[S47.004] Safety and Tolerability of Selisistat for the Treatment of Huntington's Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Trial
Ralf Reilmann,1,1Ferdinando Squitieri,2Josef Priller,3Carsten Saft,4Caterina Mariotti,5Sigurd Suessmuth,6Andrea Nemeth,7Sarah Tabrizi,8Oliver Quarrell,9David Craufurd,10Hugh Rickards,11Anne Rosser,12Darpo Borje,13Tessari Michaela,14Szynol Angieszka,14David Fischer,14Douglas Macdonald,15Ignacio Munoz-Sanjuan,16Robert Pacifici,15Chris Frost,17Ruth Farmer,8Bernhard Landwehrmeyer,6Goran Westerberg18
1Muenster, Germany, 2Pozzilli, Italy, 3Berlin, Germany, 4Bochum, Germany, 5Milan, Italy, 6Ulm, Germany, 7Oxford, United Kingdom, 8London, United Kingdom, 9Sheffield, United Kingdom, 10Manchester, United Kingdom, 11Birmingham, United Kingdom, 12Cardiff, United Kingdom, 13Stockholm, Sweden, 14Leiden, Netherlands, 15Los Angeles, CA, USA, 16Princeton, NJ, USA, 1718Siena, Italy
OBJECTIVE: To evaluate safety and tolerability of selisistat over 12 weeks in patients with Huntington's Disease (HD).
BACKGROUND: Selisistat is a first-in-class SirT1 inhibitor shown to be safe and well tolerated in healthy volunteers and HD patients in short-term studies.
DESIGN/METHODS: This was a double-blind, placebo-controlled, international multi-centre study of selisistat in individuals with Stage I-III HD. Participants (30-70 yrs) with genetically confirmed HD, a Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score of >=5 and a Total Functional Capacity >=5 were randomized (1:1:1) to selisistat 50 or 200 mg or placebo once daily for 12 weeks. Safety and tolerability were evaluated by monitoring adverse events, vital signs, ECG and laboratory safety data throughout the study. Blood sampling for pharmacokinetics and soluble mutant huntingtin levels were collected throughout.
RESULTS: A total of 144 patients were randomized and 125 patients (87%) completed the study. There were 9 serious adverse events, three in each treatment group, including one death in the placebo group. The most common adverse events were reversible increases in liver function tests without accompanying increases in bilirubin. All of these occurred in the selisistat groups; while most of these increases were <3×ULN, three events were classified as serious. No clinically relevant changes in the UHDRS readouts were observed during the relatively short treatment period. Levels of soluble mutant huntingtin in peripheral blood mononuclear cells showed borderline statistically significant (p=0.058 , p=0.075) increases of similar magnitude at 12 weeks compared to placebo in the 50mg and 200mg groups respectively, that reverted to levels consistent with the placebo group at follow-up.
CONCLUSIONS: Apart from increases in liver function tests in a subset of patients, selisistat was safe and well tolerated, and a trend for modulation of the levels of soluble mutant huntingtin was observed.
Study supported by: Siena Biotech SpA.
Category - Movement Disorders: Huntington's Disease and Other Choreas
Thursday, May 1, 2014 1:45 PM
S47: Platform Session: Movement Disorders: Huntington's Disease, Ataxia, and Wilson's Disease (1:00 PM-2:45 PM)