CVN424, a GPR6 inverse agonist, for Parkinson's disease and motor fluctuations: a double-blind, randomized, phase 2 trial

Abstract

Background: CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations.

Methods: This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2-4) who were on a stable dose of levodopa and experiencing ≥2 h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50 mg or 150 mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time.

Findings: The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n = 47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50 mg, 9% with CVN424 150 mg, and 2% with placebo) and nausea (4% with CVN424 50 mg, 6% with CVN424 150 mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean ± standard deviation (SD) change from baseline in daily OFF-time was -1.3 ± 3.0 h in the CVN424 50 mg group, -1.6 ± 2.5 h in the CVN424 150 mg group, and -0.5 ± 2.9 h in the placebo group. The placebo-adjusted LS mean ± standard error (SE) treatment difference was significant for the CVN424 150 mg dose (1.3 ± 0.56 h, [95 CI% -2.41 to -0.19], nominal p = 0.02).

Interpretation: Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150 mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD.

Funding: Cerevance.

Keywords: CVN424; GPR6; Indirect pathway; Motor fluctuations; Parkinson's disease; Striatum.

Fig. 1

Trial profile. ∗Participants received CVN424 50 mg during dose escalation; one participant had an unrelated cardiac arrest and subsequent epileptic seizure on Day 2 and died on Day 7.

Fig. 2

CVN424 plasma concentration-time plots by dose (PK analysis set). Data shown are mean (±SE) concentrations.

Fig. 3

Mean (SE) change from baseline in daily OFF time by visit (a) Efficacy population (b) FDA standardised analysis (≥3 h OFF time at baseline) population. The standard FDA analysis included patients with ≥3 h of OFF-time at baseline and normalises Hauser diary data to a 16-h period of wakefulness and excludes incomplete diaries (fewer than 44 of 48 entries completed in a day). Data shown are LS mean (±SE). Blue stars correspond to 150 mg group ∗ p < 0.05; ∗∗p < 0.01 compared to vehicle (MMRM).