Fixed-Dose Tavapadon for Early Parkinson Disease: A Randomized Clinical Trial.

Importance: Tavapadon is an oral, once-daily, selective D1/D5 agonist that may improve Parkinson disease (PD) motor symptoms while minimizing adverse events (AEs) associated with D2/D3 receptor activation. Objective: To evaluate the efficacy, safety, and tolerability of tavapadon in adults with early PD. Design, Setting, and Participants: TEMPO-1 was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted at 102 sites across 12 countries between December 2019 and June 2024. Adults with early PD (<3 years' disease duration) who were treatment naive or had less than 3 months of prior dopaminergic treatment were eligible for enrollment. Data analysis was completed from July 2024 to May 2025. Intervention: Participants were randomized 1:1:1 to receive 1 of 2 fixed doses of tavapadon (5 or 15 mg once daily) or placebo for 27 weeks, followed by a 4-week safety follow-up period. Main Outcomes and Measures: The primary end point was least-squares mean (LSM) change from baseline to week 26 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III combined score. Key secondary end points were LSM change from baseline to week 26 in MDS-UPDRS part II scores and the proportion of participants with a score of "much improved" or "very much improved" on the Patient Global Impression of Change. Results: Overall, 751 adults with early PD who were treatment naive or had less than 3 months of prior dopaminergic treatment were screened, and 529 participants were enrolled (187 female participants [35.3%]; mean [SD] age, 63.7 [9.6] years; mean [SD] disease duration, 0.7 [0.8] years) and randomized to receive tavapadon, 5 mg (n = 177), tavapadon, 15 mg (n = 177), or placebo (n = 175). The change from baseline to week 26 in the MDS-UPDRS parts II and III combined score was significantly improved in participants treated with both the 5-mg dose of tavapadon (9.7-point decrease vs 1.8-point increase with placebo; treatment difference, -11.5 points; 95% CI, -13.8 to -9.2; P < .001; d = 1.14) and 15-mg dose of tavapadon (10.2-point decrease vs 1.8-point increase with placebo; treatment difference, -12.1 points; 95% CI, -14.4 to -9.8; P < .001; d = 1.20). Tavapadon had a favorable safety profile; most AEs were nonserious and mild to moderate in severity. Common AEs with tavapadon were nausea (90 of 354 with tavapadon [25.4%]), headache (59 of 354 [16.7%]), and dizziness (45 of 354 [12.7%]). Conclusions and Relevance: In the TEMPO-1 randomized clinical trial, tavapadon improved motor function in participants with early PD and was well tolerated with a favorable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04201093.