Acadia Pharmaceuticals Inc. kicked off the first of two pivotal Phase III trials planned for pimavanserin in Parkinson's disease psychosis.

The second Phase III trial is scheduled to begin after the first is "completely up and running," according to Thomas Aasen, Acadia's vice president, CFO, secretary and treasurer. Acadia has not yet provided specific timelines relating to the trials, but its successful completion is likely to serve as the basis for a regulatory filing.

The designs of the two Phase III trials will be similar, Aasen said. The first is a double-blind, placebo-controlled study that will randomize 240 patients to receive 10 mg of pimavanserin, 40 mg of pimavanserin, or placebo once-daily for six weeks. Patients also will receive stable doses of their existing dopamine replacement therapy. The primary endpoint is antipsychotic efficacy as measured by the Scale for the Assessment of Positive Symptoms (SAPS), while the secondary endpoint is motoric tolerability according to the Uniform Parkinson's Disease Rating Scale (UPDRS).

In a Phase II trial, pimavanserin met its primary endpoint of motoric tolerability as measured by the UPDRS. The drug did not worsen motor function as antipsychotics often do. However, in the secondary endpoint of antipsychotic efficacy, pimavanserin hit statistical significance according to Part I of the UPDRS (p<0.05) but not according to the SAPS (p<0.09) in the overall population. (See BioWorld Today, March, 27, 2006.)

Acadia's executive vice president of development, Roger Mills, explained that the Phase II trial was powered only to achieve the primary endpoint of motoric tolerability, although the company was "pleased to see" the indications of antipsychotic efficacy as well. He said Acadia chose SAPS as the primary endpoint measurement in the Phase III trial because the "clinical manifestations of psychosis are primarily around positive symptoms such as hallucinations and delusions."

As of now, there are no FDA-approved treatments for Parkinson's disease psychosis, which affects up to 40 percent of the 1.5 million Americans with Parkinson's and often necessitates the transition into a nursing home. Physicians respond by reducing the dopamine agonist therapy used to control tremors, which can result in a loss of motor control. Failing that, they prescribe atypical antipsychotics off-label.

Yet atypical antipsychotics antagonize both 5-HT2A and dopamine D2 receptors, Mills explained. That dopamine antagonism once again counters the effects of dopamine agonist therapy and reduces motor control. And the atypicals "carry other baggage in terms of side effects," he added.

Enter pimavanserin (ACP-103), which is selective for the 5-HT2A receptor, also is an inverse agonist rather than an antagonist, which gives it a more "complete block" of the signal, Mills said.

Another company selectively targeting 5-HT2A is Arena Pharmaceuticals Inc., which has the 5-HT2A antagonist APD125 in Phase II for insomnia and the 5-HT2A inverse agonist APD791 in preclinical trials for cardiovascular indications.

Acadia also has an insomnia program for pimavanserin, as well as a schizophrenia program. A proof-of-concept trial in insomnia demonstrated that the drug significantly increased slow wave sleep and positively impacted sleep maintenance, and Acadia is considering additional studies. In schizophrenia, positive Phase II data showing a statistically significant antipsychotic effect in combination with Risperdal (risperidone, Johnson & Johnson) doubled Acadia's stock price. The company is completing the final analysis from that study. (See BioWorld Today, March 20, 2007.)

In both insomnia and schizophrenia, Acadia plans to explore strategic alliances for pimavanserin. The company plans to retain commercial rights in Parkinson's disease psychosis, which Aasen characterized as a "high-value specialty market."

Beyond pimavanserin, Acadia is developing a schizophrenia drug called ACP-104 that will begin Phase IIb trials later this month. The company also has a Phase II neuropathic pain drug and preclinical ophthalmologic drug partnered with Allergan Inc., as well as a muscarinic receptor discovery deal with Sepracor Inc. And then there's the slew of preclinical programs resulting from Acadia's in-house discovery engine.

As of March 31, Acadia reported $69.9 million in cash, equivalents and investments available to fund its programs. Additionally, the company raised $96.1 million in net proceeds through a public offering in April 2007. (See BioWorld Today, April 6, 2007.)

Shares of San Diego-based Acadia (NASDAQ:ACAD) traded up 3.5 percent, or 50 cents, to close at $14.46 on Monday.