Efficacy and Safety of SEP‑363856, a Non–D2-Receptor Binding Drug With Antipsychotic Activity, in Patients With Parkinson’s Disease Psychosis
Stuart Isaacson1, Mark Goldstein2, Rajesh Pahwa3, Carlos Singer4, Kevin Klos5, Ian Zhang6, David Crandall6, Bradford Navia6
1Parkinson's Dis & Mov Dis Ctr of Boca Raton, 2JEM Research Institute, 3University of Kansas, 4University of Miami Health System, 5The Movement Disorder Clinic of Oklahoma, 6Sunovion Pharmaceuticals Inc.
Objective:
To evaluate the efficacy and safety of SEP-363856 for Parkinson’s disease psychosis (PDP) treatment.
Background:
PDP is a frequent, debilitating symptom of PD; current treatments may worsen motor function. In a pivotal study, SEP-363856—a trace amine-associated receptor-1 agonist with 5-hydroxytryptamine 1A agonist activity—was effective and generally well-tolerated for acute psychosis in schizophrenia. 
Design/Methods:
In this controlled study (NCT02969369), patients with PDP requiring treatment were randomized (2:1) to flexibly dosed SEP-363856 (25, 50, or 75 mg/day) or placebo. Primary endpoint was Scale for Assessment of Positive Symptoms–Parkinson’s Disease (SAPS-PD). 
Results:
The modified intention-to-treat population included 38 patients (SEP-363856, n=24; placebo, n=14). Mean (SD) baseline SAPS-PD total score was 14.6 (7.19) and Mini-Mental State Examination (MMSE) score was 24.3 (4.63). Numerical improvements in SAPS-PD total scores for SEP-363856 versus placebo occurred as early as week 1; least-squares mean (SE) change from baseline at week 6 was ─2.5 (1.62) versus ─1.4 (2.06; P=0.681). Remission (≥100% improvement in SAPS-PD total score) occurred in 25% versus 0% of patients. Greater effects were seen for SAPS-PD Hallucinations subscale score [─3.6 (1.07) versus ─1.9 (1.35; P=0.339)] and SAPS-PD total score in patients with baseline MMSE score ≤24 [─5.2 (2.81) versus ─2.1 (3.00; P=0.460)]. Unified Parkinson’s Disease Rating Scale Parts II and III demonstrated no change at 6 weeks in motor parkinsonism. Neuropsychiatric Inventory-Hallucination subscale but not Clinical Global Improvement–Severity scores showed similar improvement. Adverse events (occurring in ≥15%) with SEP-363856 versus placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), and falls (12% vs 21%). Incidence of CNS adverse events appeared dose-related.
Conclusions:
In this proof-of-concept study, improvements across several scales without worsening motor parkinsonism suggest that SEP-363856 may provide a novel non-D2-receptor blocking treatment for PDP, particularly for patients with cognitive impairment. SEP-363856 was generally well-tolerated. Additional studies are warranted.