Tavapadon, a novel, investigational, selective D1/D5 agonist with once-daily oral dosing, provides clinically meaningful and sustained benefit adjunctive to levodopa and has a favourable safety profile in patients with Parkinson’s disease (PD) experiencing off fluctuations, according to findings of the TEMPO-3 trial.
The phase III, double-blind, placebo-controlled randomized clinical trial, conducted between September 2020 and February 2024, included 507 adults with PD (mean age, 64.9 years; male, 63 percent; mean disease duration, 6.7 years; mean baseline daily off time, 5.5 hours) from 148 sites across 14 countries. They were randomized 1:1 to receive flexible-dose tavapadon (5–15 mg once daily; n=252) or placebo (n=255) adjunctive to oral levodopa for 27 weeks. At baseline, all participants were experiencing motor fluctuations while receiving stable oral levodopa (≥400 mg daily). [JAMA Neurol 2026;doi:10.1001/jamaneurol.2026.0577]
At week 26, patients in the tavapadon group had significantly increased daily good-on-time vs the placebo group (1.70 vs 0.60 hours; p<0.001). Daily off-time was also significantly reduced from baseline with tavapadon vs placebo (-1.88 vs -0.93 hours; difference, -0.94 hours; p<0.001).
Participants treated with tavapadon also showed nominally significant greater reductions from baseline in Movement Disorder Society-Unified Parkinson Disorder Rating Scale (MDS-UPDRS) parts II and III scores at week 26 vs placebo (least-squares mean [LSM] decrease, 1.4 vs 0.1 points and 7.0 vs 4.6 points, respectively), corresponding to improvements in activities of daily living and investigators’ evaluations of motor function, respectively. There was no notable difference in MDS-UPDRS part I score (non-motor experiences of daily living).
The safety profile of tavapadon was favourable and consistent with findings of earlier-phase tavapadon trials, although more adverse events (AEs) occurred with tavapadon vs placebo (in 71.7 vs 55.1 percent of participants). Most AEs were nonserious (93.2 percent) and mild to moderate in severity. Common AEs with tavapadon (occurring in ≥5 percent of participants) were nausea (14.3 percent), dyskinesia (10.0 percent), and dizziness (7.6 percent). Treatment with tavapadon did not increase the risk of somnolence based on both incidence of AEs of somnolence or fatigue and mean changes from baseline in Epworth Sleepiness Scale (ESS) scores.
Levodopa, the current standard of care for PD, is limited by progressive motor fluctuations driven by its short half‑life and variable absorption, and progressive loss of striatal terminals that store, release and reuptake dopamine. Existing D2/D3 dopamine agonists used as adjuncts to levodopa therapy can reduce off time and increase on time without troublesome dyskinesia while avoiding complications associated with increased levodopa doses, but are associated with increased AEs, including impulse‑control disorders, hallucinations, and somnolence. [JAMA Neurol 2026;doi:10.1001/jamaneurol.2026.0577]
Tavapadon, a once‑daily, selective D1/D5 agonist, represents a mechanistically distinct approach aimed at improving motor control while minimizing D2/D3‑associated adverse effects, addressing the need for effective and better‑tolerated long‑term treatment options for PD.