Tavapadon Improves Early PD Symptoms: Full Phase 3 Results

An investigational once-daily dopamine agonist improved motor symptoms in patients with early Parkinson’s disease (PD) while showing low rates of somnolence and impulse control disorders — side effects that have long limited use of the drug class.The full results of the phase 3 TEMPO-2 trial confirmed that tavapadon significantly improved motor function and activities of daily living compared with placebo over 26 weeks, with benefits emerging as early as 5 weeks into treatment.The study was published online on July 15 in Lancet Neurology.Meaningful Benefits, Fewer Side EffectsTEMPO-2 is the third and final pivotal phase 3 trial of tavapadon to report results, Cindy Zadikoff, MD, MSc, senior medical director of clinical development, neuroscience, at AbbVie and a study co-author, told Medscape Medical News.Unlike the TEMPO-1 trial, which evaluated fixed doses of tavapadon, the TEMPO-2 trial used a flexible-dose regimen. The results were very similar, Zadikoff said, reinforcing the evidence supporting tavapadon in patients with early PD.The TEMPO-3 trial previously showed that tavapadon significantly improved motor fluctuations when used as adjunctive therapy to levodopa in patients with PD.Current dopamine agonists primarily stimulate D2/D3 receptors and are associated with adverse effects including somnolence, impulse control disorders, hallucinations, and peripheral edema. Tavapadon selectively targets D1/D5 receptors and is designed to preserve motor efficacy while reducing these nonmotor adverse effects.Zadikoff said tavapadon’s selective D1/D5 mechanism is intended to “provide the motor benefits that people expect to see and need to see for the treatment of their symptoms, while avoiding many of the side effects that people have come to expect from the D2/D3 agonists,” which she said have led many clinicians to prescribe those agents less frequently.The TEMPO-2 trial enrolled 304 adults aged 40-80 years with early PD (< 3 years’ disease duration) who were treatment-naive or had received less than 3 months of dopaminergic therapy. Participants were randomly assigned to flexible dose tavapadon (5-15 mg daily) or placebo for 27 weeks.The primary endpoint of change from baseline to week 26 in the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Parts II and III combined score was significantly improved with tavapadon vs placebo.Patients treated with tavapadon experienced a least-squares mean reduction of 10.3 points compared with 1.2 points for placebo. The 9.1-point difference (P < .0001) exceeded the approximately 4.9-point threshold considered the minimum clinically important difference, the investigators noted.Tavapadon also significantly improved the key secondary endpoint of MDS-UPDRS Part II (activities of daily living), with a placebo-adjusted difference of -1.5 points (P = .0007).Nearly half of the patients receiving tavapadon (46%) rated themselves as “much improved” or “very much improved” on the Patient Global Impression of Change compared with 19% of placebo-treated patients (odds ratio, 3.94; P < .0001).No significant differences were observed in PD Questionnaire-39 quality-of-life scores, which investigators suggested may reflect the relatively short follow-up and low baseline disability in this early-stage population.Overall, adverse events were more common with tavapadon than placebo (76% vs 55%). Most adverse events were mild or moderate, and no deaths occurred.The most common adverse events with tavapadon were nausea (30%), headache (17%), and dizziness (16%). Hallucinations occurred in 4% of patients receiving tavapadon vs none receiving placebo. Notably, rates of somnolence (3% vs 4%) and impulse control disorders (1% vs 0%) were low, consistent with tavapadon’s selective D1/D5 mechanism. No cases of dyskinesia were observed.Treatment discontinuation due to adverse events occurred in 24% of patients receiving tavapadon vs in 4% of those receiving placebo, with most discontinuations occurring during dose titration.An ongoing open-label extension study, TEMPO-4, is evaluating the long-term safety and efficacy of tavapadon.A Real Step Forward?The FDA has accepted AbbVie’s new drug application for tavapadon in PD and the company remains on track for FDA action later this year, Zadikoff told Medscape Medical News.The co-authors of a linked Comment wrote that the TEMPO-2 findings “clearly confirm” that selective D1 receptor stimulation improves motor symptoms in early PD.“Adding a D1 agonist into the panel of available dopaminergic antiparkinsonian medications has been long awaited. Tavapadon could fill this gap,” wrote Olivier Rascol, MD, PhD, and Margherita Fabbri, MD, from University Hospital of Toulouse in Toulouse, France.They noted, however, that the TEMPO-2 trial does not answer some key questions that are “mandatory” to anticipate the future positioning of tavapadon among other antiparkinsonian dopaminergic options in clinical practice, especially D2 agonists and levodopa.“This missing evidence is due to the absence of an active comparator in the trial, its limited sample size, and a short follow-up,” they wrote. They also noted the relatively high treatment discontinuation rate in the TEMPO-2 trial and said larger, longer-term comparative studies will be needed to fully define the drug’s benefit-risk profile and place in therapy.“Time will tell,” they concluded, whether tavapadon represents “a real step forward” over existing dopamine agonists or simply “a ‘me too’ drug.”The study was funded by AbbVie. Disclosures for the authors are available with the original study publication. Rascol disclosed having relationships with Bial, Biogen, Britannia, Cerevel, Contera, GE Healthcare, Ionis, Jazz, Kyowa, LGD Nuvamid, Lundbeck, Merz, NeuraLight, NeurATRIS, Neuroderm, Orion Pharma, Parexel, Roche Therapeutics, Sanofi, Thelonius Mind, Teva, UCB, and Zambon. Fabbri disclosed having relationships with AbbVie, BIAL, Medtronic, Orkyn, Ever Pharma, Teitur Trophics, and Zambon.