Patients with mitochondrial myopathies (MM), sometimes referred to as mitochondrial disease with myopathy, present a complex array of symptoms that can vary widely in terms of their severity, although the main symptoms that generally result from mitochondrial dysfunction include muscle weakness, exercise intolerance, and fatigue. Decreased muscle function can affect major muscle groups used for walking, climbing, lifting, and maintaining posture. Muscle weakness is also evident in smaller muscle groups that control, for example, movements of the eyes and eyelids. In addition to the skeletal muscular effects associated with mitochondrial dysfunction generally, patients with MM can also experience seizures, impaired gastrointestinal motility, impaired respiratory function, difficulty swallowing, impaired vision or hearing, and impaired balance and coordination. The prognosis for patients with MM varies widely depending on the degree of involvement of various organ systems in the disease, with disease progression leading to significant physical impairment and even to death in some individuals1,2.
Based on literature, we believe there are approximately 80,000 people globally with MM, including 20,000 in the United States3. However, the true prevalence of MM is difficult to obtain as many MM patients remain undiagnosed due to similarity of their symptoms to those associated with other cellular metabolic diseases. We believe that, with the emergence of an effective therapy, testing for MM may increase.
There are currently no approved therapies for the treatment of MM. Reata is enrolling patients in part one of the two-part MOTOR trial and expect to have data from part one in the second half of 2017.
Mitochondrial myopathies, sometimes referred to as mitochondrial diseases with myopathy, are a multi-systemic group of myopathies associated with mitochondrial dysfunction that are caused by over 200 different genetic mutations. Despite the different array of symptoms of the diseases, a unifying feature of MM is dysfunctional mitochondrial respiration, which subsequently leads to a reduced ability to produce ATP.
Pathogenesis of mitochondrial myopathies comes from genetic mutation in the mtDNA or nuclear DNA that encodes for respiratory chain proteins. While the origination of the myopathies may vary, the histological effect of “ragged red fibers” is present in almost all patients4. This is due to non-uniform presence of cytochrome c oxidase (COX), an enzyme important in the electron transport chain that is encoded by both the nuclear and mtDNA genes. Its deficiency is suggestive of a mitochondrial myopathy4,5. The deficiency of COX in muscle fibers results in irregular cellular respiration and ATP production. Over time, this will result in deficient fibers and eventually lead to overall muscle atrophy. Many affected cells contain a mixture of healthy and defective mitochondria.
Mechanism of Action
We are evaluating omaveloxolone in the MOTOR study, a two-part randomized, placebo-controlled, multi-center Phase 2 study of the safety and efficacy of omaveloxolone in mitochondrial myopathies. In 2014, we met with the FDA to discuss our MM program. Based on discussions with the FDA, we designed a two-part trial with evaluation of a broad dose range in part one and a confirmatory evaluation of efficacy and safety in part two that could support registration. Part one of the trial focuses on the evaluation of safety and efficacy of omaveloxolone at multiple doses, with the primary efficacy endpoint being the change in peak work. Part two is designed to provide additional confirmatory efficacy and safety data and has the potential to be used for registration.
Data from the first part of MOTOR are expected in the second half of 2017, and if successful, we expect to initiate the second part of MOTOR after receiving these data.
- Goldstein and Wolfe. The elusive magic pill: finding effective therapies for mitochondrial disorders. Neurotherapeutics 2013; 10:320-8.
- MacFarland et al. The neurology of mitochondrial DNA disease. Lancet Neurol. 2002 Oct;1(6):343-51.
- Schaefer et al. The epidemiology of mitochondrial disorders—past, present and future. Biochim Biophys Acta. 2004 Dec 6;1659(2-3):115-20.
- Taylor and Turnbull. Mitochondrial DNA mutations in human disease. Nat Rev Gen. 2005; 6:389-402.
- Murphy et al. Cytochrome c oxidase-intermediate fibres: Importance in understanding the pathogenesis and treatment of mitochondrial myopathy. Neuromusc Disord. 2012; 22:690-98.
- Neymotin et al. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamaide, in a mouse model of amyotrophic lateral sclerosis. Free Rad Biol Med. 2011; 51:88-96.
- Saha P et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic-acid methyl ester has potent anti-diabetic effects in deit-induced diabetic mice and Lepr(db/db) mice. J Biol Chem. 2010; 285:40581-92.