Idebenone | Prevage | PrevageMD

Friedreich's ataxia (FA) is the most common hereditary ataxia in Europe and North America, and affects approximately 1 in 40 000 individuals.^[1] The condition is characterised by progressive gait and limb ataxia, dysarthria, areflexia, loss of vibratory and position sense, and distal extremity weakness. Additional features include hypertrophic cardiomyopathy, scoliosis, and diabetes.^[2] FA is inherited in an autosomal recessive pattern, with a homozygous expansion of a GAA trinucleotide repeat in the first intron of the frataxin gene as the causative mutation in 97% of cases. The expansion causes decreased transcription of the gene and consequent reduction in the concentration of the gene product, frataxin, which is a mitochondrial protein.^[3] Loss of frataxin has a deleterious effect on mitochondrial function. In FA patients' cells and in model systems, there is a loss of iron-sulphur proteins, including the respiratory chain complexes I, II, III, and aconitase, which results in reduced ATP generation, as confirmed in patients by magnetic resonance spectroscopy.^[4] In addition, mitochondria become overloaded with iron, leading to the formation of reactive oxygen species through Fenton chemistry, as indicated by increased concentrations of markers of oxidative damage in blood and urine samples from FA patients.^[5] ^, ^[6]Thus, mitochondrial dysfunction and oxidative tissue damage may both contribute to FA pathogenesis.

On the basis of these findings, use of lipid-soluble antioxidants has been explored as a potential treatment. Idebenone, a short-chain benzoquinone structurally related to coenzyme Q10, is a potent antioxidant and electron carrier.^[7] Clinical studies in FA patients with idebenone treatment at a daily dose of 5 mg/kg have shown reduction in oxidative stress markers and cardiac hypertrophy,^[6] ^, ^[8] ^, ^[9] ^, ^[10]but not in neurological function. One small, open-label trial in young FA patients found an improvement in overall neurological function that was related to plasma idebenone concentrations.^[11] This suggests that treatment may be effective if given early in the disease course, and that improvement may be dependent on higher doses of idebenone. This suggestion is supported by the finding in two other trials that patients who still had cardiac hypertrophy after treatment with 5 mg/kg idebenone daily subsequently responded when the dose was increased to 10 mg/kg daily.^[8] ^, ^[9]In phase 1 dose-escalation and tolerability trials in FA patients, we found that idebenone at 60 mg/kg daily was well tolerated over a 1-month period in children, adolescents, and adults with FA, with no clinically significant adverse events or laboratory abnormalities.^[12] We therefore did a double-blind, placebo-controlled study to examine the safety and feasibility of higher doses of idebenone in young FA patients.

Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial