Idebenone: An emerging therapy for Friedreich ataxia

Abstract

This paper reviews the history and pre-clinical development of idebenone and summarises the results of clinical studies, published from 1999 to 2008, on the use of idebenone in the treatment of patients with Friedreich ataxia (FRDA). As a benzoquinone that can undergo reversible redox reactions, idebenone influences the electron balance in mitochondria. In vitro studies have shown that it acts both as an anti-oxidant, preventing damage to the mitochondrial membrane, and, more importantly, as an electron carrier, supporting mitochondrial function and adenosine triphosphate (ATP) production. In clinical studies, idebenone has been well tolerated by patients with various pathological conditions. The most common adverse events have been gastrointestinal effects of mild to moderate severity. No neurotoxic or adverse cardiac reactions have been reported in pre-clinical or clinical studies. The good safety profile of idebenone is supported by large clinical trials in Alzheimer's disease and by post-marketing surveillance. Phase 1 studies demonstrated the safety and tolerability of idebenone at relatively high doses (up to 60 mg/kg/day). Results from 11 clinical studies (randomised, controlled, and open-label trials), involving a total of about 200 patients, provide evidence of improvement in both cardiac hypertrophy and neurological symptoms among patients with FRDA treated with idebenone.

Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports

“…(2)) and is a potent antioxidant and electron carrier [75]. It was originally developed by Takeda Pharmaceuticals Company Limited (Osaka, Japan) and was approved in Japan in 1986 for treatment of Alzheimer's disease and other cognitive disorders [76], Although idebenone have shown efficacy in Alzheimer diseases in some studies [77,78] and has been better than tacrine [79], due to the lack of sufficient evidence [80] its clinical use for this purpose has been limited. According to the WHO Collaborating Centre Idebenone is an analog of coenzyme Q10 that carries a benzoquinone ring.…”

“…Idebenone is able to function as an antioxidant by inhibition of lipid peroxidation and protection of cell membranes and mitochondria from oxidative stress [81][82][83]. It is also able to interact with the respiratory chain and electron balance in the mitochondria [76,84]. It is not very clear which one of the two (antioxidant activity or electron transportation) is the main mechanism responsible for beneficial effects of idebenone [12].…”

“…Several clinical studies have been conducted on the efficacy of idebenone in treatment of FRDA (reviewed in 2 recent articles [76,84]). In these studies, idebenone consistently improved cardiac hypertrophy, which is an important feature of FRDA.…”

“…In these studies, idebenone consistently improved cardiac hypertrophy, which is an important feature of FRDA. Neurological symptoms have not been improved as much as cardiac problems, however higher doses of idebenone especially in younger patients seem to be much more promising for neurological efficacy [76,[85][86][87].…”

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

“…Deficiency of frataxin results in intramitochondrial iron accumulation and progressive neurological degeneration, cardiomyopathy, and diabetes. Over the last 13 years there have been 13 clinical trials of idebenone in FA, using progressively larger does and emerging to phase III trials, indicating that higher doses of idebenone are well tolerated and may stabilize neurological function in young patients with FA [35][36][37]. Again, these successive trials are instructive for smaller trials in less common mitochondrial disorders in that they involve multicenter collaboration, carefully controlled trial design, agreed upon primary outcomes, and build upon the experience of previous trials [3].…”