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.
To evaluate the efficacy and safety of SEP-363856 for Parkinson’s disease psychosis (PDP) treatment.
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. 
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). 
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.
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.