U.S. Approval of Nuplazid: Exploring Physicians’ Take

Pills tipped over in the orange bottle with "FDA Approved" stamped in red

On April 29th, the FDA approved Acadia Pharmaceuticals’ Nuplazid (pimavanserin) for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP), making it the first drug approved in the United States with this label. Browsing the news stories covering this ground-breaking approval, you’ll find facts, figures, and conjecture relaying the commercial importance of this event—a sizable 40% of PD patients suffer from psychosis (DRG’s epidemiology estimates are slightly lower), and Nuplazid has the potential to be a blockbuster (in principle we agree, with a hefty price tag, expected European launch, and a potential for expanded labeling in Alzheimer’s disease*). But what is the clinical significance of this new drug that underlies those potential blockbuster sales? What does Nuplazid’s approval mean for the physicians actually treating PDP?

Even before Nuplazid’s approval, KOLs interviewed by DRG were enthusiastic about the drug’s potential labeling for PDP and its promising clinical trial results. They emphasized the clinical importance of having an approved PDP drug: the hallucinations and delusions associated with PDP can severely impair quality of life for patients and their caregivers, and are the primary cause for placement of PD patients in nursing homes. Until now, physicians needing to treat PDP with medication have had to make do prescribing marketed atypical antipsychotics off-label. DRG research shows that although physicians often use the relatively safe antipsychotic quetiapine (Seroquel/Seroquel XL), they bemoan its overall lack of efficacy in this population, noting that the drug doesn’t really suppress psychosis so much as it sedates PDP patients. Alternatively, physicians may prescribe clozapine, which is considered to be much more effective (and is approved for PDP in Europe) but is associated with serious risks and requires burdensome blood monitoring. In addition, many atypical antipsychotics can often worsen motor symptoms in PD patients. Because of these issues, the need is real for a safer, better tolerated, and more effective PDP treatment.

For interviewed physicians, the most important differentiator will be Nuplazid’s proven efficacy. In the March FDA Advisory Committee meeting for Nuplazid, panel members voted 12-2 that Nuplazid’s benefits outweigh its risks, but they also noted that Nuplazid’s effect size was small. Generally speaking, the potentially modest overall efficacy has not concerned our interviewed experts, who suggest that even a small effect could provide meaningful benefits for both PDP patients and their caregivers. To paraphrase one physician interviewed after the meeting: when it comes to quality of life, even if Nuplazid isn’t a cure for PDP, there’s a real difference between struggling to distinguish between reality and hallucinations or delusions, and being able to recognize a hallucination when it happens.

Nuplazid also benefits from having a unique mechanism of action. In addition to the serotonergic system, other atypical antipsychotics act on the dopaminergic system, which can interfere with dopaminergic therapy required to control motor function in PD patients. However, Nuplazid has no effect in this system, and Acadia made sure to prove that the drug does not exacerbate motor symptoms in clinical studies. With Nuplazid’s proven efficacy and lack of motor side effects, interviewed KOLs indicate that Nuplazid may become the first-line antipsychotic for their PDP patients.

Nuplazid is not without its risks, however. The FDA Advisory Committee expressed concern about a safety signal for increased mortality in elderly patients and about the possibility of off-label use in other indications*. Upon approving Nuplazid, the FDA classified it as an atypical antipsychotic and—just like for others in the class—slapped it with a black box warning for increased risk of mortality in elderly patients with dementia-related psychosis. In their conference call on May 2nd, Acadia was quick to point out that this warning does not preclude the use of Nuplazid in PDP patients who happen to have dementia—the drug is approved for use in all PDP patients experiencing hallucinations and delusions. That said, the warning implies that PDP patients with dementia may be at risk of increased mortality.

So what impact will the black box warning have on future uptake? Physicians interviewed by DRG before Nuplazid’s approval report that they believe Nuplazid is safer and better tolerated than other atypical antipsychotics, despite the potential at that time for a black box warning. In fact, one expert familiar with the clinical trial results expressed astonishment that the FDA would consider a black box warning, suggesting that Nuplazid’s unique mechanism of action and safety data from its clinical trials differentiated it from atypical antipsychotics, and predicted that he and his colleagues would be undeterred by it. Indeed, physicians who treat PDP are already accustomed to weighing the risks and benefits of antipsychotic use with their patients, and most use available atypical antipsychotics off-label despite the warning.

In the end, we at DRG expect that Nuplazid’s uptake will be gradual, despite physicians’ eagerness for the drug. Today, the first line of treatment for PDP is adjusting the patients’ dopaminergic therapy (PDP can be a complication of the dopaminergic therapy used to treat PD motor dysfunction as well as a symptom of the disease itself). Only after this fails—either because motor symptoms re-emerge or PDP is not resolved—do physicians turn to atypical antipsychotics. We do not expect this to change with the launch of Nuplazid. We envision physicians will try Nuplazid in a few patients with the most disruptive symptoms (those patients whose symptoms are not currently controlled by off-label antipsychotics) or patients who are experiencing tolerability issues. Indeed, in their conference call, Acadia announced that they would be providing free samples to help support the early trial period. Separately, at Acadia’s price point of more than $23,000/year, it’s a sure bet (and Acadia has acknowledged) that payers will impose prior authorization to ensure only PDP patients receive treatment; meanwhile, tiering, copays, and coinsurance could pose access barriers for some patients, though Acadia has indicated it will provide financial assistance in various forms. DRG will assess U.S. physician prescribing of, and payer reactions to, Nuplazid (among other topics) in an upcoming primary market research study to be published later in 2016.

Ultimately, while many interviewed physicians familiar with the trial results believe that pimavanserin will be a “game-changer,” the drug will have to live up to its high price and reputation in clinical practice. One thing is sure, the early trial and adoption period will be the clincher: Nuplazid must prove itself to be clinically superior to the current antipsychotics used off-label, or all bets are off.

*The potential for/risk of off-label use of Nuplazid in other indications understandably surfaced during the FDA’s Advisory Committee meeting; use in Alzheimer’s disease (AD), especially, is a topic we at DRG have considered at length. At this point, with a label that expressly states that Nuplazid is “not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson's disease psychosis,” a considerable price tag, and no evidence of efficacy in AD to date, we would expect very little off-label use in AD psychosis. Things could change if the ongoing Phase II study in AD psychosis reports positive results later this year (of note, Acadia also expects to start a Phase II study in AD agitation by mid-year). Stay tuned.