Schizophrenia

Disease and Market Overview

Schizophrenia is a chronic, debilitating mental illness characterized by disturbances in thinking, emotional reaction and behavior. These disturbances may include positive symptoms, such as hallucinations and delusions, and a range of negative symptoms, including loss of interest, emotional withdrawal, and cognitive disturbances. Schizophrenia is associated with persistent impairment in a patient's social functioning and productivity, and patients often are under medical care for their entire lives.

According to the National Institute of Mental Health, approximately one percent of the population develops schizophrenia during their lifetime and more than two million people in the United States suffer from this disease. Worldwide sales of drugs to treat schizophrenia and other psychoses exceeded $15 billion in 2005.

Currently, schizophrenia is treated by administration of first generation (typical), or second generation (atypical) antipsychotic agents. The typical antipsychotic agents that were introduced in the late-1950s block dopamine receptors. This class of compounds is effective against positive symptoms of schizophrenia but also produces disabling motor disturbances, including akathisia, an extremely distressful motor disturbance characterized by feelings of inner restlessness and an urge to move. Typical antipsychotic drugs fail to address or worsen most of the negative symptoms of schizophrenia, and their use has decreased in the United States and Europe.

Atypical antipsychotic drugs produce fewer motor disturbances than typical antipsychotic drugs, but also fail to address most of the negative symptoms of schizophrenia. It is believed that the efficacy of atypical antipsychotic drugs is due to their interactions with dopamine and 5-HT_2A receptors. The side effects produced by the atypical agents include severe obesity, type II diabetes, hyperprolactinemia, cardiovascular side effects, and motor disturbances, including akathisia. We believe that these side effects arise from either non-essential receptor interactions that are unrelated to their efficacy or from excessive dopamine blockade.

Despite the availability of a variety of antipsychotic agents, only a portion of the negative symptoms of schizophrenia are treatable and the cognitive disturbances are poorly addressed by current therapies. Clozapine, more so than other atypical antipsychotics, appears to have the ability to partially address cognitive disturbances while typical antipsychotic drugs frequently worsen the cognitive function of the patients. We believe there is a large unmet medical need for therapies that address both the positive and negative symptoms of schizophrenia and produce fewer side effects.

ACADIA has two development programs that we believe offer innovative therapeutic solutions to major unmet medical needs in schizophrenia.

Our Schizophrenia Programs

Pimavanserin as a Co-Therapy for Schizophrenia

We are developing pimavanserin (previously referred to as ACP-103), a potent and selective 5-HT_2A inverse agonist, as a co-therapy for schizophrenia. By adding pimavanserin in combination with currently-available antipsychotic drugs, we believe that the optimal combination of 5-HT_2A inverse agonism and dopamine receptor blockade can be achieved. This co-therapy may result in enhanced efficacy and lower side effects.

In March 2007, we announced top-line results from a Phase II study that was designed to evaluate pimavanserin co-therapy when used together with either risperidone, a commonly prescribed atypical antipsychotic drug, or haloperidol, a generic typical antipsychotic drug. The co-therapy arms with pimavanserin demonstrated statistically significant antipsychotic efficacy as measured by reduction in the Positive and Negative Syndrome Scale (PANSS), which was the primary endpoint of the trial. In addition, pimavanserin co-therapy with low-dose risperidone demonstrated a statistically significant improvement in antipsychotic efficacy as compared to low-dose risperidone plus placebo, and comparable efficacy to high-dose risperidone plus placebo. Co-therapy with pimavanserin also led to a faster onset of antipsychotic action and an improved side effect profile, including less gain in weight and lower prolactin levels.

In December 2005, we announced top-line results from a Phase II study that was designed to evaluate the ability of pimavanserin to treat akathisia, a side effect often induced by antipsychotic drugs. The double-blind, placebo-controlled clinical study involved 34 patients. Results of the study showed that pimavanserin reduced haloperidol-induced akathisia in patients with schizophrenia. Pimavanserin was safe and well tolerated and no serious adverse events were reported.

