Novel and selective dopamine D1 and D5 partial agonist tavapadon improved motor symptoms in both early and advanced Parkinson’s disease (PD), with consistent benefits across disease stages and a distinct safety profile, detailed results from two phase 3 trials showed.

As part of the TEMPO clinical development program which is evaluating the safety and efficacy of tavapadon as monotherapy in early PD (TEMPO-1) and as adjunctive therapy in patients treated with levodopa with motor fluctuations (TEMPO-3) supported the new drug application submission to the FDA in September 2025.

A regulatory decision is anticipated following FDA review. If approved, tavapadon would be among the first therapies to selectively target the D1 and D5 receptor pathway, which could offer a mechanistically distinct approach from traditional dopaminergic treatments.

In the randomized, double-blind, placebo-controlled trials, tavapadon significantly improved motor scores and patient-reported outcomes in early PD, while in patients treated with levodopa, it reduced daily off-time and increased good-on-time without troublesome dyskinesia. Together, the findings show a consistent treatment effect across diverse patient populations.

“Tavapadon has the potential to provide the efficacy that clinicians and patients enjoyed with its older predecessors, but with much less likelihood of developing idiosyncratic side effects,” TEMPO-3 lead investigator Hubert H. Fernandez, MD, professor of neurology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and director, Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, told Medscape Medical News.

The findings of both trials were published online on March 20 in JAMA Neurology.

Meaningful Motor Gains

The TEMPO-1 trial evaluated the efficacy and safety of tavapadon as a monotherapy in 529 adults (mean age, 63.7 years; 35.3% women) with early PD. Participants were predominantly White individuals, with a mean disease duration of 0.73 years and baseline Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) parts II and III scores of 7.4 and 24.4, respectively.

They were randomly assigned 1:1:1 to receive tavapadon 5 mg (n = 177), tavapadon 15 mg (n = 177), or placebo (n = 175) once daily for 26 weeks, with dose titration completed by approximately week 6 for the 5 mg group and week 10 for the 15 mg group.

Tavapadon significantly improved motor function compared with placebo. At week 26, least-squares mean reductions in MDS-UPDRS parts II and III scores were -9.7 points with 5 mg and -10.2 points with 15 mg vs a +1.8-point worsening with placebo (treatment differences, -11.5 and -12.1; P < .001 for both), with improvements observed as early as week 5 and maintained through week 26.

Efficacy was similar between doses, suggesting a potential ceiling effect in early disease.

“There is a sort of ceiling effect in the motor benefit one can reach in early PD…it is not surprising that increasing the dose does not result in additional improvement,” said TEMPO-1 investigator Angelo Antonini, MD, PhD, professor of neurology at the University of Padua, Padua, Italy, told Medscape Medical News. “The interpretation is to start with the 5 mg and increase the dose only in patients who do not experience full benefit.”

Secondary outcomes supported these findings, including improvements in MDS-UPDRS part II (-2.5 points vs placebo; P < .001) and higher Patient Global Impression of Change (PGIC) responder rates (45.5% and 44.4% vs 12.2% with placebo).

Reduced Off-Time, Increased ‘Good-On-Time’

The TEMPO-3 trial evaluated tavapadon as adjunctive therapy in 507 adults (mean age, 64.9 years; 63% men) with a mean disease duration of 6.7 years who were experiencing motor fluctuations while receiving stable oral levodopa 400 mg or more daily.

Patients were randomly assigned 1:1 to flexible-dose tavapadon (5-15 mg once daily; n = 252) or placebo (n = 255) for 27 weeks, with background levodopa maintained.

The study met its primary endpoint, with tavapadon increasing daily good-on-time by 1.70 hours vs 0.60 hours with placebo (difference, 1.10 hours; 95% CI, 0.60-1.70; P < .001). Off-time was also reduced (-1.88 vs -0.93 hours; difference, -0.94 hours; 95% CI, -1.48 to -0.41; P < .001).

Secondary outcomes were consistent, including improvements in MDS-UPDRS parts II and III, with a combined reduction of approximately -3.7 points vs placebo (nominal P < .001). This reflects benefits in motor symptoms and daily functioning.

Across both TEMPO-1 and TEMPO-3, improvements in patient-reported outcomes and global assessments, including higher PGIC responder rates and better clinician-rated scores, further supported the clinical relevance of these findings.

Consistent but Manageable Safety Profile

Across both trials, tavapadon demonstrated a safety profile consistent with selective D1 and D5 receptor activity.

