In a news-heavy week for depression drugs, with offerings from Alkermes $ALKS and Sage $SAGE under FDA scrutiny, Acadia Pharmaceuticals $ACAD on Wednesday said “weighted average results” suggest pimavanserin (Nuplazid) met the main goal in a mid-stage study involving patients with major depressive disorder (MDD) — but a controversial two-stage trial design indicated the drug failed to impress in the second tranche of the trial, despite the p-value that emerged from the pooled data.
Although initial enthusiasm pushed the stock up in pre-market trading, it was in the red once the market opened on Wednesday morning.
Trials testing drugs for psychiatric disorders are susceptible to a large placebo effect and typically fail. In an effort to avoid this, Acadia’s CLARITY trial tested pimavanserin using the same sequential parallel comparison design (SPCD) as Alkermes’ depression drug ALKS 5461, which was also the subject of much confusion in a staff review posted by the regulator on Tuesday — the design brought up a host of unresolved statistical questions regarding the most appropriate method of analysis in SPCD.
The SPCD design involves two stages:
- In the first stage, patients either get the drug or a placebo, but more patients are randomized to get the placebo
- In the second stage, non-responders from the placebo group are re-randomized to get the drug or the placebo
Results from the two stages are then pooled to provide a single overall test of hypothesis. The trial tested pimavanserin against a placebo in 207 adult MDD patients who had not adequately responded to existing first-line therapy.
In the first stage, patients on pimavanserin (n=52) demonstrated a significant improvement in HAMD-17 (p=0.0003) versus placebo (n=155).
But significantly, in the second stage, patients on pimavanserin (n=29) did not show a significant separation from placebo (n=29), prompting critics to suggest the trial was a failure dressed in sheep’s clothing.
Acadia concluded that in the “weighted merged analysis” of the two stages, the drug just met the main goal (p=0.039) of inducing a statistically significant reduction in depressive symptoms on the Hamilton depression rating scale (HAMD-17) compared to placebo. Discontinuations due to adverse events were 1.2% for pimavanserin and 3.2% for placebo, and one patient in the pimavanserin group and the placebo arm reported serious adverse events, but these SAEs were deemed not to be related to the drug and both subjects completed the study, Acadia said.
Pimavanserin belongs to a class of drugs called selective serotonin inverse agonists (SSIA), which targets the 5-HT2A receptor that is believed to play a critical role in depression, psychosis, and other neuropsychiatric disorders.
The controversial drug, which is already sold under the brand name Nuplazid for Parkinson’s disease psychosis, gained notoriety after a series of reports suggested its maker had misrepresented the dangers of using the drug and had employed questionable tactics to market it, prompting an FDA review that later reaffirmed the drug’s safety profile.
Acadia aims to test the drug for MDD in a Phase III trial in the first half of 2019, and — to the surprise of analysts in a post-announcement conference call — suggested the CLARITY trial would serve as one of two pivotal trials required to submit a supplemental marketing application for an MDD approval.
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