Pimavanserin is an investigational new drug for Parkinson's Disease Psychosis (PDP), which successfully completed clinical development by Acadia Pharmaceuticals Inc. (NASDAQ: ACAD), an R&D company headquartered in San Diego focused on CNS and expanding into ophthalmic indications. The New Drug Application (NDA) was accepted by the Food and Drug Administration (FDA) in November 2015 and the drug was designated a breakthrough therapy warranting a priority review with the PDUFA date on May 1st, 2016.
Non-Motor Dysfunction Symptoms of Parkinson's Disease is Psychosis: Hallucinations, Delusions, and Illusions
An estimated seven to ten million people worldwide are affected by Parkinson's disease (PD), including one million Americans. Furthermore, 60,000 Americans are diagnosed with PD each year, which contributes to the global cost of $60 billion per year.
Neurodegeneration, present in PD, leads to motor dysfunction and non-motor symptoms, such as psychosis. Over 50% of patients with PD develop psychosis later in the course of the disease, which translates into estimates of 5 million affected patients worldwide. It typically accompanies the dementia in PD and is characterized by hallucinations (seeing things that are not there), delusions (false, often paranoid beliefs), disorganized thoughts, and agitation. It results in a significant distress for patients and caregivers. The psychosis can be progressive, extremely challenging to treat by currently available therapies, and leads to increased likelihood of placement in nursing homes and increased mortality.
Pimavanserin (ACP-103, Nuplazid) addresses the severe side effects and low efficacy of the current standard of care for PDP
The current therapies for PDP are antipsychotics that are non-specific for this disease. They all exhibit severe side effects or low efficacy. Antipsychotics can be classified as typical and atypical. The typical antipsychotics, while treating psychosis, worsen parkinsonism. The atypical antipsychotics are poorly tolerated or not efficacious. For example, the atypical antipsychotic clozapine brings significant benefits in psychosis without worsening of motor symptoms in PD, but carries a black box warning for a series of severe side effects, such as agranulocytosis (low white blood cell counts), mortality, seizures, cardiovascular and respiratory adverse effects. Other antipsychotic drugs, such as risperidone, olanzapine, or quetiapine trigger severe parkinsonian side effects without any benefit. Therefore, safe and efficacious treatment options for PDP are a clinical priority.
There are multiple possible ways of repairing neurotransmission (i.e., communication between the cells of the central nervous system) which went awry in PDP. While the currently marketed atypical antipsychotics target the so-called 5-HT2 (serotonergic) pathway of neurotransmission, they are "dirty" in the sense that they also interfere with several other pathways (such as dopaminergic and others), leading to side effects. Acadia reasoned that the key to treating PDP in an efficacious way without side effects is in developing a "clean" molecule, which hits its target very specifically, without affecting any other (non-specific) targets and thus eliminating the possibility of causing any collateral damage. Therefore, the company developed pimavanserin, a compound exquisitely selective for the 5-HT2A pathway of neurotransmission.
Pimavanserin is more efficacious and less risky than the current standard of care
Acadia carried out a randomized, double-blind, parallel group, placebo-controlled clinical trial at 52 centers in the US and Canada, which enrolled patients of at least 40 years of age whose psychotic symptoms developed at least 1 year after PD diagnosis. The study was published in The Lancet, a highly influential medical journal (Cummings et al, Lancet, 2014, 383(9916):533-40). The symptoms were present for over one month, occurred at least weekly, and were severe enough to require treatment with antipsychotics. Exclusion criteria included psychosis due to metabolic disorders, intoxications or other drug side effects, dementia concurrent with/or preceding the diagnosis of PD, history of stroke, a serious medical illness, clinically significant laboratory abnormalities or previous use of antipsychotics and centrally acting anticholinergics. Participants receiving antiparkinsonian drugs or having deep brain stimulation were required to be on stable dosage and settings throughout the trial and one month before enrollment. Inclusion criterion was a combined score of at least 6 or an individual score of at least 4 on the neuropsychiatric inventory items A (delusions) and/or B (hallucinations).
Assessments were done at baseline and days 15, 29, and 43. The primary outcome was a change in total SAPS-PD score (scale for assessment of positive symptoms in PD, assessing nine items, seven individual symptoms and two global: hallucinations and delusions) from baseline to day 43, whereas the secondary outcomes were a change in clinical global impression-severity by day 43 and improvement scale scores (caregiver burden scale, disease sleep, daytime wakefulness) by day 43.
The patients receiving a single oral dose of 40 mg pimavanserin exhibited a significant improvement in psychosis compared with placebo by day 43 (p=0.001). The study met all of its primary and secondary end points. The authors demonstrated that side effects (adverse events) were overall not severe (most common were urinary tract infections, fall, and nausea). They were observed in an essentially equal number of patients in the group receiving placebo (94 participants) and pimavanserin (104 participants), which indicates that the symptoms were not caused by the drug. FDA review initially noted that serious adverse events occurred in 16/202 (7.9%) patients taking pimavanserin- versus 8/231 (3.5%) placebo-treated patients and consequently raised a red flag. However, a subsequent meeting of the Advisory Committee recognized that the benefits of the drug seem to strongly outweigh the risks. The panel eventually voted 12 to 2 in favor of approving the drug on March 29th, 2016. The conclusion was that pimavanserin clearly improved the PDP symptoms without worsening PD motor symptoms, which is a major advancement in the field and a key feature that sets it apart from all currently available therapies.
Pimavanserin will become the new standard of care - without any competitors
The clinical data and the outcome of the Advisory Committee meeting demonstrate that pimavanserin will be a game-changer for millions of patients suffering from PDP. It will be the best in class for PDP and is estimated to become a blockbuster generating $1.4 billion in revenues by 2020. While the FDA is not obliged to follow the recommendation of its Advisory Committee, most often it does so, and odds are that this will be such a case. Even though the stock price already skyrocketed on the outcome of the Advisory Committee meeting, there is significant potential to profit from its further run. For example, on the short term through the PDUFA date on May 1st, as well as on the long term, as Acadia is currently carrying out Phase II clinical trials of pimavanserin for two other indications (Alzheimer's disease psychosis and schizophrenia), for which it owns worldwide commercialization rights. In addition, Acadia maintains a robust pipeline in other disease areas, which is partially partnered and thus de-risked.
Disclosure: I am/we are long ACAD.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: Beacon VP Investments is a team of analysts. This article was written by Goran Malojcic, PhD.This article contains forward-looking statements and information, including statements regarding the safety, efficacy and statements regarding the timing of the FDA's review of NDA. Acceptance of the NDA filing does not determine the final evaluation of the adequacy of the data submitted in the NDA and is not a guarantee of approval.