A randomized, double-blind, placebo-controlled, parallel-group, multi-centre study of the efficacy andsafety of nicotinamide in patients with Friedreich ataxia

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Friedreich ataxia is the most frequent early-onset autosomal recessive hereditary ataxia. It is caused by a pathological expansion of a GAA repeat in the first intron of the frataxin gene (FXN), which is present in 98% of the disease alleles. The expansion of the intronic GAA repeat beyond the pathologic threshold inhibits frataxin expression, resulting in decreased levels of frataxin protein. Frataxin is a mitochondrial protein involved in the control of iron homeostasis and in the biogenesis of iron-sulphur clusters. In peripheral blood mononuclear cells, mean residual levels of frataxin are reduced to 36% in typical patients with Friedreich ataxia. Frataxin deficiency results in a relentlessly progressive neurodegenerative condition which frequently presents around puberty. Patients gradually lose coordination, become dysarthric and are frequently wheel-chair bound as adolescents. There is no disease modifying therapy and many patients die prematurely of cardiomyopathy. It has been demonstrated that GAA-triplet repeats can trigger abnormal compaction of a linked reporter gene in vivo leading to the archetypal epigenetic gene silencing phenomenon of position effect variegation (PEV) (Saveliev, 2003). This GAA-repeat silencing was exquisitely sensitive to the gene dosage of PEV modifiers which encode enzymes that modify chromatin. It was subsequently found that the FXN gene is silenced at the chromatin level by the formation of heterochromatin and that this heterochromatin formation can be antagonised by histone deacetylase inhibitors (HDACi) (Chan, 2013).A recent proof-of-concept clinical study on ten patients with Friedrich ataxia demonstrated that frataxin levels can be restored to levels of healthy heterozygous genetic carriers using the class III HDACi, nicotinamide, at a dose that is well tolerated by patients (Libri, 2014). Therefore, restoration of frataxin expression to these levels might be expected to halt disease progression. Nicotinamide readily crosses the blood brain barrier and has previously been given at high doses for long periods to normal individuals without serious adverse effects (Gale, 2004; Knip, 2000). This study addresses this hypothesis in the form of a randomised double-blind, placebo-controlled, parallel group study for clinical efficacy. The primary endpoint is the stabilisation of the neurological condition compared to the control group using the scale for assessment and rating of ataxia (SARA), which has been validated by our previous natural history study for this condition (Reetz, 2015). Further measures will assess quality of life, motor function and cognition, cardiac function as well as brain alteration. This study will be the first to provide clinical evidence for the efficacy and safety of nicotinamide in patients with Friedreich ataxia.