CVN424 for Parkinson's Disease
Recruiting in Palo Alto (17 mi)
+25 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Cerevance
Must be taking: Levodopa
Must not be taking: Antipsychotics, Strong CYP3A4/5 inhibitors
Disqualifiers: Atypical parkinsonism, Severe dyskinesias, Heart disease, others
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This is a randomized, double-blind, placebo-controlled, multicenter study in participants with Parkinson's disease (PD) with motor fluctuations. Participants will be randomized to receive once-daily oral doses of either 75 milligrams (mg) CVN424, 150 mg CVN424, or a matching placebo for 12 weeks. Participants who successfully complete this study and retain eligibility/suitability will be invited to participate in a future open-label extension (OLE) study.
Will I have to stop taking my current medications?
The trial requires that your Parkinson's medications be stable for at least 4 weeks before screening, and certain medications like MAO-B inhibitors need to be stable for 12 weeks. You should not be using strong CYP3A4/5 inhibitors or inducers, or medications with dopamine antagonist activity. It's best to discuss your current medications with the study team to see if any changes are needed.
Eligibility Criteria
This trial is for people with Parkinson's Disease who have motor complications. They must meet specific diagnostic criteria, respond well to levodopa, and experience at least 3 hours of 'OFF' time daily. Participants should be able to walk (with or without help), have a certain cognitive score, maintain stable PD medication use before the trial, and fall within a specified weight range.Inclusion Criteria
I've been on stable medication for drooling for 30 days without expecting changes.
Average of ≥ 3 h total OFF time/day on Screening home diaries, with at least 2.5 hours OFF on each diary day.
Approved as an appropriate and suitable candidate by the Enrollment Authorization Committee (EAC)
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Exclusion Criteria
I often feel dizzy when standing up and need medication for it.
I experience specific types of movement issues without peak-dose involuntary movements.
Tests positive at Screening for drugs of abuse (opiates, tetrahydrocannabinol [THC], methadone, cocaine, and amphetamines [including ecstasy]).
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive once-daily oral doses of either 75 mg CVN424, 150 mg CVN424, or a matching placebo for 12 weeks
12 weeks
Regular in-person visits for assessments
Follow-up
Participants are monitored for safety and effectiveness after treatment
2 weeks
1-2 visits (in-person)
Open-label extension (optional)
Participants may opt into continuation of treatment long-term
Treatment Details
Interventions
- CVN424 (Dopamine Agonist)
Trial OverviewThe study tests CVN424 at two different doses (75 mg and 150 mg) against a placebo in patients with Parkinson's Disease over 12 weeks. It's randomized and double-blind, meaning neither the researchers nor participants know who gets the real drug or placebo. Successful candidates may join a future open-label extension study.
Participant Groups
3Treatment groups
Experimental Treatment
Placebo Group
Group I: CVN424 75 mgExperimental Treatment1 Intervention
Participants will be administered with oral doses of 75 mg CVN424.
Group II: CVN424 150 mgExperimental Treatment1 Intervention
Participants will be administered with oral doses of 150 mg CVN424.
Group III: PlaceboPlacebo Group1 Intervention
Participants will be administered with placebo.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Veracity Neuroscience LLCMemphis, TN
Central Texas Neurology ConsultantsRound Rock, TX
CenExel Rocky Mountain Clinical ResearchEnglewood, CO
SFM Clinical Research, LLCBoca Raton, FL
More Trial Locations
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Who Is Running the Clinical Trial?
CerevanceLead Sponsor
References
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. [2022]CVN424 is a novel small molecule and first-in-class candidate therapeutic to selectively modulate GPR6, an orphan G-protein coupled receptor. Expression of GPR6 is largely confined to the subset of striatal projection neurons that give rise to the indirect (striatopallidal) pathway, important in the control of movement. CVN424 improves motor function in preclinical animal models of Parkinson's disease. Here, we report results of a phase 1, first-in-human study investigating the safety, tolerability, and pharmacokinetics of CVN424 in healthy volunteers. The study (NCT03657030) was randomized, double-blind, and placebo controlled. CVN424 was orally administered in ascending doses to successive cohorts as inpatients in a clinical research unit. Single doses ranged from 1 mg to 225 mg, and repeated (7 day) daily doses were 25, 75, or 150 mg. CVN424 peak plasma concentrations were reached within 2 h post-dose in the fasted state and increased with increasing dose. Dosing after a standardized high-fat meal reduced and delayed the peak plasma concentration, but total plasma exposure was similar. Mean terminal half-life ranged from 30 to 41 h. CVN424 was generally well tolerated: no serious or severe adverse effects were observed, and there were no clinically significant changes in vital signs or laboratory parameters. We conclude that CVN424, a nondopaminergic compound that modulates a novel therapeutic target, was safe and well tolerated. A phase 2 study in patients with Parkinson's disease is underway. SIGNIFICANCE STATEMENT: This is the first-in-human clinical study of a first-in-class candidate therapeutic. CVN424 modulates a novel drug target, GPR6, which is selectively expressed in a pathway in the brain that has been implicated in the motor dysfunction of patients with Parkinson's disease. This study paves the way for investigating this novel mechanism of action in patients with Parkinson's disease.