In 2004, we announced results of a clinical study that assessed the ability of pimavanserin to reduce the side effects associated with haloperidol, an antipsychotic drug treatment. The double-blind, placebo-controlled clinical study involved 18 healthy volunteers. Results of the study indicated that a single treatment with pimavanserin reduced akathisia in most patients and that pimavanserin could also reduce hyperprolactinemia.

In 2003, we completed two Phase I clinical trials that assessed the safety, tolerability and blood drug levels of pimavanserin following oral administration in a total of 57 healthy volunteers. The results showed that pimavanserin was well tolerated at plasma levels of 229 nanograms per milliliter and below. No serious adverse events were reported at any plasma level of pimavanserin. In addition to our Phase I clinical trials with pimavanserin, we conducted drug receptor occupancy studies in healthy volunteers using positron emission tomography, or PET, with various single doses of pimavanserin. This study demonstrated that even low acute doses of this drug candidate produced significant occupancy of 5-HT_2A receptors in the human brain.

ACADIA is also developing pimavanserin for treatment of Parkinson's disease psychosis and sleep maintenance insomnia. For more information about these programs, please click here.

ACP-104 for Treatment of Schizophrenia

ACP-104, or N-desmethylclozapine, is the major metabolite of clozapine, and is being developed by ACADIA as a novel, stand-alone therapy for schizophrenia. It combines an atypical antipsychotic efficacy profile with the added potential benefit of enhanced cognition, thereby addressing one of the major challenges in treating schizophrenia today. ACP-104 combines M₁ muscarinic agonism, 5-HT_2A inverse agonism, and D₂ and D₃ dopamine partial agonism in a single compound and, therefore, uniquely addresses what ACADIA believes are the three most promising target mechanisms for treating schizophrenia.

In June 2007, we initiated a Phase IIb clinical trial with ACP-104 in patients with schizophrenia. The trial is designed to evaluate the safety and efficacy of ACP-104 as a treatment for patients with schizophrenia.

In July 2006, we announced results from three initial clinical studies of ACP-104 in patients with schizophrenia. We conducted a single ascending-dose study, a multiple ascending-dose study, and a positron emission tomography study that were designed to evaluate the safety, tolerability, and pharmacokinetics of ACP-104, explore preliminary signals of antipsychotic effects, and determine the relationship between plasma levels of ACP-104 and occupancy of 5-HT2A receptors in the brain. The three studies enrolled an aggregate of 74 patients with schizophrenia and were conducted in collaboration with Professor Carol Tamminga, M.D., from the University of Texas Southwestern Medical School in Dallas, Texas.

The results of these clinical studies demonstrated that ACP-104 is safe and well tolerated after repeated dosing of up to 600 mg per day, and that initial signals of antipsychotic effects were observed within the tolerated dose range of ACP-104. In addition, plasma levels of ACP-104 correlate with brain receptor occupancies indicating good penetration of ACP-104 into the brain.

In September 2005, we published research showing that ACP-104 is a partial-agonist that causes weak activation of dopamine D₂ and D₃ receptors, whereas clozapine and most other antipsychotic drugs block these receptors. We believe that these partial agonist properties of ACP-104 may lead to less motoric side effects than seen with most other antipsychotic drugs.

In July 2004, we published research linking the mechanism of ACP-104 to the superior clinical effects of clozapine, a well-characterized antipsychotic drug. The research shows how ACP-104 uniquely stimulates brain cells known as M₁ muscarinic receptors that play an important role in cognition. The journal article also describes the analysis of drug blood levels relative to clinical response obtained in two clinical trials that included 92 schizophrenia patients treated with clozapine. This analysis showed that high ratios of ACP-104 relative to clozapine resulted in better response by these patients in a wide range of clinical measures reflecting cognitive performance. We believe that by directly administering ACP-104 to schizophrenia patients, without the highly variable step of having it metabolized in the body from clozapine, we can develop an improved therapy that provides a more consistent cognitive benefit to patients.

The clinical program for ACP-104 is supported in part through a development agreement with The Stanley Medical Research Institute, the leading nonprofit organization focused on cutting edge research into treatments for schizophrenia.