary mitochondrial myopathy. In October 2017, FDA granted elamipretide orphan drug status for this indication.
In June 2016, Stealth announced the topline results from MMPOWER, which were simultaneously presented at the United Mitochondrial Disease Foundation (UMDF) symposium Mitochondrial Medicine 2016. Subjects treated with the highest dose of elamipretide enjoyed a statistically significant increase in their 6MWT, increasing their mean distance walked by 51 m versus just 3 m in subjects receiving the placebo (P=0.03). Additionally, there was a trend toward a dose-response effect at lower doses. The company also noted that the largest improvement in 6MWT was in patients whose baseline distances were most impaired. Elamipretide was also well-tolerated, with no serious adverse events observed.
The results were formally published in April 2018. Whereas the 6MWT improvements were reported as 51.2 m in subjects who received the highest dose of elamipretide vs 3.0 m in the placebo group (p = 0.0297), consistent with the press release, these data were reported to be in a model that adjusted for additional covariates that might affect the test; the raw values were 64.5 m and 20.4 m, respectively (p = 0.053). The dose-dependent trend remained. There were no significant differences in other efficacy or safety endpoints, including cardiopulmonary exercise testing (CPET) and changes in the exploratory biomarkers.
In September 2016, Stealth announced the initiation of MMPOWER-2 (NCT02805790), a randomized, double-blind, placebo-controlled, crossover trial that extends longitudinally from the original MMPOWER trial. Subjects who completed the MMPOWER trial were invited to be randomized 1:1 to four additional weeks of once-daily subcutaneous injections of 40 mg elamipretide or placebo for four additional weeks, wash out for four weeks, and then take the opposite treatment for the final four weeks. The 40 mg daily dose was larger than the highest one-time dose in MMPOWER (30 mg). 6MWT was again the primary endpoint, with several functional and biochemical secondary endpoints.
In March 2017, Stealth announced the launch of RePOWER, a prospective observational study and pre-trial registry of patients with genetically confirmed or suspected PMM. RePOWER was to enroll approximately 300 volunteers aged 16 to 65, with the intention of exploring the relationship between patient genetics and clinical presentation, as well as regional differences in standard of care for people with PMM. Additionally, the study aimed to identify potential subjects for an eventual Phase III trial of elamipretide in patients with PMM.
In June 2017, Stealth announced the results of the MMPOWER-2 extension trial, with detailed results presented at UMDF’s Mitochondrial Medicine Symposium 2017. The trial ultimately enrolled 30 subjects from MMPOWER. In MMPOWER-2, subjects gained an additional 20 m on the 6MWT while taking elamipretide versus placebo ( p=0.08). While this (primary) endpoint was not statistically significant, a prespecified analysis showed that subjects with more limited baseline 6MWT (< 450 m) achieved a greater improvement on drug (24 m) than did the more able subjects (6MWT>450 m), consistent with the results of MMPOWER.
Among secondary endpoints, subjects’ Neuro-QoL Fatigue Short Form score improved more on elamipretide than on placebo (an additional 4 points on a scale that ranges from 20 to 80 points; p=0.01). So did their scores on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue Score (1.7 units, on what appears to be a 16-unit instrument; p=0.0006).
Elamipretide also led to significant improvements in several other PMMSA subscores, including the subscore for each patient’s most troublesome symptom (p=0.01). However, there was no difference in the triple Timed-Up-and-Go test. When the trial was published in February 2020, it additionally revealed that there was no difference in Physician Global Assessment (P = 0.0636) or in activity measured via wrist- or hip-based accelerometry (P = 0.9345 and P = 0.7326, respectively). Elamipretide was well-tolerated, with no serious adverse events.
In November 2017, Stealth announced the launch of MMPOWER-3, a 24-week Phase III trial of daily elamipretide in PMM (NCT03323749). As previously suggested, the trial was to enroll eligible patients with PMM from the RePOWER observational study. MMPOWER-3 was planned as a randomized, double-blind, placebo-controlled trial in approximately 200 volunteers with PMM, followed by an open-label extension period. The primary endpoints were the 6MWT and PMMSA Total Fatigue Score. At some point no later than August 2018, Stealth launched the Mitotrials website to recruit for RePOWER and MMPOWER-3.
In April 2019, Stealth announced that it had completed subject enrollment in MMPOWER-3 and anticipated topline data by the end of that year.
In December 2019, Stealth announced that MMPOWER-3 failed to meet its primary endpoints, while confirming that elamipretide was well-tolerated.
The results of MMPOWER-3 were published in July 2023. Relative to placebo, subjects randomized to elamipretide had no improvement on 6MWT (−3.2 m (95% CI −18.7 to 12.3; p = 0.69)) or on the PMMSA total fatigue score (−0.07 points (95% CI −0.10 to 0.26; p = 0.37)). It also failed on a per-protocol analysis. There were also no significant differences in patient or clinician global impression of PMM symptoms.
