Psychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.
NNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.
NNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are <10, and as robust as 4, denoting that PIM is a potentially efficacious intervention. NNH values for tolerability outcomes for PIM 34 mg/d (as well as for doses that range from 8.5 mg/d to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.
Using the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.
Clinical study was funded by ACADIA Pharmaceuticals Inc.