Acadia's Nuplazid Alzheimer's psychosis bid looks shaky after FDA panel's thumbs-down

Acadia’s bid to expand Nuplazid to a larger group of psychosis patients just hit yet another setback.

Friday, an independent expert panel voted 9 to 3 that existing data don’t support Nuplazid for the treatment of hallucinations and delusions in Alzheimer’s disease psychosis.

The thumbs-down makes an approval even less likely given that the FDA’s panel of advisers raised many of the same concerns previously voiced by FDA staffers.

First approved by the FDA in 2016 for Parkinson’s disease psychosis, Nuplazid suffered an FDA rejection in a broad dementia-related psychosis indication last April. For its second try, Acadia is asking for FDA approval in the Alzheimer’s psychosis subgroup, which makes up roughly two-thirds of the overall dementia psychosis population.

At the Friday meeting, most FDA advisors said Nuplazid’s phase 2 Study-019 trial in Alzheimer’s psychosis wasn’t well controlled. More than half of patients in both the treatment and placebo groups had deviations from the trial protocol, they noted.

Study-019 did hit its primary goal. After six weeks, Nuplazid showed a 1.8-point improvement over placebo on a psychosis score called NPI-NH-PS, but it coincided with a mysterious and sudden worsening among the placebo patients. As the FDA and the advisers noted, the drug’s benefit quickly disappeared in longer follow-ups. The FDA has also questioned whether that 1.8-point improvement on a 24-point scale is clinically meaningful.

The scoring system used for the primary endpoint “only captures a narrow slice of symptom presentation,” Walter Dunn, M.D., Ph.D., from the University of California Los Angeles’ Department of Psychiatry, said during the meeting. “I agree it’s challenging to win on all of your outcomes. However, I think at least a signal on the agitation and aggression domain would have made the case more compelling.”

What’s more, even the 1.8-point showing just barely passed the statistical significance bar, Dean Follmann, Ph.D., a biostatistician with the National Institutes of Health, noted in his comments. To make matters worse, the trial failed to meet all its secondary endpoints, which some panelists said gave them reason to suspect that the primary endpoint only hit by chance.

All things considered, Dunn said Study-019 is “technically” a win, but “the totality of evidence” leaves questions about Nuplazid’s efficacy.

Acadia also ran the phase 3 Harmony trial, also known as Study-045, which enrolled various dementia-related psychosis patients. But as the FDA’s own reviewers noted, the positive trial outcome was largely driven by the Parkinson’s subgroup, in which Nuplazid is already approved.

For its part, Acadia has argued that Alzheimer’s and Parkinson’s psychosis are similar, and the imbalance in their responses observed in Harmony was caused by the concomitant use of dopaminergic medications among Parkinson’s patients.

The experts were skeptical of that claim and most ended up agreeing with the FDA’s reviewers.

“I strongly believe the results from Study-045 suggest that Parkinson’s disease and Alzheimer’s disease psychosis are different illnesses with different responses” to Nuplazid, Dunn said.

But not all experts sided with the FDA.

While Study-019 isn’t perfect, it’s “supportive of an effect” by Nuplazid, Merid Cudkowicz, M.D., at Massachusetts General Hospital, said during her comments.

Cudkowicz wasn’t surprised to see trial protocol deviations given the complexity of doing a study in a nursing home among patients with Alzheimer’s disease, she said. She also wasn’t concerned about the deviations because the FDA’s analysis showed they were balanced between the trial arms. She did, however, admit that the lack of a sustained effect over the longer, 12-week period is a concern.

After adjusting for the deviations, Study-019 still hit its main goal, and the responder analysis was “convincing,” Liana Apostolova, M.D., a practicing Alzheimer’s disease specialist with the Indiana University School of Medicines, said at the meeting.

As for Study-045, “the effect size in [Alzheimer’s disease] meets my expectations,” Apostolova said. “I don’t anticipate it to ever match Parkinson’s disease dementia or dementia with Lewy body.”

“These advanced dementia trials are very hard to conduct,” Apostolova added, “and I cannot help but see more positive than negative in the data presented today.”

After the vote, an FDA approval for Nuplazid in Alzheimer’s psychosis is not likely, SVB Securities analysts said in a Monday note. The FDA will likely require another phase 3 trial, which was also proposed by many panelists, the team noted.

Without the large Alzheimer’s indication, SVB figured the Nuplazid’s current Parkinson’s psychosis indication could drive sales to over $800 million by the end of the decade, from just under $500 million in 2021.