Epigenetic Therapy for Friedreich’s Ataxia: A Phase I Clinical Trial (PL1.003)

OBJECTIVE Demonstrate oral histone deacetylase inhibitors increase frataxin expression in Friedreich’s ataxia (FRDA) patients at doses that can be safely administered. BACKGROUND In culture, histone deacetylase inhibitors (HDACi) increased FXN mRNA and protein expression in ex vivo treated patient blood cells. In vivo treatment using transgenic animal models for FRDA increased FXN mRNA and protein in target tissues and reduced disease related pathology. A 2-aminobenzamide HDACi (109/RG2833) was evaluated in nonclinical toxicology, pharmacology and safety studies to support use of this compound in FRDA patients. DESIGN/METHODS A Phase I clinical study to evaluate the safety, pharmacokinetics and pharmacodynamics of orally administered 109/RG2833 in 20 adults with FRDA was approved after national and hospital regulatory review. Four cohorts of 5 FRDA patients where Cohort 1 and 2 were open label, with single 30-120mg doses. Cohorts 3 and 4 were randomized, double blind, placebo controlled crossover studies. Cohort 3, a single 180mg or placebo dose; cohort 4, two 120mg or of placebo doses, 4 hours apart. Primary outcome was safety and pharmacodynamic response on HDAC inhibition and FXN mRNA and protein levels in patient blood cells. HDAC activity in patient PBMC was measured with a deacetylase assay using the Fluor-de-LysTM substrate. qRT-PCR and frataxin dipstick assays were used to measure FXN mRNA and protein respectively. RESULTS RG2833 was well tolerated with no limiting toxicities reported. We detected dose dependent suppression of deacetylase activity in the PBMC lysates from the RG2833 treated subjects. An average induction of 1.5-1.6 fold of FXN mRNA levels was observed in patients treated with 120-240mg doses. Small frataxin protein induction was observed in 3 patients with 180-240mg doses. CONCLUSIONS This study provides proof of principal for orally administered class I HDAC inhibitor as potential therapeutics for Friedreich’s ataxia. Study Supported by: Repligen Corporation, GoFAR and EFACTS Disclosure: Dr. Jacoby has received personal compensation for activities with Repligen and BioMarin as an employee. Dr. Rusche has received personal compensation for activities with Repligen Corp. Dr. Rusche holds stock and/or stock options in Repligen Corp. which sponsored research in which Dr. Rusche was involved as an investigator. Dr. Rusche has received research support from Repligen Corp. Dr. Iudicello has nothing to disclose. Dr. De Mercanti has nothing to disclose. Dr. Clerico has nothing to disclose. Dr. Gibbin has nothing to disclose. Dr. Longo has nothing to disclose. Dr. Miao has received personal compensation for activities with Repligen. Dr. Miao holds stock and/or stock options in Repligen which sponsored research in which Dr. Miao was involved as an investigator. Dr. Rai has nothing to disclose. Dr. Piga has received personal compensation for activities with Repligen as a member of a Safety Committee Board. Dr. Pandolfo has received personal compensation for activities with Repligen and Apopharma. Dr. Pandolfo has received royalty payments from Athena Diagnostics. Dr. Pandolfo has received research support from Repligen. Dr. Durelli has received research support from Repligen Corp.