Therapeutics

CVN424

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Overview

Name: CVN424
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Cerevance

Background

Cerevance performs single-nuclei RNA sequencing of defined cell types isolated from postmortem brain tissue to identify therapeutic targets for neurologic diseases (Xu et al., 2018).

CVN424 is an orally available, brain-penetrant small molecule. It suppresses activity of the orphan G-protein-coupled receptor GPR6, present in striatal neurons that express dopamine receptor D2 (Sun et al., 2021). These neurons are part of a brain circuit that shows abnormal overactivity in Parkinson’s disease patients. The company claims that CVN424 does not affect D1-dependent pathways, hence affects dopaminergic signaling indirectly. This selective targeting will help avoid dyskinesia, a side effect of long-term therapy with current Parkinson’s therapies associated with D1 activation. CVN424 is being developed as an add-on to levodopa therapy for Parkinson’s disease.

In preclinical work, CVN424 induced locomotor activity in mice, and reversed haloperidol-induced catalepsy, both indications that it suppresses activity in D2-dependent pathways. It also improved movement in a rat 6-hydroxydopamine lesion model of Parkinson’s disease (Brice et al., 2021).

Findings

In May 2019, Cerevance completed a Phase 1 single- and multiple-dose safety study in healthy adults. Sixty-four volunteers received single CVN424 doses from one to 225 mg, or seven daily doses of 25, 75, and 150 mg or matching placebo. According to an April 2019 company press release, the drug caused no serious adverse events or changes in common safety measures including vital signs, cardiac function, and laboratory analyses. Results were later published (Margolin et al., 2022).

In December 2019, a Phase 2, randomized, placebo-controlled study began enrolling 141 people with Parkinson's who experience motor fluctuations on a stable dose of levodopa. To be eligible, patients must average more than two hours per day of “off time,” i.e., periods when symptoms reappear between levodopa doses. Participants were randomized to high- or low-dose drug or placebo, taken as an oral suspension once daily for one month. The primary outcome was adverse events, and secondary outcomes included additional safety measures, as well as an efficacy endpoint of daily off time, as reported by patients. This trial took place at 21 sites across the U.S., and ended in December 2021. In March 2022, the company announced positive top-line results. At the high dose, CVN424 improved off time by 1.3 hours a day compared to placebo, which was statistically significant. The company said the drug also increased on time without dyskinesia, and reduced daytime sleepiness (press release). The most common side effects, were nausea, vomiting, or headache, reported by 4 percent of patients.

For details on CVN424 trials, see clinicaltrials.gov.

Last Updated: 16 Aug 2022

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References

Paper Citations

  1. Margolin DH, Brice NL, Davidson AM, Matthews KL, Carlton MB. A Phase I, First-in-Human, Healthy Volunteer Study to Investigate the Safety, Tolerability, and Pharmacokinetics of CVN424, a Novel G Protein-Coupled Receptor 6 Inverse Agonist for Parkinson's Disease. J Pharmacol Exp Ther. 2022 Apr;381(1):33-41. Epub 2022 Feb 2 PubMed.
  2. Xu X, Stoyanova EI, Lemiesz AE, Xing J, Mash DC, Heintz N. Species and cell-type properties of classically defined human and rodent neurons and glia. Elife. 2018 Oct 15;7 PubMed.
  4. Brice NL, Schiffer HH, Monenschein H, Mulligan VJ, Page K, Powell J, Xu X, Cheung T, Burley JR, Sun H, Dickson L, Murphy ST, Kaushal N, Sheardown S, Lawrence J, Chen Y, Bartkowski D, Kanta A, Russo J, Hosea N, Dawson LA, Hitchcock SH, Carlton MB. Development of CVN424: A Selective and Novel GPR6 Inverse Agonist Effective in Models of Parkinson Disease. J Pharmacol Exp Ther. 2021 Jun;377(3):407-416. Epub 2021 Apr 1 PubMed.

External Citations

  1. company press release
  2. press release
  3. clinicaltrials.gov

Further Reading

No Available Further Reading