Analysis published in The Journal of Clinical Psychiatry showing long-term efficacy and a consistent safety profile of Ingrezza (valbenazine) capsules in older adults with tardive dyskinesia - Neurocrine Biosciences

Neurocrine Biosciences, Inc. announced publication of a post-hoc analysis from two 48-week studies, the KINECT 3 extension and KINECT 4, demonstrating the long-term safety profile and robust efficacy of Ingrezza (valbenazine) capsules in adults aged 65 years and older with tardive dyskinesia (TD) in The Journal of Clinical Psychiatry. This represents the first and only published peer-reviewed analysis of a vesicular monoamine transporter 2 inhibitor for the treatment of TD in older adults (≥65 years), a group at higher risk for TD and associated consequences.

Individuals aged 60 years and older may develop TD after as little as one month of exposure to antipsychotics and other dopamine receptor blocking agents. The involuntary movements of TD can also have a substantial impact on older adults, affecting their balance, gait, ability to swallow and respiratory conditions. The data from this post-hoc analysis show substantial and sustained improvements in TD symptoms in older adults, with no new treatment-emergent adverse events of clinical concern found when compared with younger adults (<65 years).

"This analysis, the first and only of its kind in a peer-reviewed publication, addresses an important gap in research on this potentially vulnerable population," said Eiry W. Roberts, M.D., Chief Medical Officer, Neurocrine Biosciences. "These data show that participants 65 years and older achieved clinically meaningful improvements in tardive dyskinesia symptoms within eight weeks of Ingrezza treatment, with substantial and sustained improvement up to 48 weeks, adding to the breadth of evidence suggesting Ingrezza is uniquely suitable for this patient population."

The pooled post-hoc analysis included 304 participants across studies who received a once-daily dose of Ingrezza (40 mg or 80 mg) for up to 48 weeks. Of the total participants, 55 (18.1%) were 65 years and older. At Week 48, efficacy and safety outcomes were analyzed by dose (40 mg, 80 mg) and age (<65 years, ≥65 years).

The efficacy of Ingrezza was assessed using mean changes from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score, AIMS response thresholds (≥30% and ≥50% improvement from baseline) and response threshold for Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) and Patient Global Impression of Change (PGIC), defined as a score ≤2 ("much improved" or "very much improved"). At baseline, participants in both age subgroups had a mean AIMS total score of approximately 12, consistent with moderate to severe severity in one or more body regions. The safety profile of Ingrezza was evaluated through adverse event monitoring and psychiatric symptom scales.

Data from this analysis of participants ≥65 years in the KINECT 3 extension and KINECT 4 studies suggest substantial and sustained improvements in TD symptoms with Ingrezza treatment (all doses). Overall, psychiatric stability was maintained through 48 weeks of treatment and Ingrezza was generally well tolerated. The most common treatment-emergent adverse events reported from Weeks 8 to 48 included urinary tract infection and somnolence; each occurred in six of the 55 participants who were 65 years and older. There were no statistically significant differences between age groups (<65 versus ≥65) for most efficacy and safety outcomes at Week 48.

KINECT 3 is a Phase III, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in which 234 participants with moderate to severe TD and underlying schizophrenia, schizoaffective disorder or mood disorder (including bipolar disorder or major depressive disorder) received six weeks of once-daily Ingrezza (40 mg or 80 mg capsules) or placebo (participants randomized to 80 mg started on 40 mg for one week). Subsequent to the completion of the six-week placebo-controlled dosing, participants receiving Ingrezza continued on their current dose and placebo participants were randomized to receive either once-daily 40 mg or once-daily 80 mg of INGREZZA, through Week 48 (42-week blinded treatment extension period; placebo participants randomized to 80 mg started on 40 mg for one week), followed by a four-week, drug-free washout. Dose reduction to 40 mg was allowed for participants who were unable to tolerate the 80 mg dose. Patients were discontinued if the new dose was not tolerated.

The study met its primary endpoint of change-from-baseline in AIMS at Week 6 in the 80 mg once-daily dosing group compared with placebo as assessed by expert central blinded video raters. The mean change from baseline to Week 6 in the AIMS rating was -3.2 for the 80 mg once-daily group as compared with -0.1 in the placebo group (P>0.0001). Sustained TD improvements were seen with Ingrezza 40 mg and 80 mg through Week 48.

Ingrezza was generally well tolerated throughout 48 weeks of treatment. The most common adverse reactions (≥ 5% and twice the rate of placebo) during the six-week, double-blind, placebo-controlled phase was somnolence with the frequency of adverse events being similar among all treatment groups. Treatment-emergent adverse events  were consistent with those of prior studies. There were no drug-drug interactions identified in participants who were utilizing a wide range of psychotropic and other concomitant medications, and participants generally remained psychiatrically stable throughout the study.

KINECT 4 is a Phase III, open-label study in which 163 participants with moderate to severe TD and underlying schizophrenia, schizoaffective disorder or mood disorder (including bipolar disorder or major depressive disorder) received 48 weeks of open-label treatment with once-daily Ingrezza (40 mg or 80 mg capsules) followed by a four-week washout. Dosing was initiated at 40 mg/day in all participants, with escalation to 80 mg/day at Week 4 based on effectiveness and tolerability. Dose reduction to 40 mg was allowed in participants who could not tolerate the 80 mg dose. Patients were discontinued if the new dose was not tolerated.

Participants experienced TD improvements during long-term treatment as demonstrated by mean change from baseline to Week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with Ingrezza 40 mg/day (-10.2) or 80 mg/day (-11.0). Consistent with previous studies, Ingrezza was generally well tolerated. After Week 4, treatment-emergent adverse events  that occurred in ≥5% of all participants (combined dose groups) were urinary tract infection (8.5%) and headache (5.2%). Changes from baseline in psychiatric stability, vital signs, electrocardiogram parameters and laboratory test values were generally small and not clinically significant.

Citation:" Improvements over time with valbenazine in elderly adults (≥65 years) with tardive dyskinesia: post hoc analyses of 2 long-term studies".  Authors: Sajatovic M,  Alexopoulos GS,  Jen E, et al.,  J Clin Psychiatry 2025;86(2):24m15550.