New Findings Offer Insight Into Minimal Clinically Important Difference on Total Maximal Chorea Scores in Huntington Disease


Data from the phase 3 KINECT-HD study of valbenazine (Neurocrine Biosciences) provided a keen understanding of the threshold for clinically meaningful improvement in TMC scores. The VMAT2 inhibitor showed promising gains for patients.

Erin Furr-Stimming, MD, a neurologist and professor of neurology at McGovern Medical School at UTHealth Houston

Erin Furr-Stimming, MD

New data from the phase 3 KINECT-HD study (NCT04102579) offer insight into the minimal clinically important difference threshold on the Unified Huntington Disease Rating Scale Total Maximal Chorea (TMC) score among patients with Huntington disease (HD) who were treated with valbenazine.1

The findings showed that a TMC score change of –4.0 points (standard error of the mean [SEM], 0.6) with Clinical Global Impression of Severity (CGI-S) anchor or –4.3 points (SEM, 0.8) with Patient Global Impression of Severity (PGI-S) anchor corresponds to a minimal clinically meaningful improvement in those with HD-related chorea.

The CGIS anchor scale ranged from 1 (normal, not at all ill) to 7 (extremely ill) and the PGI-S anchor scale ranged from 1 (none) to 5 (very severe), with a 1-point change on either considered to be clinically meaningful. TMC scores range from 0 to 28, and the investigators defined “clinically meaningful” as the mean of within-subject TMC score change that corresponded to a 1-point reduction on the impression scales.

Erin Furr-Stimming, MD, a neurologist and professor of neurology at McGovern Medical School at UTHealth Houston, and colleagues presented the data in a poster at the 2nd Annual Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress, held by the PMD Alliance from June 8 to 11, 2023, in Washington, DC. “The primary end point not only indicates a statistically significant improvement in chorea with valbenazine versus placebo; it also reflects chorea improvements that are clinically meaningful from both clinician and patient perspectives. Collectively, these results suggest that valbenazine shows potential to be an effective treatment of chorea in adults with HD,” Furr-Stimming et al wrote.

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The study included 125 patients (54.4% women) with a mean age of 53.7 years (SD, 10.8) who were randomly assigned to valbenazine (n = 56) or placebo (n = 53). Mean TMC scores in the screening and baseline periods were similar between the valbenzaine (12.2; SD, 2.3) and placebo groups (12.1; SD, 2.8). CGI-S scores of 4 or higher (moderately ill to extremely ill) were reported in 48.8% (n = 61) of all participants at baseline; PGI-S scores in that range (≥3; moderate to very severe) were reported in 44.8% (n = 56) of patients.

After 12 weeks, there was a higher percentage of individuals treated with valbenazine with a 1-point global improvement in chorea severity compared with those in the placebo group. On CGI-S, this percentage was 37.5% (n = 21) for the treatment group compared with 24.5% (n = 13) of the placebo group. On PGI-S, those respective percentages were 25% (n = 14) and 15.1% (n = 8).

The TMC primary end point in those treated with valbenazine exceeded the minimal clinically important difference threshold (least-squares mean change, –4.6 points) based on both anchor scales for improvement. Additionally, a reduction in TMC of at least 4 points was reported by 56.9% (n = 32) of patients in the treatment arm compared with 20.4% (n = 11) of those in the placebo arm.

The therapy, developed by Neurocrine Biosciences, is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is currently under review by the FDA, with a scheduled PDUFA date of August 20, 2023.2 The drug’s supplemental new drug application is supported by findings from KINECT-HD and the ongoing open-label KINECT-HD2 study (NCT04400331). Each study features adults aged 18 to 75 years who have a diagnosis of either manifest HD or motor manifest HD who have sufficient chorea symptoms.

Click here for more coverage of ATMRD 2023.

1. Furr-Stimming E, Claassen DO, Kayson E, et al. A Minimal Clinically Important Difference for UHDRS® Total Maximal Chorea Score as a Measure of Chorea Severity in Huntington Disease. Presented at: ATMRD; June 9-11, 2023; Washington, DC.
2. Neurocrine Biosciences announces US FDA accepts supplemental new drug application for valbenazine as a treatment for chorea associated with Huntington disease. News release. Neurocrine Biosciences. December 22, 2022. Accessed June 11, 2023.
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