FDA Approves Sprinkle Formulation of Neurocrine Biosciences’ Valbenazine for Tardive Dyskinesia or Huntington disease Chorea

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The original approval for chorea associated with Huntington disease was based on the phase 3 KINECT-HD study, an 128-patient cohort trial in which valbenazine met its primary end point.

Eiry W. Roberts, MD, the chief medical officer at Neurocrine Biosciences

Eiry W. Roberts, MD

Credit: Neurocrine Biosciences

The FDA has approved Neurocrine Biosciences’ therapy valbenazine (Ingrezza) oral granules, a new sprinkle formulation of the treatment capsules for oral administration, for patients with tardive dyskinesia (TD) or chorea associated with Huntington disease (HD). The oral granules capsules (40 mg, 60 mg and 80 mg) are intended to be opened for sprinkling on soft foods prior to administration.1

The new drug application (NDA) filing for the sprinkle formulation included chemistry, manufacturing, and controls information and data demonstrating the bioequivalence and tolerability of the oral granule sprinkle capsules compared with the currently approved valbenazine capsules.2 Valbenazine is currently available as the only single-capsule, once-daily treatment option with no complex titration for adults with TD and the treatment of chorea associated with HD. It is the only selective vesicular monoamine transporter 2 (VMAT2) inhibitor that offers three effective dosages (40 mg, 60 mg and 80 mg) that can be adjusted by the healthcare provider based on patient response and tolerability.

"We developed Ingrezza Sprinkle to make administration easier for patients who have difficulty swallowing or prefer not to take a capsule," Eiry W. Roberts, MD, the chief medical officer at Neurocrine Biosciences, said in a statement.1 "We are pleased to offer the proven efficacy of Ingrezza in reducing uncontrollable movements in a new formulation."

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 its approval for HD chorea in August 2023. 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 12.3

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).4

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.

Previously, in April 2017, valbenazine became the first FDA-approved treatment for patients with TD. 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.5

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.

REFERENCES
1. Neurocrine Biosciences Announces U.S. FDA Approval of INGREZZA® SPRINKLE (valbenazine) Capsules. News release. Neurocrine. April 30, 2024. Accessed April 30, 2024. https://www.prnewswire.com/news-releases/neurocrine-biosciences-announces-us-fda-approval-of-ingrezza-sprinkle-valbenazine-capsules-302132283.html
2. Neurocrine Biosciences Announces U.S. FDA Accepts New Drug Application for INGREZZA® (valbenazine) Oral Granules Sprinkle Formulation. News Release. Published September 14, 0223. Accessed April 26, 2024. https://www.prnewswire.com/news-releases/neurocrine-biosciences-announces-us-fda-accepts-new-drug-application-for-ingrezza-valbenazine-oral-granules-sprinkle-formulation-301926943.html
3. Neurocrine Biosciences Announces FDA Approval of INGREZZA® (valbenazine) Capsules for the Treatment of Chorea Associated With Huntington's Disease. News Release. Neurocrine Biosciences. Published August 18, 2023. Accessed August 18, 2023.
4. Stimming EF, Claassen DO, Kayson E, et al. 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. Lancet Neurol. 2023;22:494-504
5. Neurocrine announces FDA approval of Ingrezza TM (valbenazine) capsules as the first and only approved treatment for adults with tardive dyskinesia (TD). News release. April 11, 2017. Accessed August 17, 2023. https://www.prnewswire.com/news-releases/neurocrine-announces-fda-approval-of-ingrezza-tm-valbenazine-capsules-as-the-first-and-only-approved-treatment-for-adults-with-tardive-dyskinesia-td-300438338.html
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