Key FDA Director Frowns at Acadia’s Pimavanserin
 







April 5, 2016
 
Last week, the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) voted 12 to 2 that the benefits of ACADIA Pharmaceuticals’ (NASDAQ: ACAD) NUPLAZID (Pimavanserin) for the treatment of psychosis associated with Parkinson’s Disease Psychosis (PDP) outweigh the risks of treatment.  Acadia currently has completed Phase III studies for the treatment of Parkinson’s Disease Psychosis with Pimavanserin.  The company currently is in the midst of Phase II studies for the treatment of both Alzheimer’s Disease Psychosis and Schizophrenia with Pimavanserin.  
 
In reviewing the Division Memorandum of the FDA Briefing Document for the PDAC meeting last week, we were fairly well surprised by the negative tone of Dr. Mitchell Mathis, Director of the Division of Psychiatry Products (DPP).  Director Mathis’ tone as well as other pertinent considerations led us to conclude there is a very good likelihood that the FDA will require additional clinical studies, or worse, disapprove the drug altogether.  These considerations consist of the following:

1.  Director Mathis believes “the safety risk (of Pimavanserin) is substantial”

2.  Pimavanserin does not meet the criteria set forth in the “Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products” publication of the U.S. Department of Health and Human Services

3.  The National Partnership to Improve Dementia Care has a specific goal of reducing antipsychotic medications prescribed to seniors in long-term care facilities by a whopping 30% in 2016, on top of a reduction of 25% in 2015
 
1:  The Safety Risk is “Substantial”:  First and foremost, Dr. Mathis’ Division Memorandum dated March 2nd to the Advisory Committee for their meeting last week on the 29th of March has one key sentence that says it all:  “While the applicant (Acadia Pharmaceuticals) will present evidence that the treatment effect (using Pimavanserin) represents a clinically meaningful change, the Division’s medical officer will present his interpretation of the same data and reach a different conclusion.”
 
According to Dr. Mathis, “Pimavanserin is an inverse agonist at serotonin receptor subtype 5-HT2A, and unlike other antipsychotics, it has a notable lack of interaction with dopamine receptors. The applicant (Acadia Pharmaceuticals) believes that this unique pharmacologic profile allows for the treatment of psychosis without worsening the motor symptoms of Parkinson’s disease.”  Currently, there are no approved drugs for the treatment of PDP.  Because psychosis can occur in up to 40% of Parkinson’s patients, especially those in nursing homes, “a drug to prevent psychosis in this population without worsening motor function would, indeed, represent an important treatment advance.”
 
“The applicant (Acadia Pharmaceuticals) has submitted a single positive Phase 3 pivotal trial (ACP-103-020) that evaluated the efficacy, tolerability, and safety of Pimavanserin in patients with PDP.  In addition, the results of three other randomized controlled trials were submitted as supportive information, but none of these three was statistically positive on its primary endpoint.  Although the Division usually requires evidence of efficacy from more than one positive, adequate, and well-controlled trial, it is within our authority to rely on one robustly positive trial, especially when we have supportive evidence from the early part of the development program…Interpretation of the clinical meaningfulness of a drug effect has to be considered in light of its toxicity.  In other words, if a drug produces a statistically significant effect on a reasonable endpoint in a trial, and if that drug is completely without safety signals, then we need not spend too much time defining clinical meaningfulness because benefit, however small, outweighs zero risk, and even a small benefit in a disabling disease is valuable.  If, as is the case with Pimavanserin, the safety risk is substantial (increased serious morbidity and increased mortality, which we will address later), the evaluation of clinical meaningfulness is critical to making a risk-benefit decision.  It will be important for the Division to have the discussion about clinical meaningfulness as it relates to the Pimavanserin development program.” 
 
2:  Pimavanserin Does Not Meet the “Effectiveness” Criteria Set Forth by Congress and the Department of Health and Human Services:  According to the U.S. Department of Health and Human Services’ publication “Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products,” manufacturers must demonstrate their products are effective to gain approval.  Specifically, the publication states: “In 1962, Congress amended the Federal Food, Drug, and Cosmetic Act to add a requirement that, to obtain marketing approval, manufacturers demonstrate the effectiveness of their products through the conduct of adequate and well-controlled studies...Sound evidence of effectiveness is a crucial component of the Agency’s benefit-risk assessment of a new product or use.”  Congress mandates that this effectiveness must be established by “substantial evidence…With regard to quantity, it has been (the) FDA's position that Congress generally intended to require at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness.”
 
