Daniel M. Keller, PhD

June 30, 2016

BERLIN — Once-daily administration of the investigational compound valbenazine significantly improved tardive dyskinesia (TD) in patients with a variety of psychiatric conditions, results of a phase 3 randomized trial show.

The drug was well tolerated, even though patients were taking a variety of concomitant medications.

At present, there are no US Food and Drug Administration-approved medications for the treatment of TD, which may occur when patients are chronically exposed to drugs that block the dopamine receptor, such as antipsychotic medications.

"This could be the very first drug approved for tardive dyskinesia in this country, and it's important because the number of people with TD is going up, and the number of prescriptions for antipsychotics has gone up 3-fold from 1997 to 2011," lead author Stewart Factor, DO, director of the movement disorders program at Emory University in Atlanta, Georgia, told Medscape Medical News.

The number of children treated with these drugs has increased 10-fold and the number of adults 3- to 4-fold. He said the number of people with TD in the United States is estimated to range from half a million to 1.2 million.

Their results were presented here at the 20th International Congress of Parkinson's Disease and Movement Disorders.

KINECT 3

For the multicenter KINECT 3 phase 3 study, researchers randomly assigned in a double-blind fashion patients with moderate to severe TD for at least 3 months before screening to VBZ 40 mg (n = 70) or 80 mg (n = 79) daily or to placebo (n = 76) for 6 weeks.

Patients had diagnoses of schizophrenia, schizoaffective disorder, or mood disorder, including bipolar disorder and major depressive disorder. Patients with a comorbid movement disorder that was more prominent than TD were excluded, as were individuals at risk for suicidal ideation, suicidal behavior, or violent behavior. Most patients (86%) were receiving antipsychotic medications during the study (16% typical, 77% atypical).

The three study groups were well matched for age (55 to 57 years), sex (49% to 57% male), schizophrenia/schizoaffective disorder (65%), Abnormal Involuntary Movement Scale (AIMS) scores (9.8 to 10.4), and various psychiatric scale scores.

Reviewers blinded to treatments observed videotapes of patients from each visit to determine AIMS scores, the main outcome parameter. The mean baseline AIMS score was 10.1 ± 4.0.

Dr Factor, one of the video reviewers, told Medscape Medical News that the study met its primary outcome, the change from baseline on the AIMS total score for the 80-mg dose vs placebo at 6 weeks.

"There was about a 3.2-point change in the 80-mg group vs 0.1 change in the placebo [P < .001], which was kind of interesting," he said. "I expected to see more of a placebo effect, but there was very little placebo effect."

There was an approximately 2.2-point reduction in AIMS score in the 40-mg group, he reported.

Statistically significant improvements in AIMS scores were apparent for both doses at 2 and 4 weeks, as well at 6 weeks (P < .001 at all time points for the 80-mg dose).

Dr Factor said drug blood level measurements to monitor adherence showed that about 20% of patients had no detectable drug in their systems. When these patients were excluded from the analysis, he said the results were just about the same.

The secondary endpoint of an improvement in the mean Clinical Global Impression of Change-TD score was not met but trended toward improvement for both doses at 2.9 each vs 3.2 for placebo (P = .0742 for VBZ 40 mg; P = .056 for VBZ 80 mg).

All groups' psychiatric status remained stable from baseline to week 6 of the trial. There were no changes in the placebo, VBZ 40 mg, or 80 mg groups on Positive and Negative Symptom Scale positive or negative symptom scores or general psychopathology score, Calgary Depression Scale for Schizophrenia, Young Mania Rating Scale, or Montgomery-Åsberg Depression Rating Scale scores.

All groups tolerated their assigned treatments well. "I've actually been surprised at how little parkinsonism and akathisia we've seen with this," Dr Factor noted.

Treatment-emergent adverse events (TEAEs) were similar for all three groups. The most common was somnolence, affecting three or four patients in each group. About 40% to 50% of patients in each group experienced any TEAE, but only four or five in each group discontinued the study because of a TEAE. Three patients in the 80-mg group experienced dyskinesia.

The investigators did not detect any safety signals for depression and suicidality, changes in laboratory parameters, or drug interactions, even though most patients were receiving concomitant antipsychotic medications.

The KINECT-3 data were presented previously at the American Academy of Neurology meeting in April by coauthor Robert A. Hauser, MD, from the University of South Florida, Tampa. He reported at that time that there was 1 death in the VBZ 80 mg group, possibly due to a cardiovascular event.

"This 73-year-old man did have cardiovascular risk factors, and both the site investigator and the data and safety monitoring board judged the event or the death unlikely related to study medication," Dr Hauser noted at that time. A second phase 3 study of the drug is underway, Dr Hauser said.

Several presentations at the current conference involved drugs that are now in trials for TD. VBZ has been granted breakthrough therapy status by the US Food and Drug Administration, and the developer intends to submit a New Drug Application for TD this year.

Rodger Elble, MD, PhD, professor of neurology at Southern Illinois University School of Medicine in Springfield, moderated a poster tour that included this study. He commented to Medscape Medical News that one strength of the KINECT-3 study is that it included patients with a variety of psychiatric conditions.

"Tardive dyskinesia is very variable, patient to patient," and can involve oral-buccal-lingual dyskinesia, tics, choreiform movements, dystonia, and even tardive tremor, he said.

Dr Elble said in practice, TD symptoms often appear when antipsychotic medications are reduced. Then a clinician may reinstate the drug, reducing the symptoms for a while, but the movements often reappear more strongly.

"So you're really adding fuel to the fire when you try to treat this by escalating doses of neuroleptics," he said. "That's why medications like this are so important."

John Nutt, MD, professor of neurology at Oregon Health and Science University in Portland, is very positive on the results of the trial.

"They have reduced the abnormal involuntary movements with their drug, and they have not produced any significant side effects," he said. Depression and suicide are the main worries, "and they have no indication of producing depression with this."

Tetrabenazine, another drug for TD, has had some signal in this regard, at least for patients with Huntington's disease.

One author (Expert Opin Investig Drugs. 2015;24:737-742) suggests investigating long-term side effects of chronic VBZ administration in naturalistic observational trials since it shares "to a certain extent…the mode of action of tetrabenazine."

Dr Nutt said that a 6-week trial may not be sufficient to show such adverse effects. Nonetheless, he said he was impressed that the adverse event profile was so good up to this point in a trial with a substantial number of patients, which "is really promising."

The study was supported by Neurocrine Biosciences Inc. Dr Factor reported that he has received compensation as a consultant to the company. Dr Hauser received similar compensation. Dr Elble and Dr Nutt have disclosed no relevant financial relationships.

20th International Congress of Parkinson's Disease and Movement Disorders. Abstract 2095. Presented June 23, 2016.

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