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Brexpiprazole (Rexulti) is effective for treating agitation associated with Alzheimer's dementia (AAD), but appears to carry the increased risk for death observed with other antipsychotics in elderly dementia patients, FDA staff said in ahead of a joint advisory committee meeting.

, the Psychopharmacologic Drugs Advisory Committee and the Peripheral and Central Nervous System Drugs Advisory Committee will consider an application for what could be the first-ever drug indicated for the common and challenging condition among patients with Alzheimer's dementia.

In phase III trials, brexpiprazole demonstrated "substantial evidence" of effectiveness for AAD, said FDA's reviewers, but collectively the studies also showed an imbalance in deaths versus the placebo groups.

The panelists will be asked to discuss whether there are populations of patients with AAD for whom the benefit/risk of brexpiprazole appears "acceptable" or conversely, "does not appear to be favorable."

In 2005, the FDA issued a boxed warning for all atypical antipsychotics based on a systematic meta-analysis that showed a 70% increased risk of death among elderly patients with dementia receiving antipsychotic treatment.

"Although there are currently no FDA-approved treatments for AAD, antipsychotics are still commonly prescribed off-label, despite the small effect sizes described in the current literature and the boxed warning for increased risk of mortality," FDA staff wrote. "Therefore, evidence-based treatments with favorable benefit/risk profiles are needed to address a serious unmet need in this patient population."

The committees will also discuss the risks with medications that are often used off-label for AAD, such as antiepileptics and benzodiazepines, which have no established evidence of efficacy.

"Given the lack of available treatment options and restrictions on the improper use of antipsychotics in elderly patients, the Agency aims to engage with the Committee to discuss brexpiprazole's clinical implications as a potential first-in-class product for the treatment of AAD, given the drug's benefit/risk profile," FDA staff wrote.

Brexpiprazole is currently approved for treating major depressive disorder (MDD) and schizophrenia. Support for the drug's application in AAD is based on evidence from three phase III studies, as well as one post-treatment observational study and an open-label extension safety study.

Results from two of the phase III studies that evaluated fixed doses found that brexpiprazole had a statistically significant treatment effect in reducing agitation over a 12-week treatment period, based on the Cohen Mansfield Agitation Inventory (CMAI). They also showed similar safety profiles relative to the treatment's use in adults with schizophrenia and MDD.

The third phase III study evaluated flexible-dose brexpiprazole and showed that the treatment did not achieve a statistically significant effect in mean change from baseline CMAI agitation score at 12 weeks.

However, in post-hoc exploratory analyses, researchers showed numerical improvement with brexpiprazole compared with placebo in the subgroup whose dosage was titrated from 0.25 mg to 2 mg/day over 4 weeks based on the participants' response and tolerability. Participants who did not require a dosage increase during the study period did not see any improvement with brexpiprazole over placebo, according to the FDA briefing document.

These additional "analyses of the AE [adverse events] data suggested no apparent dose-dependent trends and a similar overall incidence relative to adult subjects enrolled in studies for MDD and schizophrenia," FDA staff wrote.

Notably, across the three phase III studies, nine deaths occurred, including eight participants who received brexpiprazole (1.2%; n=655) and one placebo patient (0.26%; n=388), for an incident rate ratio of 4.16 (95% CI 0.51-33.83). Six of those deaths, including the placebo patient, occurred after the last dose but prior to 30-day follow-up.

"Risk of death associated with brexpiprazole ... follows a similar trend with the mortality risk estimated for other antipsychotics," FDA staff wrote. "Due to the evidence that the use of antipsychotics to treat dementia-related behavioral disorders (i.e., psychosis and agitation) results in higher mortality, the Boxed Warning should remain to adequately inform healthcare providers."

While the FDA typically follows the advice of its advisory committees, isn't required to do so.

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