According to Dr. Mathis, “The applicant (Acadia Pharmaceuticals) has submitted a single positive Phase 3 pivotal trial (ACP-103-020) that evaluated the efficacy, tolerability, and safety of Pimavanserin in patients with PDP.  In addition, the results of three other randomized controlled trials were submitted as supportive information, but none of these three was statistically positive on its primary endpoint…Although Trial 020 is strongly statistically positive, there has been a fair amount of consideration among the review team members about how to characterize the clinical meaningfulness of the statistically significant change seen in this trial…Clinical meaningfulness is difficult to quantify, but it is, in the most general sense, an effect produced by the drug that matters to the patient or to the treating clinician.  While the applicant will present evidence that the treatment effect represents a clinically meaningful change, the Division’s medical officer will present his interpretation of the same data and reach a different conclusion.”
 
Acadia Pharmaceuticals has clearly not conducted two “adequate and well-controlled studies.”  In certain cases, the FDA, at its discretion, has relied on only a single adequate and well-controlled efficacy study to support approval, generally “only in cases in which a single multicenter study of excellent design provided highly reliable and statistically strong evidence of an important clinical benefit, such as an effect on survival, and a confirmatory study would have been difficult to conduct on ethical grounds.”
 
Does Acadia Pharmaceuticals’ one study meet this high threshold of an important clinical benefit, such as an effect on survival?  Clearly not.  According to Acadia’s own data, the SAPS-PD change (in Trial ACP-103-020) was -23.1%.  Dr. Mathis interprets this result stating that, “A 22-34% change has been defined as ‘minimally improved.’ Therefore, as interpreted from these data, Pimavanserin produced a minimally improved clinical change in patients with Parkinson’s psychosis.”  Dr. Mathis goes on to say that the “sample of patients compared to their appropriate control group demonstrates more than double the risk of death and serious adverse events (SAE) in the PDP6 trial population (Observed Risk of death or SAE is 2.38 times greater [95% CI 1.00 to 5.73, p=0.05]) for 34 mg Pimavanserin vs. placebo.”  Overall, 5.3% of Pimavanserin-treated patients died compared to 0.5% of those who received placebo.  The incidence of death raises to 11.1% of deaths among the PDP long-term exposure patients.  Dr. Mathis clearly states while death associated with PDP is a common event, “The deaths that occurred in the Pimavanserin development program…were numerically more frequent in the Pimavanserin group versus the placebo group over the six-week treatment period.”  Additionally, serious adverse events occurred in 7.9% of the patients taking Pimavanserin versus only in 3.5% of the placebo-treated patients.
 
With Pimavanserin, the safety risk is, without a doubt, substantial, “increased morbidity and increased mortality.”  Because of this “substantial” safety risk with Pimavanserin and because a confirmatory study would not be difficult on ethical grounds, it appears likely that the FDA will require additional clinical trials, despite the 12-2 vote by the Advisory Committee.  The purpose of the Advisory Committee is to give the FDA unbiased expert opinions firmly grounded in sound science.  The FDA, however, is certainly not bound by the recommendation of its Advisory Committee, especially given the fact that a study published in Milbank Quarterly recently gave some alarming statistics:
 
• “On average, 13% of the members in any given Advisory Committee had a financial interest in the company whose drug was up for a review by that committee.”       
 
• “About one­third of financial interests involved consulting for a drug maker; 25 percent involved ownership interest; 14 percent involved serving on an industry advisory board or steering committee.”     
  
• “Committee members with financial ties to the company sponsoring the drug under review voted in favor of approval 63% of the time, while members who did not have financial ties had a 52% chance of favoring approval.”
 
• “Committee members who served on a sponsoring firm's advisory board had a whopping 84 percent chance of voting in favor of the drug's approval.”
       
We do not know if there are any conflicts of interest with this particular Advisory Committee, but thankfully for our seniors, the FDA is independent of its Advisory Committees and ignores its recommendations approximately 25% of the time. 
 
3:  Reducing Antipsychotic Medications Prescribed to Seniors:  Finally, the National Partnership to Improve Dementia Care, a public-private coalition that includes the Centers for Medicare and Medicaid Services, the American Health Care Association/National Center for Assisted Living and Leading Age, have made it a priority to reduce the use of antipsychotic medications among residents of long-term care facilities by 30% by the end of 2016.  Impressive reductions have already occurred in 2014 and 2015.  According to AHCA President and CEO, the honorable Mark Parkinson, “The results speak for themselves…thousands of lives are being improved.”  Nursing homes are being encouraged to re-think their approach to dementia care, re-connect with residents and their family members, and use a comprehensive team-based approach versus more drugs.
 

Disclosure:  None, but we may institute a short position within the next 24-48 hours.  We do not have a financial relationship with the company.



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