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FDA advisors voted in favor of brexpiprazole (Rexulti) for treating agitation associated with Alzheimer's dementia (AAD), despite increased mortality risk.

By a vote of 9-1 on Friday, members of the agency's Psychopharmacologic Drugs Advisory Committee (PDAC) and the Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) said the data presented by the drug's sponsors, Lundbeck and Otsuka Pharmaceutical, were sufficient to identify a population in whom the benefits of treating AAD with brexpiprazole outweighed its risks.

"I was very impressed with the sponsor's data and I also thought the agency and sponsor worked really well together to address a very, very difficult area with such a great need," said PDAC chairperson Rajesh Narendran, MD, of UPMC Western Psychiatric Hospital and the University of Pittsburgh School of Medicine. "Given that there are no good options, I feel like this data could be very helpful in informing providers and families and patients you know about the risks."

"The studies were well done. The analysis was quite convincing," said PDAC committee member Satish Iyengar, PhD, of the University of Pittsburgh. "Generally speaking, I'm always a little bit leery of secondary analyses looking at severity, but in this particular case, I think what people know already from their experience matches the data."

Kim Witczak, PDAC consumer representative and co-founder of Woodymatters, a drug safety advocacy group based in Minneapolis, provided the lone no vote.

"I don't think that the data demonstrated outweighs the dangers of an antipsychotic," Witczak said. "I do agree that it is an unmet need, and I hope I'm proven wrong in time. But with this limited amount [of data], I'm not willing to vote yes for this product."

Advisors highlighted a lack of options of evidence-based treatment for AAD and current reliance on off-label antipsychotics for these patients. They agreed brexpiprazole would not be appropriate for people with mild symptoms and emphasized the treatment also would not be appropriate for patients with severe symptoms of agitation. However, they stopped short of recommending a specific patient population because of the lack of available data.

Brexpiprazole currently is approved for treating major depressive disorder (MDD) and schizophrenia. In 2005, the FDA issued a boxed warning for all atypical antipsychotics after a systematic meta-analysis showed elderly patients with dementia who received antipsychotic treatment experienced a 70% increased risk of death.

During Friday's advisory committee meeting, the drug's sponsors presented data on the safety and efficacy profile of brexpiprazole based on phase III studies, a post-treatment observational study, and an open-label extension safety study.

Brexpiprazole's efficacy was supported by data from three phase III studies, two of which showed that over a 12-week treatment period, the drug had a statistically significant treatment effect in reducing agitation, based on the Cohen Mansfield Agitation Inventory (CMAI).

However, the third study found that flexible-dose brexpiprazole did not achieve statistical significant effect in the mean change from baseline CMAI agitation score at 12 weeks. Post-hoc exploratory analyses found numerical improvement in participants' response and tolerability with brexpiprazole compared with placebo in a subgroup of individuals who received a titrated dose from 0.25 mg to 2 mg/day over 4 weeks.

Brexpiprazole's safety profile was similar to the treatment's use in adults with schizophrenia and MDD.

Concerns about increased mortality were based on nine deaths that occurred during the phase III studies. Of those deaths, eight occurred among participants who received brexpiprazole (1.2%; n=655) and one occurred in a patient who received placebo (0.26%; n=388). The overall incident rate ratio was 4.16 (95% CI 0.51-33.83).

The FDA advisory committees expressed concern over the increased mortality risk, and questioned the lack of a proven target treatment group beyond a broad group of patients between the ages of 55-90 who have Alzheimer's dementia and may experience agitation.

"Right now, there is no standard of care," noted PCNS panelist David Weisman, MD, of the Abington Neurologic Associates Clinical Research Center in Pennsylvania. "So there's this witch's brew of every medication, every intervention that you could imagine being used ... It's a mess."

"This is an unmet need," he added. "Whom would this benefit? It would benefit agitated people because the alternatives are so bad."

The FDA is not required to follow the recommendations of its advisory committees, but it often does. If approved, brexpiprazole would be the first drug indicated for AAD.

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