Positive Long-term Results for Tardive Dyskinesia Drug

Deborah Brauser

April 03, 2018

HONOLULU, Hawaii — Valbenazine (Ingrezza, Neurocrine Biosciences) is safe and effective over the long term as a treatment for tardive dyskinesia (TD) in older patients, new research suggests.

Dr Martha Sajatovic

Further results from the KINECT 3 and KINECT 4 phase 3 trials were presented here at a poster session at American Association for Geriatric Psychiatry (AAGP) 2018.

In open-label extensions, pooled analyses of more than 200 patients aged 55 years and older with TD showed that those who received valbenazine 40 mg/day and 80 mg/day experienced significant improvements between baseline and week 48 of treatment, as reflected in scores on the Abnormal Involuntary Movement Scale (AIMS), the Clinical Global Impression of Change-TD (CGI-TD), and the Patient Global Impression of Change (PGIC).

Analyses that combined data for both dosing groups showed that the medication "was reasonably well-tolerated," note the investigators. Although 74% of the patients reported having any treatment-emergent adverse event (TEAE), only 19% had a TEAE that led to discontinuation of treatment.

The most common adverse events were headaches and urinary tract infections. There were no significant changes in movement disorder scores, in vital signs, or in electrocardiogram (ECG) readings.

"I think the take-home message is that people maintained their clinically meaningful differences in efficacy," coinvestigator Martha Sajatovic, MD, University Hospitals Case Medical Center, Cleveland, Ohio, told Medscape Medical News.

She noted that the goal of any open-label extension study is to see that patients "aren't falling off the wagon or getting worse or relapsing," and that was achieved in this study. There was a drop in efficacy after a 4-week drug washout, "which was expected.

"In some ways, I'd say the safety is even more important than the efficacy in these findings," because efficacy has already been proven," said Sajatovic. Because of the positive long-term safety results, physicians don't need to cut off the drug for their patients, she added.

"You don't have to be fearful or steer older people away from being treated with this medication," she said.

FDA Approved

Valbenazine is a highly selective vesicular monoamine transport 2 (VMAT2) inhibitor. It was approved by the US Food and Drug Administration (FDA) in April 2017 for the treatment of TD in adults.

Valbenazine and deutetravenazine (Austedo, Teva), which the FDA approved in August 2017, are the only drugs indicated for this treatment.

The approval for valbenazine was based on several studies, including the KINECT trials. Previously released results showed that the medication, taken once daily, improved TD after 6 weeks of use in both younger adults and those older than 55 years.

However, "compared to younger adults, older adults may be particularly susceptible to developing [TD] after a shorter duration of treatment with dopamine receptor blocking agents (DRBAs), such as antipsychotics," write the investigators. Therefore, they wanted to assess long-term effectiveness and safety in both age groups.

Because patients with schizophrenia or bipolar disorder may have a shortened life span, "an age of ≥55 years may be considered 'older' in this population," the researchers note.

"The rationale is that people who have serious mental illness, where they're typically prescribed antipsychotic drugs, lose about 1 to 2 decades of life on average compared to the general population," added Sajatovic.

"If you only enrolled people 65 or older, which is typically the case when talking about elderly in a general population, what you would have is a subgroup of healthy survivors, which would totally bias your data. That's why we thought it was reasonable to use that 55 and older group, even though chronologically, they're not considered elderly in many situations."

"Consistent, Clinically Meaningful"

In the effectiveness analysis, data were pulled from the KINECT 3 trial (which randomly assigned patients with TD to 6 weeks of treatment with the study drug at 40 or 80 mg or to placebo, followed by a 42-week extension) and from the open-label KINECT 4 trial (which randomly assigned patients to receive either valbenazine at 40 or 80 mg/day for 48 weeks).

Among the inclusion criteria were a prior clinical diagnosis of schizophrenia, schizoaffective disorder, or a mood disorder (but currently deemed "psychiatrically stable") and a diagnosis of moderate or severe DRBA-induced TD of at least 3 months' duration before screening.

Patients were divided by age at baseline. Those considered "younger" were aged less than 55 years (n = 167); those considered "older" were at least 55 years of age (n = 262). Patients were also divided into low-dose (40 mg/day) and high-dose (80 mg/day) subgroups.

