study to evaluate efficacy and safety of elamipretide in subjects with primary mitochondrial disease from nuclear dna mutations (npmd)

Conditions: Mitochondrial Myopathies; Mitochondrial Pathology; Mitochondrial DNA Mutation; Mitochondrial Diseases; Mitochondrial DNA Deletion; Mitochondrial DNA Depletion; Mitochondrial Metabolism Defect; Mitochondrial Complex I Deficiency

Summary: spimd-301 is a 48-week, randomized, double-blind, parallel-group, placebo-controlled trial to assess efficacy and safety of single daily subcutaneous (sc) administration of elamipretide as a treatment for subjects with primary mitochondrial myopathy associated with nuclear dna mutations (npmd).

this 48-week randomized, double-blind, parallel-group, placebo-controlled trial will enroll approximately 130 subjects, consisting of 90 subjects who have npmd associated with pathogenic mutations of the mitochondrial replisome("replisome-related mutations") for primary analysis and an additional subset of up to 40 subjects who have npmd associated with other non-replisome-related pathogenic mutations specific to the nuclear dna. efficacy and safety of single daily sc doses of elamipretide administered as a treatment for subjects who have primary mitochondrial myopathy associated with npmd will be determined. subjects will be randomized 1:1 to 60mg elamipretide or matching placebo groups.

Eligibility criteria:
inclusion criteria: a subject must meet all of the following inclusion criteria at the screening and baseline visit (unless otherwise specified) to be eligible for inclusion in the spimd-301 trial: 1. willing and able to provide a signed informed consent form (icf) prior to participation in any trial-related procedures. 2. agrees and is able to adhere to the trial requirements for the length of the trial, including administration of assigned treatment. 3. is ≥18 years and ≤ 70 years of age at the time of screening. 4. diagnosed with npmd with a predominant clinical manifestation of myopathy, which must include progressive external ophthalmoplegia (peo) and exercise intolerance and/or skeletal muscle weakness, with genetic confirmation of either: 1. nuclear dna mutation of the mitochondrial replisome (replisome-related mutations), which include the following genes: * polg 1/2 * twinkle (c10orf2) * tymp * dguok * tk2 * rrm2b * rnaseh1 * ssbp * mgme1 * dna2 * ant1 (slc25a4) * suclg1 * sucla2 * mpv17 or 2. other pathogenic mutations specific to nuclear dna. 5. women of childbearing potential must agree to use one of the following methods of birth control from the date they sign the icf until 28 days after the last dose of imp: 1. abstinence, when it is in line with the preferred and usual lifestyle of the subject. subject agrees to use a highly effective method of contraception should they become sexually active. 2. relationships with male partners who have been surgically sterilized by vasectomy (the vasectomy procedure must have been conducted at least 60 days prior to the screening visit). 3. barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream and either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system. note: non-childbearing potential is defined as surgical sterilization (e.g., bilateral oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as permanent cessation of menstruation for at least 12 consecutive months prior to the screening visit). 6. male subjects with female partners of childbearing potential must be willing to use a highly effective method of contraception from the date they sign the icf until 28 days after the last dose of imp. exclusion criteria: 1. is unable to perform the 6mwt, 3tug, or 5xsst functional tests. the use of a gait assist device is allowed; however, use should remain consistent for the entire duration of the trial. 2. female subjects who are pregnant, planning to become pregnant, or breastfeeding/lactating. 3. walks \ 450 meters during the 6mwt (screening visit only). 4. the estimated glomerular filtration rate (egfr) is \< 30 ml/min/1.73 m2, using the modification of diet in renal disease (mdrd) study equation (screening visit only). 5. has undergone an in-patient hospitalization within 30 days prior to screening or has a planned hospitalization or a surgical procedure during the trial, unless, in the opinion of the investigator, it is concluded that it will not impact the outcome measurements of the trial. 6. has clinically significant respiratory disease and/or cardiac disease that would interfere with trial assessments, in the opinion of the investigator. 7. has had any prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening. 8. has history of or current severe neurologic impairment, severe epilepsy, severe ataxia, or severe neuropathy that may interfere with their ability to complete all trial requirements, in the opinion of the investigator. 9. active malignancy or any other cancer from which the subject has been disease-free for \< 2 years. localized squamous or non-invasive basal cell skin carcinomas are allowed, if appropriately treated prior to screening. 10. has had a solid organ transplant. 11. has been previously diagnosed with human immunodeficiency virus (hiv), hepatitis b, or hepatitis c infection. 12. has a history of a systemic eosinophilic illness and/or an eosinophil count \>1,000 cells x106/l at the screening visit. 13. is currently participating or has participated in an interventional clinical trial (i.e., investigational product or device, stem cell therapy, gene therapy) within 30 days prior to current trial; or is currently enrolled in a non-interventional clinical trial that, in the opinion of the investigator, may be potentially confounding to the results of the current trial (e.g., exercise therapy trial). 14. has received elamipretide (mtp-131) within the past one year of the screening visit. 15. has a history of active substance abuse during the year prior, in the opinion of the investigator.

Keywords: primary mitochondrial myopathy (pmm) nuclear dna mutations n(pmd) exercise intolerance muscle weakness mitochondrial dysfunction polg twinkle progressive external ophthalmoplegia elamipretide mitochondrial replisome replisome related mutations mtp-131 primary mitochondrial disease (pmd)