Exploring the Role of Brexpiprazole in Alzheimer Dementia Agitation

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TRANSLATING RESEARCH INTO PRACTICE

Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor

This is the first of a monthly column dedicated to reviewing the literature and sharing clinical implications.

In May 2023, brexpiprazole (Rexulti) became the first medication to receive supplemental approval from the FDA for the treatment of agitation associated with dementia due to Alzheimer disease (AD). Its effectiveness for this indication was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies.

This particular study was chosen as it is the second of the 2 studies that evaluated its effectiveness for treatment of agitation associated with dementia due to AD; it was recently published in a leading scientific journal.

Study

Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. Published online November 6, 2023.¹

Study funding

Otsuka Pharmaceutical Development & Commercialization, Inc; and H. Lundbeck A/S

Study objectives

To determine the efficacy, safety, and tolerability of brexpiprazole for the treatment of agitation in patients with AD.

Methodology

This study was a 12-week randomized, phase 3, double-blind, placebo-controlled trial that ran from May 2018 to June 2022. Patients were screened at 123 AD clinical trial sites in Europe and the United States.

There were 3 requirements to meet the diagnosis of AD: (1) diagnosis based on National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria; (2) screening and baseline Mini-Mental State Examination scores between 5 and 22; and (3) brain imaging consistent with an AD diagnosis.

To meet the definition of agitation, the requirements included meeting the International Psychogeriatric Association definition for agitation, onset of symptoms at least 2 weeks prior to screening, an agitation/aggression score of 4 or greater on the Neuropsychiatric Inventory (NPI) or NPI–Nursing Home Version (NPI-NH) at screening and baseline, and positive Cohen-Mansfield Agitation Inventory (CMAI) factor 1 criteria.

Other key inclusion criteria included age of 55 to 90 years, the need for pharmacotherapeutic intervention based on investigator judgment, living in a community-based setting or care facility, and having an identifiable caregiver. Pertinent exclusion criteria included memory impairments due to reasons other than AD and clinically significant and symptomatic neurological, psychiatric, or other unstable medical comorbidities.

Participants were randomly assigned using a computer model to the brexpiprazole and placebo arms in a 2:1 ratio. Individuals in the brexpiprazole arm were further randomly assigned to receive 2 or 3 mg/day of medication in a 1:2 ratio. Participants, caregivers, investigators, and sponsors were blinded to randomization. Study drugs were administered at the same time once per day, and patient’s visited clinical trial sites once every 2 weeks for progressive assessment.

Efficacy was measured by change in CMAI total scores from baseline to week 12, the clinician-rated Clinical Global Impression Severity of illness (CGI-S) and Improvement (CGI-I) scales specifically applied to agitation, and the NPI-NH. Safety was assessed by treatment-emergent adverse events (TEAEs), routine vital signs, weights, laboratory testing, the Sheehan Suicidality Tracking Scale, the MMSE, and 3 extrapyramidal symptom scales.

Study Results

A total of 345 participants at 68 sites across 7 countries (United States, Ukraine, Bulgaria, Serbia, Slovakia, Spain, and Hungary) enrolled. Participants were randomly assigned as follows: 75 to brexpiprazole 2 mg/day, 153 to brexpiprazole 3 mg/day, and 117 to placebo. Two participants in the brexpiprazole 2-mg group and 1 in the placebo group did not receive treatment and were not included in the safety and efficacy samples.

Baseline demographic and clinical characteristics were similar across the groups. The mean age was 74.5 years in the brexpiprazole group and 73.0 years in the placebo group. A total of 93.9% of participants in the brexpiprazole group and 98.3% in the placebo group were White.

Study completion rates were 88.9% in the placebo group and 86.8% in the brexpiprazole groups (90.7% and 85.0% for the brexpiprazole 2-mg/day 3-mg groups, respectively). Discontinuation rates due to adverse events were 4.3% in the placebo group and 5.3% in the brexpiprazole groups (1.4% and 7.2% in the brexpiprazole 2-mg and 3-mg groups, respectively.

The mean difference in CMAI total scores at week 12 was –22.6 from baseline in the brexpiprazole groups, whereas the placebo group had a change of –17.3 from baseline (difference of −5.32; 95% CI, −8.77 to −1.87; P = .003; effect size = 0.35). All other secondary efficacy end point measures (CGI-S, CGI-I, CMAI subscale scores and response rates, and NPI-NH) also showed statistically significant greater improvement in the brexpiprazole group compared with placebo.

For the CGI-S score as related to agitation, there was a mean difference of –1.2 for the brexpiprazole group compared with a –0.9 mean difference in the placebo group (difference of –0.27; 95% CI, –0.47 to –0.07; P = .008; effect size = 0.31).

However, when looking at the brexpiprazole subgroups, only the 3-mg group showed statistically significant improvement in the CGI-S score. The CGI-I mean score for the brexpiprazole group at the end of 12 weeks was 2.7, whereas the placebo group had a mean score of 3.0 (difference of –0.33; 95% CI, –0.57 to –0.09; P = .007). The NPI-NH total score in the brexpiprazole group showed a mean difference of –17.3 from baseline compared with –12.7 for placebo (difference of –4.60; 95% CI, –7.33 to –1.88; P = .01; effect size = 0.39).

Less than half (40.7%) of participants reported at least 1 TEAE in the brexpiprazole group vs 31% in the placebo group. The TEAEs with an incidence of greater than or equal to 2% occurred with more frequency in the brexpiprazole vs placebo group (Figure).

Figure. Percentage of TEAEs in Brexpiprazole vs Placebo

The mean change in body weight was +0.3 kg for the brexpiprazole group; there was no mean change in body weight in the placebo group.

Rates of weight gain of 7% or more from baseline were 1.5% in the brexpiprazole group and 0.0% in the placebo group. Rates of weight loss of 7% or more from baseline were 1.0% for both the brexpiprazole and placebo groups.

Conclusions

Evidence from this high-quality, 12-week randomized, double-blind, and placebo-controlled trial indicated that brexpiprazole at fixed doses of 2 or 3 mg/day is more efficacious than placebo at reducing agitation associated with AD. Similarly, brexpiprazole at these doses is well tolerated.

Practical Applications

Among older adults who exhibit agitation associated with AD, brexpiprazole is an efficacious and well-tolerated treatment option. Based on this trial’s data and the published data from 1 of the 2 prior trials,³ brexpiprazole was the first medication to receive FDA approval for the treatment of agitation associated with dementia due to AD.

Bottom Line

This high-quality phase 3 trial indicated that brexpiprazole (at 2 and 3 mg/day) is more efficacious than placebo in treating AD-associated agitation over 12 weeks. Brexpiprazole was generally well tolerated when compared with placebo; headache was the most commonly reported adverse effect in both groups. Brexpiprazole was also associated with a mild increase in sedation and no statistically significant difference in weight gain or extrapyramidal symptoms.

Dr Allen and Dr Dickan are second-year psychiatry residents at Creighton University School of Medicine in Omaha, Nebraska. Dr Woo is a first-year psychiatry resident at Creighton University. Dr Mullen is a fourth-year psychiatry resident at Creighton University. Dr Tampi is professor and chairman in the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut.

References

1. Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. 2023:e233810. 

2. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-12.

3. Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400.