Full Phase 3 trial data: Valbenazine eases chorea in Huntington’s
Findings form basis of FDA application for therapy to treat uncontrolled movements
The oral therapy valbenazine significantly reduces involuntary muscle contractions, or chorea, and patient-reported disease burden in people with Huntington’s disease, according to results from the Phase 3 KINECT-HD clinical trial.
Top-line data were announced by Neurocrine Biosciences, the therapy’s manufacturer, in 2021. The full findings have been published in The Lancet Neurology in “Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington’s disease (KINECT-HD): a phase 3, randomized, double-blind, placebo-controlled trial.”
“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 Roberts, MD, Neurocrine’s chief medical officer, said in a company press release. “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.”
The findings form the basis of Neurocrine’s application before the U.S. Food and Drug Administration for valbenazine to treat Huntington’s-associated chorea. The agency is reviewing the application. A decision is expected in August.
The therapy received orphan drug status last year to control chorea with Huntington’s. The designation is meant to expedite a therapy’s clinical development and regulatory approval.
These “positive study results remind us there is a reason for hope,” Erin Furr-Stimming, MD, the study’s first author at UTHealth Houston, Texas and the trial’s principal investigator on behalf of the Huntington Study Group, said in a university press release.
The Huntington Study Group is a clinical research network that helped run KINECT-HD.
“Chorea associated with Huntington’s disease can negatively impact quality of life and functional independence; therefore, studying additional medications to address this hallmark motor symptom is imperative,” said Furr-Stimming, a professor of neurology at UTHealth Houston and the director of the Huntington’s Disease Society of America Center of Excellence at UTHealth Houston Neurosciences.
Valbenazine is thought to work by reducing the activity of certain movement-controlling signaling molecules in the brain, thereby preventing uncontrolled movements. It’s approved for people with a movement disorder called tardive dyskinesia. Neurocrine markets it under the brand name Ingrezza.
The KINECT-HD trial (NCT04102579) enrolled 128 adults with Huntington’s-associated chorea at sites across North America. Just over half were women and most identified as non-Hispanic white.
Assessing changes in chorea severity
Participants were randomly assigned to take oral capsules of either valbenazine or a placebo, once daily for 12 weeks (about three months). Patients on valbenazine started at a daily dose of 40 mg, which was gradually increased up to 80 mg a day, based on tolerability. Among the 109 patients (85%) who completed the treatment period, 82% of those on valbenazine were taking the maximum dose by week 12.
The study’s main goal was to assess changes in chorea severity as measured by the Unified Huntington’s Disease Rating Scale-Total Maximal Chorea score. This measure evaluates chorea in the face, mouth/jaw, trunk, and each limb, with higher scores indicating worse chorea.
Results showed score reductions were significantly greater, by more than 3 points on average, for valbenazine-treated patients compared with a placebo. Group differences were evident as early as two weeks after starting treatment.
Compared with the placebo group, patients given valbenazine were significantly more likely to experience considerable improvements in overall health, as reported both by them (43% vs. 13%) and by clinicians (53% vs. 26%).
There were no statistically significant group differences in changes in arm and leg skills, as assessed with a standard measure called Neuro-QoL. However, the researchers noted most patients had scores near the maximum at the study’s start, which may have limited the ability to detect a meaningful improvement.
In addition to these well-established measures, KINECT-HD was the first Phase 3 trial to use the Huntington’s Disease Health Index (HD-HI), a new test validated for assessing patient-reported disease burden in Huntington’s.
“This instrument was developed using input from individuals with Huntington’s disease to reflect the physical, mental, and social issues that have the greatest impact for them and their caregivers,” the researchers wrote.
HD-HI data showed that valbenazine-treated patients reported greater reductions in disease burden associated with uncontrolled movements, and greater improvements in mobility and hand and arm function than with a placebo.
Valbenazine was generally well tolerated, with most common side effects including sleepiness (16%) and fatigue (14%). Hives or rash also were reported, leading to valbenazine being discontinued in some cases. Measures of depression, anxiety, other movement problems, and vital signs showed no notable effects with treatment.
Participants who completed KINECT-HD had the option to enter an extension study, called KINECT-HD2 (NCT04400331), conducted by Neurocrine and the Huntington Study Group. All participants are receiving valbenazine for up to three years to assess its long-term effects in Huntington’s patients with chorea.