Use of Tavapadon Without Levodopa in Early Parkinson’s Disease: Understanding TEMPO-1 and TEMPO-2

Learn about the use of tavapadon therapy without levodopa in early Parkinson’s disease.

Hello, and welcome to this discussion of tavapadon therapy in early Parkinson’s disease, or PD, with a focus on the TEMPO-1 and TEMPO-2 clinical trials. 

I’m Dr Stuart Isaacson, Director of the Parkinson’s Disease & Movement Disorders Center in Boca Raton, Florida. 

In this video, we will review the TEMPO-1 and TEMPO-2 data and consider how they may guide treatment selection in early stages of PD before levodopa is introduced.

Evidence for tavapadon therapy without levodopa is clinically relevant because clinicians may consider options before levodopa use, including when balancing motor benefits against the risk of longer-term motor complications and adverse events.

Oral levodopa is an initial treatment option, but long-term use with increasing dose is associated with motor fluctuations and dyskinesias. Dopamine agonists may be considered in some patients with PD early in the course of disease before initiating oral levodopa therapy. They are associated with reduced risk of dyskinesia, although currently available agents commonly target D2/D3 receptors and have known tolerability considerations.  

Clinicians must consider symptom burden, functional impairment, age, comorbidities, patient preferences, treatment goals, and tolerability when selecting therapy. Within this context of an unmet need for early PD therapy that can improve motor symptoms and has a consistent safety profile, TEMPO-1 and TEMPO-2 provide data in early PD prior to oral levodopa use. TEMPO-1 evaluated fixed-dose tavapadon, while TEMPO-2 evaluated flexible-dose tavapadon. Reviewing both trials provides complementary evidence across dosing approaches.

Let’s begin with TEMPO-1.

TEMPO-1 evaluated tavapadon without levodopa at fixed doses of 5 mg and 15 mg once daily in adults with early PD.

The study was a phase 3, double-blind, placebo-controlled, 27-week randomized clinical trial.

TEMPO-1 included adults with early PD who had a disease duration of less than 3 years and were treatment-naïve or had less than 3 months of prior dopaminergic treatment.

Participants were randomized 1:1:1 to tavapadon 5 mg once daily, tavapadon 15 mg once daily, or placebo.  

The primary endpoint was change from baseline to week 26 in Movement Disorder Society–Unified Parkinson Disease Rating Scale, or MDS-UPDRS, Parts II and III combined score.

Key secondary endpoints included change from baseline in MDS-UPDRS Part II score and Patient Global Impression of Change, or PGIC, responder status.

These endpoints provide complementary perspectives. The MDS-UPDRS Parts II and III combined score captures activities of daily living and motor examination findings, while PGIC offers a patient-centered view of perceived changes.

At week 26, tavapadon demonstrated improvement on the primary endpoint in both fixed-dose arms.

In TEMPO-1, both tavapadon 5 mg and tavapadon 15 mg significantly improved MDS-UPDRS Parts II and III combined scores versus placebo.

For tavapadon 5 mg, the MDS-UPDRS Parts II and III combined score showed a 9.7 decrease from baseline, compared with a 1.8 increase from baseline with placebo. For tavapadon 15 mg, the decrease from baseline was 10.2, compared with a 1.8 increase from baseline with placebo.

Improvements in the combined MDS-UPDRS Parts II and III scores were observed as early as week 5 and continued through the end of treatment.

The MDS-UPDRS Part II findings were also supportive, with both tavapadon fixed-dose groups showing improvement versus placebo at week 26. 

Tavapadon 5 mg had a least-squares mean change of –1.6, and tavapadon 15 mg had a least-squares mean change of –1.7, both with a P value of less than 0.0001.

Patient-reported global improvement followed a similar pattern. At week 26, PGIC responders were reported in 45.5% of participants receiving tavapadon 5 mg versus 12.2% with placebo, with the odds ratio of 6.15. For tavapadon 15 mg, PGIC responders were reported in 44.4% of participants versus 12.2% with placebo, with the odds ratio of 5.97.

In addition, TEMPO-1 included a post-hoc analysis of MDS-UPDRS Part II and Part III tremor-related items, which indicated that tavapadon was associated with larger response and greater symptom resolution in tremor symptoms than placebo.  

At 26 weeks, the proportions of participants experiencing improvement in tremor symptoms were 46% and 48% in the tavapadon 5 mg and 15 mg groups, respectively, compared with 20% in the placebo group. Further, 19% of participants who received tavapadon in both the 5 mg and 15 mg groups experienced resolution of tremor symptoms, compared with 7% in the placebo group.  

In addition, improvement in consistency of rest tremor was reported by 64% of participants in the tavapadon 5 mg group and 71% in the tavapadon 15 mg group, compared with 33% in the placebo group. Resolution of consistency of rest tremor was experienced by 29% and 35% of participants in the tavapadon 5 mg and 15 mg groups, respectively, compared with 14% in the placebo group.  

Ultimately, TEMPO-1 provided fixed-dose evidence of improvements in motor and daily living measures, patient-reported global impression of change, and tremor items in adults with early PD.

