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NUPLAZID™ (pimavanserin)

Overview

NUPLAZID™ (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 psychosis associated with Parkinson's disease. Pimavanserin is also in Phase II development for Alzheimer's disease psychosis and has successfully completed a Phase II trial in schizophrenia. NUPLAZID is our proprietary small molecule that is a selective serotonin inverse agonist preferentially targeting 5-HT2A receptors believed to play an important role in psychosis. We believe that NUPLAZID, if approved, will establish a new and distinctly different pharmacological approach to treating psychosis. We hold worldwide rights to NUPLAZID and have established a broad patent portfolio that includes numerous issued patents covering NUPLAZID in the United States, Europe and several additional countries.

Parkinson's Disease Psychosis (PDP)

We have selected PDP as our lead indication for NUPLAZID and we are focused on advancing our program to registration for this indication. PDP is a debilitating disorder that occurs in about 40 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 NUPLAZID may represent an effective, safe and well-tolerated treatment for 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 NUPLAZID in patients with PDP. NUPLAZID met the primary endpoint of the study by demonstrating a highly significant reduction in psychosis versus placebo. NUPLAZID 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, NUPLAZID 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 U.S. Food and Drug Administration (FDA) and thereafter announced that the agency agreed that the data from the -020 Study, together with supportive data from our other studies with NUPLAZID, can serve as the basis for submitting a New Drug Application (NDA) for the treatment of PDP. In addition, the FDA has granted Breakthrough Therapy designation to NUPLAZID for the treatment of PDP. This designation was created by the FDA to expedite the development and review of drugs that are intended to treat serious or life-threatening indications. For indications without an approved therapy, drugs qualifying for this designation must show a substantial and clinically meaningful effect on an important outcome when compared with placebo. 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, referred to as the -015 Study, consisting of patients who completed the -020 Study, as well as patients from previous PDP trials, and who, in the opinion of their treating physician, may benefit from continued treatment with NUPLAZID. 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 NUPLAZID.

Alzheimer's Disease Psychosis (ADP)

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 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 also 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 serotonin inverse agonist preferentially targeting 5-HT2A receptors may allow it to be effective for treatment in the maintenance phase of schizophrenia. We believe that it may be desirable to avoid interaction with dopamine receptors, which may be associated with many of the side effects caused by existing antipsychotic drugs. As a stand-alone treatment, we believe pimavanserin can provide a well-tolerated, maintenance therapy for schizophrenia patients that may result 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 an additional study for this indication.

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