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Pimavanserin

Overview

Pimavanserin is a new chemical entity that we discovered and have advanced to Phase III development, potentially positioning it to be the first drug approved in the United States for the treatment of Parkinson's disease psychosis (PDP). Pimavanserin is also in Phase II development for Alzheimer's disease psychosis and has successfully completed a Phase II trial as a co-therapy in schizophrenia. Pimavanserin is a small molecule that is formulated as a tablet and can be taken orally once-a-day. Pimavanserin selectively blocks the activity of the 5-HT2A receptor, a drug target that plays an important role in psychosis. We hold worldwide rights to pimavanserin and have established a broad patent portfolio, which includes numerous issued patents covering pimavanserin in the United States, Europe and several additional countries.

Parkinson's Disease Psychosis

We have selected PDP as our lead indication for pimavanserin and we are focused on advancing our Phase III program to registration for this indication. PDP is a debilitating disorder that develops in up to 60 percent of patients with Parkinson's disease. This disorder, commonly consisting of visual hallucinations and delusions, substantially contributes to the burden of Parkinson's disease and deeply affects the patient's quality of life. PDP is associated with increased caregiver distress and burden, nursing home placement, and increased morbidity and mortality. Currently, no drug is approved to treat PDP in the United States. We believe that pimavanserin has the potential to be the first safe and effective drug that will treat PDP without compromising motor control, thereby significantly improving the quality of life for patients with Parkinson's disease.

We have reported successful results from a pivotal Phase III clinical trial, referred to as the -020 Study, evaluating the efficacy, tolerability and safety of pimavanserin in patients with PDP. Pimavanserin met the primary endpoint of the study by demonstrating a highly significant reduction in psychosis. Pimavanserin also met the key secondary endpoint for motoric tolerability. These results were further supported by highly significant improvements in all secondary efficacy measures and by statistically significant benefits in exploratory efficacy measures of nighttime sleep, daytime wakefulness, and caregiver burden. Consistent with previous studies, pimavanserin was safe and well tolerated in this Phase III trial. Results of the -020 Study were published in The Lancet.

Following our successful -020 Study, we met with the FDA and thereafter announced that the agency agreed that the data from the -020 Study, together with supportive data from our other studies with pimavanserin, are sufficient to support the filing of an NDA for the treatment of PDP. We are currently completing the remaining aspects of our development program that are needed for submission of this NDA.

We also are continuing to conduct an open-label safety extension trial (‑015 Study) consisting of patients who completed the ‑020 Study, as well as patients from previous PDP trials, who, in the opinion of their treating physician, may benefit from continued treatment with pimavanserin. This open-label study coupled with a similar extension study in connection with our earlier Phase II PDP trial has generated a considerable amount of long-term safety data on pimavanserin.

Alzheimer's Disease Psychosis

We believe that pimavanserin also has the potential to treat the psychosis associated with a range of other neurological and psychiatric disorders that are underserved by currently available antipsychotics and represent large unmet medical needs. These may include treatment for psychoses associated with other neurological disorders, including Alzheimer's disease.

According to the Alzheimer's Association, an estimated 5.2 million people in the United States have Alzheimer's disease and it is currently the fifth leading cause of death for people age 65 and older. While diagnostic criteria for Alzheimer's disease mostly focus on the related cognitive deficits, it is often the behavioral and psychiatric symptoms that are most troublesome for caregivers and lead to poor quality of life for patients. These symptoms include agitation, aggressive behaviors, and psychosis. Studies have suggested that approximately 25 to 50 percent of Alzheimer's disease patients may develop psychosis, commonly consisting of hallucinations and delusions. The diagnosis of Alzheimer's disease psychosis (ADP) is associated with more rapid cognitive and functional decline and increased institutionalization.

The FDA has not approved any drug to treat ADP. As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in ADP patients. Current antipsychotic drugs are associated with a number of side effects, which can be problematic for elderly patients with Alzheimer's disease. In addition, antipsychotic drugs may exacerbate the cognitive disturbances associated with Alzheimer's disease. Current antipsychotic drugs also have a black box warning for use in elderly patients with dementia-related psychosis due to increased mortality and morbidity.

Because of its selective mechanism of action and its efficacy and safety profile observed to date in studies conducted in elderly patients with Parkinson's disease psychosis, we believe that pimavanserin also may be ideally suited to address the need for a new treatment for ADP that is safe, effective, and well tolerated.

We are currently conducting a Phase II trial, referred to as the -019 Study, designed to examine the efficacy and safety of pimavanserin as a treatment for ADP. The -019 Study is a randomized, double-blind, placebo-controlled study designed to enroll about 200 patients with ADP. The study will assess several key efficacy endpoints, including psychosis, agitation/aggression, and sleep/nighttime behavior, as well as additional exploratory endpoints, including the cognitive status of patients and the durability of response to pimavanserin.

Schizophrenia

We believe pimavanserin may be able to play a beneficial role in the treatment of schizophrenia. Schizophrenia is a severe chronic mental illness that involves disturbances in cognition, perception, emotion, and other aspects of behavior. Schizophrenia is associated with persistent impairment of a patient's social functioning and productivity. Cognitive disturbances often prevent patients with schizophrenia from readjusting to society. As a result, patients with schizophrenia are normally required to be under medical care for their entire lives.

According to the National Institute of Mental Health, approximately one percent of the U.S. population suffers from schizophrenia. Current drugs used to treat schizophrenia have substantial limitations, including a range of side effects and inadequate efficacy.

Pimavanserin's selective blockade of the 5-HT2A receptor may enable it to be used in two different treatment approaches for patients with schizophrenia. First, pimavanserin may be used as a co-therapy, together with low doses of existing atypical antipsychotic drugs such as risperidone, to obtain a more optimal balance between 5-HT2A receptor blockade and partial dopamine receptor blockade. This co-therapy approach has the potential to result in enhanced efficacy and fewer side effects relative to existing treatments.

Second, in the maintenance phase of schizophrenia therapy, we believe that it may be desirable to use a treatment that selectively blocks the 5-HT2A receptor and avoids interaction with dopamine receptors, which may be associated with many of the side effects caused by existing antipsychotic drugs. Therefore, we believe that pimavanserin also may have the potential to be used as a stand-alone treatment to provide a well-tolerated maintenance therapy for schizophrenia patients that results in better compliance compared to existing antipsychotic drugs.

We published results in 2012 from an earlier multi-center, double-blind, placebo-controlled Phase II trial designed to evaluate pimavanserin as a co-therapy in patients with schizophrenia. The trial results showed several advantages of co-therapy with pimavanserin and a 2 mg, or low, dose of risperidone in patients with schizophrenia. These advantages included efficacy comparable to that of a 6 mg, or standard, dose of risperidone, combined with a faster onset of antipsychotic action and an improved side effect profile, including significantly less weight gain, compared to the standard dose of risperidone. We are currently planning additional studies for this indication.

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