Bruce Cohen, MDBruce Cohen, MD
Primary mitochondrial myopathy (PMM) is a relatively rare disorder that affects about 1 in 5000 individuals. Faced with a dismal amount of treatment options, Stealth BioTherapeutics is throwing its weight behind elamipretide,1 a novel, small mitochondrial-targeting tetrapeptide that has been shown to stabilize cardiolipin, the phospholipid responsible for the optimization of the electron transport chain for adenosine triphosphate (ATP) generation.2

The agent is currently being assessed in the MMPOWER-3 clinical trial (NCT03323749), a phase 3 study assessing the safety and efficacy of daily subcutaneous injections of elami- pretide in patients aged 16 to 80 with a confirmed diagnosis of PMM (FIGURE).

Study investigator Bruce H. Cohen, MD, explained that many PMM experts are turning away from the vitamin therapy that has long been the mainstay of treatment, as no other disease-modifying agents have proven effective. This, he noted, has opened the door for elamipretide to not only become the first treatment for PMM, but to “spur more interests in the area and hopefully bring more pharma into the field.”

“The clinical trials that have been done—and there haven’t been a lot of them—and the comprehensive reviews of some of those clinical trials have suggested that, in groups of patients, vitamin supplements provide limited, if any, benefit,” Cohen, professor of pediatrics at Northeast Ohio Medical University and director of the NeuroDevelopmental Science Center at Akron Children’s Hospital, told NeurologyLiveTM. “[Elamipretide] is a drug that was designed to affect the inner mitochondria membrane in a beneficial way, so it has a designer concept in mind,” he explained. “It got through its preclinical trials showing a benefit to the mitochondria in hypoxia-reperfusion injury models, and it showed a preclinical benefit on the animal models.”

The trial, which completed enrollment of 218 participants in April 2019, is a 6-month, parallel-group, placebo-controlled study that will measure change from baseline in 6-minute walk test (6MWT) and total fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA), a patient-reported outcome, as its primary end points. The study is expected to be completed by December 2020.1

Secondary end points are safety and tolerability related to treatment-emergent adverse events through 28 weeks, as well as patient- and clinician-reported outcomes, including change in fatigue during activities score on the PMMSA, change in the Neuro-Quality of Life Fatigue Item Bank score, and change in most bothersome symptom score on the PMMSA, all over 24 weeks.

Patients completing the double-blind portion of the study, during which they will be randomly assigned to receive either daily 40-mg elamipretide subcutaneous injections or placebo, are eligible to continue into an open-label extension where they will receive the study drug for up to 144 weeks. Notably, 80 of the 85 patients who have completed the randomized portion so far have offered to participate in the open-label extension study.

Elamipretide was previously assessed in the phase 1/2 MMPOWER trial (NCT02367014), which included 36 participants with genetically confirmed PMM. Ultimately, participants who received the highest dose of elamipretide (0.25 mg/kg/h) walked a mean of 64.5 m farther on day 5 compared with 20.4 m in the placebo group (P =.053); they also had a dose-dependent increase in distance walked on the 6MWT (P = .014). In a model that adjusted for additional covariates possibly affecting response, the adjusted change for the highest dose of elamipretide was 51.2 m compared with 3.0 m in the placebo group (P = .0297).3

“Although the early trial was not designed primarily to show benefits, there were some clues of benefit, again, to the point that there was a benefit when we were doing a phase 1/phase 2 study. The data were pointing in the right direction,” Cohen said. “There was enough evidence for the company to want to proceed with a definitive trial that we’re in the middle of right now.”

"Elamipretide is a drug that was designed to affect the inner mitochondria membrane in a beneficial way, so it has a designer concept in mind," Bruce H. Cohen, MD, said in a statement.

Much of the same was observed in MMPOWER-2 (NCT02805790), a phase 2, placebo-controlled crossover study that enrolled patients who completed the MMPOWER study. The results showed that over a longer, 4-week treatment period, those treated with subcutaneous elamipretide 40 mg walked an average of 20 additional meters compared with placebo in the 6MWT (P = .08). Treatment with the study drug also was associated with a significant difference in Neuro-Quality of Life Fatigue Short Form score (P = .01) and PMMSA total fatigue score (P = .0006), as well as improvement in the most bothersome symptom reported by each patient (P = .01).4

Cohen told NeurologyLiveTM that the most encouraging data from the early MMPOWER trials have been the improvement in patient perceptions of their well-being, energy, and pain. MMPOWER-3, on the other hand, is powered to “answer the question regarding improving myopathy signs and symptoms.”
1. Stealth BioTherapeutics completes enrollment of pivotal study in primary mitochondrial myopathy [press release]. Boston, MA: Stealth Biotherapeutics; April 25, 2019. stealthbio/English/5030/news.html. Accessed September 16, 2019.
2. 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.
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. 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; June 29, 2017. apeutics-presents-phase-2-data-mmpower-2-continuation-trial-supporting-phase-3-develop- ment-elamipretide-primary-mitochondrial-myopathy. Accessed September 16, 2019.