Could Tavapadon Change Parkinson's Care?

Parkinson's disease (PD) treatment could be on the cusp of its first new dopamine agonist strategy in decades, as the FDA nears a decision on the investigational drug tavapadon later this month. If approved, the once-daily oral medication will be the first to selectively and partially activate D1/D5 dopamine receptors, establishing a novel pathway for motor symptom management.Across three pivotal phase 3 trials, tavapadon demonstrated clinical benefit both as an early-stage monotherapy and as an add-on to levodopa in patients experiencing "wearing-off" episodes. This effectiveness across the continuum of care highlights the drug's potential versatility. The breadth of patients tavapadon could potentially treat could be one of the drug's biggest advantages, said Hubert H. Fernandez, MD, professor of neurology and director of the Center for Neurological Restoration at Cleveland Clinic, and global principal investigator for two of the pivotal trials, TEMPO-2 and TEMPO-3. "We haven't seen a Parkinson's drug with such a broad spectrum of use — from early to advanced disease — in decades," Fernandez told Medscape Medical News. "Tavapadon could give us another option that bridges that gap." How Is Tavapadon Different?Tavapadon is a dopamine agonist, meaning it mimics dopamine by stimulating dopamine receptors. Levodopa, the mainstay of PD treatment, works differently: The brain converts it into dopamine. Unlike traditional dopamine agonists that target D2 and D3 receptors, tavapadon is the first selective D1/D5 receptor partial agonist. D1-family receptors sit primarily in the brain pathways that govern movement. By contrast, D2-family receptors are scattered across regions tied to reward, cognition, and autonomic function. By specifically targeting the D1/D5 receptors, tavapadon aims to preserve motor control while lowering the risk for typical D2-related side effects, such as impulse-control disorders, sudden sleep attacks, and leg swelling.TEMPO trial data showed low rates of impulse-control issues and somnolence. Typical dopaminergic side effects still occurred, however, including nausea, dyskinesia, hallucinations, and orthostatic hypotension. Longer-term follow-up remains essential to confirm whether neuropsychiatric complications are genuinely reduced or merely delayed, Fernandez emphasized.Tavapadon would also offer a simplified schedule, which he said is especially relevant for newly diagnosed patients facing a growing pill burden. While standard therapies such as levodopa generally require multiple doses, which can increase to four, five, or even more over time, tavapadon "starts and ends with once a day," Fernandez noted. What Does the Research Show?The TEMPO clinical program evaluated tavapadon across early- and later-stage PD. TEMPO-1 and TEMPO-2 focused on early-stage PD, testing fixed-dose tavapadon in 529 patients and a flexible-dose regimen in 304 patients, respectively. Both 27-week, placebo-controlled trials met their primary endpoints at week 26 on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Parts II and III combined score. In TEMPO-1, the placebo-adjusted treatment differences reached 11.5 points for the 5-mg dose and 12.1 points for the 15-mg dose (P < .0001). In TEMPO-2, the flexible-dose group demonstrated a 9.1-point placebo-adjusted improvement (P < .0001). TEMPO-3 enrolled 507 levodopa-treated patients with motor fluctuations to evaluate flexible-dose tavapadon as add-on therapy. Daily good "on" time without troublesome dyskinesia increased by 1.7 hours from baseline vs 0.6 hours with placebo, a 1.1-hour net treatment difference (P < .0001). Concurrently, daily "off" time fell by 1.88 hours with tavapadon vs 0.93 hours with placebo. "There's good news and bad news about that," Fernandez noted regarding the trial's net gain. "The bad news is that it looks like 1 hour. What is 1 hour? The good news is that every FDA-approved oral adjunctive treatment falls in that 1-hour range. Tavapadon is in keeping with everyone else." TEMPO-4, a 58-week open-label extension, provided longer-term follow-up data. Across 58-85 weeks, 86%-94% of early-stage participants did not require the initiation of levodopa, while 81%-88% of those already taking it maintained stable doses. Without a control group, however, these open-label data cannot definitively establish that tavapadon delays the need to start or escalate levodopa therapy, researchers noted. What About Adverse Events?Tolerability remains a primary clinical consideration, driven by high discontinuation rates during the initial dose-escalation phase. In TEMPO-2, 24% of tavapadon-treated patients discontinued due to adverse events (AEs) compared to 4% in the placebo cohort. Similarly, TEMPO-3, recorded