The approval was based on the phase 3 KINECT-HD study, an 128-patient cohort trial in which valbenazine met its primary end point, demonstrating a statistically significant reduction in UHDRS TMC scores vs placebo.
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The FDA has approved an expanded indication for Neurocrine Biosciences’ therapy valbenazine (Ingrezza) to include the treatment of chorea associated with Huntington disease (HD). The therapy becomes the only selective vesicular monoamine transporter 2 inhibitor approved for the condition, offering an effective starting dosage that can be adjusted according to response and tolerability with no complex titration.1
Data from the phase 3 KINECT-HD study (NCT04102579), a double-blind trial, and its ongoing open-label extension, KINECT-HD2 (NCT04400331), served as the basis for the approval. Similar in design, each study featured adults aged 18 to 75 years who had been diagnosed with either manifest HD or motor manifest HD who have sufficient chorea symptoms. In KINECT-HD, the agent met its primary end point, demonstrating a statistically significant placebo-adjusted reduction in the Unified Huntington’s Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score of 3.2 units (P <.00001) from baseline to weeks 10 and 12.2
"Clinical results that led to this important approval showed reduction in the severity of chorea as early as two weeks after starting Ingrezza at an initial dose of 40 mg, with consistently greater improvements versus placebo seen at all subsequent visits," principal investigator Erin Furr Stimming, MD, FAAN, FANA, a professor of neurology at McGovern Medical School of UTHealth Houston said in a statement.1 "Data also demonstrated Ingrezza was generally well tolerated and showed clinically meaningful improvement in adults with chorea associated with HD."
Valbenazine also showed a tolerable safety profile, with serious treatment-emergent adverse events (TEAEs) reported in 1.6% of treated participants. The most common TEAEs included somnolence, fatigue, fall, and akathisia, although all were mild to moderate in nature and consistent with prior safety findings. 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%).
Traditionally, antipsychotic medications such as risperidone (Risperdal), haloperidol (Haldol), and chlorpromazine (Thorazine) were used off-label to treat HD because they suppress chorea. In addition to suppressing chorea, antipsychotic medications can help manage psychiatric symptoms associated with HD, including agitation and psychosis; however, they still come with risks as off-label therapies.
In KINECT-HD, treatment with valbenazine 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 period. The study also met its secondary end points on change in Clinical Global Impression-Clinician (CGI-C) and Patient Global Impression-Clinician (PGI-C).2
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.
"We are proud to bring Ingrezza to people living with HD and their caregivers who now have the option of a one-capsule, once-daily treatment that has demonstrated significant improvement in HD chorea in clinical studies," Kevin C. Gorman, chief executive officer at Neurocrine Biosciences said in a statement.1 "We are thankful for those in the HD community who helped contribute to this important milestone, and we remain committed to bringing medicines to patients with unmet medical needs for debilitating neurological disorders."
Previously, in April 2017, valbenazine became the first FDA-approved treatment for patients with tardive dyskinesia. Later that year, a capsule strength form of the medication also gained greenlight. The drug’s approval was based on more than 20 clinical studies that included more than 1000 individuals.3
Using additional safety scales, investigators from KINECT-HD 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]).
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.