TEMPO-2 builds on this evidence in early PD by evaluating flexible-dose tavapadon.

It was a phase 3 trial evaluating the efficacy, safety, and tolerability of flexible-dose tavapadon 5 mg to 15 mg once daily in adults with early PD.

TEMPO-2 included adults aged 40 to 80 years with PD whose disease duration was less than 3 years and who were treatment-naïve, with Modified Hoehn & Yahr stage 1, 1.5, or 2.

Participants were randomized 1:1 to tavapadon 5 mg to 15 mg once daily or placebo.  

The primary endpoint was change from baseline in MDS-UPDRS Parts II and III combined score. Key secondary endpoints included change from baseline in MDS-UPDRS Part II score and PGIC responder status.  

At week 26, tavapadon significantly reduced the combined MDS-UPDRS Parts II and III score from baseline compared with placebo, with the LSM difference versus placebo of -9.1.  

Tavapadon demonstrated separation from placebo within 4 to 8 weeks of treatment initiation.  

Secondary endpoint findings in TEMPO-2 were generally consistent with the TEMPO-1 findings, with tavapadon showing improvement versus placebo on MDS-UPDRS Part II and PGIC responder outcomes.  

Similarly to TEMPO-1, a post-hoc analysis of the tremor items indicated that tavapadon was associated with a higher rate of response and resolution of tremor items in TEMPO-2 participants compared with placebo.  

As you can see, the efficacy results from TEMPO-2 showed similar patterns to those of TEMPO-1. When viewed together, TEMPO-1 and TEMPO-2 provide a consistent evidence base in early PD, with TEMPO-1 supporting fixed-dose tavapadon and TEMPO-2 supporting flexible-dose tavapadon. This is clinically useful because real-world treatment often involves dose individualization based on response, tolerability, patient characteristics, and shared decision-making.  

In addition to the efficacy data, safety findings are central to applying these data in practice.

In TEMPO-1, adverse events occurred in 79.4% of participants treated with tavapadon compared with 57.1% of participants treated with placebo.

Most adverse events were nonserious and mild to moderate in severity, with common adverse events with tavapadon being nausea, headache, and dizziness.

Adverse events led to discontinuation in 18.1% of participants treated with tavapadon versus 4.0% of participants treated with placebo.

Somnolence occurred in 3.1% of participants treated with tavapadon compared with 3.4% of placebo-treated participants. Impulse control disorder-related adverse events occurred in 0.8% of tavapadon-treated participants versus 0% with placebo.

In TEMPO-2, the safety findings were generally similar to those of TEMPO-1. The majority of treatment-emergent adverse events were nonserious and mild or moderate in severity, and no deaths were reported.  

Common treatment-emergent adverse events included nausea, headache, and dizziness, and the most common treatment-emergent adverse events occurred during titration and decreased afterward.  

Somnolence incidence was similar to that with placebo. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale, or QUIP-RS, changes were comparable between groups. The overall incidence of impulse control disorders was low in the 27-week study.  

These safety data help clinicians contextualize tavapadon’s use in early PD. For patients who may be initiating dopaminergic therapy, tolerability can strongly influence adherence, confidence, and willingness to continue treatment. Understanding which events were most common, and how somnolence and impulse control disorder-related events were reported can support more informed benefit-risk discussions.

The key takeaways from evidence on tavapadon therapy without levodopa reinforce how fixed-dose and flexible-dose data can inform clinical interpretation in early PD.

First, TEMPO-1 and TEMPO-2 provide complementary evidence in early PD across fixed- and flexible-dose designs.  

Second, in both studies, tavapadon showed improvements in MDS-UPDRS outcomes in adults with early PD across fixed-dose and flexible-dose trial designs, supporting tavapadon’s efficacy in this treatment context.  

Third, the safety findings were generally consistent across studies. Nausea, headache, and dizziness were among the most commonly reported events. Most adverse events were nonserious and mild to moderate in severity, somnolence was similar to placebo, and impulse control disorder-related events were low.  

For healthcare providers, these data help characterize tavapadon’s clinical profile in early PD and support benefit-risk interpretation when considering treatment options before oral levodopa use.

Thank you for joining this discussion of TEMPO-1 and TEMPO-2 and the clinical evidence supporting tavapadon for adults with early Parkinson’s disease.

INDICATION

Tavapadon is indicated for the treatment of Parkinson’s disease in adults.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Hypotension/Orthostatic Hypotension: Patients with Parkinson’s disease (PD) may have an impaired capacity to respond to an orthostatic challenge. In clinical studies and clinical experience, dopaminergic medications appear to impair the systemic regulation of blood pressure, resulting in hypotension and/or orthostatic hypotension, especially during dose escalation. Patients with PD being treated with tavapadon should be monitored for signs and symptoms of hypotension/orthostatic hypotension, especially during dose escalation, and should be informed of this risk.

Impulse Control/Compulsive Behaviors: Patients may experience intense urges while on tavapadon. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while on tavapadon. Consider reducing the dose or discontinuing tavapadon if a patient develops such urges.