Efficacy was assessed at week 48 (end of treatment) and at week 52, which was the end of a 4-week washout period. Outcome measures included improvement/reduction from baseline on the total score of the AIMS; treatment "response," defined as an AIMS total score improvement from baseline of at least 50%; and improvement on the CGI-TD and PGIC.

Mean baseline AIMS total score was 11.0 for the younger group taking valbenazine at 40 mg and 12.2 for those taking the 80-mg dose; it was 10.9 and 12.9 for the older group at each dose, respectively.

At both doses, both age groups showed significant improvement in AIMS total scores at week 48. There were no significant differences between the ages:

  • Younger group at 40 mg: -3.8; at 80 mg: -6.9

  • Older group at 40 mg: -5.4; at 80 mg: -8.7

"Some loss of improvement was found at week 52...in both subgroups," report the investigators. At the end of the washout period, the scores were -1.3 and -2.7 for the younger group at 40 and 80 mg, respectively, and -2.4 and -3.3 for the older group. More than 65% of the patients who received the 80-mg dose demonstrated an AIMS response at week 48:

  • Younger group at 40 mg: 31.3%; at 80 mg: 68.0%

  • Older group at 40 mg: 52.1%; at 80 mg: 73.7%

Again, the percentage of those who showed a response decreased by week 52 to 12.5% and 28.6% of the young group and 27.1% and 28.4% of the older group.

The same pattern was found for CGI-TD and PGIC mean scores. There were significant improvements at week 48 and some loss of effect during washout, as shown in the following table.

Table 1. Outcomes by Age, Dose, and Time of Assessment

Subgroup CGI-TD – Week 48 CGI-TD – Week 52 PGIC – Week 48 PGIC – Week 52
<55 yr, 40 mg 2.4 3.2 2.2 2.7
<55 yr, 80 mg 1.9 3.0 1.9 2.7
>55 yr, 40 mg 2.1 3.3 1.9 2.6
>55 yr, 80 mg 1.8 3.3 1.9 2.7

 

In their analysis, the investigators assessed CGI-TD and PGIC response (defined as "much" or "very much" improved). CGI-TD response was achieved by 57.6% and 86.3% of the younger group at 40 and 80 mg, respectively, and by 72.9% and 85.3% of the older group.

PGIC response was achieved by 69.7% and 82.4% of the younger group and 77.1% and 83.2% of the older group.

"Consistent, clinically meaningful TD improvements occurred" in both age groups at week 48, write the researchers. Because of the loss of effect after washout, "patients may require ongoing therapy with valbenazine to maintain TD improvements," they add.

Safety, Tolerability

A separate poster was presented on safety and tolerability at 48 and 52 weeks in the same trial participants.

Measures included the Barnes Akathisia Rating Scale (BARS) and Simpson-Angus scale (SAS) for assessing movement disorders, as well as the Positive and Negative Syndrome Scale, the Calgary Depression Scale for Schizophrenia, the Young Mania Rating Scale, the Montgomery-Åsberg Depression Rating Scale, and the Columbia-Suicide Severity Rating Scale. In addition, vital signs were assessed, and the patients underwent an ECG.

TEAEs were also evaluated in pooled analyses of these patients and those from the first KINECT trial. The latter trial assessed valbenazine 50 mg or placebo for 6 weeks or the medication at 100 mg for 2 weeks and then at 50 mg for 4 weeks. All patients could then participate in an additional 6-week open-label extension at the 50-mg dose.

There were significant differences between the age subgroups for any TEAE (P = .002), any serious TEAE (P = .01), and any TEAE leading to discontinuation (P = .01).

These findings, which are shown in more detail in the table below, "may be due to various factors associated with aging (eg, changes in metabolism, multiple comorbidities, [and] chronic exposure to multiple medications including antipsychotics)," write the investigators.

"This would be in line with what you might expect, as older people usually have more side effects," Sajatovic added.

