Objective: To evaluate the safety and preliminary efficacy of SYN120 in patients with Parkinson’s disease dementia (PDD).

Background: SYN120 is an antagonist of serotonin receptors (5-HT6 and 5-HT2A) shown to improve cognition in pre-clinical models.

Methods: This was a Phase 2a, randomized (1:1), double-blind, placebo-controlled, parallel-group, 16-week study conducted at 20 PSG sites in PDD patients taking a cholinesterase inhibitor. Eligible patients (i.e., meeting UKPDSBBC + NINDS/NIMH Working Group Criteria for PDD) were randomized to SYN120 100 mg daily or placebo for 16 weeks. Adverse events (AEs), UPDRS scores and study discontinuation were tracked to assess safety and tolerability. The primary and key secondary efficacy outcomes were the Computerized Drug Research Cognition Battery (CDR) Continuity of Attention (COA; sustained attention); and CDR Quality of Episodic Memory (QEM). Other secondary outcomes included: ADAS-cog, ADCS-Clinician’s Global Impression of Change (CGIC), and Penn Parkinson’s Daily Activity Questionnaire-15 (PDAQ-15), a measure of cognition-related daily function.

Results: A total of 82 patients were randomized and started study medication (SYN120=38, placebo=44), of whom 5 terminated prior to post-baseline COA assessment (i.e., SYN120=36, placebo=41 in the modified ITT efficacy sample). Treatment groups were well matched at baseline. From baseline to week 16 no significant effect of SYN120 was observed on CDR COA (effect size [ES] = 0.39 in favor of placebo; p=0.13), CDR QEM (ES=0.14 in favor of SYN120; p=0.52), ADAS-cog ([ES] = 0.05; p=0.82), ADCS-CGIC (3.8 vs 4.3; p=0.07). PDAQ-15 improved with SYN120 ([ES] = 0.54; p=0.03), while motor symptoms (UPDRS Part III) worsened (+3.6 vs -1.2 points on placebo; p=0.01). Seventy-six percent of participants experienced an AE, 11% a serious AE, and 16% discontinued study treatment with no between-group differences. Although infrequent, incidence of nausea and vomiting were two-fold higher with SYN120.

Conclusions: SYN120 did not improve cognition in PDD patients, but it may have improved cognition-based daily function. SYN120 was generally well tolerated, but a worsening in motor symptoms was observed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/syn120-a-dual-5-ht6-5-ht2a-antagonist-study-to-evaluate-safety-tolerability-and-efficacy-in-parkinsons-disease-dementia-synapse-phase-2a-study-results/