Background

Brexpiprazole is an orally available dopamine receptor D2 partial agonist, and an atypical antipsychotic. This quinolinone derivative is a successor to aripiprazole (Abilify, Aripiprex), an approved, widely used drug that is also a dopamine D2 receptor partial agonist. Brexpiprazole is approved in the United States for the treatment of schizophrenia, and as an add-on therapy for depression. It was the first treatment approved for agitation associated with dementia in patients with Alzheimer's disease. In addition, it is being tested in people with bipolar and post-traumatic stress disorder.

In preclinical work with transgenic mouse models of AD, brexpiprazole reduced agitation-like behaviors including attacking intruder mice and nighttime activity (Amada et al. 2024).

Findings

In July 2013, Otsuka and Lundbeck started a Phase 3 study in the U.S., Europe, and Russia to evaluate brexpiprazole for the treatment of agitation in 560 patients with moderate to severe Alzheimer's dementia living in an institution or with a caregiver at home. The trial compared safety, efficacy, and tolerability of three months of 0.5, 1, and 2 mg of brexpiprazole or placebo once daily. The primary endpoint was change on the Cohen-Mansfield Agitation Inventory, but the trial also measured changes in aggression, global clinical status, and quality of life. In April 2015, this trial dropped the 0.5 mg dose and continued with a target enrollment of 420 patients. The trial offered a two-month safety follow-up study.

In September 2013, a second Phase 3 trial started enrolling an anticipated 230 patients. This trial explored brexpiprazole using a flexible dose titrated between 0.5 and 2 mg/day depending on efficacy and tolerability in a given patient, but is otherwise identical. In June 2014, Otsuka added a two-month follow-up study for participants in either of these two trials.

Top-line results of both trials were announced in May 2017 (see press release); more details were presented at the meeting of the American Association of Geriatric Psychiatry in March 2018 (press coverage). Results were later published after peer review (Grossberg et al., 2020). In the fixed-dose trial, patients on 2 mg daily were reported to have shown statistically significant improvement over placebo on the CMAI after three months. In the flexible-dose trial, the change in CMAI missed significance. A post hoc analysis of only the 2 mg/day group found a significant improvement in the CMAI compared to placebo. The full study group showed improvement on the Clinical Global Impression-Severity of Illness (CGI-S), a secondary measure of agitation.

Common adverse events were insomnia, residual agitation, and drowsiness in some patients. The investigators noted variability in data from different countries, which might be related to differences in standard of care. Patients in the U.S. responded well; patients from Russian sites did not.

Following discussions with the FDA, the sponsors started two new Phase 3 trials in 2018. In May, they initiated a three-month trial testing 2 and 3 mg daily doses of brexpiprazole or placebo in 345 Alzheimer's patients with agitation and aggression in the U.S. and Europe. In August, a similar trial started in Japan; it planned to treat 407 patients with 1 or 2 mg brexpiprazole per day or placebo for 10 weeks. For both, the primary endpoint is the change from baseline in CMAI at three months. The secondary endpoint is change in CGI-S. To monitor safety, the U.S. study offered a 12-week extension, the Japanese study a 14-week extension. The U.S. trial finished in June 2022, and met its primary endpoint. According to results presented at the 2022 CTAD conference (Dec 2022 conference news), either dose of brexpiprazole or placebo substantially reduced CMAI scores, but the drug did slightly better. The same pattern held for the key secondary endpoint, CGI-S. Brexpiprazole was generally well-tolerated and safe, with no increase in adverse events in treated patients compared to placebo. It was not sedating. There were more deaths in the treatment groups than placebo across three Phase 3 studies, but none were deemed related to drug. The companies planned to file for FDA approval by the end of 2022. Trial results were published after peer review (Lee et al., 2023; commentary by Ballard, 2023). In the 12-week open-label extension, the most common adverse events were headache and falls in a few percent of patients. Five severe adverse events included three severe falls. The average CMAI score improved by 9.1 points over 12 weeks (Behl et al., 2024). A safety analysis covering the entire 24-week treatment was presented at the October 2024 CTAD conference. Longer-term treatment with brexpiprazole was not associated with increased risk of adverse events. Most adverse events were mild to moderate and of short duration, expect for extrapyramidal symptoms, which were long-lived. Cardiovascular events were rare and occurred later in treatment. The analysis of patients in the extension trial may reflect those better able to tolerate the drug.

A subsequent analysis of adverse events reported, across indications, from 2015 to 2023 to the FDA Adverse Event Reporting System (FAERS) noted additional side effects (Jiang et al., 2024), whereas a meta-analysis of trial data found no adverse event signals but confirmed efficacy (Marinheiro et al., 2024).

On January 7, 2023, the company announced that brexpiprazole was granted priority review by the FDA for the treatment of agitation in Alzheimer's dementia. In April 2023, the FDA issued a briefing document that said the Phase 3 trials had provided substantial evidence of efficacy, and an outside advisory committee voted 9-1 in favor of approval (press release). On May 10, 2023, Rexulti was approved (May 2023 news). It carries a black box warning due to an observed increase in mortality associated with this class of antipsychotic agents in people with dementia (see Zhong and Cummings, 2024).

The study in Japan finished in May 2023, and results were published after peer review (Nakamura et al., 2024). Brexpiprazole 1 or 2 mg improved CMAI total scores after 10 weeks. Adverse events were mild to moderate, but occurred with a higher incidence in this population compared to previous studies. For all trials of brexpiprazole, see clinicaltrials.gov.

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