Pam Harrison

October 11, 2016

WASHINGTON, DC — The efficacy of valbenazine, a drug being tested for use in the treatment of tardive dyskinesia, does not depend on the underlying psychiatric illness being treated, nor does the drug destabilize psychiatric status, new phase 2 trial data show.

"I was one of the principal investigators in Kinect 2 and Kinect 3, and I can tell you that in both of these studies, there was a very impressive treatment response to the drug in terms of reduction in tardive dyskinesia severity by week 6, and we're talking a 50% to 60% reduction in the overall severity of tardive dyskinesia at 6 weeks, depending on the study," Richard Josiassen, PhD, translational neuroscience research, Drexel University College of Medicine, Philadelphia, Pennsylvania, told Medscape Medical News.

"But this is the first time we've looked at subgroup response to treatment, and we showed that it's not just psychotic patients who respond to valbenazine. Patients with mood disorders respond equally well to it, too."

The study was presented here at the Institute of Psychiatric Services (IPS): The Mental Health Services 2016 Conference.

Efficacy Analyses

Kinect 2 was a randomized, double-blind, 6-week, placebo-controlled trial in patients with schizophrenia, schizoaffective disorder, mood disorder, or gastrointestinal disorder, all of whom had moderate to severe tardive dyskinesia.

Moderate or severe tardive dyskinesia was determined on the basis of Abnormal Involuntary Movement Scale (AIMS) video scores. Videos were assessed by a reviewer using a video recording of the patients' AIMS assessments at screening.

All patients were randomly allocated to receive either valbenazine or placebo. Patients who were given valbenazine received 25 mg once a day for 2 weeks, after which the dose could be increased to 50 mg once a day and then to 75 mg a day at week 4, depending on patient response. More than three quarters of patients who received active treatment reached the 75-mg, once-daily dose threshold.

The analysis was carried out in the intent-to-treat (ITT) population. The primary endpoint was the change from baseline to week 6 in the AIMS dyskinesia total score.

Of 102 patients who were enrolled in the study, 89 were included in the ITT population; 45 patients received valbenazine, and 44 received placebo.

Of the ITT population, 60%, or 53 patients, had been diagnosed with schizophrenia or schizoaffective disorder; 35 patients had been diagnosed with a mood disorder.

As reported in a previous trial, at week 6, responses to valbenazine, as assessed by both AIMS and the Clinical Global Impression of Change–Tardive Dyskinesia (CGI-TD) scores, were significantly better in the active treatment group than in the group that received placebo.

Table. ITT Population: Primary and Eecondary Efficacy Putcomes

 

Placebo

Valbenazine

P Value

AIMS, mean change from baseline to week 6

-0.2

-2.6

0

CGI-TD, mean score at week 6

3.1

2.2

<.0001

 

As determined on the basis of AIMS score, almost 50% of patients responded to valbenazine at week 6 vs approximately 18% of patients who received placebo. As determined on the basis of CGI-TD score, two thirds of patients responded to valbenazine by week 6 vs 16% of patients who received placebo.

"The AIMS score change from baseline to week 6 was consistent with the overall ITT population in subjects categorized by psychiatric diagnosis and by baseline tardive dyskinesia severity," investigators report.

Patients with schizophrenia had a 3.0-point reduction in their AIMS score by week 6; by comparison, patients who received placebo had a 1.0-point reduction (P < 0.05). Those with baseline mood disorder had a 4.5-point reduction in their AIMS score at week 6, whereas patients who received placebo had a 1.4-point reduction in score (P < .05).

Reductions in AIMS scores were also more pronounced in those with more severe baseline tardive dyskinesia than in those with milder forms of the disorder.

Mean CGI-TD scores at week 6 were very similar in both diagnostic subgroups in the active therapy arm, with a mean score of 2.4 in the schizophrenia/schizoaffective disorder group and a mean score of 2.1 in the mood disorder group.

With respect to CGI-TSD criteria, more than 61% of patients in the schizophrenia/schizoaffective disorder group responded to active treatment at week 6, as did almost 74% of those in the mood disorder group.

"I think the bigger issue now is that the newer antipsychotics are being used in populations outside of those with psychotic disorders, so there is a growing population of people with sleep disorders, anxiety disorders, posttraumatic stress disorder, and other psychiatric diagnoses that are being treated with second-generation antipsychotics, which renders them somewhat vulnerable to the development of tardive dyskinesia as well," Dr Josiassen said.

"And while it seems like the severity of symptoms is not as great with the second-generation drugs, tardive dyskinesia has certainly not gone away, and it is an important factor in the quality of life for these patients."

Psychiatric Stability

In a related poster presentation, Dr Josiassen pointed out that valbenazine is the grandchild of the drug tetrabenazine (Xenazine, Valeant).

"Tetrabenazine was developed some years ago to treat Huntington's disease, and it was effective, but it had a lot of serious side effects, including an increased risk of depression and suicide and lots of cardiac toxicities," Dr Josiassen explained to Medscape Medical News.

Because valbenazine is derived from tetrabenazine, "the question was, would this drug have the same side-effect profile as the parent drug?" he added.

To answer this question, a series of psychological tests were carried out in the same Kinect 2 study population to see whether patients became destabilized while receiving treatment during the 6-week trial.

Comparing changes in scores in a series of psychiatric rating scales from baseline to week 6 and week 8, investigators found that psychiatric status, as measured by rating scales for depression, manic symptoms, and schizophrenic psychopathology, generally remained stable or improved from baseline to week 6, and patients also remained stable at week 8, after a 2-week washout period.

Suicidal ideation and behavior were also assessed, and again, from the start of the study to week 8, no patients reported suicidal behavior, and of those who reported suicidal ideation, "all three subjects had a lifetime history of suicidal ideation," the investigators observe.

"I've been around schizophrenia research for about 30 years, and to see the severity of tardive dyskinesia really remarkably reduced within 6 weeks is very satisfying," Dr Josiassen concluded.

"And it's also really comforting that treating tardive dyskinesia did not cause patients to become psychiatrically destabilized."

"Very Promising"

Commenting on the findings for Medscape Medical News, John Kane, MD, adjunct clinical professor of psychiatry and behavioral sciences, Albert Einstein College of Medicine, New York City, said the data look "very promising."

"Tardive dyskinesia is a condition that in my opinion hasn't received much attention in recent years, because the second-generation drugs are associated with less risk," Dr Kane said.

"But what's happened is that many more people are being treated with these medications, so the number of cases is still a concern," he added.

Moreover, symptom severity can vary enormously; some patients have very mild forms of the disorder, whereas others have more severe involvement.

"Certainly in its severe form, tardive dyskinesia can be very disabling, but even in the milder forms, it's the kind of thing that can be socially disadvantageous," Dr Kane said.

"What we hope is that with treatment, it will subside," he noted, adding that in some cases, a patient may have to continue treatment long term, but that "it will probably vary from patient to patient."

On the basis of the strength of the phase 2 and phase 3 Kinect trial evidence supporting valbenazine, investigators have now submitted the drug for US Food and Drug Administration (FDA) approval.

In a significant departure from the standard drug approval process, investigators are only required to submit one phase 3 trial, the Kinect 3, for FDA consideration, owing to the fact that there is no other therapy for the treatment of the disorder.

The study was funded by Neurocrine Biosciences, Inc. Dr Josiassen has disclosed no relevant financial relationships. Dr Kane has served as a consultant to Neurocrine Biosciences, Inc.

Institute of Psychiatric Services (IPS): The Mental Health Services 2016 Conference. Abstracts 16 and 17. Presented October 7, 2016.

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