Acadia Pharmaceuticals’ plan to expand use of its anti-psychosis drug to dementia patients has been rejected by the FDA, but the company pins the blame squarely on the regulator.
The FDA and the San Diego-based company had agreed on the clinical trial design and the benchmarks that study needed to hit in order to support approval of the drug, pimavanserin, as treatment for psychosis in a broad group of dementia patients. Despite hitting those marks, the FDA’s rejection letter cited analysis of subgroups that were not part of the agreed upon plan, according to Acadia. CEO Steve Davis said the complete response letter (CRL) was the first time the company heard that the FDA’s division of psychiatry wanted subgroup analyses.
“The views expressed in the CRL represent an apparent recent shift in their position by the division,” Davis said on an investor call. “The pivotal program we agreed upon, simply put, was not designed to address the division’s expectations now stated in the CRL.”
Davis went on to say the FDA is taking the wrong approach to evaluating dementia patients. The correct way to study these patients is by analyzing them as a single group because while dementias may have different underlying causes, the psychosis that results is similar across subtypes, he explained. Davis added that diagnosis of a subtype is frequently wrong, and many patients have a mixed cause for their condition.
“In other words, they don’t fall cleanly into a single subtype,” he said.
The rejection is not a complete surprise. On March 8, Acadia disclosed that the FDA notified the company of unspecified deficiencies in the drug application.
Pimavanserin is a small molecule that targets 5-HT2A, a serotonin receptor that plays a key role in psychosis. In 2016, the FDA approved the once-daily capsule as a treatment for the hallucinations and delusions associated experienced by Parkinson’s disease patients. It’s marketed under the name Nuplazid.
Of the estimated 8 million people in the U.S. who are living with dementia, Acadia has said that studies suggest about 30% (2.4 million) of them have psychosis. About 1.2 million of those patients are currently receiving treatment, consisting mainly of off-label use of anti-psychotic drugs. There is no FDA-approved therapy for dementia-related psychosis.
Acadia Phase 3 clinical trial for pimavanserin started as an an open-label study enrolling nearly 400 dementia-related psychosis patients who received a daily dose of the drug for 12 weeks. Those who met pre-specified treatment response criteria at weeks eight and 12 were randomly assigned to continue treatment with the Acadia drug or be switched to a placebo. The groups were followed for up to 26 weeks or until a relapse of psychosis.
The main goal of the study was to measure the time to a psychosis relapse. In results released in late 2019, the risk of relapse in the treatment group was reduced by 2.8-fold compared to the placebo group, showing statistical significance. The company’s application seeking approval in dementia-related psychosis included additional data from a mid-stage study in Alzheimer’s disease psychosis and Phase 3 data in patients with Parkinson’s disease psychosis.
When the FDA accepted Acadia’s drug application for the dementia-related psychosis indication last summer, it set an April 3, 2021 target date for a decision. Acadia said the FDA’s communication with the company did not identify any potential review issues.
CRLs are private communication made from the regulator to a drug sponsor so any disclosures about their contents come from the companies that receive them. According to an Acadia investor presentation, the FDA’s letter stated that the clinical trial results “suggest a differential response to pimavanserin across dementia subtypes, questioning whether ‘dementia-related psychosis’ is a useful construct for a potential indication for pimavanserin.” The results led to a lack of statistical significance in some of the subgroups, while in some of the less common subtypes there was an an insufficient number of patients to evaluate, according to Acadia’s telling of the FDA’s conclusions.
In addition to calling out differences among dementia subtypes, the FDA also dismissed Acadia’s Alzheimer’s study, saying the results in this subgroup “were not nominally significant,” according to the investor presentation.
Pimavanserin is Acadia’s only FDA-approved product. The drug accounted for $441.7 million in 2020 sales, a more than 30% increase over the prior year, according to the company’s annual report. Acadia believes the drug’s approach has potential use in other neurological and psychiatric disorders and the biotech has tested its drug in some of them. Not all of those tests have been successful. In 2019, the drug failed a Phase 3 study in schizophrenia. Last year, the drug failed a different Phase 3 study in major depressive disorder.
Davis said Acadia stands by the positive results from the Phase 3 study in dementia-related psychosis. He added that the company will request a meeting with the FDA to address the CRL and determine a path forward for the drug in that indication.
Shares of Acadia, which trade on the Nasdaq under the stock symbol “ACAD,” opened Monday at $21.33, down 16.6% from Friday’s closing price.
Photo: sarawuth702, Getty Images
