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  • Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study.

Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study.

Lancet (London, England) (2014-05-06)
Vincenzo Libri, Cihangir Yandim, Stavros Athanasopoulos, Naomi Loyse, Theona Natisvili, Pui Pik Law, Ping Kei Chan, Tariq Mohammad, Marta Mauri, Kin Tung Tam, James Leiper, Sophie Piper, Aravind Ramesh, Michael H Parkinson, Les Huson, Paola Giunti, Richard Festenstein
ABSTRACT

Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia. In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2-8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809. Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5-6 g resulted in a sustained and significant (p<0·0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes. Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted. Ataxia UK, Ataxia Ireland, Association Suisse de l'Ataxie de Friedreich, Associazione Italiana per le Sindromi Atassiche, UK National Institute for Health Research, European Friedreich's Ataxia Consortium for Translational Studies, and Imperial Biomedical Research Centre.

MATERIALS
Product Number
Brand
Product Description

Supelco
Nicotinamide (Niacinamide), analytical standard
Supelco
Niacinamide, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Niacinamide, meets USP testing specifications
Sigma-Aldrich
Nicotinamide, ≥98% (HPLC), powder
Sigma-Aldrich
Nicotinamide, BioReagent, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
Nicotinamide, ≥99.5% (HPLC)
Sigma-Aldrich
Nicotinamide, ≥98.5% (HPLC)
USP
Niacinamide, United States Pharmacopeia (USP) Reference Standard
Nicotinamide, European Pharmacopoeia (EP) Reference Standard
Supelco
Nicotinamide (Vitamin B3) solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®