Introduction

Parkinson’s disease psychosis (PDP), with its high prevalence (60%), is a major risk factor for prolonged hospitalization and mortality. Pimavanserin, a USFDA approved selective 5-HT_2A inverse agonist, was effective for management of hallucinations and delusions associated with PDP.

Aim

To evaluate the efficacy and safety of pimavanserin in an open-label extension (OLE) study

Patient Profile

• PDP patients with moderately severe psychotic symptoms

Method

Study Design

• Open label, blinded, prespecified prospective extension study of 4 weeks
• Patients had already completed a randomized, double-blind, placebo-controlled, 6-week (Core) study with 34 mg pimavanserin or placebo
• Patients either continued treatment with pimavanserin 34 mg for 10 weeks (i.e., randomized to pimavanserin arm in Core study) or began treatment with pimavanserin 34 mg (i.e., had been randomized to placebo in the Core study) for 4 weeks

Endpoints

• Assessments with Scale for the Assessment of Positive Symptoms - Parkinson’s Disease (SAPS - PD, modified 9-item SAPS hallucinations and delusions subscales), SAPS - H+D scales (combined 20-item SAPS hallucinations and delusions subscales), Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales (CGI-S and CGI-I)
• Safety assessments

Results

Efficacy

• Pimavanserin administration in the OLE improved SAPS-PD score among patients on prior placebo in the Core Study (mean change: -3.4 from OLE baseline to Week 4, p < 0.0001) (Figure 1)
• It achieved a similar improvement in the SAPS-PD score in patients on prior pimavanserin and prior placebo treatment (mean change -6.86 vs. -6.28 at week 10, from Core study baseline to OLE Week 4)
• The improvement in SAPS - PD score with pimavanserin treatment was durable at Week 10 from Core Study baseline (mean change in SAPS - PD score: -0.43 from OLE baseline to Week 4) in patients on prior pimavanserin in the Core study (Figure 1)
• Pimavanserin reduced the SAPS – H+D scores from OLE baseline to Week 4 in the overall population (-2.3) and in those receiving prior placebo (-3.88; p < 0.0001); the improvement persisted in patients receiving prior pimavanserin (-0.69; p = 0.44)
• Improvement with pimavanserin treatment in the SAPS-H and SAPS-D scores, which was observed during the Core Study, persisted through Week 4 of OLE (mean change from OLE baseline to Week 4: -0.18 and -0.51, p = 0.18, resp.), while scores improved among patients switched from placebo to pimavanserin (mean change -2.45, p < 0.0001 and -1.43; p = 0.0027)
• In the OLE, pimavanserin achieved highest improvement in CGI-S in patients previously on placebo in the Core study (mean change from OLE baseline to OLE Week 4: -0.86, p < 0.0001) and modest significant improvement in patients previously on pimavanserin (-0.24, p = 0.04)
• Pimavanserin treatment improved the CGI-I scores from OLE baseline to Week 2 and Week 4 of the OLE in patients previously on placebo (2.9 and 2.5, respectively) while maintained them in patients previously on pimavanserin (2.5 and 2.6, respectively)
• It achieved a CGI-I response rate (very much improved/much improved) of 46.6% at Week 2 and 57.1% at Week 4
• Pimavanserin improved the CBS from Core baseline to OLE Week 4 in patients prior on placebo (mean change -1.62) while it achieved stable improvement in patients prior on pimavanserin (mean change -2.6)

Figure 1: Effect of pimavanserin on SAPS-PD score from OLE baseline to Week 4

Safety 

• Adverse events (AEs) occurred in 53.8% patients during the 4-week OLE
• AEs leading to study discontinuation were reported by 3.5% patients
• Majority of AEs were mild or moderate with serious AEs reported in 1.2% patients
• Fall (7.0%), hallucination (3.5%), urinary tract infection (5.8%), and peripheral edema (2.9%) were most commonly reported AEs
• Drug-related AEs occurred in 23.8% previous placebo-treated patients and 13.8% previous pimavanserin-treated patients
• No clinically relevant changes in serum chemistry, hematology or urinalysis or ECG findings were reported

Conclusion

The sustained improvement in the severity of psychotic symptoms with pimavanserin in the 6-week Core Study in patients with PDP, was maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks.

J Parkinson’s Dis. 2020; 10: 1389–1396