To describe the novel mechanism of solengepras and provide an overview of clinical trials involving solengepras in Parkinson’s Disease(PD).

Most common PD therapies target the dopamine pathways and are efficacious but lead to complications of dyskinesia and motor fluctuations.  GPR6 is a novel G-protein-coupled receptor involved in regulating movement and is enriched in medium spiny neurons (MSNs) of the indirect (striatopallidal) pathway.  Solengepras is a clinical-stage, oral, brain-penetrant, inhibitor of GPR6.  Solengepras is designed to act as an inverse agonist, reducing constitutive activity of GPR6, which decreases intracellular cyclic AMP levels and inhibitory signaling in MSNs without directly affecting the dopamine pathway. In a Phase 2 study of PD patients with motor fluctuations, solengepras was well-tolerated with low rates of dopaminergic-related side effects. Additionally, there was a clinically meaningful reduction in OFF-time in the Phase 2 study after only four weeks of solengepras treatment.

Solengepras is being studied in two ongoing clinical trials; ASCEND: a Phase 2 study as monotherapy in early untreated PD patients, and ARISE: a Phase 3, global, registrational study as adjunctive therapy in PD patients with motor fluctuations.

ASCEND is a randomized, double-blind, placebo-controlled study of 62 participants with early PD who are naïve to dopaminergic therapy.  Participants are randomized to solengepras 150mg daily or placebo, with the primary endpoint being change from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II + III at 12 weeks.  ARISE is a randomized, double-blind, placebo-controlled study of 330 participants with PD and motor fluctuations.  Participants will be randomized to solengepras 75mg, 150mg daily, or placebo, and the primary endpoint will be change from baseline in OFF-time at 12 weeks. 

Solengepras is a novel investigational agent that targets the indirect pathway through GPR6 and is being studied for PD in the ASCEND and ARISE clinical trials.