Treatment with valbenazine at doses of up to 80 mg once per day significantly improved chorea, as demonstrated by the mean change in UHDRS Total Maximal Chorea scores.
Neurocrine Biosciences has published the complete data from its phase 3 KINECT-HD study (NCT04102579) in The Lancet Neurology, highlighting the efficacy and safety of valbenazine (Ingrezza) as a potential treatment for chorea associated with Huntington disease (HD). Valbenazine, a selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is currently under review by the FDA, with a scheduled PDUFA date of August 20, 2023.
KINECT-HD included 128 adults aged 18 to 75 years old with manifest HD and sufficient chorea symptoms who were randomly assigned 1:1 to either valbenazine or placebo. Ultimately, the study met its primary end point of change in the Unified Huntington’s Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score, with valbenazine-treated patients demonstrating a placebo-adjusted mean reduction of 3.2 units in TMC score (P <.0001) over a 12-week period.
KINECT-HD, along with KINECT-HD2, the open-label extension to the study, were the basis for the supplemental new drug application (sNDA), which was accepted by the FDA in August 2022. In the study, treatment with valbenazine, a selective vesicular monoamine transporter 2 (VMAT2) inhibitor, resulted in improved chorea as early as 2 weeks after administration in the lowest study dose (40 mg), with consistently greater improvement relative to placebo in all subsequent visits (Weeks 4 to 12), as the dose was adjusted from 40 mg to 60 mg to 80 mg over the 12-week study.
"More than 90% of adults with HD experience chorea," lead investigator Erin F. Stimming, MD, professor, Department of Neurology, and Memorial Hermann Chair, UTHealth Houston, said in a statement. "The KINECT-HD study data demonstrated statistically significant improvement in chorea associated with HD as compared with placebo. The safety profile for participants with chorea associated with HD was consistent with the known safety profile of valbenazine. By the end of the 12-week study, 82% of valbenazine-treated participants were taking 80 mg."
Performed from November 2019 to October 2021, findings from KINECT-HD showed least-square mean changes in UHDRS TMC score of –4.6 for valbenazine and –1.4 for placebo. The study also met its secondary end points on change in Clinical Global Impression-Clinician (CGI-C) and Patient Global Impression-Clinician (PGI-C). By the end of the 12-week period, 43% and 53% of patients on valbenazine were classified as "much improved" or "very much improved" on CGI-C and PGI-C, respectively, compared with rates of 13% and 26% for those on placebo. Notably, the change in Neuro-QoL Upper Extremity Function T-score was not statistically significant after 12 weeks.
As for safety, somnolence, fatigue, and falls were among the most commonly reported treatment-emergent adverse events (TEAEs) for valbenazine. Of note, the placebo group showed a similar incidence of falls. Nine (14%) participants in the active treatment group had a dose reduction because of TEAEs, most commonly for fatigue (n = 4) and somnolence (n = 3). More than 5% of participants on valbenazine reported urticaria (9%) and rash (8%).
Using additional safety scales, investigators found no worsening in anxiety or depression, akathisia, or parkinsonism with either valbenazine or placebo. No clinically meaningful differences between treatment groups were found for vital signs, electrocardiograms, or laboratory tests. After 12 weeks of treatment, mean changes in orthostatic blood pressure were small in both treatment groups, for both systolic blood pressure (valbenazine, –1.8 [SD, 15.9; placebo, –0.8 [SD, 11.7]) and diastolic blood pressure (valbenazine, –0.8 [SD, 12.1]; placebo, –2.5 [SD, 10.5]).
"We’re pleased to share the KINECT-HD full study results with the scientific community and its acceptance in an esteemed journal following rigorous peer-review," Eiry W. Roberts, MD, chief medical officer, Neurocrine Biosciences, said in a statement. "There remains a need for symptomatic treatments for chorea associated with Huntington’s disease, and this manuscript provides an in-depth overview of the KINECT-HD study data and the potential of valbenazine to fulfill this need."
To the study authors knowledge, KINECT-HD was the first phase 3 study in HD to the Neuro-QoL, Huntington’s Disease Health Index (HD-HI), and Anosognosia Scale as outcome measures. Results on HD-HI, a novel, validated, disease-specific outcome measure, indicated greater reductions with valbenazine relative to placebo in patient-reported disease burden related to mobility, abnormal movements, and hand and arm function.
"Although chorea is only one of the many symptoms experienced by individuals with Huntington’s disease, it is treatable. Early detection of chorea, assessment of its impact on physical, mental, emotional, and social functioning, and evaluation of the need for treatment might decrease burden and improve outcomes in individuals living with this devastating neurodegenerative disease."