Objective: To describe the effects of valbenazine (VBZ) over time on chorea in adults with Huntington disease (HD).

Background: The Ph3 KINECT^TM-HD (NCT04102579) trial met its primary endpoint of chorea reduction, as assessed using the Unified Huntington’s Disease Rating Scale (UHDRS®) Total Maximal Chorea (TMC) score. Two secondary endpoints for chorea reduction were also met, assessed using the Clinical Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C). Prespecified exploratory endpoints with these scales (TMC, CGI-C, and PGI-C over time) were analyzed to better understand the onset and trajectory of chorea severity improvements.

Method: Participants were randomized 1:1 to 12 weeks of double-blind treatment with once-daily VBZ or placebo (PBO). VBZ was initiated at 40 mg (Wks1-2) and increased to 60 mg (Wks3-4) and 80 mg (Wks5-6) as tolerated. UHDRS® TMC was analyzed as least squares mean (LSM) changes from Scr/BL (average of screening and baseline values) at all post-BL visits (Wk2 to Wk12), with LSM differences (LSMDs) between treatment groups. Analyses for CGI-C and PGI-C response (rating of “much improved” or better) were conducted from Wk2 to Wk10. Results are presented with nominal P‑values.

Results: The full analysis set included 125 participants (VBZ=64, PBO=61). As early as Wk2 (with initial VBZ dose of 40mg), LSM changes from Scr/BL in TMC scores indicated significantly greater improvements with VBZ versus PBO (-2.9 vs -1.6; LSMD -1.3; P=0.0077). These improvements continued to increase over time through Wk12 (-4.5 vs -1.2; LSMD -3.2; P<0.0001). CGI-C and PGI-C response rates were higher with VBZ than PBO at all post-BL visits, with significance for CGI-C found at all visits from Wk4 (VBZ=23.8%, PBO=3.4%; P=0.0012) to Wk10 (VBZ=42.1%, PBO=17.3%; P=0.0065). Significance for PGI-C was found at all visits from Wk2 (VBZ=23.4%, PBO=4.9%; P=0.0042) to Wk8 (VBZ=43.1%, PBO=16.7%; P=0.0037).

Conclusion: Improvements in chorea were consistently greater with VBZ than PBO throughout the treatment period, from the first study visit (Wk2) to the end of treatment (Wk12). Along with the primary endpoint (TMC change from Scr/BL to Wk10/12) and two secondary endpoints of KINECT-HD (CGI-C and PGI-C response at Wk12), these longitudinal exploratory endpoints provide evidence for the efficacy of VBZ for reducing chorea associated with HD as early as 2 weeks at the initial 40mg dose.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/chorea-improvements-over-time-with-once-daily-valbenazine-treatment-in-adults-with-huntington-disease/