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 a monotherapy, and as an add-on to levodopa therapy for Parkinson’s disease.

The molecular structure of CVN424 bound to GPR6 gave insight into the drug’s mechanism of inverse agonism (Barekatain et al., 2024).

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 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. Results were published after peer review (Brice et al., 2024).

In 2022, a Phase 1 study evaluated pharmacokinetics and safety of suspension versus tablet formulations, and food effects.

In September 2023, a second Phase 2 trial began testing CVN424 as a monotherapy in people with early Parkinson’s disease who are not yet taking dopamine drugs. The 62 participants received 150 mg tablets or placebo for 12 weeks, against a primary outcome of change from baseline on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and III. Secondary outcomes are patient and clinician impression of severity, non-motor symptoms including sleepiness, signs of abuse or withdrawal, and other adverse events. Completion is slated for February 2025.

In September 2024, the company started Phase 3. The study plans to recruit 330 Parkinson’s patients with motor symptoms that require levodopa, and three or more hours of off time per day. They will take 75 or 150 mg CVN424 or placebo once daily for 12 weeks, in addition to their other medications. The primary outcome is average daily off time on 150 mg compared to placebo, based on patient diaries. Secondary measures are on time without troublesome dyskinesias, the MDS-UPDRS, patient and clinician impression of severity, sleepiness, apathy, CogState digital cognitive battery, safety, adverse events, and other standard scales. The trial will use an artificial intelligence interface to assess cognitive, speech, and motor skills during engagement with an internet bot. The study, at 20 locations in the U.S. and one in the Philippines is expected to finish in in March 2026.

For details on CVN424 trials, see clinicaltrials.gov.