A substantial majority of the mitochondrial myopathies in MMPOWER-3 (n = 162 [74%]) were due to mitochondrial DNA (mtDNA) mutations, with the remaining quarter having mutations in mitochondrial genes housed in the nuclear DNA (nDNA). After reclassifying three subjects from the mtDNA to the nDNA groups, the investigators performed a post hoc exploratory subgroup analysis comparing the effects of elamipretide in subjects with mtDNA vs. nDNA mutations separately.
In the mtDNA subgroup, 6MWT tended to increase more in the placebo group (n = 79, +25.0 (±6.1) m than in the elamipretide group (n = 74, +14.0 (±6.1) m; between-group difference −11.0 m (95% CI −28.1 to 6.1; p = 0.21). By contrast, 6MWT increased by 25.5 (±8.0) m in nDNA mutation carriers that received elamipretide (n = 29) versus just 0.3 (±7.7) m for those that received placebo (n = 29) — a 25.2 m advantage for elamipretide (95% CI 3.1–47.3; p = 0.03). However, there was no difference in the PMMSA Total Fatigue Score between elamipretide- and placebo-treated subjects with either nDNA or mtDNA mutations.
To interpret the apparent differential effect of elamipretide in subjects with mutations in genes encoded in the nuclear rather than the mitochondrial genome, the investigators noted that elamipretide’s best-characterized actions are in protecting the mitochondrial phospholipid cardiolipin from oxidative damage and maintaining its physiological interactions with cytochrome c. Mitochondrial proteins encoded in nDNA need to be synthesized in the cytosol and transported across the mitochondrial membranes, and cardiolipin is required for the assembly and activity of the proteins that effect this translocation, as well as for the assembly and coupling of electron transport chain supercomplexes. The investigators therefore speculated that the nDNA mutation-specific benefit of elamipretide was the result of improved transport of nDNA-encoded mitochondrial proteins into the organelles, and improved mitochondrial Complex assembly and morphology. (The authors also noted that elamipretide might augment mtDNA stability and/or stabilize mtDNA packaging into nucleoids, but these mechanisms would not explain a benefit specific to nDNA-encoded mitochondrial gene mutation carriers).
Additionally, the investigators noted that the increase in 6MWT in the nDNA cohort was significantly correlated with plasma elamipretide area under the curve, and therefore argued that a greater dose of the drug may be warranted.
In April 2022, Stealth launched the NuPOWER trial (NCT05162768), a 48-week Phase III randomized, double-blind, parallel-group, placebo-controlled trial to assess elamipretide as therapy for primary mitochondrial myopathy caused by nuclear DNA mutations (nPMM). The primary efficacy endpoint was once again 6MWT, with the five-times sit-to-stand and triple timed up-and-go tests as secondary endpoints.
In May 2022, Stealth announced that the European Medicines Agency (EMA) had granted elamipretide orphan drug designation (ODD) for the treatment of myopathic mitochondrial DNA depletion syndrome (M-MDS), which the press release asserted applied to patients with nPMM eligible for enrollment in NuPOWER. MDS is caused by mutations in nuclear genes that code for enzymes involved in mtDNA maintenance and replication, leading to mtDNA depletion. Myopathic MDS, specifically, is most often caused by mutations in TK2, which is required for the salvage pathways of several deoxyribonucleoside triphosphates (dNTPs) in the mitochondria.
In September 2023, Stealth announced that NuPOWER had reached its enrollment target, though the trial would continue enrolling subjects through the end of that month. It additionally stated that it anticipated having topline data in 2024.
In November 2024, Stealth-affiliated scientists published a further post hoc analysis of MMPOWER-3. The authors note that most of the mutations in subjects with nDNA mutations were in genes required for mtDNA maintenance, particularly POLG and TWNK. Among this mtDNA-maintenance mutation subset of the nDNA cohort (n = 59), elamipretide treatment led to a numerical increase in 6MWT, though it was not statistically significantly different from placebo (25.2 ± 8.7 vs. 2.0 ± 8.6 m, p = 0.06). They also noted a significant change in 6MWT in elamipretide-treated vs. placebo-treated subjects in the subset of nDNA mutation carriers with chronic progressive external ophthalmoplegia (CPEO) (n = 18) (37.3 ± 9.5 vs. − 8.0 ± 10.7 m, p = 0.0024).
As of October 2025, the Clinicaltrials.gov entry for NuPOWER continues to list October 2024 as its estimated study completion date, with no results posted and the last entry update having been made in December 2023. Similarly, the UC San Diego webpage for NuPOWER states that “This study is in progress, not accepting new patients.” Stealth’s Pipeline and Programs page shows NuPOWER as still in process and continues to indicate that they anticipate results in Q4 2024.
