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.