Inhibition of Novel G-Protein Improves Parkinson Disease Symptoms 

In a phase 2 clinical trial (NCT04191577) participants with Parkinson disease (PD) treated with an inverse agonist of novel G-protein receptor 6 (GPR6)(CVN424; Cerevance, Boston, MA) had statistically significant, dose-dependent reductions of “OFF time.”  

Individuals treated with the higher of 2 doses had a 1.3-hour decrease in OFF time compared with those treated with placebo (P=0.042) after 4 weeks of treatment. An increase in ON time without troublesome dyskinesia was also observed in those treated with CVN424. Individuals treated with the lower of the 2 doses also had decreases in OFF time and more ON time without troublesome dyskinesia.  

Efficacy improvements were seen at 2 weeks and 4 weeks. People treated with CVN424 had less daytime sleepiness as measured with the Epworth Sleepiness Scale than those treated with placebo. Daytime sleepiness is common side effect of PD treatments adjunctive to levodopa treatment. 

Participants in this study (n=135) were on stable doses of levodopa and other treatments for PD, with 2 or more hours/day of OFF time. After baseline safety and efficacy assessments, participants were randomly assigned to receive once-daily doses of low-dose CVN424, high-dose CVN424, or matching placebo for 4 weeks.
“CVN424’s positive results demonstrate the power of the deep, cell-type-specific transcriptional and epigenetic data we are generating by applying our NETSseq platform technology to thousands of post-mortem human brain tissue samples,” said Mark Carlton, PhD, chief scientific officer, Cerevance.

“For more than 50 years, physicians have relied on therapeutics that work by directly increasing dopaminergic signaling,” said Karl Kieburtz, MD, president,  Clintrex. “This new mechanism holds great promise for treating the motor fluctuations eventually experienced by all PD patients and has potential for treating patients in the earlier stages of the disease.”

The most common adverse reactions to the drug were nausea, vomiting, and headache, occurring in 2 participants (4%), each at the higher dose. All other adverse reactions occurred in only 1 participant.