Could Elamipretide Become the First Treatment Option for Primary Mitochondrial Myopathy?


A phase 3 trial of the therapy is ongoing after a number of positive signs from earlier assessments. Thus far, the tetrapeptide has shown potential to become the first treatment for PMM.

Dr Bruce Cohen

Bruce H. Cohen, MD

Currently, the treatment landscape for primary mitochondrial myopathy (PMM) is an arid one, forcing physicians to resort to palliative care and vitamin regimens to manage patients with PMM. Although, in recent years, some research has begun to seek a better solution.

One of the few potential options in development is elamipretide, also known as MTP-131, a small mitochondrial-targeting tetrapeptide which has been shown to stabilize cardiolipin, the phospholipid responsible for the optimization of the electron transport chain for adenosine triphosphate (ATP) generation.1

In November 2017, shortly after the FDA granted the treatment an Orphan Drug Designation and just days before it was granted a Fast Track Designation for Barth syndrome, Stealth BioTherapeutics announced it was initiating the MMPOWER-3 trial (NCT03323749), a phase 3 study of the safety and efficacy of daily subcutaneous injections of elamipretide compared to placebo (NCT03323749). The treatment is set to be explored in 200 patients at a dose of 40 mg administered as a 0.5-mL injection for 24 weeks. It will be followed by an open-label extension where patients may receive the treatment for up to 144 weeks.

At the time the MMPOWER-3 trial was announced, Bruce H. Cohen, MD, the director of the Neurodevelopmental Science Center at Akron Children’s Hospital and investigator in the MMPOWER clinical program, emphasized that due to the lack of FDA-approved therapies, patients are left with little to address the “debilitating muscle weakness and fatigue” that impact their ability to go about their day-to-day tasks.2

He explained that the “encouraging results from two prior phase 2 clinical trials with elamipretide in this population make us optimistic about this investigational compound’s potential to treat patients with PMM.”

Cohen told NeurologyLive that, if approved, elamipretide would not only become the first treatment for PMM, but it “will spur more interests in the area and hopefully bring more pharma into the field.” He added that he expects additional indications could be achieved for the treatment. It is being investigated for Barth syndrome, Leber’s hereditary optic neuropathy, and dry age-related macular degeneration, in addition to PMM.

The previous trials of elamipretide, MMPOWER and its continuation MMPOWER-2, were phase 2 explorations of the agent. MMPOWER (NCT02367014) included 36 patients (30 of which continued onto MMPOWER-2) with PMM who were randomized to intravenous elamipretide in a dose-escalating sequence of 0.01 mg/kg/h (n = 9), 0.1 mg/kg/h (n = 9), and 0.25 mg/kg/h (n = 9) compared to placebo (n = 9) over 2 hours.

Those who were treated with the mitochondrial therapy walked a mean distance of 64.5 m farther after 5 days of treatment in the 6-minute walk test (6MWT), the primary end point, compared to the placebo group, which saw a 20.4 m change (P = .053). A dose-dependent increase in distance walked was observed with the elamipretide group (P = .014).3

Although there was no difference between the highest-dose group (61.7 m) and the placebo group (38.5 m) 2 days after halting treatment (P = .387), the investigators noted that this could be attributed to the short half-life of elamipretide.

Adverse events (AEs) in MMPOWER were most commonly present as headache (n = 6; 16.7%) and dizziness (n = 3; 8.3%), with no significant differences in AEs between the treated groups and the placebo group.

The investigators concluded that “despite the inherent limitations of a small phase I/II trial, this trial supports the proposed mechanism of action of elamipretide, improving ATP synthesis regardless of the underlying genetic defect impairing mitochondrial respiration.”

After the MMPOWER data were published, Reenie McCarthy, JD, Stealth’s CEO, said that the company is “diligently working toward developing the first generation of targeted therapies focused on mitochondrial dysfunction in rare genetic diseases and common diseases of aging,” noting that the MMPOWER program was the focal point of that work.4

In MMPOWER-2 (NCT02805790), the results showed more of the same promise. Presented at the Mitochondrial Medicine Symposium 2017, the United Mitochondrial Disease Foundation’s (UMDF) meeting, the findings showed that over a longer, 4-week treatment period, those treated with subcutaneous elamipretide 40 mg walked an average of 20 additional meters compared to placebo in the 6MWT (P = .08).5

At the time of the presentation, Amel Karaa, MD, another of the trial investigators, and an internist and clinical geneticist at Massachusetts General Hospital, said that the results “merit study in a phase 3 trial.”

As well, the treatment arm was associated with a significant difference in Neuro-Quality of Life Fatigue Short Form score (P = .01), the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue score (P = .0006), and the improvement in the most bothersome symptom reported by each patient (P = .01).

Like in its predecessor trial, the AEs in MMPOWER-2 were not serious. The most common AE reported was injection-site reactions, which occurred in 80% of those given elamipretide compared to 17% of those in the placebo group. Most reactions were considered mild.

“These findings confirm the potential of elamipretide for these patients and help us establish and validate critical details for our planned phase 3 study,” McCarthy said at the time the results of MMPOWER-2 were announced. “We look forward to working closely with U.S. and European regulatory officials to finalize the design of our phase 3 trial, which will enroll patients with primary mitochondrial myopathy caused by a variety of genetic mutations.”

McCarthy called the MMPOWER-2 results encouraging in its identification of proper end points which Stealth could utilize in phase 3. Stealth also announced the launch of RePOWER, a multi-national pre-trial registry of patients with PMM regarding questions of quality of life and functional assessments.

Cohen told NeurologyLive that the most encouraging data from the early MMPOWER trials were the improvements of patients’ perceptions of their well-being, energy, and pain. He explained that MMPOWER-3 is planned to be “a large controlled trial that is powered to answer the question regarding improving myopathy signs and symptoms.”

MMPOWER-3 is still enrolling patients at more than 20 locations in the United States and Canada, and a number of European sites. It is expected to be completed by December 2020. In June 2018, Stealth announced that it had raised $100 million from investors to support elamipretide’s development, along with its other compounds in the space.6


1. Kloner RA, Shi J, Dai W. New therapies for reducing post-myocardial left ventricular remodeling. Ann Transl Med. 2015;3(2):20-24. doi: 10.3978/j.issn.2305-5839.2015.01.13.

2. Stealth BioTherapeutics Initiates Phase 3 Study of Elamipretide in Patients with Primary Mitochondrial Myopathy [press release]. Boston, MA: Stealth BioTherapeutics; Published November 6, 2017. Accessed February 5, 2019.

3. Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14): e1212-e1221. doi: 10.1212/WNL.0000000000005255.

4. MMPOWER Data Published in Neurology [press release]. Boston, MA: Stealth BioTherapeutics; Published March 29, 2018. Accessed February 5, 2019.

5. Stealth BioTherapeutics Presents Phase 2 Data From MMPOWER-2 Continuation Trial Supporting Phase 3 Development of Elamipretide in Primary Mitochondrial Myopathy [press release]. Boston, MA: Stealth BioTherapeutics; Published June 29, 2017. Accessed February 5, 2019.

6. Stealth BioTherapeutics Announces $100M Financings to Advance Clinical Development of Elamipretide and Pipeline [press release]. Boston, MA: Stealth BioTherapeutics; Published June 18, 2018. Accessed February 5, 2019.

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