An efficient trial design and continuous, open communication with the US Food and Drug Administration (FDA) were important in getting approval for the first treatment of tardive dyskinesia (TD) — and highlight important lessons for other researchers and drug companies, according to a new editorial in the New England Journal of Medicine (NEJM).
In April, the FDA approved the vesicular monoamine transporter 2 (VMAT2) inhibitor valbenazine (Ingrezza, Neurocrine Biosciences) for the treatment of adult patients with TD. The condition is thought to be caused by long-term exposure to dopamine receptor blockers, including antipsychotic medications.
"A well-executed development program that addresses both regulatory and clinical requirements is critical for making novel therapeutics available as quickly as possible to patients with unmet medical needs," write Michael C. Davis, MD, Division of Psychiatry Products at the Center for Drug Evaluation and Research in Silver Spring, Maryland, and colleagues.
"The valbenazine story reveals how a pharmaceutical company with no products on the market was able to navigate regulatory demands effectively and develop a novel treatment for an important iatrogenic condition that was first identified more than 50 years ago," they add.
The Perspective article was published online May 10.
Dr Davis and colleagues report an estimated annual incidence of 8.5% for TD associated with typical antipsychotics and an annual incidence of 3.1% with atypical/second-generation antipsychotics.
Symptoms of TD include uncontrollable movements in the face, tongue, and extremities and often cause interference with walking, talking, swallowing, and breathing.
"Public perceptions of involuntary movements can lead to shame, depression, and increased social isolation," write the editorialists, adding that "stigmatizing representations" in pop culture include Heath Ledger's portrayal of the Joker in the movie The Dark Knight.
They note that abnormalities in dopamine signalling "have long been suspected" to cause TD. Understanding this, and that valbenazine is a VMAT2 inhibitor, helped lead the FDA to designate the medication as a breakthrough therapy in 2014.
In addition, its new drug application was designated for priority review in August 2016, "a classification triggered by the drug's potential as a medical advance." These types of specialized pathways helped in approving the medication just 8 months later, write the authors.
Development program data submitted by the company included findings from the Kinect 3 phase 3 trial, which compared 80-mg and 40-mg doses of the medication with matching placebo in patients with moderate to severe TD and schizophrenia, schizoaffective disorder, or a mood disorder.
The participants receiving the 80-mg/day dose had a significant decrease in TD symptoms at 6 weeks, as measured on the Abnormal Involuntary Movement Scale (AIMS), compared with those receiving placebo. An extension period showed significant efficacy for the 80-mg dose up to 48 weeks.
Neurologists who were specialists in movement disorders acted as AIMS raters while watching videos of the study participants. "The sponsor's use of remote video raters is noteworthy, given the challenges and high costs of drug development," write the Perspective authors.
The study outcomes were supported through "judicious use of multiple design elements — such as crossover from placebo to active treatment, dose comparison, rater evaluation of withdrawal, and well-blinded AIMS rating," they write, adding that they also applaud the stringent safety review of the medication.
"An important lesson for drug developers is that creativity and partnership in both development and review can effectively overcome long-standing clinical challenges," conclude the editorialists.
Teva Pharmaceutical Industries announced in February that the FDA granted priority review for its own TD treatment, SD-809 (deutetrabenazine, Austedo), based on the phase 3 ARM-TD and AIM-TD studies. A Prescription Drug User Fee Act goal date has been assigned by the FDA for August 30.
Interestingly, this drug was approved by the FDA in April for the treatment of chorea associated with Huntington's disease.
N Engl J Med. Published online May 10, 2017. Full text
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