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 also in Phase II development for Alzheimer's disease psychosis and has completed a Phase II trial as a co-therapy in schizophrenia. 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.
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 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 this disorder in the United States. Physicians may attempt to address PDP initially by decreasing the dose of the dopamine replacement drugs that are administered to manage the motor symptoms of Parkinson's disease. However, this approach is generally not effective in alleviating psychotic symptoms and often comes at the cost of significantly worsening the motor functions of patients.
Despite substantial limitations, currently marketed antipsychotic drugs often are used off-label to treat patients with PDP. Due to their dopamine blocking properties, these drugs may counteract the dopamine replacement therapy and, therefore, often worsen motor symptoms in patients with Parkinson's disease. 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 risks of 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.
In November 2012, we announced successful top-line results from our pivotal Phase III trial (‑020 Study) evaluating the efficacy, tolerability and safety of pimavanserin in patients with PDP. Jeffrey Cummings, M.D., Sc.D., Director of the Cleveland Clinic Lou Ruvo Center for Brain Health, presented detailed results from our ‑020 Study at the 65th American Academy of Neurology Annual Meeting in March 2013, and The Lancet published results of this study in November 2013. The ‑020 data showed robust and consistent efficacy of pimavanserin across a wide array of study measures and confirmed the positive top-line results we had announced earlier.
Pimavanserin met the primary endpoint in the Phase III ‑020 Study by demonstrating highly significant antipsychotic efficacy on the 9-item SAPS-PD scale (p=0.001). The mean-change in SAPS-PD score represented a 37% improvement for pimavanserin versus 14% for placebo (p<0.001). Pimavanserin also met the key secondary endpoint for motoric tolerability as measured using Parts II and III of the Unified Parkinson's Disease Rating Scale, or UPDRS. Pimavanserin showed highly significant improvements in all secondary efficacy measures, including the Clinical Global Impression Severity, or CGI-S, scale (p<0.001), the Clinical Global Impression Improvement, or CGI-I, scale (p=0.001), and a CGI-I responder analyses (p=0.002). The CGI-I responder results showed that approximately twice as many subjects in the pimavanserin treatment arm, as compared to placebo, were rated as much improved or very much improved at the conclusion of the study. Statistically significant benefits were also observed in exploratory measures of nighttime sleep, daytime wakefulness, and caregiver burden. In addition, consistent with previous studies, pimavanserin was safe and well tolerated in this Phase III trial.
Following the successful ‑020 Study, we met with the U.S. Food and Drug Administration (FDA) in April 2013. The FDA agreed that the data from our pivotal Phase III ‑020 Study, together with supportive data from other studies with pimavanserin, are sufficient to support the filing of a New Drug Application (NDA) for the treatment of PDP. We are focused on completing the remaining elements of our pimavanserin PDP development program that are needed for submission of an NDA. These include customary supportive studies, such as drug-drug interaction studies, and CMC development, such as stability testing of registration batches.
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 be used to address 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.
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 and PDP share many common characteristics. They are typically elderly and frail, and often exhibit similar psychiatric symptoms associated with their underlying neurodegenerative disease. Similar to PDP, there is no therapy approved to treat 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 and also have a black box warning for use in elderly patients with dementia-related psychosis due to increased risks of mortality and morbidity.
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 for ADP that is safe, effective and well tolerated.
We are currently conducting a Phase II feasibility trial, referred to as the -019 Study, designed to examine the efficacy and safety of pimavanserin in about 200 patients with ADP. The -019 Study is being conducted through a large network of research care homes established as part of the National Institute for Health Research (NIHR) Maudsley Biomedical Research Unit. 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.
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 treatments, thereby providing an improved therapy for patients with schizophrenia and, potentially, related psychiatric disorders.
During 2012, data from our earlier Phase II co-therapy trial were published in the journal Schizophrenia Research. Our data demonstrated that co-therapy with pimavanserin and a low, sub-therapeutic dose of risperidone provided an attractive clinical profile with efficacy comparable to a high, standard dose of risperidone but with a much improved side effect profile and faster onset of action. We are planning for additional studies that we may pursue with pimavanserin in this indication.back to top