Table 2. Safety Outcomes by Age Group

Outcome <55 Years (%) ≥55 Years (%)
Any TEAE 59.3 73.7
Any serious TEAE 9.6 18.7
Any TEAE leading to discontinuation 10.2 19.1
Any TEAE leading to death 0.6 0.8

The most common TEAS in both age groups were headaches (in 6.6% and 8.8% of each, respectively), urinary tract infections (in 6.6% and 8.4%), and somnolence (in 5.4% and 7.3%). No specified TEAE occurred in more than 10% of either subgroup.

In addition, "mean changes in psychiatric scale scores indicated that schizophrenia and mood symptoms generally remained stable," the researchers report. Mean score changes at week 48 and week 52 on the BARS and SAS "were minimal."

"In both subgroups, more than 90% had no suicidal ideation at baseline and continued to not have any," reported Sajatovic.

"There were a minority of people that had some worsening of suicidal ideation [4.9% vs 6.2%], but it's not a significant difference between the older vs the younger people. And I'm not sure how much clinical relevance that has because of the bias you have when dealing with people with mental illness," she said.

There were no clinically important biological differences in laboratory values or ECG.

"This type of long-term safety data is particularly helpful for people that are in clinical practice," Sajatovic said.

As for efficacy, "It's great to know you can see changes short-term, but we wanted to know if that's sustained for the long term, which it was. Most clinicians treat for the long haul."

No Worsening of Psychiatric Symptoms

Commenting on the findings for Medscape Medical News, Joseph M. Pierre, MD, health science clinical professor at the David Geffen School of Medicine at the University of California, Los Angeles, said that these longer-term data are "a new addition in terms of our current state of knowledge" in the treatment of TD.

Dr Joseph Pierre

He noted that when the short-term efficacy results were first released, he thought they were "fairly modest," but the extended findings, showing that the degree of improvement increased, "was nice to see."

"It looks like the amount of benefit one might be able to get from this medication is larger," said Pierre, who is also chief of the Hospital Psychiatry Division at the West Los Angeles VA Medical Center. He was not involved with the current research.

Pierre noted that the other big question about the drug was its tolerability and safety, specifically, exacerbation of psychiatric symptoms, which has been a problem with other VMAT2 inhibitors.

"So it was also good to see, in terms of longer-term data, that psychiatric symptoms were not worsened over the course of basically a year's worth of treatment," he added.

However, he said the decrease in efficacy found after discontinuing the medication was interesting, as was "what looks like a tiny blip showing that depressive symptoms might worsen" after a washout.

"That's a little bit of a concern and kind of highlights the idea that discontinuing the medication is something clinicians will have to do rather carefully," he said.

A Reawakening in the Field?

Asked what it means to the field to now have two medications approved for treating TD, Pierre said, "the more options we have, the better. I think the data we have now are really encouraging."

However, he added that to his knowledge, the only long-term data that have been released are for valbenazine.

Before the FDA approvals, there weren't really any options for treating TD, he said.

"Clinicians in the past resorted to tapering or discontinuing antipsychotics. But when you're talking about treating schizophrenia, that often isn't possible. The only other option [at that time] that showed potential efficacy was clozapine, which has more than its share of side effects," he said.

"With that backdrop, the idea that we now have pretty encouraging short-term and long-term data of a medication, and perhaps a class of medication, that can have an impact on tardive dyskinesia is pretty big."

He added that in the past, TD was likely underdiagnosed because there were no good treatment options.

"I think this will lead to a reawakening in the detection and screening of [TD]. And it certainly argues for greater use of this class of medication," concluded Pierre.

The analyses were funded by Neurocrine Biosciences. Dr Sajatovic has been a consultant for Neurocrine, Bracket, Otsuka, Sunovion, Supermus, and Health Analytics. She has also received research grants from Otsuka, Merck, Alkermes, Janssen, Reuter Foundation, Woodruff Foundation, Reinberger Foundation, National Institutes of Health, and the Centers for Disease Control and Prevention and royalties from Springer Press, Johns Hopkins University Press, Oxford Press, and UpToDate. Dr Pierre has disclosed no relevant financial relationships.

American Association for Geriatric Psychiatry (AAGP) 2018 Annual Meeting. Abstracts NR-30 and NR-32, presented March 17, 2018.

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