Hallucinations and Psychotic-like Behavior: Medications for the treatment of PD, including tavapadon, can have effects on thinking and behavior. Age appears to increase the risk of hallucinations in patients taking tavapadon. The risk of hallucination may be increased when tavapadon is co-administered with strong CYP3A inhibitors during the maintenance phase. Consider the risks and benefits prior to initiating treatment with tavapadon in patients with a major psychotic disorder because of the risk of exacerbating psychosis. Consider stopping tavapadon if hallucinations or psychotic-like behaviors occur.

Dyskinesia: Tavapadon may cause or exacerbate pre-existing dyskinesia. Consider decreasing the dosage of tavapadon or other dopaminergic medications if dyskinesia occurs.

Adverse Reactions 

The most common adverse reactions (≥5%) for tavapadon without concomitant levodopa were nausea, headache, dizziness, fatigue, dysgeusia, vomiting, dry mouth, and anxiety.

The most common adverse reactions (≥5%) for tavapadon with concomitant levodopa were nausea, dyskinesia, dizziness, headache, hallucinations, and orthostatic hypotension.

Drug Interactions 

Strong CYP3A inducers: Avoid use with tavapadon. Strong and moderate CYP3A inhibitors: avoid use with tavapadon during titration; tavapadon dosage modification is recommended during maintenance.

Moderate CYP3A inducers: Tavapadon dosage modification is recommended during titration and maintenance. Consult the full Prescribing Information for tavapadon for more information on drug interactions and recommended dosage modifications.

Dosage Forms and Strengths 

Tavapadon is available as 5 mg, 10 mg, and 15 mg tablets, as well as 0.25 mg and 1 mg tablets contained in a Titration Pack.

Please see full Prescribing Information or visit https://www.rxabbvie.com/pdf/juvmo_pi.pdf.

1. Aradi SD, Hauser RA. Medical management and prevention of motor complications in Parkinson's disease. Neurotherapeutics. 2020;17(4):1339-1365. doi:10.1007/s13311-020-00889-4
2. Fernandez HH, Isaacson SH, Hauser RA, et al. Tavapadon as adjunctive treatment for Parkinson disease: the TEMPO-3 randomized clinical trial. JAMA Neurol. 2026;83(5):442-451. doi:10.1001/jamaneurol.2026.0577
3. Navaratnam P, Arcona S, Friedman HS, Leoni M, Shaik S, Sasane R. Natural history and patterns of treatment change in Parkinson’s disease: a retrospective chart review. Clin Park Relat Disord. 2021;6:100125. doi:10.1016/j.prdoa.2021.100125
4. Poewe W, Mahlknecht P. Pharmacologic treatment of motor symptoms associated with Parkinson disease. Neurol Clin. 2020;38(2):255-267. doi:10.1016/j.ncl.2019.12.002
5. Sachithanandan S, Vijayaraghavan A, Venugopal R, Puthenveedu DK, Krishnan S. Pharmacotherapy in early Parkinson’s disease: a pragmatic approach. Ann Indian Acad Neurol. 2025;28(4):512-518. doi:10.4103/aian.aian_676_25
6. Isaacson SH, Hauser RA, Pahwa R, Gray D, Duvvuri S. Dopamine agonists in Parkinson’s disease: impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment. Clin Parkinsonism Relat Disord. 2023;9:100212. doi:10.1016/j.prdoa.2023.100212
7. Pringsheim T, Day GS, Smith DB, et al. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: a report of the AAN Guideline Subcommittee. Neurology. 2021;97(20):942-957. doi:10.1212/WNL.0000000000012868
8. Pahwa R, Moro E, Espay AJ, et al. Fixed-dose tavapadon for early Parkinson disease: a randomized clinical trial. JAMA Neurol. 2026;83(5):452-460. doi:10.1001/jamaneurol.2026.0590
9. Torres-Russotto D, Harmer L, Nicholson T, Perminder B. Impact on tremor in phase 3 trials of tavapadon, a selective D1/D5 agonist for treatment of Parkinson’s disease. Poster presented at: American Academy of Neurology Annual Meeting (AAN); April 18-22, 2026; Chicago, IL.
10. Fernandez HH, Bhatia P, Cloud L, et al. Efficacy and safety of flexible-dose tavapadon, an oral, once-daily, selective D1/D5 dopamine agonist for the treatment of early Parkinson’s disease. Poster presented at: American Academy of Neurology (AAN) Annual Meeting; April 5-9, 2025; San Diego, CA.
11. Brehm ZP, Schneider RB, Venuto CS, et al. Constructing a personalized treatment rule for initial therapy in early Parkinson's disease. Pharmacotherapy. 2026;46:e70069. doi:10.1002/phar.70069
12. Richards K, Avanceña ALV, Johnsrud M, et al. Quantifying the tolerability of dopamine agonist antiparkinsonian medication side effects: a best-worst scaling survey. Patient Prefer Adherence. 2026;20:570840. doi:10.2147/PPA.S570840