A CADIA Pharmaceuticals has reported successful Top-line results from its pivotal Phase III trial evaluating the efficacy, tolerability and safety of pimavanserin (ACP-103) in patients with Parkinson's disease psychosis (PDP). Pimavanserin is ACADIA's proprietary, non-dopaminergic product candidate that selectively blocks 5-HT2A receptors.
The primary endpoint of the trial was antipsychotic efficacy as measured using the SAPS-PD, a nine-item scale adapted from the hallucinations and delusions domains of the Scale for the Assessment of Positive Symptoms, by comparing the mean change from baseline to day 43 for pimavanserin versus placebo. SAPS-PD assessments were performed by blinded, independent centralized raters. The pimavanserin arm demonstrated a 5.79 point improvement in psychosis at day 43 compared to a 2.73 point improvement for placebo, representing a highly significant and clinically meaningful treatment difference of 3.06 points on SAPS-PD (p=0.001).
The key secondary endpoint of the trial evaluated motoric tolerability and functional outcome using Parts II and III of the Unified Parkinson's Disease Rating Scale (UPDRS). The objective of this secondary endpoint was to demonstrate that pimavanserin could achieve its antipsychotic effects without worsening motor function as compared to placebo in PDP patients. A pre-specified, non-inferiority analysis was used to compare the mean change from baseline to day 43 for pimavanserin versus placebo using a two-sided 95% CI for the treatment difference. Motoric improvements were seen in both the pimavanserin and placebo arms, and the CI associated with the treatment difference did not exceed a pre-specified margin of five points for clinically relevant change, confirming that pimavanserin met this key secondary endpoint and did not worsen motor function in PDP patients.
The secondary efficacy measure in the trial was an assessment of clinical global improvement by the investigator using the Clinical Global Impression Improvement (CGI-I) scale. Pimavanserin demonstrated a highly significant improvement on this measure (p=0.001), further supporting its antipsychotic efficacy. In addition, other clinical benefits of pimavanserin were observed in exploratory efficacy measures of sleep and caregiver burden. Sleep was assessed using the SCOPA-sleep scale, which was designed to enable the investigator to evaluate nighttime sleep and daytime wakefulness in PD patients. Pimavanserin demonstrated significant improvements on both nighttime sleep (p=0.045) and daytime wakefulness (p=0.012) on SCOPA.
Caregiver burden was assessed using the Caregiver Burden Scale. This scale was completed by the caregiver to provide a quantitative assessment of burden associated with the patient's functional/behavioral impairments, the circumstances of at-home care, as well as the caregiver's health, social life and interpersonal relations. Pimavanserin demonstrated a highly significant improvement on the Caregiver Burden Scale (p=0.002).
Consistent with previous studies, pimavanserin was safe and well tolerated in this trial. Based on a preliminary analysis of safety data, the most common adverse events were urinary tract infection (11.7 per cent for placebo versus 13.5 per cent pimavenserin) and falls (8.5 per cent versus 10.6 per cent). Adverse events were generally characterized as mild-to-moderate in nature. The only serious adverse events that occurred in more than one patient were urinary tract infection (1-placebo versus 3-pimavenserin) and psychotic disorder (0 versus 2). Ninety per cent of the patients who completed the clinical phase of this trial elected to roll over into the ongoing open-label safety extension study. Patients were only eligible to participate in the extension study if the treating investigator also deemed them to be likely to benefit from continued treatment with pimavanserin.
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