作者
Erin Furr Stimming,Daniel O. Claassen,Elise Kayson,Jody Goldstein,Raja Mehanna,Hui Zhang,Grace Liang,Dietrich Haubenberger,Jamie Adams,Christopher Beck,Cheryl Chen,Martha Nance,Claudia Testa,P Huffman,Amy M. Chesire,Frederick J. Marshall,Praveen Dayalu,Angela Stovall,Deborah A. Hall,Jacob Hawkins,Letty Ginsburg,Henry Moore,Tiago Mestre,Tanya Thompson,Natalie K. Connors,H. Diana Rosas,Allison M. Daley,Sandra K. Kostyk,Casey G. Mitchell,Amy Hellman,Stephen Houston,Danielle Buchanan,Katherine E. McDonell,Stewart A. Factor,Elaine Sperin,Andrea Hurt,Joanne Wojcieszek,Mike Adurogbangba,Lynn A. Raymond,Jody Corey‐Bloom,Chase Snell,Courtney Blair,Victor Sung,Sophia Antonioli,Jacqueline Fung,Simon Laganiere,Luis Sierra,William Mallonee,Greg Suter,Danny Bega,Zsa Zsa Brown,Lawrence Elmer,Nils Vollmar,Debra del Castillo,Yihan Lin,Kelly L. Andrzejewski,Patricia Weigel,Trevor Hawkins,Katharine A. Kirby,Cimmaron Retzik-Stahr,Lauren Seeberger,Rohit Dhall,Anja Rassmann,McKenzie Luxmore,B.L. Scott,Bisena Bulica,James T. Boyd,Kin Chan,Nikolaus R. McFarland,Kyle Rizer,Patricia Conlon,Valerie Suski,Federico Rodríguez‐Porcel,Sandra R. Wilson,Christine Farrell,David J. Hunter,David Houghton,Samuel Seoane,Clare Gibbons,Philippe Rizek,Robin Kuprewicz,Steven Lo,Miroslav Cuturic,Vicki Segro,Kate Greenly,Fredy J. Revilla,Enrique Urrea‐Mendoza,Kevin J. Black,Thomas L. Davis,Natividad Stover,Andrew P. Duker,Jay Van Gerpen,Peter Hedera,William G. Ondo,Karen E. Anderson,Stephen Bradley,Ying Kuen Cheung,Samuel Frank
摘要
Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease.KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing.KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine.In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea.Neurocrine Biosciences.