Prevalence of Alzheimer Disease Worldwide & In Asia Pacific
Alzheimer disease (AD) [1] is the leading cause of cognitive impairment, a neurological condition affecting the elderly (aged 65 and above) in terms of language, memory, comprehension, attention, judgment, and reasoning. The global prevalence of dementia [2] is reported to be as high as 44 million and is predicted to increase 4 times by the year 2050. In the Asia Pacific region alone, the proportion of people with dementia is similarly expected to triple by 2050.
FDA Approval of Brexipiprazole (Rexulti) for Agitation
Among patients with AD, agitation [3] is one of the primary aspects of care as it is, challenging. On 11 May 2023, the U.S. Food and Drug Administration [3] announced the supplemental approval of Rexulti (Brexpiprazole) oral tablets for the treatment of dementia-associated agitation caused by AD, marking the first FDA-approved treatment option for this indication.
Clinical Studies of Brexipiprazole: Efficacy End Points
The approval was based on two 12-week, randomized, double-blind, placebo-controlled trials [4]. In study 1, 433 patients were selected from 81 clinical sites in 7 countries. A fixed dose regime of brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) were given to randomized patients for 12 weeks. In study 2, 270 patients were selected from 62 clinical sites in 9 countries. A fixed dose regime of brexpiprazole 0.5−2 mg/day or placebo (1:1) were given for the same amount of time. The clinical results were measured using Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29−203; higher scores indicate more frequent agitated behaviours), and Clinical Global Impression − Severity of illness (CGI-S) as related to agitation.
In Study 1, the following are the key findings:
- Brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score over 12 weeks than placebo as well as better numerical improvement in CGI-S.
- Brexpiprazole 1 mg/day cohort’s results were not statistically significant to placebo
In Study 2, key findings are as below:
- Brexpiprazole 0.5−2 mg flexible daily dosing was not statistically superior over placebo in CMAI Total score.
- Post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day at week 4 showed superiority compared with similarly titrated placebo patients.
- CGI-S improved in Brexpiprazole 0.5−2 mg/day group over placebo
The adjusted mean change from baseline figures for both studies are attached below.
Figure 1 Primary endpoint in Study 1: effects of brexpiprazole on symptoms of agitation (CMAI Total).
Figure 2 Secondary endpoint in Study 1: effects of brexpiprazole on symptoms of agitation (CGI-S as related to agitation).
Figure 3 Primary endpoint in Study 2: effects of brexpiprazole on symptoms of agitation (CMAI Total) in a) total efficacy sample and b) subgroup titrated to 2 mg (or equivalent placebo) at Week 4 (post hoc analysis).
Figure 4 Secondary endpoint in Study 2: effects of brexpiprazole on symptoms of agitation (CGI-S as related to agitation) in a) total efficacy sample and b) subgroup titrated to 2 mg (or equivalent placebo) at Week 4 (post hoc analysis).
Clinical Studies of Brexipiprazole: Safety Profile
In terms of its side effect profile, in Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5−2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity.
Clinical Studies of Brexipiprazole: Conclusion
In conclusion, the results of these two clinical trials suggest that brexpiprazole 2 mg/day has the potential to be an efficacious, safe, and well-tolerated treatment for agitation in dementia with Alzheimer’s Disease. However, both clinical trials were limited to less than a thousand patients with potentially very limited patient cohorts. Once on the market, more data could be collected regarding its efficacy, side effects profile and potential long term usage.
Reference:
- Kumar A, Sidhu J, Goyal A, Tsao JW. Alzheimer Disease [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 May 9]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499922/#:~:text=Alzheimer%27s%20disease%20is%20a%20neurodegenerative
- Dementia in the Asia Pacific Region Dementia in the Asia Pacific Region [Internet]. 2014 Nov. Available from: https://www.alzint.org/u/Dementia-Asia-Pacific-2014.pdf
- Commissioner O of the. FDA Approves First Drug to Treat Agitation Symptoms Associated with Dementia due to Alzheimer’s Disease [Internet]. FDA. 2023 [cited 2023 May 17]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-agitation-symptoms-associated-dementia-due-alzheimers-disease
- Grossberg GT, Kohegyi E, Mergel V, Josiassen MK, Meulien D, Hobart M, 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. The American Journal of Geriatric Psychiatry. 2020 Apr;28(4):383–400.
