Safety, tolerability, and efficacy of flexible-dose tavapadon for Parkinson's disease (TEMPO-2): a phase 3, randomised, placebo-controlled, double-blind trial.

Abstract (English)

BACKGROUND: Current dopaminergic therapies for Parkinson's disease carry significant limitations: levodopa can cause long-term motor complications, while D2/D3 receptor-targeting dopamine agonists can produce non-motor adverse effects. Tavapadon is an oral, once-daily, selective D1/D5 agonist that might improve Parkinson's disease motor symptoms. We aimed to evaluate the safety, tolerability and efficacy of flexible-dose tavapadon in people with early-stage Parkinson's disease. METHODS: TEMPO-2 was a phase 3, randomised, double-blind, placebo-controlled trial conducted at 75 clinical sites (both hospital or academic and community settings) across 13 countries. Adults aged 40-80 years with early-stage Parkinson's disease (<3 years' disease duration) who were treatment-naive or had less than 3 months of previous dopaminergic treatment were eligible. Participants were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg) or placebo orally once daily for 27 weeks. The primary endpoint was change from baseline to week 26 in the combined score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III (reflecting activities of daily living and motor performance). Safety endpoints included adverse events, clinical laboratory values, vital signs, and electrocardiograms. The primary endpoint was assessed in the modified intent-to-treat population (participants who received one dose or more of study drug and had both a baseline and one or more post-baseline MDS-UPDRS assessments) and safety was assessed in the safety analysis set (all participants who received one dose or more of tavapadon or placebo). This study is registered with ClinicalTrials.gov (NCT04223193) and is now complete. FINDINGS: Between Jan 6, 2020, and Feb 22, 2024, 473 individuals were screened and 304 were randomly assigned to receive tavapadon 5-15 mg (n=151) or placebo (n=153). The majority of participants were male (169 [56%] of 304 male; 135 [44%] of 304 female), the mean age was 62&#xb7;9 (SD 9&#xb7;2) years, and the mean disease duration was 0&#xb7;86 (0&#xb7;79) years. 80 (26%) of 304 participants discontinued from the trial (57 [38%] of 151 on tavapadon and 23 [15%] of 153 on placebo), most commonly due to adverse events (42 [14%] of 304; 36 [24%] of 151 on tavapadon and six [4%] of 153 on placebo). The primary endpoint of change from baseline to week 26 in the MDS-UPDRS Parts II and III combined score was significantly improved with tavapadon versus placebo (least squares mean [LSM] decrease of 10&#xb7;3 [95% CI -12&#xb7;2 to -8&#xb7;3] points vs 1&#xb7;2 [-2&#xb7;9 to 0&#xb7;6] points; LSM treatment difference -9&#xb7;1 [95% CI -11&#xb7;7 to -6&#xb7;5]; p<0&#xb7;0001). Most adverse events were non-serious and mild to moderate in severity. More adverse events were observed with tavapadon than with placebo (115 [76%] of 151 participants vs 84 [55%] of 153 participants). The incidence of adverse events in the tavapadon group was higher during the titration phase (92 [61%] of 151) than during the dose adjustment (44 [37%] of 151) and maintenance (47 [43%] of 151) phases. The most commonly reported adverse events with tavapadon versus placebo (>10% of participants) were nausea (45 [30%] of 151] vs five [3%] of 153), headache (25 [17%] vs eight [5%]), and dizziness (24 [16%] vs five [3%]). INTERPRETATION: Tavapadon showed significant and clinically meaningful improvements in Parkinson's disease motor symptoms, with low incidence of somnolence and impulse control disorders. However, the short observation period limits conclusions about long-term tolerability. An ongoing extension study aims to confirm its long-term safety and efficacy. FUNDING: AbbVie.