An FDA advisory panel rejected pimavanserin (Nuplazid) for the treatment of hallucinations and delusions in patients with Alzheimer’s disease psychosis on Friday.
In a vote of 9-3, the Psychopharmacologic Drugs Advisory Committee decided against recommending the drug for approval for these patients, citing a slew of shortcomings in supporting trial data.
This could have been the second indication for pimavanserin, a serotonin selective inverse agonist that preferentially targets the 5-HT2A receptor subtype. The agent was first approved in 2016 for hallucinations and delusions associated with Parkinson’s disease psychosis.
“The questions before the committee have been narrow and precise,” said Walter S. Dunn, MD, PhD, of the University of California Los Angeles, who voted no. “So, I trust that the agency will take a broad approach in their final decision about approval.”
“As a clinician, I am a proponent for having as many tools in the toolbox as possible,” he added. “This is an approved medication, already on the market. The real issue at hand in this approval is about lowering the financial barriers to access to this treatment. Therefore, improving access is something well within the capability of the company and the payors without having to involve the agency.”
Panel members were simply not convinced by the supporting evidence — two studies and the prior approval in Parkinson’s disease. Ultimately serving as the Achilles’ heel, the sweeping majority of the committee called the data “not compelling” for Alzheimer’s disease patients.
One of the trials submitted by the sponsor, the phase III HARMONY trial, was originally designed to test relapse prevention in patients with dementia-related psychosis — the original indication developer Acadia Pharmaceuticals was seeking the first time it submitted the supplemental new drug application last year.
The 26-week trial showed a statistically significant reduction in the risk of psychosis relapse, but only two-thirds of the study participants had Alzheimer’s disease and most of the benefit appeared driven by a different subgroup — those with Parkinson’s disease dementia where the drug is already approved. Because of this, many panel members felt the trial was ultimately underpowered for the Alzheimer’s population.
While the other trial homed in on Alzheimer’s patients specifically, and met its primary efficacy endpoint, it was a phase II trial and had a small study population. This led several panel members to call it “inadequate.”
The panel completely dismissed prior data on Parkinson’s disease psychosis, noting that this evidence is simply not applicable.
Many panel members said they would have preferred to see a phase III randomized clinical trial in just an Alzheimer’s patient population. Some suggested Alzheimer’s blood markers also be included, as well as a larger and more racially diverse patient population.
“I do also have concerns that once medications or treatments are made available for problems like this, it’s a little like the genie being let out of the bottle,” commented Paul Stander, MD, MBA, of the University of Arizona College of Medicine-Phoenix, who also voted against recommending approval. “They tend to get used for a wide range of symptoms and patients who may not really be applicable … I would recommend, as others have said, a more fine study focused entirely on an Alzheimer’s population and preferably, from my perspective, a longer duration of efficacy.”
Although the panel members weren’t convinced by the data for this indication, they noted that there is an urgent unmet need for a treatment for Alzheimer’s disease psychosis.
“There are many factors that we have not formally discussed today, such as safety and unmet clinical need,” Dunn said. “There’s clearly a need in this highly vulnerable population.”
Echoing this, Madhav R. Thambisetty, MD, PhD, of the National Institute on Aging, said he was “extremely moved” by the patient testimony during the meeting, but landed in the ‘no’ column as well.
“I’m a neurologist who has cared for patients for more than 20 years. I recognize the unmet need,” Thambisetty said. “I just think the unmet need should not be a justification to cut corners. It should, on the other hand, inspire us to do the best science and apply the most rigorous standards towards analyzing the results from those studies.”
Many panel members did point out that since this drug is already approved, it’s not uncommon for it to be used off-label. Sonia L. Krishna, MD, of the University of Texas at Austin, said she’s particularly interested to see some real-world, anecdotal information on how clinicians have used this drug off-label over the past several years.
Although the FDA is not required to follow its advisory committees’ recommendations, it typically does.