Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial

Hubert H Fernandez; Daniel Weintraub; Eric Macklin; Irene Litvan; Michael A Schwarzschild; Jamie Eberling; Aleksandar Videnovic; Christopher J Kenney; Parkinson Study Group SYNAPSE Investigators

doi:10.1016/j.parkreldis.2023.105511

Safety, tolerability, and preliminary efficacy of SYN120, a dual 5-HT6/5-HT2A antagonist, for the treatment of Parkinson disease dementia: A randomized, controlled, proof-of-concept trial

Parkinsonism Relat Disord. 2023 Sep:114:105511. doi: 10.1016/j.parkreldis.2023.105511. Epub 2023 Jul 13.

Authors

Hubert H Fernandez¹, Daniel Weintraub², Eric Macklin³, Irene Litvan⁴, Michael A Schwarzschild³, Jamie Eberling⁵, Aleksandar Videnovic³, Christopher J Kenney⁶; Parkinson Study Group SYNAPSE Investigators

Affiliations

¹ Cleveland Clinic Neurological Institute, USA. Electronic address: fernanh@ccf.org.
² University of Pennsylvania School of Medicine, Departments of Neurology and Psychiatry, USA.
³ Massachusetts General Hospital/Harvard Medical School, USA.
⁴ University of California San Diego, Department of Neurology, USA.
⁵ Michael J. Fox Foundation, USA.
⁶ Acorda Therapeutics, USA.

PMID: 37532622
DOI: 10.1016/j.parkreldis.2023.105511

Abstract

Background: SYN120 is a dual serotonin receptor (5-HT6/5-HT2A) antagonist hypothesized to improve cognition and psychiatric symptoms.

Objectives: We evaluated the safety, tolerability, and efficacy of SYN120 in patients with Parkinson disease dementia (PDD).

Methods: In a multicenter, double-blind, parallel-group, 16-week phase 2a proof-of-concept trial in PDD with concomitant cholinesterase inhibitor use, eligible patients were randomized to oral SYN120 (100 mg/day) or placebo. Adverse events (AEs), Unified Parkinson's Disease Rating Scale (UPDRS) scores, and discontinuations assessed safety and tolerability. The primary and key secondary efficacy measures were the Cognitive Drug Research (CDR) computerized assessment system Continuity of Attention and Quality of Episodic Memory scores. Other efficacy measures were: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), Brief Penn Parkinson's Daily Activity Questionnaire-15 (PDAQ-15), Scales for Outcomes in Parkinson's Disease-Sleep Scale (SCOPA-Sleep), and Neuropsychiatric Inventory (NPI).

Results: Eighty-two patients were randomized to SYN120 (N = 38) or placebo (N = 44), AEs occurred in 74% and 77% of patients, and treatment discontinuation in both groups was 16%. Nausea and vomiting were more frequent, and motor symptoms (UPDRS) worsened in the SYN120 group. At week 16, the SYN120 and placebo groups did not differ significantly for any cognitive assessment. Cognitive activities of daily living (PDAQ-15) and the NPI-Apathy/Indifference scores improved nominally in the SYN120 group compared with placebo (unadjusted p = 0.029 and 0.028).

Conclusions: SYN120 was adequately tolerated, mild worsening of motor symptoms was noted and it did not improve cognition in PDD patients. Its potential benefits for cognitive activities of daily living and apathy warrant further study.

Registration: Clinicaltrials.gov as NCT02258152.

Keywords: 5-HT2A antagonist; 5-HT6 antagonist; Apathy; Clinical trial; Cognitive impairment; PDAQ-15; Parkinson disease dementia; SYN120.

Publication types

Randomized Controlled Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Activities of Daily Living
Alzheimer Disease* / complications
Cholinesterase Inhibitors / therapeutic use
Dementia* / complications
Double-Blind Method
Humans
Parkinson Disease* / complications
Parkinson Disease* / drug therapy
Serotonin 5-HT2 Receptor Antagonists / therapeutic use
Treatment Outcome

Substances

Serotonin 5-HT2 Receptor Antagonists
Cholinesterase Inhibitors

Associated data

ClinicalTrials.gov/NCT02258152