“Very disappointing” and “strongly disagree.” Those are the words Acadia Pharmaceuticals had for an FDA rejection of its label expansion for Nuplazid, criticizing the agency for suddenly changing its mind despite a prior agreement that was repeatedly reinforced over four years of communication.
The FDA issued a complete response letter over Nuplazid for the treatment of hallucinations and delusions associated with dementia-related psychosis (DRP), the California company said Monday. Its stock price slid roughly 17% on the news Monday morning.
The rejection came after the FDA surprisingly called for a halt to an expected discussion of labeling and post-marketing requirements around a potential approval merely a month before the decision date, citing deficiencies in Acadia’s filing. At that point, industry watchers were simply expecting a delay in review.
With the rebuff, now we know just how irreconcilable the company’s and the FDA’s positions are. And by Acadia CEO Steve Davis’ account, the FDA’s stance is very new and represents a clear shift in its thinking around not only Nuplazid itself, but also the DRP indication.
The FDA’s division of psychiatry took issue with the design of the pivotal phase 3 Harmony trial Acadia used to support Nuplazid’s new application. Specifically, it said the trial wasn’t enough to prove the drug’s effectiveness because of a lack of statistical significance in some patient subgroups—including those with Alzheimer’s disease—and the small numbers of patients with certain less common dementia subtypes.
But Davis said the trial was never designed to detect differences in individual patient subgroups and was not powered for statistical analysis for different disease subtypes. Basically, to hear him tell it, the FDA previously agreed that the company could use the big DRP umbrellas to include different dementia patients in a single analysis. DRP refers to behavioral changes, namely symptoms, while various dementia types may have different underlying pathological changes.
The company and the FDA reviewers agreed to the phase 3 trial design at different points during the process, Davis said, including at the end of the phase 2 meeting, at the Harmony trial protocol submission, at the pre-sNDA meeting and at the time of the application submission.
Davis repeated “they did not say” five times during a Monday conference call to stress that Nuplazid met all prespecified standards agreed upon by the FDA, and that the current rejection was only the result of the FDA abruptly changing its standards. When Nuplazid posted that phase 3 win in December 2019, SVB Leerink analyst Marc Goodman put the DRP indication’s peak sales at $ 2.5 billion.
While the company “strongly” disagrees with the FDA review process, it considers the FDA’s understanding of DRP, as reflected in the CRL, even more troublesome.
“The subtypes of dementia are often mixed and can be very difficult to distinguish in the clinical setting,” Acadia President Serge Stankovic explained on the call. “Furthermore, these diseases are overlapped pathologically, and the rates of overlapping pathology increases with age.”
Translation? It could be difficult to group patients according to disease subgroups anyway. The Harmony trial enrolled different subtypes in line with the actual prevalence of those in the real world, according to Stankovi.
While DRP may be caused by different diseases, the symptoms are treated similarly, he said. “Therefore, the approach to look at the measure broadly when developing a symptom-based treatment makes sense,” he added.
Stankovi noted that there have been significant changes in leadership at the division of psychiatry and the FDA office of neuroscience, but also said the team the company’s been working with regarding this application has been the same through the review process.
Acadia will now request a Type A meeting with the FDA, which will allow the company to better understand the agency’s rationale for the decision and bring its argument forward, Stankovi said.
Because the Harmony trial is simply not powered to analyze subgroup performance, the company will be forced to conduct another trial if the agency insists on its stance. But Davis appeared to be averse to that idea, saying the drugmaker remains confident in Harmony supporting a DRP indication.