Novel non–D2-receptor-binding treatment for Parkinson’s disease psychosis

Parkinson’s disease psychosis (PDP) is a frequent, debilitating symptom of Parkinson’s disease and current treatments may worsen motor function. In a proof-of-concept study, a novel non–D2-receptor-binding treatment for PDP called SEP-363856 improved PDP symptoms without worsening the motor parkinsonism manifestations and was well tolerated.

PDP is progressive, debilitating, and common, with a prevalence of around 60% as Parkinson’s disease progresses. Most treatment options are limited due to lack of efficacy, safety concerns, and/or exacerbation of motor symptoms. SEP-363856 is a full agonist of the TAAR1 and 5HT1A receptors. It is a potent regulator of dopamine neurotransmission and represents a novel way to prevent hyperactivity of the dopaminergic system. In a previous study, SEP-363856 demonstrated antipsychotic-like activity [1]. A proof-of-principle study evaluated safety and efficacy of SEP-363856 in PDP patients [2]. The results were shared by Dr Stuart Isaacson (Parkinson's Disease and Movement Disorders Center of Boca Raton, FL, USA).

PDP patients requiring treatment were randomised to SEP-363856 (25, 50, or 75 mg/day) or placebo. Primary endpoint was change in Scale for Assessment of Positive Symptoms–Parkinson’s Disease (SAPS-PD) after 6 weeks. The intention-to-treat population included 38 patients (SEP-363856, n=24; placebo, n=14). Mean time since onset of Parkinson’s disease and PDP were 9.0 and 2.4 years, respectively. Mean baseline SAPS-PD total score was 13.6; mean Mini-Mental State Examination (MMSE) score was 25.0.

Improvements in SAPS-PD total scores for SEP-363856 compared with placebo occurred as early as week 1; least-squares mean change from baseline at week 6 was -2.5 versus -1.4 (P=0.681; see Figure). A ≥100% improvement in SAPS-PD total score was seen in 25% versus 0% of patients. Regarding SAPS-PD subscores, there was a greater effect of SEP-363856 on hallucinations (-3.6 vs -1.9; P=0.339). Dr Isaacson also noted that SEP-363856 was relatively more effective in patients with cognitive impairment. SAPS-PD total score in patients with baseline MMSE score ≤24 was -5.2 versus -2.1 (P=0.460). No change at 6 weeks in motor parkinsonism was noted.

Figure: SAPS-PD total score over 6 weeks [2]



SAPS-PD, Scale for Assessment of Positive Symptoms–Parkinson’s Disease; SE, standard error; LS, least squares; ES, effect size.

Adverse events occurring in ≥15% with SEP-363856 versus placebo included hallucinations (24% vs 14%), confused state (20% vs 14%), dizziness (16% vs 7%), and falls (12% vs 21%). CNS adverse events seemed dose-related. Adequately powered studies are needed to confirm these findings.

1. Koblan KS, et al. N Engl J Med. 2020;382(16):1497-1506.
2. Isaacson S, et al. Efficacy and Safety of SEP-363856, a Non–D2-Receptor Binding Drug With Antipsychotic Activity, in Patients With Parkinson’s Disease Psychosis. S3.005, AAN 2021 Virtual Congress, 17-22 April.

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Posted on 16 June 202117 May 2024