The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) over Acadia Pharmaceuticals’ supplemental New Drug Application (sNDA) for Nuplazid for hallucinations and delusions associated with dementia-related psychosis. The drug, pimavanserin, is the first and only drug approved for hallucinations and delusions associated with Parkinson’s disease psychosis.
The FDA’s CRL noted a lack of statistical significance in some of the dementia subgroups, claiming not enough patients with specific less common dementia subtypes failed to show effectiveness. The company points out that they had previous agreements with the Division of Psychiatry over the study design for the pivotal Phase III HARMONY study that targeted a broad DRP patient population analyzed as a single group.
The HARMONY study hit its prespecified primary and secondary endpoints. They further noted that statistical separation by dementia subgroups and patient minimums for different subgroups were not in the prespecified requirements.
There has been speculation this year that the FDA has been getting tougher on approvals, and this rejection would seem to support that argument.
The Acadia press release hints that the company is unhappy with this decision. It had been forewarned. Only a few weeks ago executives shocked investors when they said the agency wasn’t willing to negotiate on the label.
“Acadia stands behind the robustly positive results from the pivotal Phase III HARMONY study and the prospectively agreed trial design and criteria for establishing efficacy in DRP. Over the entire course of the review, the Division did not raise any concerns regarding the agreed upon study design, including the issues raised in the CRL,” said Steve Davis, Acadia’s chief executive officer. “We will immediately request a Type A meeting to work with the FDA to address the CRL and determine an expeditious path forward for the approval of pimavanserin in DRP.”
Paul Matteis, analyst with Stifel, wrote in a note to investors, “Pimavanserin’s efficacy in the relapse prevention trial was most robust in the Parkinson’s sub-population, and one could argue that this is the primary reason why the trial was stopped at the interim. We had figured this detail could be overlooked since the data for ADP was still pretty good (14 relapses placebo, 8 drug), but data in some of the other rarer subgroups is less consistent, and perhaps if one is not a believer in the ‘acute’ Phase II trial the same numbers issue with the Phase III become more prominent. Bottom line: our view is that Acadia will likely need to run one or even two more trials here, and while pimavanserin has always seemed to be a very safe drug, it’s efficacy is at the low end of the range for atypical antipsychotics, which makes any future trial (especially one that needs to demonstrate clear acute efficacy in a placebo-controlled manner) fairly risky, in our opinion.”
The FDA has said in its CRL that the company’s Phase II Alzheimer’s disease psychosis study -019, which was used for supportive data in the sNDA, was not adequate and well controlled. Acadia, on the other hand, argues that “these observations impact neither the positive results on the study’s primary endpoint, nor the study’s overall conclusions of efficacy.”
