An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease.

Abstract

AIMS:

Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers.

METHODS:

This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers.

RESULTS:

Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen.

CONCLUSIONS:

Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.

• Authors: Sigurd D Süssmuth, Salman Haider, G Bernhard Landwehrmeyer, Ruth Farmer, Chris Frost, Giovanna Tripepi, Claus A Andersen, Marco Di Bacco, Claudia Lamanna, Enrica Diodato, Luisa Massai, Daniela Diamanti, Elisa Mori, Letizia Magnoni, Jens Dreyhaupt, Karin Schiefele, David Craufurd, Carsten Saft, Monika Rudzinska, Danuta Ryglewicz, Michael Orth, Sebastian Brzozy, Anna Baran, Giuseppe Pollio, Ralph Andre, Sarah J Tabrizi, Borje Darpo, Goran Westerberg, PADDINGTON Consortium
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 79 Issue 3 Pg. 465-76 (Mar 2015) ISSN: 1365-2125 [Electronic] England
• PMID: 25223731 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
• Carbazoles
• SIRT1 protein, human
• Sirtuin 1

Topics

• Administration, Oral
• Adolescent
• Adult
• Aged
• Area Under Curve
• Carbazoles (administration & dosage, adverse effects, blood, therapeutic use)
• Cognition (drug effects)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Huntington Disease (blood, drug therapy, psychology)
• Male
• Middle Aged
• Neuropsychological Tests
• Severity of Illness Index
• Sirtuin 1 (antagonists & inhibitors)
• Tissue Distribution
• Treatment Outcome
• Young Adult