NeuroVoices: Hubert Fernandez, MD, on Tavapadon, TEMPO-4, and Improving Parkinson Disease Management

As the Parkinson disease (PD) treatment landscape continues to evolve, there remains a strong clinical interest in therapies that can provide sustained symptomatic benefit while minimizing long-term complications associated with levodopa use. Dopamine agonists have historically filled this role, but their use has been limited by tolerability concerns, particularly related to neuropsychiatric and autonomic adverse effects.

Tavapadon (AbbVie), an investigational once-daily, selective D1/D5 dopamine receptor agonist, has demonstrated efficacy across multiple phase 3 trials, including TEMPO-1 and TEMPO-2 in early PD and TEMPO-3 in patients with motor fluctuations. In the 58-week open-label extension TEMPO-4 study (NCT04760769), long-term data suggest that tavapadon may help maintain symptom control while reducing the need for levodopa initiation or dose escalation. Across cohorts, approximately 86% to 94% of early PD participants avoided levodopa initiation, while more than 80% of those already on levodopa maintained stable dosing, with dose reductions occurring more frequently than increases.

Following the 2026 American Academy of Neurology (AAN) Annual Meeting, Hubert Fernandez, MD, Director of the Center for Neurological Restoration at Cleveland Clinic, sat down with NeurologyLive® to provide deeper clinical context around tavapadon’s mechanism, the nuances of D1 receptor selectivity, and how the long-term TEMPO-4 data may reshape thinking around dopamine agonists. As part of a new iteration of NeuroVoices, Fernandez not only detailed the efficacy and safety signals observed to date, but also reflected on how these findings compare with historical expectations for dopamine agonists, the importance of levodopa-sparing strategies, and where a therapy like tavapadon could realistically fit across both early and advanced stages of PD care.

NeurologyLive: Can you briefly explain tavapadon’s mechanism and how it differs from existing Parkinson therapies?

Hubert Fernandez, MD: Tavapadon is a dopamine agonist. It is a D1 selective, once-daily dopamine agonist. It is unique in several respects. Firstly, it is one of the few drugs as of late that is being developed, or that has been studied and now is kind of in the docket of the FDA for consideration and approval, for both early and later stage Parkinson disease. Most of the medications have been only for late stage. A few have been for very early. We have a few disease-modifying trials, but this is a symptomatic treatment that has been studied in pretty much a good spectrum of Parkinson patients, from newly diagnosed and ready to be treated to those already on levodopa and having a harder time. So that’s one kind of special thing about the medication.

The second, and probably the most special feature of the medication, is its D1 selectivity in its dopamine agonist mechanism of action. Dopamine agonists stimulate the dopamine receptors so that they work more efficiently. In Parkinson patients, they do not replace dopamine. That’s the strategy or the mechanism of action of levodopa, and that’s why levodopa remains the best drug we have up to this day. Perhaps what is unofficially the second-best class of drugs are dopamine agonists, because they stimulate the dopamine receptors instead of replacing dopamine that is not being produced in enough quantities.

Now, dopamine receptors—there are five types: D1, D2, D3, D4, and D5. For simplicity, we group them into families, the D1 family and the D2 family. Both, if stimulated, improve motor symptoms of Parkinson disease, very similar to replacing dopamine. The difference is that the D2 family is more widely distributed throughout the brain and in regions responsible not only for motor function but also thinking, emotions, autonomic function, and other processes. The D1 family is more concentrated in regions responsible for motor functioning.

If you stimulate both, you improve motor symptoms, but stimulating D2 carries the baggage of causing non-motor side effects, such as hallucinations, orthostatic hypotension, impulse control disorders, and others. Older dopamine agonists are primarily D2 or nonselective, meaning they stimulate both D1 and D2 families. While they clearly improve motor symptoms, they also carry those risks. Because of that, although they are still approved, they are used more cautiously now.

Tavapadon is a D1 selective agonist, and in earlier clinical trials, it proved to be just as efficacious as its predecessors. The theoretical hope is that it achieves that efficacy without the side effects associated with D2 stimulation. That’s the second unique feature.

The third is usability. Previous dopamine agonists are typically dosed three times daily. That is already an improvement over levodopa, which can be taken four, five, six, or even seven times a day. Tavapadon has an even longer half-life, allowing for once-daily dosing. This is a significant advantage for patients, especially those early in disease who are not yet used to taking multiple medications.

What were the key efficacy and clinical takeaways from the 58-week TEMPO-4 extension?

There were close to 1000 patients in TEMPO-4, rolling over from TEMPO-1, TEMPO-2, and TEMPO-3. So, this represents a large population exposed to the medication for over a year. TEMPO-4 is still ongoing, so this is the first cut of a longer study. About 48% of patients had completed the study at the time of analysis.

Efficacy-wise, it kept the magnitude of effect seen in TEMPO-1 and TEMPO-2 in terms of Parkinson motor score improvement, and that was sustained in TEMPO-4. For TEMPO-3 participants, there was sustained improvement in “on” time. But again, since this is an open-label study, everyone knows they are on the drug, so that needs to be interpreted with caution.

What is more meaningful, in our opinion, is how levodopa use changed. For early Parkinson patients from TEMPO-1 and TEMPO-2, historically, when we study non-levodopa therapies, about 25% to 50% of patients require levodopa supplementation within a year. In this case, less than 10% required levodopa by the end of the study. So more than 90% remained on tavapadon alone. We have not seen this with other non-levodopa therapies.

For patients already on levodopa, from TEMPO-3, more than 90% did not require dose adjustment or were able to decrease their levodopa dose. Less than 10% required an increase. So across both early and advanced populations, there was consistent efficacy with minimal need for levodopa escalation.

What did the long-term safety and tolerability data show?

This was the biggest question for us. Every dopaminergic therapy has been reported to cause both general and idiosyncratic side effects. These include impulse control disorders like gambling or hypersexuality, as well as drowsiness and orthostatic hypotension.

With tavapadon, about 1.5% of patients developed possible impulse control behaviors. That’s very low compared with older dopamine agonists. Less than 5% experienced drowsiness, and similarly low rates were seen for orthostatic hypotension.

Nausea and headache were the most common side effects, but the more concerning ones—drowsiness, orthostasis, and impulse control disorders—were much lower than expected. Even compared with levodopa, these rates appear quite favorable, although again, we don’t have direct comparisons.

Overall, the tolerability profile was very encouraging and supports the idea that D1 selectivity may translate into fewer side effects.

If approved, how could tavapadon fit into the Parkinson treatment landscape?

It really comes down to options. Compared with even 10 years ago, patients today have more treatment options, which is good. But we still have a long way to go. The ultimate goal is a cure, but until then, we focus on improving quality of life.

In early Parkinson disease, treatment decisions often come down to levodopa or less potent options like rasagiline. Dopamine agonists used to be widely used in early disease, especially in younger patients, but side effects limited their use. If tavapadon can provide similar efficacy with better tolerability, it could reestablish that role.

In advanced disease, we have many options, including levodopa adjustments, different formulations, on-demand therapies, infusion therapies, and deep brain stimulation. The fact that we have many options reflects both success and ongoing need. Surveys consistently show that motor fluctuations remain the most bothersome symptom for patients.

So, having another option that can help manage motor symptoms, potentially reduce levodopa burden, and avoid some of the side effects of older dopamine agonists would be a meaningful addition for both clinicians and patients.

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REFERENCE
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