title: An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease.
abstract: OBJECTIVE
  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.affiliation: Department of Neurology, Ulm University Hospital, Ulm, Germany.
authors.forename: Sigurd D
authors.initials: SD
authors.lastname: Süssmuth
authors.forename: Salman
authors.initials: S
authors.lastname: Haider
authors.forename: G Bernhard
authors.initials: GB
authors.lastname: Landwehrmeyer
authors.forename: Ruth
authors.initials: R
authors.lastname: Farmer
authors.forename: Chris
authors.initials: C
authors.lastname: Frost
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tripepi
authors.forename: Claus A
authors.initials: CA
authors.lastname: Andersen
authors.forename: Marco
authors.initials: M
authors.lastname: Di Bacco
authors.forename: Claudia
authors.initials: C
authors.lastname: Lamanna
authors.forename: Enrica
authors.initials: E
authors.lastname: Diodato
authors.forename: Luisa
authors.initials: L
authors.lastname: Massai
authors.forename: Daniela
authors.initials: D
authors.lastname: Diamanti
authors.forename: Elisa
authors.initials: E
authors.lastname: Mori
authors.forename: Letizia
authors.initials: L
authors.lastname: Magnoni
authors.forename: Jens
authors.initials: J
authors.lastname: Dreyhaupt
authors.forename: Karin
authors.initials: K
authors.lastname: Schiefele
authors.forename: David
authors.initials: D
authors.lastname: Craufurd
authors.forename: Carsten
authors.initials: C
authors.lastname: Saft
authors.forename: Monika
authors.initials: M
authors.lastname: Rudzinska
authors.forename: Danuta
authors.initials: D
authors.lastname: Ryglewicz
authors.forename: Michael
authors.initials: M
authors.lastname: Orth
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brzozy
authors.forename: Anna
authors.initials: A
authors.lastname: Baran
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pollio
authors.forename: Ralph
authors.initials: R
authors.lastname: Andre
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.forename: Goran
authors.initials: G
authors.lastname: Westerberg
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002227:Carbazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D012720:Severity of Illness Index; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Huntington's disease; SirT1 inhibition; pharmacodynamics; pharmacokinetics; selisistat