June 17, 2022
I am Dr. Nina Zeldes, a senior fellow at the National Center for Health Research. We analyze scientific data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug companies, so I have no conflicts of interest.
As we all know, in 2018 FDA was concerned about “the numbers of reports of death and other serious adverse events” regarding this drug, which already carries a black box warning that there is “increased mortality in elderly patients with dementia-related psychosis.” And in September 2021, a study published in Neurology found a statistically significant increase in hospitalizations among Parkinson’s patients taking this drug compared to nonusers.1
To outweigh such serious safety risks, the benefits of this drug would need to be substantial. There is no such evidence. Moreover, this resubmission of a previously rejected application for a broader indication relies on the same two studies which FDA previously criticized: They described study 019 as “not an adequate and well-controlled study” and noted that there were several study design concerns and protocol deviations. And although NUPLAZID (pimavanserin) showed a statistically significant improvement compared to placebo, it only translated to a treatment difference of less than 2 points on a 24-point scale. Is that a clinically meaningful improvement for patients, especially since there is no evidence that this tiny improvement lasts more than a few days or weeks? The validity is questionable since statistical significance was not reached for the secondary endpoint.
FDA described Study 045 as not “powered to determine an effect in the included dementia subgroups”. The results for AD patients are not statistically significant. We agree with the FDA that the proposed post-hoc analysis for this subgroup “are very challenging to interpret”. For example, there is no scientific reason for the sponsor to use the Open-Label baseline score instead of the Double-Blind baseline score when testing the treatment effect on relapse in the Double-Blind period.
Lack of diversity is a serious problem. For example, in study 019, only 3 patients were Black and only 17 were men in the treatment group. That is not enough to draw any conclusions about either group and together those 2 groups comprise close to half of Alzheimer’s patients. If the sponsor had made a serious effort to recruit more men and more nonwhite patients, they could have done so.
My final point is that AD drugs are taken for years. The 12-week study 019 cannot provide adequate evidence of long-term benefit or safety. To determine if the benefits outweigh the risks, we need longer placebo-controlled studies.
In conclusion, I respectfully urge you to consider whether the evidence of a possible small benefit is clinically meaningful and if so, does it outweigh the known, serious safety risks of NUPLAZID?
References
- Hwang, Y. J., Alexander, G. C., An, H., Moore, T. J., & Mehta, H. B. (2021). Risk of hospitalization and death associated with pimavanserin use in older adults with Parkinson disease. Neurology, 97(13), e1266-e1275.
The Psychopharmacologic Drugs Advisory Committee voted 9 to 3 that the available evidence does not support NUPLAZID for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis.