For Acadia’s Pimavanserin, The Second Time Is The Charm

Acadia’s serotonin 5-HT2A receptor blocker demonstrated efficacy in a Phase III trial in patients with Parkinson’s disease psychosis, giving the drug a second chance to reach the market. Pimavanserin previously failed to demonstrate efficacy in an original Phase III trial.

Acadia Pharmaceuticals Inc.’s late-stage drug pimavanserin demonstrated statistically significant efficacy in patients with Parkinson’s disease psychosis in a Phase III trial, reigniting investor interest in the asset, which failed to demonstrate efficacy in an initial Phase III trial back in 2009. Acadia announced the new data Nov. 27, sending the company’s shares up 181% in pre-market trading to open at $6.48.The stock closed the day up 136% at $5.43.

The positive news marks a turning point for Acadia, which has held out hope for pimavanserin even after the first Phase III trial failed due to a high placebo effect and the drug lost its development partner Valeant Pharmaceuticals International Inc. The development deal originated with [Biovail SA], which was acquired by Valeant in September 2010. Valeant returned rights to pimavanserin to Acadia shortly after the acquisition closed because the product was not consistent with the new company’s vision to be a traditional specialty pharma with a focus on emerging markets (Also see "Deals Of The Week: Sanofi, Teva, Ablexis; Kadmon Emerges From Stealth Mode" - Pink Sheet, 1 Nov, 2010.).

Investors haven’t shared management’s optimism, however; Acadia’s stock hasn’t traded above $3 since August 31, 2009, the day prior to the original data release, and frequently has struggled to stay above $1. Acadia did manage to convince investors, including New Enterprise Associates and Venrock Associates, to back a private placement in January 2010, however, with the company grossing $15 million to put toward the Phase III study [See Deal]. Pimavanserin was discovered in Acadia’s laboratories and the company currently owns full rights to the drug.

“Our strategy currently focuses on advancing our Phase III PDP program toward registration,” said CEO Uli Hacksell during a same-day conference call, outlining the 020 study results. Acadia is planning to initiate a second confirmatory Phase III study, 021, which will be identical to the 020 in study design. The company would not provide a timeline for starting the study. However, in an interview, Hacksell said the study should take about two years to complete, on par with the length of the 020 trial.

“We also intend to use this program as a foundation to develop and commercialize pimavanserin for other neurological and psychiatric disorders that are underserved by currently available antipsychotic drugs,” he added during the conference call, pointing to conditions like Alzheimer’s disease psychosis and schizophrenia as other potential areas of study.

Pimavanserin is a non-dopaminergic product so it doesn’t block dopamine, the primary target of existing Parkinson’s treatments that address motor symptom impairments. Existing antipsychotics typically aren’t given to Parkinson’s disease patients because they target the dopamine receptors.

Enhancements To The 020 Study Design

The 020 study tested a single 40 mg dose of pimavanserin versus placebo. The trial met the primary endpoint of demonstrating a highly significant antipsychotic efficacy in treated patients, measured using the SAPS-PD scale, a nine-item scale adapted from the hallucinations and delusions domains of the Scale for the Assessment of Positive Symptoms. Patients treated with pimavanserin had a 5.79 point improvement in psychosis at day 43 compared to a 2.73 point improvement for those on placebo. Acadia called the results “highly significant and clinically meaningful.”

The study also met the secondary endpoint for motoric tolerability as measured using Parts II and III of the Unified Parkinson’s Disease Rating Scale, demonstrating that treatment did not impact motor symptoms. Additionally, clinical benefits were observed in exploratory efficacy measures including improvements in nighttime sleep, daytime wakefulness and caregiver burden. Developing trial endpoints in neurological conditions like PDP is particularly challenging given that endpoints generally are not well validated. However, FDA reviewed the design of the 020 study and looked at it “favorably,” Hacksell said.

The primary and secondary endpoints in the 020 study were the same as those in the original 012 trial, but there were several modifications that likely influenced the different outcomes. The 020 study exclusively enrolled patients in North America, whereas the original study enrolled about half the patients in the U.S. and half in Eastern Europe and India, where the standard of care is inferior, which could have impacted the high placebo response rate.

Acadia also used a higher threshold to measure moderate to severe psychosis in patients as it screened them on the Neuropsychiatry Inventory Scale before they could enter the trial. That helped the company screen out patients who might respond to placebo, Executive VP-Development Roger Mills said during the conference call.

“The modifications that we made to the study really gave the drug a chance to show what it’s capable of doing,” he said.

If the second trial is successful and pimavanserin reaches the market, the opportunity in Parkinson’s alone could be quite significant. There are about 1 million people in the U.S. and 4 million to 6 million people worldwide with Parkinson’s disease, Acadia said, citing statistics from the National Parkinson’s Foundation. Psychosis develops in about 60% of those patients and there currently is no FDA-approved treatment for the disorder, which includes visual hallucinations and delusions and is associated with increased institutionalization and increased morbidity and mortality.

But in the meantime, Acadia will need access to financing to complete the second trial and move pimavanserin toward registration unless it signs a new partner. The trial will cost about $15 million to run, the company estimated. Acadia had $23.1 million in cash and equivalents as of Sept. 30, 2012, enough money to fund operations for about one year.

As for partnering plans, Hacksell said the company isn’t rushing to find a new partner. “We may consider in the future partnering opportunities in particular when it comes to seeing if it is possible to accelerate development of pimavanserin in other regions of the world outside of the U.S.,” he said. Ultimately, the company hopes to commercialize pimavanserin for PDP in the U.S.