Initial experience in the treatment of inherited mitochondrial disease with EPI-743

Abstract

Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

“…EPI-743 is a designed para-benzoquinone analog, differing structurally from CoQ 10 and idebenone by having bis-methyl groups substituting for bis-methoxy groups on the quinone ring and a shorter side chain of 3 isoprene units (vs 10 in CoQ 10 ) linked via a hydroxybutyl group [41]. This structural modification increases the antioxidant protective effect of EPI-743 for cells in culture more than 1000-fold compared with CoQ 10 and idebenone.…”

“…This structural modification increases the antioxidant protective effect of EPI-743 for cells in culture more than 1000-fold compared with CoQ 10 and idebenone. To evaluate EPI-743 as a therapeutic agent for mitochondrial disorders, a open-label, expanded access, multicenter trial with patients approaching end-of-life care was initiated at Stanford University and 4 other medical centers [41]. The trial design was to start with 100 mg/day (not weight based), escalating to 200 mg/d after 2 weeks, then 300 mg/d for the duration of the protocol, lasting a total of 12 weeks, followed by a long-term extension (Table 1).…”

The Elusive Magic Pill: Finding Effective Therapies for Mitochondrial Disorders

“…Twelve of the 13 patients patients treated with EPI-743 survived with various levels of clinical improvement and/or improved quality of life. EPI-743 had modified disease progression in >90 % of patients in this open-label study, as assessed by clinical, quality-of-life, and noninvasive brain imaging parameters [41]. In the second open-label trial, EPI-743 successfully stopped disease progression and reversed vision loss in 4 of 5 patients with LHON [42].…”

“…Epi-743 has a unique redox potential secondary to its lipid side chain structure making it more potent than either CoQ or Idebenone and affording improved protection to cells subjected to oxidative stress related to mitochondrial disease [41]. To date, two open-label clinical trials have been completed using Epi-743 in multiple mitochondrial diseases.…”

“…The first study included 13 children and 1 adult with molecularly confirmed polymerase γ (POLG1) deficiency, Leigh syndrome, MELAS, mtDNA deletion syndrome, and Friedreich ataxia-all of which were at risk for end-of-life care. Safety and efficacy measures included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99 m-hexamethylpropyleneamine oxime single photon emission computed tomography radionuclide imaging [41]. Twelve of the 13 patients patients treated with EPI-743 survived with various levels of clinical improvement and/or improved quality of life.…”