Tavapadon in Parkinson’s disease: D1/D5 receptor pharmacology, clinical evidence, and translational perspectives

Tavapadon is an oral, once-daily, non-catechol partial agonist selective for the D1 and D5 dopamine receptors and represents a mechanistically distinct option currently under clinical investigation for Parkinson disease (PD). This narrative review critically evaluates the biological rationale for D1/D5 receptor targeting, the pharmacological and preclinical development of tavapadon, and the accumulating phase 1–3 clinical evidence for its use as monotherapy in early PD and as adjunctive therapy in patients with motor fluctuations, while highlighting remaining evidence gaps and methodological limitations. A non-systematic literature search of PubMed/MEDLINE, Embase, ClinicalTrials.gov , and Scopus (through May 2026) was performed to identify representative and pivotal randomized controlled trials, pharmacokinetic/pharmacodynamic studies, and mechanistic preclinical investigations relevant to tavapadon and D1/D5 receptor agonism; this narrative approach was not intended to be exhaustive or fully reproducible in the manner of a systematic review. Mechanistically, selective stimulation of the direct striatal pathway together with submaximal intrinsic efficacy at the D1 receptor has been proposed, as a mechanistic hypothesis rather than a demonstrated clinical mechanism, to preserve antiparkinsonian benefit while limiting the receptor-signaling intensity implicated in levodopa-induced dyskinesia. In the phase 2 PARKWAY-II study and the now fully published phase 3 TEMPO-1 and TEMPO-2 trials, fixed- and flexible-dose tavapadon produced clinically meaningful improvements in MDS-UPDRS motor scores compared with placebo in early PD, and in the phase 3 TEMPO-3 trial, adjunctive tavapadon significantly increased daily good ON time and reduced OFF time in levodopa-treated patients with motor fluctuations; efficacy in all trials has been demonstrated only against placebo, with no head-to-head data against levodopa or other dopamine agonists. Adverse events were more frequent with tavapadon than placebo (approximately 72–76% versus 55% across TEMPO-2 and TEMPO-3), with nausea, headache, and dizziness the most common; no excess signal of impulse-control disorders relative to placebo was detected over the available 26–27-week controlled treatment period, and no clinically significant QTc prolongation was observed. The 58-week open-label TEMPO-4 extension, now reported in a peer-reviewed AAN abstract publication in Neurology alongside earlier interim conference data, suggests sustained benefit and a stable long-term levodopa requirement, but lacks a randomized control and cannot yet establish long-term safety superiority over existing agents. Tavapadon is a mechanistically novel candidate with preliminary evidence of efficacy; its ultimate clinical utility will depend on head-to-head trials and long-term safety data.