Huntington’s Disease Chorea Improved With Valbenazine

Valbenazine (Ingrezza) calmed the involuntary, jerky movements associated with Huntington’s disease, the phase III KINECT-HD trial showed.

In the 12-week double-blind trial, the Unified Huntington’s Disease Rating Scale Total Maximal Chorea (UHDRS TMC) scores decreased by 4.6 points with valbenazine and by 1.4 with placebo, a difference of 3.2 points on the 28-point scale (P<0.0001), reported Erin Furr Stimming, MD, of the McGovern Medical School at UTHealth Houston, and co-authors.

Somnolence was the most commonly reported treatment-emergent adverse event, seen in 16% of patients with valbenazine and 3% with placebo, the researchers wrote in Lancet Neurology.

“KINECT-HD is, to our knowledge, the first phase III trial of valbenazine for chorea associated with Huntington’s disease,” Furr Stimming and co-authors noted.

Valbenazine is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor. Its pharmacokinetic profile allows for once-daily dosing and a relatively short titration period.

Two other VMAT2 inhibitors, tetrabenazine (Xenazine) and deutetrabenazine (Austedo), are approved for treating Huntington’s-related chorea; the FDA is expected to decide whether to approve valbenazine for this indication in August 2023. In the U.S., valbenazine and deutetrabenazine are approved to treat tardive dyskinesia.

Tetrabenazine and deutetrabenazine are metabolized into four dihydrotetrabenazine stereoisomers with varying degrees of affinity for VMAT2. Valbenazine produces only the stereoisomer with the strongest affinity for VMAT2, Furr Stimming and co-authors noted.

“With the completion of KINECT-HD, there is now robust evidence that all three VMAT2 inhibitors can alleviate chorea in individuals with Huntington’s disease,” wrote Beatrice Heim, MD, PhD, and Klaus Seppi, MD, both of the Medical University of Innsbruck, Austria, in an accompanying editorial.

“Without head-to-head trials, no inferences can be drawn on the efficacy and safety of valbenazine relative to the other two VMAT2-inhibitors, but the phase III trials suggest a favorable side-effect profile of the tetrabenazine derivatives compared with the original drug, presumably related to their pharmacokinetic profiles,” Heim and Seppi added.

An estimated 90% of patients with Huntington’s disease experience chorea. “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,” Furr Stimming and colleagues wrote.

THE KINECT-HD trial included 128 participants at Huntington Study Group sites in North America. Patients taking antipsychotics or other dopamine receptor blockers, CYP3A4 inducers, dopamine agonists and precursors, or monoamine oxidase inhibitors were excluded from the study.

Patients with genetically confirmed Huntington’s disease and chorea were randomized to receive either valbenazine or placebo. During an 8-week dose-adjustment phase, investigators could increase the dose up to 80 mg. This was followed by a 4-week maintenance phase. The primary efficacy endpoint was change in UHDRS TMC scores from the screening and baseline period to the maintenance period (the average of week 10 and week 12 assessments for each participant).

Of 55 participants treated with valbenazine at the week 12 visit, 45 (82%) were taking 80 mg. The most common treatment-emergent adverse events with valbenazine were sleepiness, fatigue, and falls, although a similar number of falls were recorded in the placebo group. Nine (14%) participants in the valbenazine group required a dose reduction because of treatment-emergent adverse events. Three participants, including one in the valbenazine group, experienced serious adverse events during the trial, but none were judged to be related to treatment.

No worsening in anxiety or depression, akathisia, or parkinsonism was seen with valbenazine or placebo. There was no evidence for treatment-emergent suicidal ideation or behavior with valbenazine.

KINECT-HD also used the Huntington’s Disease Health Index (HD-HI), a new measure validated for assessing patient-reported disease burden, as an exploratory endpoint. HD-HI results showed that the valbenazine group reported greater reductions in disease burden related to mobility, abnormal movements, and hand and arm function than the placebo group.

The study had several limitations, including its short duration, the researchers acknowledged. Additionally, the study design prohibited antipsychotic use.

“Monotherapy with either a VMAT2 inhibitor or antipsychotic is generally preferred; however, some individuals require dual therapy because of intractable chorea, neuropsychiatric symptoms, or both,” Furr Stimming and co-authors wrote. “Therefore, the prohibition of antipsychotics during the double-blind, placebo-controlled phase might not reflect real-world treatment patterns in Huntington’s disease.”

The ongoing continued access study, KINECT-HD2, addresses both these limitations. This study will follow approximately 150 patients treated with valbenazine for Huntington’s-related chorea for up to 156 weeks.