A deeper look a the sole FDA-approved treatment for Tardive Dyskinesia.
In April, 2017, valbenazine (Ingrezza) became the only medication approved by the US Food and Drug Administration (FDA) with a specific indication for treating tardive dyskinesia (TD).
This usually irreversible condition typically results from the use of dopamine receptor blockers to treat psychiatric disorders and is characterized by involuntary, repetitive, and aimless movements. Moreover, because patients’ social contacts may find these involuntary movements disconcerting, TD may further stigmatize many patients already stigmatized because of a psychiatric diagnosis.
To evaluate the clinical utility of valbenazine — a reversible inhibitor of vesicular monoamine transporter 2 (VMAT2) — Leslie Citrome (pictured), MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla, New York, recently conducted a systematic review of all available clinical reports of studies of valbenazine for the treatment of TD.
Citrome then extracted the principal results of these studies and used them to calculate the number needed to treat (NNT) and the number needed to harm (NNH) for relevant outcomes. These two numbers are measures of a drug’s effect size, either positive (for NNT) or negative (for NNH), and indicate how many patients must be treated with one agent instead of another to obtain one more outcome of interest.
Using data from the Phase III trial supporting valbenazine’s efficacy in its product labeling, Citrome calculated that the number of patients that need to be treated to obtain a response from valbenazine, 80 mg daily, compared with placebo was 4 (95% confidence interval (CI), 3—6). In that Phase III trial, the investigators defined response as a 50% or greater reduction from baseline in the Abnormal Involuntary Movement Scale dyskinesia score.
They found that 40% of the treated group had a response, compared with 8.7% in the placebo group.
However, when Citrome pooled all available efficacy data for valbenazine and used it to calculate the NNT, he found that the NNT was 5. In addition, after pooling all available tolerability and safety data, Citrome determined that the discontinuation rate due to an adverse event was 2.9% for valbenazine and 1.6% for placebo.
Using these percentages, Citrome determined that the NNH of valbenazine versus placebo for discontinuation due to an adverse event was 76. Dividing this NNH by the NNT based on all available data, he found that valbenazine was 15 times more likely to result in a response than in a discontinuation due to an adverse event.
Furthermore, Citrome noted that somnolence — a category that incorporated fatigue and sedation — was the only valbenazine-associated adverse event with at least a 5% incidence and a rate at least twice that for placebo. The rate of somnolence was 10.9% for valbenazine at all doses compared with 4.2% for placebo.
Using these percentages, Citrome determined that the NNH of valbenazine versus placebo for somnolence was 15 (95% CI, 9—52). However, he noted that this NNH for somnolence indicates that valbenazine is less sedating than the antipsychotic agents lurasidone (Latuda) and extended-release quetiapine (Seroquel XR).
Citrome also noted that the product labeling warns that valbenazine may prolong the QT segment on an electrocardiogram. Furthermore, according to Citrome, the small sample sizes of the studies evaluated limit the sensitivity of the NNH for assessing the impact of uncommon adverse events such as QT segment prolongation.
Regarding the relevance of these numbers, Citrome explained that a drug is useful if it has a low NNT and a high NNH relative to those for another intervention. He also presented a rule of thumb for assessing a treatment: Single-digit NNTs for efficacy indicate that an agent may have useful advantages, and double-digit or greater NNHs for adverse events indicate that an agent may be well-tolerated.
The review, “Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication—What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?,” was published online last month in the International Journal of Clinical Practice.