Acadia scores big with pimavanserin data but new trial awaits

Acadia Pharmaceuticals has learned its lesson well. Restricting recruitment to moderate and severely psychotic Parkinson’s disease patients in its pivotal trial of pimavanserin appears to have limited the placebo response that had waylaid the drug in earlier tests.

Shares more than doubled to $5.43 on the news, breaking them out of the range-bound state they have been in since a first trial failed in 2009. The California company is now planning a confirmatory phase III. And with $23m in the bank, a $15m pricetag on the trial and potentially two more years to wait for results, a new fundraising is likely if no partners sign on the dotted line soon.

Eliminating the positive

The placebo effect is the bane of clinical trial designers and is especially problematic in neurological indications – as demonstrated by the inability of the ACP-103-012 trial to show that pimavanserin statistically reduced hallucinations, delusions and other psychotic symptoms (All or nothing strategy leaves Acadia in reduced circumstances, September 2, 2009).

Thus, when Acadia designed the ACP-103-020 trial, which reported on Tuesday, it took great pains to select more severely ill patients – 37% of those initially screened did not meet trial inclusion criteria – and restrict the trial to North America (Event – Acadia hopes to avoid placebo effect, September 10, 2012). The geographic focus enabled investigators to “use a small centralised group of highly trained and independent raters” in assessing patient symptoms, Dr Roger Mills, executive vice-president of development, told investors in a conference call. The ‘012 trial suffered from variability in patient care because of its global design.

“In a study, patients shouldn’t improve in a placebo arm, and in this one they didn’t,” Dr Mills said. “The placebo arm behaves like a placebo arm is supposed to.”

The care to control the placebo effect is unusual, but probably necessary to confirm whatever signs of efficacy there were in phase II; done prospectively, Acadia can probably avoid the data-mining charges that are frequently levelled at companies reporting sub-population results gleaned from post-hoc analyses.

Of course, the danger of restricting the patient population narrowly in a trial is that regulators will follow through in labelling, a worry the company sought to assuage – especially as it is so keen to point out that 60% of Parkinson’s disease patients will experience psychotic symptoms and that the alternative is to lower dopaminergic medications.

“If we can have pimavanserin in our medicine chest to treat patients we would treat (psychoses) earlier,” said Dr Stuart Isaacson, a neurology professor at Florida International University who spoke on the Acadia conference call. “We would consider its use in mild patients off-label. If we had pimavanserin, I think we would use that before we began to lower dopaminergic drugs.”

Still a long road

With an eye towards erasing any leftover doubt from the earlier failed trial, the company is now planning an ‘021 trial for pimavanserin, known also as ACP-103. Given that it began recruiting for the ‘020 trial in July 2010 and completed enrolment more than two years later, a completion date in 2014 or later seems plausible – certainly, executives said there was no plan to deviate from the “winning team” in design of its new trial, so patient recruitment will be just as selective.

That raises questions of funding: the company closed out the third quarter with $23m in cash and equivalents, and has been burning about $6m a quarter this year, primarily in R&D. Executives estimated the cost of a new trial at $15m, so the company needs money.

Whether that comes in the form of a new partnership – not long after the ‘012 failure, Acadia and Valeant Pharmaceuticals International unwound a North American deal that was a legacy from pre-merger Biovail – or a fundraising is a question that cannot be answered just yet. However, with shares now at a three-year high, a share sale in the coming weeks would be a wise move if a partner and attendant licensing fees are not immediately forthcoming; shares were down 5% in early trading today as investors took profits.

Acadia has answered some longstanding questions about whether its lead candidate actually works – but it still has to answer some important strategic ones.

To contact the writer of this story email Jonathan Gardner at [email protected]