, 2025-04-15 17:06:00
SAN DIEGO — Tavapadon, a novel and highly selective partial agonist of dopamine D1 and D5 receptors, significantly improved motor function without increasing impulse control disorders in patients with early Parkinson’s disease (PD), results of two separate phase 3 studies showed.
The findings reflect outcomes from both fixed daily doses of 5 mg or 15 mg and flexible dosing regimens. An earlier phase 3 trial (TEMPO-3) also showed tavapadon to be a promising adjunct to levodopa in patients with PD experiencing motor fluctuations.
“We have now shown D1/D5 agonists provide efficacy both in early and advanced disease, and the side effect profile was very similar across the three studies. This drug seems to be better than the current D2, D3 agonists,” study investigator Rajesh Pahwa, MD, professor of neurology and director of the Parkinson’s Disease and Movement Disorder Center, University of Kansas, told Medscape Medical News.
The findings were presented April 7 at the American Academy of Neurology 2025 annual meeting.
Multiple Advantages Over Current Treatments
None of the currently approved PD therapies, including dopaminergic agents such as levodopa and dopamine agonists (DAs) provided sustained relief from motor symptoms without a significant risk of adverse events (AEs).
DAs, particularly levodopa, may initially offer strong motor control, but efficacy often diminishes as the disease progresses, with some patients experiencing unpredictable motor fluctuations. AEs associated with both levodopa and DAs include excessive daytime sleepiness and impulse control disorders — potentially linked to the strong, repeated stimulation of D2/D3 dopamine receptors.
Tavapadon offers several advantages over existing PD treatments. By targeting D1/D5 receptors, it selectively activates direct pathway medium spiny neurons, which may provide more robust relief of motor symptoms compared to D2/D3-selective DAs.
Its long half-life supports once-daily oral dosing, potentially enabling more consistent motor control than current therapies. Additionally, partial agonism at D1/D5 receptors may help minimize receptor desensitization, increasing the likelihood of sustained therapeutic benefit.
Results of one of the new studies, TEMPO-1, included 529 treatment-naive PD patients diagnosed within the previous 3 years who had a Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II score of 2 or more and an MDS-UDRS Part III score of 10 or more.
The MDS-UPDRS Part II includes self-evaluation of activities of daily life — including swallowing, dressing, hygiene, walking, and cutting food — while Part III includes clinician-scored motor evaluations.
Immediate Improvement
Participants had a mean age of 63.7 years, with a greater proportion of men (64.7%) than women. The average MDS-UPDRS score was 7.4 for Part II, 24.4 for Part III, and 31.8 for the combined total of Parts II and III.
Patients were randomly assigned to receive placebo or tavapadon at 5 mg or 15 mg per day. The primary endpoint was change in the combined score on the MDS-UPDRS Part II and Part III at 26 weeks versus placebo.
Those receiving the active drug showed a significant reduction in the primary outcome compared to placebo. The least squares mean (LSM) difference vs placebo was -11.5 (95% CI, -13.8 to -9.2; P < .0001) for the 5 mg dose and -12.1 (95% CI, -14.4 to -9.8; P < .0001) for the 15 mg dose.
“The improvements pretty much started right away and were maintained throughout the study, with the placebo group showing a slight improvement earlier and then worsening overall,” said Pahwa. Efficacy of the 5 mg and 15 mg doses “looked very, very similar,” he added.
The study also showed that tavapadon significantly reduced MDS-UPDRS Part II scores at week 26 compared to placebo, with an LSM difference of -2.5 (95% CI, -3.3 to -1.7) for the 5 mg dose and -2.6 (95% CI, -3.4 to -1.7) for the 15 mg dose (both P < .0001).
Changes in Epworth Sleepiness Scale scores were similar across groups: -0.2 for placebo, -0.3 for 5 mg tavapadon, and -0.5 for 15 mg tavapadon.
Similarly, changes in total scores on the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS) were comparable across all arms. The QUIP-RS assesses symptom severity and supports the diagnosis of impulse control and related disorders in PD.
The 5 mg dose was associated with fewer side effects than the 15 mg dose. For example, rates of nausea were 24% vs 27%, headache occurred in 12% vs 21%, and fatigue in 6% vs 8%, respectively.
The bottom line is that the 5 mg dose has about the same efficacy as the 15 mg dose and has somewhat of a safer side effect profile, said Pahwa. “Why would I use three times the dose with the risk of higher side effects when the efficacy is so similar,” he said.
Tavapadon appears to meet the need for a more effective dopamine agonist with fewer side effects than currently available options, said Pahwa. However, he noted that the drug has not yet been directly compared with existing D2 and D3 agonists in head-to-head studies.
Similar Findings for TEMPO-2
The second study, TEMPO-2, closely mirrored TEMPO-1 but evaluated flexible dosing of tavapadon. It enrolled 304 treatment-naive patients with early PD who were randomized to receive either placebo or flexible-dose tavapadon (5-15 mg per day).
As in TEMPO-1, participants receiving tavapadon experienced a significant improvement in the primary outcome — change in the combined MDS-UPDRS Part II and III scores at week 26 — compared to placebo (LSM difference, -9.1; 95% CI, -11.7 to -6.5; P < .0001).
Tavapadon also significantly improved MDS-UPDRS Part II scores compared to placebo (LSM difference, -1.5; 95% CI, -2.4 to -0.6; P = .0007).
As in TEMPO-1, separation from placebo emerged within 4-8 weeks of treatment initiation. The side effect profile was also similar, with most treatment-emergent AEs in the tavapadon group were mild to moderate in severity.
“We are very, very encouraged by these results,” Fernandez told delegates.
AbbVie is on track to submit a New Drug Application to the US Food and Drug Administration sometime this year.
Encouraging Research
Commenting for Medscape Medical News, Michael S. Okun, MD, Adelaide Lackner professor of neurology at the University of Florida and executive director of the Norman Fixel Institute for Neurological Diseases, said the findings are encouraging in the search for new treatments for PD.
“There’s great interest and need for drugs with selective D1/D5 dopamine receptor partial agonist activity as a path to minimize the common side effects of current dopamine agonist drugs, including impulse control disorders,” said Okun, who is also a medical advisor to the Parkinson’s Foundation.
“A drug that that can be given once a day and improve the amount of time Parkinson’s folks are in the ‘on’ state, with less impulse control, would be a welcome addition to our treatment armamentarium.’
Pahwa reports receiving compensation for consultancy and research funding from AbbVie. Fernandez reports serving as a consultant and advisory board member AbbVie. Okun has no relevant disclosures.