12 May 2023

Otsuka Pharmaceutical Co. Ltd. and Lundbeck LLC announced on May 10 that their D2 dopamine receptor agonist, brexpiprazole, aka Rexulti, had been approved by the U.S. Food and Drug Administration for the treatment of agitation associated with Alzheimer’s disease. The drug had met its primary endpoint, the Cohen-Mansfield Agitation Inventory, in two Phase 3 trials in the U.S. Another Phase 3 trial was completed in Japan.

Rexulti is the first drug approved for agitation in AD. The term refers to a group of common behavioral symptoms—pacing, gesturing, profanity, shouting, shoving, and hitting—that are difficult for caregivers to manage and can lead to patients being placed in nursing homes. Physicians often prescribe other drugs off-label to treat these symptoms, and clinicians generally welcomed the Phase 3 data when presented at CTAD last December (Dec 2022 conference news).

Brexpiprazole is a derivative of aripiprazole, aka Abilify, an atypical antipsychotic. As a group, such drugs have a sketchy track record in treating agitation in AD, and their side effects had prompted the agency to issue “black box” warnings (Steinberg and Lyketsos, 2012). 

The Rexulti label also warns of this but, overall, this drug seems to have a better safety profile than its predecessors, possibly because it also modulates signaling through noradrenaline and certain serotonin receptors. Phase 3 data presented last year indicated that the drug was generally well-tolerated and safe. While more people died in the treatment group than in the placebo group, these deaths were deemed unrelated to the drug.

Aripriprazole is already approved for major depressive disorder and schizophrenia.—Tom Fagan