AAN 2026: Tavapadon helps delay levodopa start in early Parkinson’s
Given as an add-on or standalone therapy, oral med shown to ease symptoms
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- New data from a long-term study show tavapadon is safe and effective in easing Parkinson's symptoms.
- The experimental medication also was found to help delay levodopa initiation or a dose increase for those already on the gold standard therapy.
- Developer Abbvie is now seeking regulatory approval of tavapadon for Parkinson's.
While on long-term treatment with Abbvie’s experimental oral drug tavapadon, most people with early Parkinson’s disease did not need to start levodopa — the mainstay therapy for the progressive condition — and most individuals already taking levodopa didn’t need to increase their dose.
That’s according to new results from the now-completed Phase 3 TEMPO-4 (NCT04760769) open-label extension study, which were presented this week at the American Academy of Neurology (AAN) annual meeting, held April 18-22 in Chicago and online. In TEMPO-4, participants in past clinical trials of tavapadon were given the medication as a standalone therapy or as an adjunctive, or add-on, to levodopa treatment.
“While the market seems saturated with adjunctive therapies to levodopa, motor fluctuations continue to be amongst the most bothersome problem[s] in advancing PD [Parkinson’s disease]. Therefore, we still have some work to do in improving the lives of individuals with PD,” Hubert H. Fernandez, MD, a professor at the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, told Parkinson’s News Today in a written interview detailing the findings.
“Tavapadon brings us one step closer to our goal,” Fernandez said.
Per Abbvie, TEMPO-4 adds to the evidence on tavapadon’s safety and effectiveness, shown in three other Phase 3 trials — TEMPO-1 (NCT04201093), TEMPO-2 (NCT04223193), and TEMPO-3 (NCT04542499). Based on the findings from these three studies, the company has submitted an application to the U.S. Food and Drug Administration (FDA) seeking approval of tavapadon for treating Parkinson’s.
William Ondo, MD, a neurologist at Houston Methodist Neurological Institute and an investigator on the TEMPO trials, presented the TEMPO-4 results at the AAN meeting. Ondo’s presentation was titled “Levodopa Initiation or Dose Adjustments in TEMPO-4: A 58-Week Open-label Trial of Tavapadon for Treatment of PD.” The presentation abstract concluded: “After a total of 14-20 months of tavapadon treatment, [approximately] 90% of participants did not require levodopa initiation or dose increases.”
In Parkinson’s disease, nerve cells that produce the signaling molecule dopamine gradually die off. Dopamine signaling is important for movement, cognition, and other processes, so the death of these cells leads to the progressive motor and nonmotor symptoms that mark the disease.
Levodopa aims to ease these symptoms by providing the body with the building blocks it needs to produce new dopamine.
Levodopa is ‘undisputed’ standard, but triggers side effects
The therapy’s been used to treat Parkinson’s since the 1960s, and nearly all patients are prescribed levodopa at some point.
However, “while levodopa remains the undisputed gold standard therapy in PD, it does not come without baggage,” said Fernandez, who is serves as the head of Movement Disorders under the Center for Neurological Restoration at Cleveland Clinic.
People taking levodopa often need to gradually increase their dosage, increasing the risk of side effects like motor fluctuations and dyskinesia, or involuntary movements. Waiting to start levodopa or keeping the medication at a lower dose may help delay or avoid these problems for many patients. Alternatives to levodopa or add-on therapies also could help meet this goal.
Tavapadon is designed to activate the receptors to which dopamine normally binds. This may boost dopamine signaling pathways without directly increasing dopamine levels like levodopa. Although similar medications exist, tavapadon is unique because it targets a specific family of dopamine receptors, the D1 receptors; other therapies target a different family, the D2 receptors.
While D2 receptors are widespread throughout the brain, D1 receptors tend to cluster in areas that support movement. Activating D1 receptors may help reduce the side effects associated with many D2-targeting medications, scientists believe.
“Tavapadon has been developed so it can be used as initial symptomatic therapy in early PD, and as an adjunctive medication to levodopa in later stages of PD,” Fernandez said.
As a once-daily oral medication, it may be more convenient for many patients than existing options, the scientist suggested.
“A significant portion of the PD population [has] a hard time keeping up with the medication schedules. Therefore, the convenience of a once daily medication could be a game changer for a lot of patients,” Fernandez said.
Study tested safety, effectiveness of long-term tavapadon use
The Phase 3 TEMPO clinical trial program was designed to test tavapadon’s safety and effectiveness in two clinical situations. TEMPO-1 and TEMPO-2 involved participants with early stages of Parkinson’s, demonstrating that tavapadon as a standalone medication could help control symptoms without causing dyskinesia. TEMPO-3 focused on later stages of the disease and found that tavapadon could be effective as an add-on to ongoing levodopa treatment.
Each of the first three TEMPO trials lasted for 26 weeks, or about six months. After this time, participants could enter TEMPO-4, a long-term extension. “The goal of this study was to demonstrate continued efficacy, safety and tolerability with long-term use,” Fernandez said.
Participants who had previously received tavapadon could continue on the medication, while those who had been in placebo groups could start treatment. The trial also included patients who had not participated in previous tavapadon trials — called de novo patients — and were on a stable levodopa dose. The main treatment period of TEMPO-4 lasted for 52 weeks, or about one year.
Throughout this time, participants from TEMPO-1 and TEMPO-2 could start taking levodopa if their doctors recommended it, and patients from TEMPO-3, as well as de novo participants, could adjust their ongoing levodopa dose as needed.
When over 90% of participants placed on tavapadon do not show the need to start levodopa or adjust their levodopa dose (for those already on it), it is a strong testament to its efficacy and ‘sustaining power.’
During the yearlong treatment period of TEMPO-4, 86% to 94% of participants from TEMPO-1 and TEMPO-2 stayed off levodopa. This indicated that they achieved symptom control without adding another medication to tavapadon. That meant that, for participants with early disease, the probability of starting levodopa remained below 10% for as long as one year.
“Indeed, when over 90% of participants placed on tavapadon do not show the need to start levodopa or adjust their levodopa dose (for those already on it), it is a strong testament to its efficacy and ‘sustaining power,'” Fernandez said.
He added: “This is highly relevant in PD because it delays the need for levodopa or the necessity of increasing its dose, thereby minimizing the occurrence of levodopa side effects.”
Individuals who started levodopa treatment during TEMPO-4 tended to start out with more severe motor symptoms than those who remained off levodopa, the researchers found.
Over 80% of those already on levodopa did not change dosage
Among participants who were already taking levodopa, 81% to 88% did not change their dosage during the TEMPO-4 study period. Those who did adjust their levodopa dose were nearly twice as likely to decrease it rather than increase it, the data showed.
In the initial TEMPO studies, common side effects included nausea, lightheadedness, and dizziness. According to Fernandez, these were expected, given older medications that also activate dopamine receptors. However, tavapadon’s predecessors were also sometimes associated with unpredictable side effects such as sudden sleepiness, weight gain, swelling in the legs, and problems with impulse control.
“Thus far, we still haven’t noticed any bump in the occurrence of these … side effects [in TEMPO-4],” Fernandez said. “We really hope the trend continues till all the participants finish the study.”
Taken together, the TEMPO-4 results support the safety and efficacy findings from the earlier TEMPO trials, which supported Abbvie’s FDA application for approval of tavapadon, according to the developer. If the application is successful, tavapadon could expand the treatment landscape for Parkinson’s, Fernandez noted.
“The approval of tavapadon would provide PD patients more options, not only when starting symptomatic therapy, but also when experiencing motor fluctuations with levodopa use,” Fernandez said.
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