Schizophrenia Drug Reduces Alzheimer's-Related Agitation

Deborah Brauser

March 19, 2018

HONOLULU, Hawaii — The atypical antipsychotic brexpiprazole (Rexulti, Otsuka and Lundbeck) is safe and effective for treating agitation in patients with dementia related to Alzheimer's disease (AD) — at least at its highest dose, new research suggests.

Findings from two phase 3 trials, with a total of nearly 700 adult participants, were presented here at American Association for Geriatric Psychiatry (AAGP) 2018. Although topline results were released last year, this was the first presentation of the details.

The first randomized controlled trial assessed flexible dosing of brexpiprazole at 0.5 mg to 2 mg per day vs placebo. Improvement in total score on the Cohen-Mansfield Agitation Inventory (CMAI) between baseline and 12 weeks (the primary endpoint) was not significantly different between the two treatment groups.

However, post hoc subgroup analyses of just those who received the study drug at 2 mg/day did show a significantly greater improvement in CMAI score over those who received placebo.

The full study-drug group also demonstrated significant superiority on the "key" secondary endpoint of Clinical Global Impression–Severity of Illness (CGI-S) score, as related to agitation.

The second trial, which compared brexpiprazole at a fixed dose with placebo, met the primary endpoint. Those receiving the study drug at 2 mg/day had a significantly greater improvement in CMAI score.

Overall, the findings "show that the higher dose works," coinvestigator George T. Grossberg, MD, Department of Psychiatry and Behavioral Neuroscience at Saint Louis University, Missouri, told Medscape Medical News.

Dr George Grossberg

Otsuka and Lundbeck recently announced that, on the basis of talks with the US Food and Drug Administration (FDA), they will initiate a third phase 3 study during the first half of 2018 that will focus on the higher dose.

"In about a year we'll start having data. If and when that happens, this will be the first compound to receive FDA approval for agitation in absence of psychosis in Alzheimer's," said Grossberg.

Differences in Compounds

As reported by Medscape Medical News, the FDA issued a warning in 2016 about the atypical antipsychotic aripiprazole (Abilify, Otsuka), noting that its use was associated with problems concerning impulse control.

Asked about similarities between the two drugs, Grossberg said that brexpiprazole, a serotonin-dopamine activity modulator, has a different mechanism of action.

"The scientists who developed aripiprazole went back to the laboratory, took the chemical moiety, and tweaked it to configure the compound so that it doesn't have the agitation, the akathisia, the impulsivity," he reported.

"It's different dosing and a different compound, but obviously it has similarities to the parent compound," he said.

The antipsychotic is a partial agonist at serotonin 5-HT1A and dopamine D2 receptors and is an antagonist at serotonin 5-HT2A and noradrenaline receptors, "all at subnanomolar potency," note the investigators.

"It is hypothesized that the partial agonist and antagonist activities of brexpiprazole at multiple serotonergic, dopaminergic, and noradrenergic receptor systems may have a therapeutic benefit" in AD-related agitation, they write.

The FDA approved brexpiprazole in July 2015 as a treatment for schizophrenia and as an adjunctive treatment with an antidepressant for major depressive disorder. Health Canada and the Department of Health in Australia approved it for the treatment of schizophrenia in 2017.

"It is estimated that agitation symptoms affect nearly 50% or more of patients with [AD] observed over a multiyear period," reported the manufacturers in a recent press release.

However, currently no drugs are indicated for the treatment of agitation, so "clinicians use multiple classes of compounds with limited empirical data and no instructions for use," write the researchers.

"This is the first time we've presented these data," noted Grossberg regarding the new studies. Participants in both were between the ages of 55 and 90 years, had been diagnosed as having probable AD, and had symptoms of agitation.

Flexible Dosing

In the flexible-dosing trial, 270 patients from 62 sites in the United States, Canada, and Europe were randomly assigned to receive either brexpiprazole (n = 133; mean age, 73.5 years; 62% women) or matching placebo (n = 137; mean age, 74.0 years; 64% women) for 12 weeks.

For both groups, the starting dose was 0.25 mg/day on days 1 to 3. The dose was then titrated to 0.5 mg/day on days 4 to 14 and to 1 mg/day during weeks 3 and 4, although the dose could be decreased to 0.5 mg/day during the latter period if needed. Dosing at 2 mg/day could be initiated the day after the week 4 visit.

