Pimavanserin
Overview
Pimavanserin is a new chemical entity that we discovered and have advanced to Phase III development as a potential first-in-class treatment for Parkinson's disease psychosis (PDP). Pimavanserin is a small molecule that can be taken orally as a tablet 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 patent portfolio, which includes numerous issued patents covering pimavanserin in the United States, Europe and several additional countries.
We have selected PDP as our lead indication for pimavanserin and we are focused on advancing our
Phase III program toward registration for this indication. PDP is a debilitating psychiatric disorder that develops in up to
60 percent of patients with Parkinson's disease. This disorder deeply affects the quality of life of patients with Parkinson’s disease and is associated with increased caregiver distress and burden, nursing home placement, and increased mortality. Treatment of PDP poses a challenge to physicians as there are no therapies currently approved to treat patients in the United States. Physicians may attempt to address this disorder initially by decreasing the dose of the dopamine replacement drugs, which are administered to manage the motor symptoms of Parkinson's disease. However, this approach is generally not effective in alleviating psychotic symptoms and is often associated with a significant worsening of motor function in these patients.
Despite substantial limitations, currently marketed antipsychotic drugs are used off-label to treat patients with PDP. Because antipsychotic drugs block dopamine receptors, and thereby may counteract the dopamine replacement therapy, these drugs often worsen motor symptoms in patients with Parkinson's disease when used at doses required to achieve antipsychotic effects. Current antipsychotic drugs also are associated with a number of side effects, which can be problematic for elderly patients with Parkinson's disease. In addition, all current antipsychotic drugs have a black box warning for use in elderly patients with dementia-related psychosis due to increased mortality and morbidity. We believe 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. As a result, we believe that, if approved, pimavanserin will offer significant advantages relative to current antipsychotics used off-label for the treatment of PDP.
We are conducting several clinical trials in our Phase III program with pimavanserin for PDP, including a pivotal Phase III trial (-020 Study), designed to evaluate the efficacy, tolerability and safety of pimavanserin as a treatment for patients with PDP. The -020 Study builds on the signals of efficacy observed in our earlier PDP studies and incorporates several study design enhancements guided by the previous data and experience we have gained in our PDP program. We also are continuing to conduct an open-label safety extension trial (-015 Study) consisting of patients who have completed our earlier Phase III studies as well as patients who complete the -020 Study. Patients are eligible to enroll in the -015 Study if, in the opinion of the treating physician, the patient 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.
In September 2009, we announced top-line results from an initial Phase III PDP trial (-012 Study). While the
-012 Study was impacted by a larger than expected placebo response and did not meet its primary endpoint, signals of antipsychotic efficacy were consistently observed in the 40 mg pimavanserin arm. These signals were most prominent in the United States portion of the study, which comprised nearly one-half of the patients in the study. The -012 Study met the key secondary endpoint of motoric tolerability and pimavanserin was generally safe and well tolerated in the study.
On the basis of the data from the -012 Study, during 2010 we concluded a second Phase III PDP trial
(-014 Study) early and analyzed this study in order to use the findings to support our design of the
-020 Study. In the -014 Study, the 20 mg pimavanserin arm showed a signal of efficacy on the primary assessment scale and a statistically significant difference from placebo on a secondary outcome measure. The -014 Study met the key secondary endpoint of motoric tolerability and pimavanserin was generally safe and well tolerated in the study.
Other Indications
We believe that pimavanserin also has the potential to address a range of other neurological and psychiatric disorders that are underserved by currently available antipsychotics and represent large unmet medical needs. This may include treatment for psychoses associated with other neurological disorders, including Alzheimer’s disease, and as a co-therapy for schizophrenia.
Current drugs used to treat schizophrenia have substantial limitations, including severe side effects and inadequate efficacy. We believe that combining pimavanserin with a low dose of risperidone, a commonly prescribed atypical antipsychotic drug, may result in enhanced efficacy and fewer side effects relative to existing treatment, thereby providing an improved therapy for patients with schizophrenia and, potentially, related psychiatric disorders.
In 2007, we reported positive results from a Phase II clinical trial that demonstrated several advantages of co-therapy with pimavanserin and a low dose of risperidone. These advantages included enhanced efficacy comparable to that of a higher, standard dose of risperidone, a faster onset of antipsychotic action, and an improved side effect profile, including significantly less weight gain compared to the standard dose of risperidone.
The diagnosis of Alzheimer’s disease psychosis (ADP) is associated with more rapid cognitive and functional decline and institutionalization for Alzheimer’s patients. Patients with ADP share many common characteristics with patients with PDP. They are typically elderly and frail, and often exhibit similar psychiatric symptoms associated with their underlying neurodegenerative disease. There is no proven safe and effective therapy for ADP in the United States. As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in these 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.
Because of its mechanism of action and the favorable safety profile observed to date in studies conducted in elderly patients with PDP, we believe that pimavanserin also may be ideally suited to address the need for a new treatment of ADP that is safe, effective and well tolerated.
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