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Outrage Of The Month: FDA Approval of Brexpiprazole for Agitation Symptoms Associated With Dementia Due to Alzheimer’s Disease — False Hopes for Patients and Families?

Health Letter, June 2023

By Nina Zeldes, Ph.D., and Robert Steinbrook, M.D.


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Agitation symptoms associated with dementia due to Alzheimer’s disease are a frequent and challenging clinical problem. Better treatments are needed. The path forward, however, was not for the Food and Drug Administration (FDA) to approve a supplemental indication for the antipsychotic medication brexpiprazole (REXULTI), as the agency did on May 10, 2023.

As Public Citizen’s Health Research Group argued in a letter to the FDA urging the agency to reject the supplemental indication, the drug’s small benefits do not outweigh its significant risks, and no population of patients for which the benefits would outweigh the risks was identified. At an advisory committee meeting in April 2023, Public Citizen’s Health Research Group also urged the FDA to reject the approval.

Brexpiprazole is the first — and, for now, the only — FDA-approved treatment option for agitation among patients with dementia due to Alzheimer’s disease. However, given that this supplemental indication will likely generate hundreds of millions of dollars for the drug companies in annual sales, other companies may seek approval for similar drugs.

The FDA granted Otsuka Pharmaceutical Company, Ltd., and Lundbeck, Inc., a fast-track review for the supplemental indication for brexpiprazole, a type of approval that is meant to “fill an unmet medical need” and “get important new drugs to the patient earlier.” The FDA first approved brexpiprazole in 2015 for adults with major depressive disorder or schizophrenia.

All antipsychotics, including brexpiprazole, have a black-box warning because they are associated with an increased risk of death among elderly patients with dementia. In contrast to these serious risks are the limited benefits of this drug: For example, the treatment difference for brexpiprazole in one of the studies used to support the approval related to Alzheimer’s disease was just 3.8 points on an “agitation inventory” score that ranges from 29 to 203 points. The improvements observed in subjects receiving placebo (17.8 points) and in those receiving brexpiprazole (21.6 points) were similar. A 2.2% difference on this score is unlikely to be clinically meaningful for patients. Even the FDA itself did not consider this result “statistically persuasive.”

Even more concerning is that the FDA and its expert external advisory committee did not identify a specific population in which the limited benefits of brexpiprazole outweigh the increased risk of death. Despite these serious concerns, nine of the 10 advisory committee members who advised the FDA on this decision recommended approval of this drug.

The only member who opposed the approval rightfully stated that “[a] glimmer of false hope should never be reason to approve dangerous and ineffective drugs” and urged the FDA to closely watch how this drug is “marketed to the doctors and patients. As we have seen too many times, the benefits are overhyped while the harms are downplayed or dismissed.”

Instead of filling an unmet medical need, this newly approved treatment for agitation symptoms associated with dementia due to Alzheimer’s disease may offer little to patients and their families. Patients and caregivers deserve better: Before granting a supplemental indication for an approved drug, the FDA should require evidence of an acceptable safety profile and substantial and clinically meaningful benefits.