Tavapadon’s rare combination of efficacy and minimal adverse effects may indicate a step forward in the treatment of Parkinson disease.
Results of the TEMPO trials, a combination of three phase 3 studies and an open-label extension, will be used to examine the effects of tavapadon, a Parkinson disease (PD) drug designed by Cerevel Therapeutics, in patients with early-onset PD and those with late-stage PD.1
Approximately 1200 individuals, aged 40 to 80 years, will be enrolled in the 3 trials; the first patients were dosed in November 2020. TEMPO-1 (NCT04201093) and TEMPO-2 (NCT04223193) will include patients with early-onset PD and, to determine tavapadon’s efficacy, will use change from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS) part 2 and part 3 combined score (FIGURE).
Patients included in TEMPO-1 and TEMPO-2 may not be on levodopa but can be on a monoamine oxidase type B inhibitor, such as rasagiline, and still qualify for the trials. TEMPO-1 will be a fixed-dose trial, while TEMPO-2 and TEMPO-3 will feature flexible dosing.
The TEMPO-3 (NCT04542499) trial will differ from the other 2 in that it will assess patients with late-stage PD, a population whose disease is severe enough to require the introduction of levodopa. The primary end point of TEMPO-3 is the change from baseline in “ON” time without troublesome dyskinesia.
All 3 trials are supported by a 58-week open-label trial that will continue to gather information on safety that will be needed for an eventual FDA submission.
Raymond Sanchez, MD, chief medical officer of Cerevel Therapeutics, told NeurologyLive®, “We are trying to understand the benefits that tavapadon may bring to PD patients as both a stand-alone treatment in early stages of PD and as a potential adjunctive treatment to levodopa in more advanced stages of the disease.”
Tavapadon was designed as an orally bioavailable, once-daily partial agonist that selectively targets dopamine D1 and D5 receptor subtypes. The agent differentially activates the direct motor pathway, potentially driving motor benefit while minimizing the adverse effects (AEs) typical of drugs that nonselectively stimulate dopamine.2
Across phase 1b and phase 2 trials conducted to date, tavapadon has demonstrated this motor control benefit with an improved tolerability profile relative to that of D2/D3-preferring agents.
Positive results from the phase 2 assessment showed that tavapadon met its primary end points by showing a statistically significant improvement in motor symptoms after 15 weeks. Researchers found a change of –9.0 points in UPDRS Part 3 scores for those treated with tavapadon, compared with –4.3 for those administered placebo (least-squares mean, –4.8; P = .0407). Additionally, treatment compliance was high in both groups, and 82% of patients who received tavapadon completed the trial.3,4
The randomized, flexible-dose study included 57 patients aged 45 to 80 years with PD and varying disease severity (their Hoehn and Yahr stage ranged from 1 to 3). The study included a 9-week dose optimization period followed by a 6-week period of stable dosing. In the phase 1 study, tavapadon doses were 0.75 mg, 1.5 mg, 3 mg, 6 mg, and 9 mg, and included an open-label multiple ascending dose study, which gave once-daily doses with up-titration to 5 mg, 15 mg, and 25 mg.
After 15 weeks, 50% of those treated with the study agent reported Patient Global Impression of Change statuses of either much improved or very much improved. In comparison, 25% of patients in the placebo group reported this status. There were no effects of significance on Epworth Sleepiness Scale score in either the placebo or tavapadon groups.
Tavapadon also showed a favorable tolerability and safety profile. Most of the AEs were deemed mild or moderate; the most common were nausea, headache, somnolence, and tremor.
Sanchez hopes that “even when [tavapadon] is introduced as an adjunct treatment to levodopa, given its long half-life and partial agonist mechanism of action, it can sustain motor control, allow practitioners to reduce the levodopa dose, reduce the dyskinesia burden, and still [give patients] the needed motor control.”
The data readouts for these trials will emerge collectively by the end of 2023. Sanchez noted that if the trials are successful, Cerevel Therapeutics plans to submit a new drug application to the FDA shortly thereafter. It will include all 3 TEMPO trials and the open-label extension.1