"After week 4, dose decreases and increases had to occur in a stepwise manner and could occur at any time," write the investigators. At end of study, the mean daily dose was 1.54 mg.

Results showed that the mean change from baseline on the CMAI total score was "numerically favorable" but not significantly different between the brexpiprazole 0.5 - 2 mg/day group and the placebo group at 12 weeks (P = .15). The treatment group's score change was statistically superior at 8 and 10 weeks (P = .01 and P = .04, respectively).

For the subgroup of patients who received active treatment titrated to 2 mg (n =77), there was a significantly greater change on the CMAI total score vs those who received equivalent placebo (n = 74) at 6, 8, 10, and 12 weeks (for all, P = .01).

Compared with the group that received placebo, improvement on the CGI-S score was significantly greater at 12 weeks for the 0.5 - 2 mg/day group (P = .02) and for the group that received active treatment titrated to 2 mg/day (P < .001).

There were no significant between-group differences in incidence of treatment-emergent adverse events (TEAEs), results of physical and neurologic examinations, vital signs, and results on clinical laboratory tests.

The most commonly reported TEAEs in the active-treatment group were headache (7.9% vs 12.7% of the placebo group), somnolence (6.3% vs 3.7%, respectively), and dizziness (4.7% vs 5.2%).

"Overall, brexpiprazole was safe and well tolerated in AD patients with agitation; no new safety signals were observed," write the investigators. They add that the 2-mg/day dose "may be an effective, safe, and well-tolerated new treatment" for agitation.

Improved Quality of Life?

The second, bigger trial was designed to compare groups receiving brexpiprazole 2 mg/day (n = 140) or 1 mg/day (n = 137) by week 4 with a group receiving matching placebo (n = 136).

The participants were enrolled at 81 sites in seven countries – the United States, Spain, Germany, Croatia, Serbia, Russian, and the Ukraine – between July 2013 and March 2017.

Results showed that the 2-mg/day group had a significantly greater improvement on the CMAI total score at 12 weeks than the placebo group (P = .04), but the 1-mg/day group did not.

Although change from baseline to week 12 on the CGI-S score was greater in the 2-mg/day group (-1.27 vs -1.11, respectively), it was not significantly different from the group that received placebo (P = .16).

Incidence of TEAEs and discontinuations were less than 10% in all groups. The most commonly reported TEAEs were headache (8.4% of all patients who received brexpiprazole vs 8.1% of patients who received placebo), insomnia (3.4% vs 1.5%, respectively), and dizziness (3.0% vs 3.0%).

"Up until these studies began, the FDA did not recognize agitation as a therapeutic endpoint in Alzheimer's disease, especially in the absence of psychosis. Eventually they became convinced that there was something to it, and this is the first compound to directly address this," said Grossberg.

"If we had something that was approved, that was safe and effective, it would improve patient quality of life and the quality of life of family caregivers. And if in long-term care, it could improve quality of life in nurses and other professional carers. It could be huge," he added.

Unique Situation

Asked to comment, Roknedin Safavi, MD, psychiatrist and director of the transcranial magnetic stimulation program at the Center for Healthy Aging, Danvers, Massachusetts, told Medscape Medical News that the studies showcase "a unique situation.

"You're looking at agitation as the target symptom, and not as a secondary thing, and looking to approve a compound for that purpose," said Safavi. "Right now we don't have anything officially sanctioned for that reason, but it's a daily issue for us to deal with."

He noted that he's concerned with the study drug's relationship with aripiprazole because of the recent warnings.

"But with all the limitations, what's out there right now is driving the practice because that's all you have. In that respect, it's good to see continued work, continued data gathering, and, eventually, newly sanctioned tools," said Safavi.

The studies were funded by Otsuka Pharmaceutical Development and Commercialization and H Lundbeck A/S. Dr Grossberg serves as a consultant to Lundbeck, Otsuka, Acadia, Allergan, Avanir, Axona, GE, Genentech, Novartis, Roche, and Takeda; has received research support from Janssen and the National Institute on Aging; has been on the speaker's bureau for Acadia; and has been on safety monitoring committees for EryDel, Merck, and Newron. Dr Safavi has disclosed no relevant financial relationships.

American Association for Geriatric Psychiatry (AAGP) 2018. Abstracts LB-12 and LB-13, presented March 17, 2018.

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