Tavapadon as treatment for Parkinson’s disease: a systematic review, meta-analysis, and trial sequential analysis of randomized clinical trials

Abstract

Background: Current Parkinson’s disease therapies are often limited by adverse events from D2/D3 receptor activation. Tavapadon, a novel selective D1/D5 partial agonist, emerges as a promising alternative for effective motor control with an improved safety profile. Objective: To perform a systematic review, meta-analysis, and trial sequential analysis (TSA) of randomized controlled trials (RCTs) evaluating the efficacy and safety of tavapadon compared to placebo in patients with Parkinson’s disease. Methods: We systematically searched PubMed, Embase, and CENTRAL for RCTs comparing tavapadon with placebo. The primary efficacy outcome was the change from baseline in the combined MDS-UPDRS Part II and III scores. Secondary outcomes included MDS-UPDRS Part II and Part III individually, as well as safety profiles (incidence of adverse events, mortality, and suicidal ideation). Meta-analysis was performed using Review Manager 5.4.1 (Cochrane Collaboration), using the generic inverse-variance method for continuous variables and the Mantel-Haenszel method for dichotomous variables, both under a random-effects model. Heterogeneity was assessed using the I² statistic. A TSA was conducted to estimate the Required Information Size (RIS) and to adjust for random errors in safety outcomes. Risk of bias was assessed with the Cochrane RoB 2 tool. Results: Five RCTs were included. Pooled analysis revealed that tavapadon significantly improved motor and daily living functions compared to placebo. The primary outcome, MDS-UPDRS Part II+III, showed a significant reduction (MD -8.33; 95% CI [-13.17, -3.48]; p < 0.001; I² = 91%). Significant improvements were also observed in MDS-UPDRS Part II (MD -1.80; 95% CI [-2.64, -0.95]; p < 0.001; I² = 62%) and Part III (MD -5.67; 95% CI [-9.00, -2.33]; p < 0.001; I² = 87%). Regarding safety, tavapadon was associated with a higher incidence of general adverse events (RR 1.27; 95% CI [1.12, 1.44]; p < 0.001; I² = 58%), a finding validated by TSA, which crossed the RIS threshold (370 patients). However, there were no significant differences in severe outcomes, such as mortality (RR 0.63; 95% CI [0.11, 3.51]; p = 0.60) or suicidal ideation (RR 2.09; 95% CI [0.49, 8.88]; p = 0.32). TSA for mortality indicated a large RIS (157,179), suggesting no clinical difference between groups. Conclusion: Tavapadon demonstrates robust efficacy in reducing motor and functional symptoms in Parkinson's disease. While associated with a predictable and significant increase in general, manageable adverse events, it shows a highly favorable safety profile concerning severe outcomes, such as mortality and suicidal ideation.