In TEMPO-1, 79.4% of patients treated with tavapadon experienced adverse events (AEs) vs 57.1% of those treated with placebo, with the most common being nausea, headache, and dizziness. Discontinuation due to AEs occurred in 18.1% vs 4.0% with placebo, largely during titration.

In TEMPO-3, 71.7% of patients on tavapadon vs 55.1% of those on placebo experienced AEs, with nausea (14.3%), dyskinesia (10.0%), and dizziness (7.6%) being most common. Serious AEs were similar between groups.

Importantly, rates of impulse control disorders, hallucinations, and excessive daytime somnolence were low, and orthostatic hypotension occurred slightly more frequently with tavapadon (6% vs 1.2%).

TEMPO-1 investigator Alberto Espay, MD, professor and endowed chair of the James J. and Joan A. Gardner Center for Parkinson’s Disease at the University of Cincinnati, in Cincinnati, told Medscape Medical News that “the low rates of impulse control disorders and somnolence are encouraging and may reflect D1/D5 selectivity, but longer-term studies will be needed to fully characterize safety in real-world use.”

Fernandez said the higher rate of AEs observed in the study was largely protocol driven. He noted that in routine clinical practice, dose titration would typically proceed more gradually, and clinicians would not necessarily need to keep increasing the dose if patients were already experiencing satisfactory benefit. In such cases, he said, it may be reasonable to maintain patients on a lower dose.

Similarly, Antonini noted that “a slower titration adjusted to patient needs would show better tolerability.”

A New Dopaminergic Strategy

With consistent effects across both trials, once-daily oral dosing, and a safety profile that may reduce dopaminergic complications, tavapadon represents a novel D1/D5 receptor-targeting option distinct from traditional D2 and D3 therapies.

“I see tavapadon less as a universal replacement and more as a new oral add-on that could often be considered before a traditional D2/D3 agonist in the right patient,” TEMPO-1 investigator, Zoltan Mari, MD, family chair and director of the Parkinson’s Disease and Movement Disorders Program, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, told Medscape Medical News.

He added that while efficacy appears comparable to existing adjunctive therapies, the tolerability profile may influence treatment decisions, particularly in patients at higher risk for behavioral or cognitive AEs.

“D1-pathway therapy is now clinically validated, not just mechanistically attractive,” Mari said, describing the program as “a meaningful inflection point for the field.”

Meanwhile, the TEMPO-4 open-label extension, which enrolled rollover participants from the phase 3 trials and de novo patients on stable levodopa, has shown encouraging interim findings, Mari noted, including stable efficacy, a favorable long-term safety profile, and that nearly 90% of patients did not require levodopa adjustment during follow-up.

However, he cautioned that additional data are needed on long-term safety, real-world use, and optimal treatment sequencing before widespread adoption of tavapadon in PD treatment.

Further studies will be needed to define how tavapadon will fit into current PD treatment, including whether it can delay levodopa initiation in early disease or improve motor fluctuations in later stages, he said.

Where Does Tavapadon Fit?

While tavapadon shows promise, its role in clinical practice and how it compares with existing therapies remains to be determined, said Michael S. Okun, MD, Medical Director of the Parkinson’s Foundation, who wasn’t involved in the research told Medscape Medical News.

“These are strong phase 3 clinical trials data, and they tell us that tavapadon may be an option for some individuals with PD,” said Okun, author of The New York Times bestseller The Parkinson’s Plan.

“The story is incomplete because both recent studies compared tavapadon to placebo and not directly to the options we already use every day, and both papers also point to the need for longer-term safety and efficacy data,” he noted.

The drug’s selective D1 and D5 receptor activity and once-daily dosing could serve as a potential differentiator from traditional dopaminergic therapies. Okun said that this specific approach might deliver dopaminergic benefits without some of the “classic D2 and D3 baggage,” such as somnolence and impulse control issues.

“Since the data available was not a head-to-head trial, it will take some time to sort out whether there is a reduced side effect profile,” he added.

From a practical standpoint, the phase 3 data suggest that dopaminergic AEs are most likely to emerge during dose escalation, which highlights the need for careful, individualized titration.

“In the real world, we usually start low and go slow. Healthcare providers should ideally be very attentive during titration for nausea, dizziness, orthostatic symptoms, dyskinesia, and to determine whether the individual is truly gaining enough benefit to justify pushing the dose higher,” Okun said.

Disclosure information for study authors is available in the original study publication. Okun reported having no relevant financial disclosures.