On Tuesday, Acadia Pharma (NASDAQ:ACAD) announced its phase II exploratory study data on pimavanserin, a selective serotonin inverse agonist 5-HT2A receptor previously approved for the treatment of Parkinson's disease psychosis (PDP), in patients with Alzheimer's disease psychosis (ADP). Acadia soared 33% premarket on the positive announcement, but traded down after the investors realized the absence of efficacy at week 12. Despite the positive "spin" by the company of a successful outcome, I view the efficacy is weak at best if it is efficacious at all.
Phase II exploratory study (-019 Study) design of pimavanserin
The Phase II -019 study was a randomized, double-blind, placebo-controlled and single-sited exploratory trial evaluating the efficacy and safety of pimavanserin (known as Nuplazid in PDP treatment) in ADP patients. A total of 181 patients were enrolled and they were given either 34 mg (a similar dose to the PDP trial) of pimavanserin or placebo once daily for 12 weeks. The rationale behind the indication expansion was that the symptoms of hallucinations and delusions were similar among AD patients and PD patients despite the different underlying causes of the diseases.
The primary endpoint was the mean change of the Neuropsychiatric Inventory-Nursing Home (NPI-NH) Psychosis score (combined hallucinations and delusions domains), a questionnaire scored by the caregiver based on a standardized interview administered by the clinicians. It includes frequency, severity and associated caregiver distress. The maximum score is 24.
Weak efficacy profile despite positive "spin" by the company
In Tuesday morning's conference call, management said it was "extremely happy" about the results, even though when taking a closer look, the positive news fell short.
The baseline mean scores for pimavanserin vs. placebo were similar (9.52 vs. 10.00 respectively). The company claimed the scores started separation at all time points but took week six instead of week 12 as the time point for the primary endpoints. There was some confusion regarding when it determined the time point. On clinicaltrials.gov, it shows the primary outcome should be measured at week 12. However, the company answered that it was always measured at week six in response to an analyst's question.
Regardless of the confusion, there was only efficacy seen at week six with significance (p=0.0451) although the p value suggested the effect size of two was not particularly robust. At week 12, even though the score change maintained, there was no separation from the placebo probably due to the rising of the score from the placebo arm. This could point to a placebo effect, which is commonly observed in psychiatric studies, masking the true efficacy of the drug.
Additionally, there were no secondary endpoints backing up the "positive" results, including the changes in cognition. In other words, the only positive outcome from this trial was at the primary endpoint of week six.
In contrast, Nuplazid (same compound) performed much better in the PDP trials. In the phase III trial, the p values were relatively small and multiple endpoints showed significant improvements in psychosis (Figure 1).
Figure 1: Nuplazid study in PDP patients showed improvement of psychosis
The outlook for a phase III success of pimavanserin is not great in my view and this has many implications for the company.
Implications for ADP, other ongoing trials and Acadia
There is no FDA approved drug for the treatment of ADP. Typically physicians prescribe antipsychotic drugs, which often worsen the cognitive functions in the patients. The positive side of pimavanserin was that no cognition impairment was seen and the drug was generally well-tolerated, as expected from previous trials. From the perspective of the market, ADP is bigger than PDP, so a successful outcome can translate into a significant increase of the top line. An estimation of 5.4 million people in the US have Alzheimer's disease, of which 25-50% may develop psychosis. However, based on the minimal efficacy shown in the phase II trial, I am not too optimistic about the prospects of this drug in ADP.
Like the company suggested, many antipsychotic drugs are treating multiple psychiatric diseases despite various underlying causes. Pimavanserin was also designed to treat the symptoms rather than the causes. The weak results from the ADP trial signaled that the positive outcome might not be replicated in other indications. Currently, Acadia only has one compound and its strategy is to expand the indications into other psychiatric domains, including schizophrenia, AD agitation and major depressive disorder (Figure 2). Whether these trials will be successful is mere speculation at this point and that's why I focus on Nuplazid only when evaluating the company.
Figure 2: Overview Acadia's pipeline
Nuplazid has been beating the market's expectation in scripts. I believe Nuplazid has blockbuster potential with the right resources and the long game for Acadia would be a buyout option from Biogen (NASDAQ:BIIB) or Allergan (NYSE:AGN) as I discussed earlier here.
Acadia's expansion into the ADP is likely to fail as the results were weak and the advance into the next stage was not adequately justified despite a "positive" label by the company. Nuplazid is still its core asset, and a buyout option is one of the better options for Acadia.
Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.