Rexulti Calms Alzheimer's Dementia-Related Agitation

NEW ORLEANS -- Brexpiprazole (Rexulti) helped ease agitation in people with Alzheimer's dementia, according to a phase III study.

Over the course of the 12-week trial, patients on either a 2-mg or 3-mg daily dose of the atypical antipsychotic saw a significant improvement in total Cohen-Mansfield Agitation Inventory (CMAI) score versus placebo (treatment difference of -5.32, 95% CI -8.77 to -1.87, P=0.0026), reported George T. Grossberg, MD, of St. Louis University School of Medicine in Missouri, and colleagues.

Patients on either dose of brexpiprazole saw an average 22.6-point drop in CMAI total score by week 12 versus a 17.3-point drop seen with placebo, meeting the study's primary endpoint. The change was significantly different from placebo by week 8 of treatment, Grossberg's group stated in a poster at Psych Congress 2022.

In a separate poster, researchers assessed brexpiprazole as a treatment for symptoms of borderline personality disorder (BPD), and found less encouraging results.

Alzheimer's Agitation

There is currently no FDA-approved treatment specifically indicated for Alzheimer's-related agitation. Acting as a dopamine D_₂ receptor partial agonist, brexpiprazole is approved as adjunctive treatment for major depressive disorder in adults, and for schizophrenia in adults and adolescents (ages 13 years and older). The agent's label carries a boxed warning for possible increased risk of death in elderly people with dementia-related psychosis.

For the current trial, 225 patients (average age 74; vast majority white) were randomized to brexpiprazole (73 for the 2-mg dose and 152 for the 3-mg dose), while 116 patients were assigned to placebo. All lived in a care or community-based facility, and had probable Alzheimer's disease as defined by the NINCDS-ADRDA diagnostic criteria.

At baseline, participants had a Mini Mental State Examination (MMSE) score between 5 and 22; met the agitation criteria defined by the International Psychogeriatric Association's criteria and the Cohen-Mansfield Agitation Inventory Factor 1; and had a score of 4 or higher on the Neuropsychiatric Inventory for Agitation/Aggression.

The average time since Alzheimer's diagnosis was 34 months for placebo and 37 months for brexpiprazole, and the average time since the first episode of agitation was 21.5 months and 24.2 months, respectively. A little more than half of participants scored moderately on the MMSE, while about 23% and 20% had mild and severe cognitive impairment, respectively.

The researchers reported that headache was the only adverse event (AEs) in 5% or more of patients (6.9% of placebo vs 6.6% of brexpiprazole). Other AEs reported in 2% to 5% of patients on treatment included nasopharyngitis, urinary tract infection, dizziness, somnolence, and diarrhea.

Looking at some other AEs of interest in this older patient population, incidence of sedation, falls, akathisia, extrapyramidal disorder, or weight gain of 7% or more was reported in less than 2% of patients on brexpiprazole. Only one death occurred in the 3-mg brexpiprazole group, but was deemed unrelated to the study drug.

Most participants completed the 12-week trial (88.9% of placebo; 86.8% of brexpiprazole), according to the researchers.

The trial also met a key secondary endpoint -- change from baseline in Clinical Global Impression-Severity of Illness (CGI-S) score as related to agitation. This was marked by a 0.93-point drop in placebo versus a 1.22-point drop seen with brexpiprazole (treatment difference -0.29, 95% CI -0.5 to -0.09, P=0.0055). Likewise, this improvement was statistically significant by week 8 of treatment.

All three CMAI subscale scores were also significantly better with either dose of brexpiprazole versus placebo at week 12:

• Aggressive subscale score: -7.13 for placebo vs -9.09 for brexpiprazole
• Physically non-aggressive: -5.04 vs -6.45
• Verbally agitated: -3.14 vs -4.39

When the doses were separated, both the 2-mg and 3-mg groups showed significant symptom improvement at the same time.

Developers Otsuka Pharmaceutical and Lundbeck announced plans to submit a supplemental new drug application to the FDA seeking this additional indication later this year.

"We think that the effective dose is 2 mg," Pedro Such, MD, lead senior medical advisor for co-developer Lundbeck, told MedPage Today.

"We mostly tested the 3-mg dose for safety and durability, and we see that the efficacy is the same," he added. "We think that it is good enough with 2 mg."

BPD

BPD does not have any treatments specifically indicated for the disorder, and outpatient psychotherapy is the most common therapy.

In a phase II trial, brexpiprazole failed to improve symptoms associated with the personality disorder, reported Brian Rothman, PhD, of Otsuka in Princeton, New Jersey, and colleagues.

The trial randomized 324 patients (ages 18-65) with DSM-5-diagnosed BPD to either 2 mg or 3 mg per day of brexpiprazole (n=159) or placebo (n=165).

Treatment with brexpiprazole wasn't significantly better at improving average Zanarini Rating Scale-BPD (Zan-BPD) total scores versus placebo at week 10 (-7.27 for brexpiprazole vs -6.25 for placebo, P=0.24), the researchers reported. And the average change from week 1 in CGI-S score was not significantly better with brexpiprazole at week 10 (secondary endpoint).

"However, brexpiprazole was associated with nominally significant improvements versus placebo at weeks 8 and 12 on the Zan-BPD and week 12 on CGI-severity," Rothman pointed out.