Development of CVN424: A Selective and Novel GPR6 Inverse Agonist Effective in Models of Parkinson Disease. [2021]GPR6 is an orphan G-protein-coupled receptor that has enriched expression in the striatopallidal, indirect pathway and medium spiny neurons of the striatum. This pathway is greatly impacted by the loss of the nigro-striatal dopaminergic neurons in Parkinson disease, and modulating this neurocircuitry can be therapeutically beneficial. In this study, we describe the in vitro and in vivo pharmacological characterization of (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one (CVN424), a highly potent and selective small-molecule inverse agonist for GPR6 that is currently undergoing clinical evaluation. CVN424 is brain-penetrant and shows dose-dependent receptor occupancy that attained brain 50% of receptor occupancy at plasma concentrations of 6.0 and 7.4 ng/ml in mice and rats, respectively. Oral administration of CVN424 dose-dependently increases locomotor activity and reverses haloperidol-induced catalepsy. Furthermore, CVN424 restored mobility in bilateral 6-hydroxydopamine lesion model of Parkinson disease. The presence and localization of GPR6 in medium spiny neurons of striatum postmortem samples from both nondemented control and patients with Parkinson disease were confirmed at the level of both RNA (using Nuclear Enriched Transcript Sort sequencing) and protein. This body of work demonstrates that CVN424 is a potent, orally active, and brain-penetrant GPR6 inverse agonist that is effective in preclinical models and is a potential therapeutic for improving motor function in patients with Parkinson disease. SIGNIFICANCE STATEMENT: CVN424 represents a nondopaminergic novel drug for potential use in patients with Parkinson disease.
Reduced Risk of Parkinson's Disease in Users of Calcium Channel Blockers: A Meta-Analysis. [2020]Aim. To pool the data currently available to determine the association between calcium channel blockers (CCBs) and risk of Parkinson's disease (PD). Methods. Literature search in PubMed, EBSCO, and Cochrane library was undertaken through March 2014, looking for observational studies evaluating the association between CCBs use and PD. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using random-effects model. Subgroup analyses, sensitivity Analysis, and cumulative meta-analysis were also performed. Results. Six studies were included in our meta-analysis according to the selection criteria, including three cohort studies and three case-control studies involving 27,67,990 subjects including 11,941 PD cases. We found CCBs use was associated with significant decreased risk of PD, compared with not using CCBs (random effects model pooled RR, 0.81 (95% CI, 0.69-0.95)); a significant heterogeneity was found between studies (P = 0.031; I (2) 54.6%). Both the classes of CCB, that is, dihydropyridine calcium channel blockers (DiCCB) (0.80 (95% CI, 0.65-0.98) P = 0.032) and non-DiCCB (0.70 (95% CI, 0.53-0.92) P = 0.013), were found to be reducing the risk of PD. Conclusion. In our analysis, we found that CCBs use was associated with a Significantly decreased risk of PD compared with non-CCB use.
Calcium channel blocker use and risk of Parkinson's disease: a meta-analysis. [2015]Whether calcium channel blocker (CCB) use contributes to a low risk of developing a first time diagnosis of Parkinson's disease (PD) remains controversial. We conducted a meta-analysis to investigate the relationship between CCB use and PD risk.
Discovery of CVN417, a Novel Brain-Penetrant α6-Containing Nicotinic Receptor Antagonist for the Modulation of Motor Dysfunction. [2023]Nicotinic acetylcholine receptor (nAChR) α6 subunit RNA expression is relatively restricted to midbrain regions and is located presynaptically on dopaminergic neurons projecting to the striatum. This subunit modulates dopamine neurotransmission and may have therapeutic potential in movement disorders. We aimed to develop potent and selective α6-containing nAChR antagonists to explore modulation of dopamine release and regulation of motor function in vivo. High-throughput screening (HTS) identified novel α6-containing nAChR antagonists and led to the development of CVN417. This molecule blocks α6-containing nAChR activity in recombinant cells and reduces firing frequency of noradrenergic neurons in the rodent locus coeruleus. CVN417 modulated phasic dopaminergic neurotransmission in an impulse-dependent manner. In a rodent model of resting tremor, CVN417 attenuated this behavioral phenotype. These data suggest that selective antagonism of α6-containing nAChR, with molecules such as CVN417, may have therapeutic utility in treating the movement dysfunctions observed in conditions such as Parkinson's disease.