a 17.1% discontinuation rate with tavapadon vs 9.1% with placebo. Regarding specific dopaminergic AEs, compared to placebo, the tavapadon-treated patients reported higher rates of visual hallucinations (5.6% vs 1.2%) and orthostatic hypotension (6.0% vs 1.2%). Notably, somnolence rates were comparable between the two groups, and impulse-control events remained rare.Fernandez suggested that rigid trial protocols probably amplified dropouts. The study required a fixed-dose escalation schedule with no option for dose reductions."In the real world, patients will let us know when we need to go a little slower," he said. "We would have the luxury of waiting. We don't have that luxury in clinical trials."Without direct head-to-head trials against older dopamine agonists, the safety signal remains difficult to evaluate, and clinicians should use restraint when evaluating preliminary results, urged Michael S. Okun, MD, medical advisor to the Parkinson's Foundation and director of the Norman Fixel Institute for Neurological Diseases at the University of Florida, Gainesville."The early studies suggest tavapadon may have a different and potentially favorable safety profile compared with traditional dopamine agonists, particularly in reducing the number of impulse control disorders," Okun told Medscape Medical News. "I would, however, be cautious about declaring it safer yet. We need longer follow-up, real-world data, and ideally head-to-head comparisons with existing dopamine agonists."An independent draft evidence review by the Institute for Clinical and Economic Review (ICER) reached a similar conclusion, rating tavapadon's net health benefit as "promising but inconclusive." This preliminary verdict stems from brief patient follow-up periods and a reliance on indirect network meta-analyses. The watchdog organization also flagged limited racial diversity in the evidence base, noting that Black patients were underrepresented across all three pivotal TEMPO trials.According to ICER's indirect analysis across separate trials, tavapadon may carry higher rates of AE discontinuations than existing dopamine agonists or monoamine oxidase B (MAO-B) inhibitors. The review also cautioned that 26-week trials are probably too brief to draw firm conclusions about impulse-control behaviors, which observational evidence suggests can take several years of dopaminergic exposure to surface.How Might Tavapadon Change PD Care?If approved for early monotherapy and adjunctive treatment, tavapadon would become the first PD therapy since rasagiline — an MAO-B inhibitor approved in 2006 — to secure FDA clearance for both indications.In clinical practice, Fernandez foresees considering tavapadon primarily as initial therapy for younger patients with mild-to-moderate symptoms, particularly working individuals who would benefit from once-daily dosing. For older patients or those with more severe motor deficits, levodopa remains his first choice due to its established efficacy and lower risk for dopaminergic side effects.Okun also envisions dual clinical roles while emphasizing targeted patient selection."I would be cautious in patients particularly vulnerable to hallucinations, impulse control disorders, orthostatic hypotension, nausea, or other dopaminergic adverse effects until we have more clinical experience," Okun said.Because the TEMPO program evaluated only diagnosed, symptomatic disease, no phase 3 data support prescribing in prodromal PD before motor symptoms emerge.Manufacturer AbbVie submitted its New Drug Application in September 2025, putting the therapy on track for a commercial debut pending FDA clearance. Market adoption would then depend heavily on formulary placement, tiering, and insurance restrictions.Evaluating tavapadon at a placeholder price of $15,000 per year, an ICER draft review concluded the drug was not cost-effective compared with inexpensive generic options. ICER noted its economic calculations will be revised once official US commercial pricing is established.Fernandez stressed that broad cost-effectiveness models evaluate group averages rather than individual clinical realities, where alternative choices remain vital when standard therapies trigger adverse reactions."Everyone has tolerability issues," he said. "Some patients might do well with Motrin and others with Aleve. If you only have Motrin, what do you give the patient who can't tolerate it? Having another option is a good thing."Fernandez reported receiving consulting and advisory fees from AbbVie and serving as global principal investigator for TEMPO-2 and TEMPO-3. TEMPO-3 was initially funded by Cerevel, which was acquired by AbbVie. Okun reported no industry conflicts. Carla Cantor is a freelance writer specializing in science, medicine, and mental health.