AAN 2025: Tavapadon offers rapid, sustained motor benefits
Risk of side effects lower than with similar medications, data show
Tavapadon, an orally available small molecule being developed for Parkinson’s disease, was generally safe and eased motor symptoms within one month of being administered at either a fixed or flexible dose to adults with early-stage disease.
It also reduced the risk of common side effects typically associated with similar classes of drugs.
These data come from TEMPO-1 (NCT04201093) and TEMPO-2 (NCT04223193), two Phase 3 clinical trials that tested the efficacy and safety of tavapadon compared with a placebo in adults with mild to moderate motor symptoms who had received minimal to no previous treatment for Parkinson’s.
Developer Abbvie has said it plans to file for regulatory approval of Tavapadon based on the data, detailed in two oral presentations during the American Academy of Neurology (AAN) annual meeting, held April 5–9 in San Diego and online.
“A key unmet need in Parkinson’s disease is finding a treatment modality that can balance the good effects of dopamine stimulation while still reducing the dopaminergic side effects,” Hubert Fernandez, MD, director of the Center for Neurological Restoration at Cleveland Clinic, said during his presentation, “Efficacy and Safety of Flexible-Dose Tavapadon, an Orally Administered, Once-Daily, Selective D1/D5 Partial Dopamine Agonist for the Treatment of Early Parkinson’s Disease.”
Extension study testing flexible dose
While TEMPO-1 and TEMPO-2 have concluded, an open-label extension, TEMPO-4 (NCT04760769), is ongoing to test the long-term safety and efficacy of flexible-dose tavapadon. Abbvie has also sponsored TEMPO-3 (NCT04542499), which tested tavapadon as an add-on to levodopa in people with late-stage Parkinson’s.
Parkinson’s symptoms result from the gradual loss of dopaminergic neurons, the nerve cells that produce dopamine in the brain. Dopamine is a neurotransmitter, or chemical messenger, that plays a key role in regulating motor control. The standard treatment for Parkinson’s typically involves levodopa, a precursor that helps replenish dopamine levels in the brain
Tavapadon is a dopamine agonist designed to partially activate D1 and D5 dopamine receptors on nerve cells, mimicking the effects of dopamine to help alleviate motor symptoms. By selectively targeting the D1 and D5 receptors, tavapadon may also reduce the risk of side effects typically associated with broader dopamine receptor activation, which include dyskinesias — involuntary, erratic movements — as well as hallucinations and impulse control disorders.
The TEMPO-2 clinical trial involved 304 patients, with a mean age of 62.9, who had been diagnosed with Parkinson’s for less than three years. They were randomly assigned to receive either tavapadon or a placebo once daily for 27 weeks (slightly longer than six months).
The tavapadon dose was adjusted to find the highest each patient could tolerate, from 5 mg to 15 mg once daily. The main goal was to watch for changes in a Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts 2 and 3 combined score, a measure of motor symptoms’ severity.
Treatment with tavapadon resulted in a significantly greater decrease in the average MDS-UPDRS combined score compared with the placebo (10.3 points vs. 1.2 points). In the MDS-UPDRS, a lower score indicates less severe motor symptoms. The difference between the two groups was apparent in four weeks (about a month) and sustained until the end of the observation period.
“Flexible dosing of tavapadon demonstrated significant and clinically meaningful improvement in the motor function in early Parkinson’s patients,” Fernandez said.
Most side effects were transient and mild to moderate in severity. The most common side effects were nausea, headache, and dizziness. Somnolence, a common side effect linked to activation of dopamine receptors other than D1 and D5, occurred at similar rates in the tavapadon and placebo groups. Hallucinations and impulse control disorders were reported in 4% and 2% of patients treated with tavapadon, respectively.
Fixed-dose trial
Data from the TEMPO-1 clinical trial, which tested two fixed doses of tavapadon, 5 mg or 15 mg, or a placebo, given once daily, were outlined in the presentation, “Efficacy and Safety of Fixed-Dose Tavapadon, an Oral, Once-Daily, Selective D1/D5 Partial Dopamine Agonist for the Treatment of Early Parkinson’s Disease,” by Rajesh Pahwa, MD, a professor of neurology at the University of Kansas Medical Center.
The trial enrolled 529 patients, mean age 63.7, and as in the TEMPO-2 trial, the study’s main goal was to watch for changes in the MDS-UPDRS combined score at week 27.
Patients in the 5 mg group had an average reduction of 11.5 points, and those in the 15 mg group had an average reduction of 12.1 points in the MDS-UPDRS combined score when compared with those given a placebo. As in the TEMPO-1 trial, this difference between the two groups was observed after a month and sustained until the end of the observation period.
Side effects were consistent with those observed in the TEMPO-2 trial. Hallucinations were reported in 6.2% of participants receiving the 15 mg dose, but none in the 5 mg group. Rates of somnolence were comparable across both treatment groups and the placebo. Dyskinesias occurred in 1.7% of participants on the 15 mg dose, with no cases reported at the 5 mg dose. Impulse control disorders occurred in 0.6% and 1.1% of those in the 15 mg and 5 mg groups, respectively.
While the efficacy of both doses was similar, the side effect profile was slightly higher in the 15 mg group. “Looking at our study, I would say the 5 mg shows the best efficacy and the side effect profile,” Pahwa said. However, he noted, the trial was not designed to directly compare the two doses, but rather to evaluate each against a placebo.
“We are encouraged by the positive results from the TEMPO-1 and TEMPO-2 trials, which highlight tavapadon’s potential as a novel, once-daily oral treatment for early Parkinson’s disease,” Pavnit Kukreja, therapeutic area lead, Parkinson’s, at Abbvie, said in an email to Parkinson’s News Today. “The significant improvements in motor symptoms … support tavapadon’s efficacy and its favorable safety profile, aligning with our commitment at AbbVie to advance meaningful treatment options. As we progress towards our goal of submitting a New Drug Application, we remain dedicated to addressing the diverse needs of the Parkinson’s community at every stage of their journey.”
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