FDA advisors voted in favor of brexpiprazole (Rexulti) for treating agitation related to Alzheimer’s dementia (AAD), regardless of elevated mortality threat.
By a vote of 9-1 on Friday, members of the company’s Psychopharmacologic Medicine Advisory Committee (PDAC) and the Peripheral and Central Nervous System Medicine Advisory Committee (PCNS) mentioned the info introduced by the drug’s sponsors, Lundbeck and Otsuka Pharmaceutical, had been adequate to establish a inhabitants in whom the advantages of treating AAD with brexpiprazole outweighed its dangers.
“I used to be very impressed with the sponsor’s information and I additionally thought the company and sponsor labored very well collectively to handle a really, very troublesome space with such an excellent want,” mentioned PDAC chairperson Rajesh Narendran, MD, of UPMC Western Psychiatric Hospital and the College of Pittsburgh Faculty of Medication. “On condition that there are not any good choices, I really feel like this information may very well be very useful in informing suppliers and households and sufferers you already know concerning the dangers.”
“The research had been properly carried out. The evaluation was fairly convincing,” mentioned PDAC committee member Satish Iyengar, PhD, of the College of Pittsburgh. “Typically talking, I am all the time a bit bit leery of secondary analyses severity, however on this specific case, I feel what folks know already from their expertise matches the info.”
Kim Witczak, PDAC client consultant and co-founder of Woodymatters, a drug security advocacy group primarily based in Minneapolis, offered the lone no vote.
“I do not assume that the info demonstrated outweighs the hazards of an antipsychotic,” Witczak mentioned. “I do agree that it’s an unmet want, and I hope I am confirmed improper in time. However with this restricted quantity [of data], I am not prepared to vote sure for this product.”
Advisors highlighted an absence of choices of evidence-based remedy for AAD and present reliance on off-label antipsychotics for these sufferers. They agreed brexpiprazole wouldn’t be applicable for folks with gentle signs and emphasised the remedy additionally wouldn’t be applicable for sufferers with extreme signs of agitation. Nevertheless, they stopped in need of recommending a selected affected person inhabitants due to the dearth of obtainable information.
Brexpiprazole at present is accepted for treating main depressive dysfunction (MDD) and schizophrenia. In 2005, the FDA issued a boxed warning for all atypical antipsychotics after a scientific meta-analysis confirmed aged sufferers with dementia who obtained antipsychotic remedy skilled a 70% elevated threat of loss of life.
Throughout Friday’s advisory committee assembly, the drug’s sponsors introduced information on the security and efficacy profile of brexpiprazole primarily based on part III research, a post-treatment observational research, and an open-label extension security research.
Brexpiprazole’s efficacy was supported by information from three part III research, two of which confirmed that over a 12-week remedy interval, the drug had a statistically vital remedy impact in lowering agitation, primarily based on the Cohen Mansfield Agitation Stock (CMAI).
Nevertheless, the third research discovered that flexible-dose brexpiprazole didn’t obtain statistical vital impact within the imply change from baseline CMAI agitation rating at 12 weeks. Put up-hoc exploratory analyses discovered numerical enchancment in members’ response and tolerability with brexpiprazole in contrast with placebo in a subgroup of people who obtained a titrated dose from 0.25 mg to 2 mg/day over 4 weeks.
Brexpiprazole’s security profile was just like the remedy’s use in adults with schizophrenia and MDD.
Issues about elevated mortality had been primarily based on 9 deaths that occurred through the part III research. Of these deaths, eight occurred amongst members who obtained brexpiprazole (1.2%; n=655) and one occurred in a affected person who obtained placebo (0.26%; n=388). The general incident fee ratio was 4.16 (95% CI 0.51-33.83).
The FDA advisory committees expressed concern over the elevated mortality threat, and questioned the dearth of a confirmed goal remedy group past a broad group of sufferers between the ages of 55-90 who’ve Alzheimer’s dementia and will expertise agitation.
“Proper now, there isn’t any commonplace of care,” famous PCNS panelist David Weisman, MD, of the Abington Neurologic Associates Scientific Analysis Heart in Pennsylvania. “So there’s this witch’s brew of each medicine, each intervention that you can think about getting used … It is a mess.”
“That is an unmet want,” he added. “Whom would this profit? It will profit agitated folks as a result of the options are so unhealthy.”
The FDA is just not required to observe the suggestions of its advisory committees, but it surely typically does. If accepted, brexpiprazole can be the primary drug indicated for AAD.