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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.

SUBMITTER: Sussmuth SD

PROVIDER: S-EPMC4345957 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Süssmuth Sigurd D SD Haider Salman S Landwehrmeyer G Bernhard GB Farmer Ruth R Frost Chris C Tripepi Giovanna G Andersen Claus A CA Di Bacco Marco M Lamanna Claudia C Diodato Enrica E Massai Luisa L Diamanti Daniela D Mori Elisa E Magnoni Letizia L Dreyhaupt Jens J Schiefele Karin K Craufurd David D Saft Carsten C Rudzinska Monika M Ryglewicz Danuta D Orth Michael M Brzozy Sebastian S Baran Anna A Pollio Giuseppe G Andre Ralph R Tabrizi Sarah J SJ Darpo Borje B Westerberg Goran G

British journal of clinical pharmacology 20150301 3

<h4>Aims</h4>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.<h4>Methods</h4>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 o ...[more]

PMID: 25223731

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Project description:ObjectiveThe purpose of this study was to explore the clinical benefit and tolerability of IQP-AO-101 in healthy subjects with sleep complaints.MethodsThis double-blind, randomized, placebo-controlled trial involved fifty subjects with sleep complaints. Subjects with a Pittsburgh Sleep Quality Index (PSQI) score between 6 and 15 were randomized to receive either IQP-AO-101 or placebo for 6 weeks, following a run-in period of one week. Sleep parameters were assessed at baseline and after 1, 4, and 6 weeks using the modified Athens Insomnia Scale (mAIS). Subjects were also instructed to wear an activity tracker and keep a sleep diary during the study. Other questionnaires administered were the Frankfurt Attention Inventory (FAIR-2) and the Profile of Mood States (POMS-65). Blood samples for safety laboratory parameters were taken before and at the end of the study.ResultsAfter 6 weeks, subjects who consumed IQP-AO-101 reported significant improvements in mAIS scores compared with placebo, including mAIS total score (11.76 ± 6.85 vs 4.00 ± 4.80; p < 0.001); night parameters composite score (5.20 ± 3.80 vs 2.04 ± 3.16; p = 0.001); and day parameters composite score (6.56 ± 4.10 vs 1.96 ± 2.65; p < 0.001). All individual parameters (Items 1 to 8) were also significantly improved from baseline after 6 weeks of IQP-AO-101 intake. Analysis of variance with baseline values as covariates showed statistically significant improvements across all individual parameters for IQP-AO-101 when compared to placebo. The measurements using the activity tracker, sleep diary, FAIR-2, and POMS did not reveal any significant differences between groups. No adverse effects related to the intake of IQP-AO-101 were reported. Tolerability was rated as very good by all the subjects and by the investigator for all cases.ConclusionsIn this study, IQP-AO-101 was well tolerated and efficacious for promoting sleep and enhancing daytime performance in subjects with moderate sleep disturbances.Clinical trial registrationThis trial is registered with ClinicalTrials.gov, no. NCT03114696.

Dataset Information

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

Publications

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

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