On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Abstract

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.

Psychedelics

“…Indirect evidence for a role of 5-HT 2A receptors in mediating psychedelic-induced hallucinations comes from a study by Huot et al (2010) (Hacksell et al, 2014). Halberstadt et al (2011a) examined the effects of several psychedelics on the mouse head twitch response (HTR) in wild-type (WT) male C57BL/6J or 5-HT 2A knockout (KO) mice.…”

Novel Treatments of Psychosis

“…In patients with PDP, pimavanserin at 40 mg demonstrated clinically meaningful improvement over placebo in phase II trials on measures of psychosis on a modified SAPS-PD scale. Importantly, pimavanserin did not worsen motor symptoms [38,39].…”

“…It has nearly 100-fold more selectivity at this receptor than to 5-HT 2B , 5-HT 2C , and 5-HT 6 , and no activity at the D 2 receptor. This unique binding profile likely accounts for the lack of motor and metabolic side effects which are commonly seen with existing antipsychotics [37,38].…”

“…Currently, pimavanserin is in phase II development for Alzheimer's disease psychosis and an additional study for the treatment of schizophrenia is planned [38]. Given the positive data for PDP, a FDA new drug application (NDA) for pimavanserin as a PDP treatment will be filed in the near future [41].…”

A New Perspective in the Treatment of Parkinson’s Disease Psychosis

“…22 However, treating PDP is challenging as typical antipsychotics should not be used and atypical antipsychotics should be used with caution as they block dopamine receptors and consequently can worsen PD motor symptoms ( Table 1 and Table 2). 23 Furthermore, the FDA has issued a black box warning for the use of antipsychotics in elderly patients, particularly those with dementia, due to increased risk of morbidity and mortality [package inserts]. To date, there is no medication that is approved by the FDA for treatment of PDP, therefore all current medications used for PDP are used off label.…”