TEMPO-4 Extension Analysis: Tavapadon Shows Levodopa-Sparing Potential in Parkinson Disease

Long-term treatment with the selective dopamine D1/D5 receptor agonist tavapadon was associated with a reduced need for levodopa initiation and dose escalation in patients with Parkinson disease (PD), according to findings from an ongoing, 58-week open-label extension study (TEMPO-4; NCT04760769).¹

Presented at the 2026 American Academy of Neurology (AAN) Annual Meeting, held April 18-22, in Chicago, Illinois, this post hoc analysis of the TEMPO clinical program indicated that approximately 90% of participants treated with tavapadon over 14 to 20 months did not require initiation or dose increases of levodopa.¹ These findings, while exploratory, provide insight into how selective D1/D5 receptor agonism may influence treatment trajectories in both early and advanced PD populations.

Trial Overview and Findings

The trial enrolled participants from prior phase 3 studies, TEMPO-1 and TEMPO-2 (early PD populations) and TEMPO-3 (patients with PD and motor fluctuations), as well as de novo participants on stable levodopa regimens. For context, TEMPO-4 aimed to evaluate the long-term safety and efficacy of tavapadon.

Led by William Ondo, MD, director of the Movement Disorders Clinic at the Houston Methodist Neurological Institute in Texas, the post hoc analysis focused on 2 key outcomes: levodopa initiation among levodopa-naive participants and levodopa dose adjustments among those already receiving therapy.¹

Among patients with early PD who entered TEMPO-4 from TEMPO-1 and TEMPO-2, most participants (86.4%–94.0%) avoided initiating levodopa over follow-up periods ranging from 58 to 85 weeks.¹ In participants already receiving levodopa (from TEMPO-3 or newly enrolled cohorts), the majority (81.3%–87.6%) maintained stable levodopa dosing throughout the study period.¹

When dose adjustments were required, reductions were more common than increases. Approximately 10% of participants reduced their levodopa dose, compared with roughly 5% who required dose escalation, with mean daily doses remaining below 1000 mg.¹

Interpretation and Limitations

The findings from TEMPO-4 suggest that tavapadon may help stabilize dopaminergic therapy requirements over time, potentially delaying the need for levodopa initiation or escalation.¹ However, several limitations should be considered.

TEMPO-4 is an open-label extension study without a control group, limiting causal inference. Additionally, the post hoc nature of the analysis introduces potential bias, and the population may be enriched for patients who tolerated or responded to tavapadon in earlier trials.

Safety outcomes were not fully detailed in the abstract, precluding a comprehensive assessment of long-term tolerability. Furthermore, while reducing levodopa exposure may be desirable in some patients, current clinical guidance emphasizes tailoring therapy to symptom burden and quality of life rather than strictly delaying levodopa use.²

Clinical Context

Levodopa remains the most effective symptomatic therapy for PD but is associated with long-term complications, including motor fluctuations and dyskinesias, particularly with prolonged use.^2,3 The cumulative incidence of these complications increases with treatment duration and total levodopa exposure.

As a result, strategies that delay levodopa initiation or reduce cumulative exposure have been explored, particularly in early-stage disease. Dopamine agonists are commonly used in this context, although their utility may be limited by adverse effects such as impulse control disorders, hallucinations, and somnolence.^3,4

Drug Background

Tavapadon is an investigational, once-daily oral therapy that selectively targets D1 and D5 dopamine receptors. Unlike traditional dopamine agonists that primarily stimulate D2-like receptors, D1/D5 agonism may more closely replicate physiologic dopaminergic signaling in motor pathways.⁵

Selective D1 receptor agonists have been investigated for decades but were historically limited by pharmacokinetic challenges and tolerability concerns.⁵ Tavapadon represents a newer generation of compounds designed to overcome these limitations, with phase 3 data from the TEMPO program suggesting symptomatic benefit and a favorable safety profile, though full peer-reviewed publications remain limited.¹

Next Steps

Additional peer-reviewed data from the TEMPO clinical program, including randomized controlled findings and longer-term safety outcomes, will be critical to determining the clinical role of tavapadon. Regulatory review and real-world data will further clarify whether selective D1/D5 agonism represents a meaningful advance in PD management.

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References
1. Ondo W, Hatcher M, Soileau M, et al. Levodopa initiation or dose adjustments in TEMPO-4: a 58-week open-label trial of tavapadon for treatment of Parkinson disease. Presented at: 2026 American Academy of Neurology Annual Meeting; April 18-22, 2026; Chicago, Illionis
2. Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020 Feb 11;323(6):548-560. doi: 10.1001/jama.2019.22360.
3. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. MovDisord. 2001;16(3):448-458. doi:10.1002/mds.1090
4. Zhang JF, Wang XX, Feng Y, Fekete R, Jankovic J, Wu YC. Impulse Control Disorders in Parkinson's Disease: Epidemiology, Pathogenesis and Therapeutic Strategies. Front Psychiatry. 2021;12:635494. Published 2021 Feb 9. doi:10.3389/fpsyt.2021.635494
5. 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 Park Relat Disord. 2023;9:100212. doi:10.1016/j.prdoa.2023.100212