CVN424 for Parkinson's Disease
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Cerevance
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.
Is the drug CVN424 a promising treatment for Parkinson's Disease?The information provided does not directly mention CVN424 or its effects on Parkinson's Disease, so we cannot determine if it is a promising treatment based on this data.3691014
What safety data is available for CVN424 in treating Parkinson's Disease?A Phase I study investigated the safety, tolerability, and pharmacokinetics of CVN424 in healthy volunteers. The study was randomized, double-blind, and placebo-controlled, with single doses ranging from 1 mg to 225 mg and repeated daily doses of 25, 75, or 150 mg. CVN424 was generally well tolerated, with no serious or severe adverse effects observed, and no clinically significant changes in vital signs or laboratory parameters. This suggests that CVN424 is safe and well tolerated, paving the way for further studies in patients with Parkinson's Disease.57111215
Do I need to stop my current medications for this trial?The trial requires that your Parkinson's disease medications be stable for at least 4 weeks before screening, and MAO-B inhibitors must be stable for at least 12 weeks. You should not use strong CYP3A4/5 inhibitors or inducers, PD on-demand medications, or medications with dopamine antagonist activity. If you meet these conditions, you may not need to stop your current medications, but check with the trial team for specifics.
What data supports the idea that CVN424 for Parkinson's Disease is an effective drug?The available research does not provide specific data on CVN424 for Parkinson's Disease. However, other treatments like CV 205-502 showed significant improvement in patients with Parkinson's Disease, with benefits sustained over six months. Amantadine also showed moderate improvement in motor fluctuations in 55% of patients at two months and 65% at three months. These comparisons suggest that while CVN424's effectiveness isn't directly supported by the data, other treatments have shown positive results.124813
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
My Parkinson's disease is at a stage where I can still walk and stand unassisted.
I can walk by myself or with help from a device.
My Parkinson's disease medication has been the same for at least 4 weeks.
I take Levodopa at least 4 times a day or Rytary 3 times a day.
I have Parkinson's disease diagnosed by UK standards, with symptoms improving on levodopa.
Exclusion Criteria
I have been diagnosed with a form of parkinsonism that is not typical Parkinson's disease.
I experience specific types of movement issues without peak-dose involuntary movements.
My kidney function is significantly impaired.
I have previously been treated with CVN424.
I need antipsychotics for severe hallucinations.
I am not taking any strong medications that affect liver enzymes.
I regularly use on-demand PD medications like inhaled levodopa.
I have not had, nor plan to have, surgery or continuous therapy for Parkinson's during the study.
I often feel dizzy when standing up and need medication for it.
I have had serious heart issues or symptoms in the last 2 years.
I have major depression or my BDI-II score is over 19.
Treatment Details
The 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.
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
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Who is running the clinical trial?
CerevanceLead Sponsor
References
CV 205-502: safety, tolerance to, and efficacy of increasing doses in patients with Parkinson's disease in a double-blind, placebo crossover study. [2013]CV 205-502 (CV) is a long-acting dopamine agonist with potent D2 and weak D1 activity, which has not as yet been tested in patients with Parkinson's disease. We performed a dosage ranging and placebo crossover study in six patients to evaluate the efficacy and tolerance of CV when used as an adjunct to Sinemet in patients with Parkinson's disease. All patients had striking improvement. This effect was lost with placebo substitution and regained with reintroduction of CV. Benefits were sustained throughout the 6 month study. Single daily dosing could sustain the response in all but one patient. Adverse effects were mild and transient and resolved with dosage manipulation or a divided dosage regimen. CV is a promising drug for use in Parkinson's disease and further studies are indicated to test its long-term safety and efficacy.
Amantadine and motor fluctuations in chronic Parkinson's disease. [2019]Twenty patients with idiopathic Parkinson's disease (PD) and motor fluctuations received open-label amantadine (100-200 mg/d) in addition to their other antiparkinson medications. One patient had unpredictable motor fluctuations (on-off) and the others had end-of-dose wearing-off. The effect of amantadine on motor fluctuations and parkinsonian disability was tested at 1, 2, and 3 months. Moderate improvement in motor fluctuations occurred in 55% of the patients at 2 months and 65% of patients at 3 months of treatment (p less than 0.01). There was also significant improvement in parkinsonian disability. The duration of improvement averaged 5.7 months, and all patients deteriorated to their baseline level of function within 12 months. This study suggests that the addition of amantadine can transiently improve motor fluctuations and have a significant impact on overall disability in patients with chronic PD.
PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of parkinsonism. [2022]We analyzed the PINK1 gene in 58 patients with early-onset Parkinsonism and detected the homozygous mutation W437X in 1 patient. The clinical phenotype was characterized by early onset (22 years of age), good response to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinson's disease and 3 further relatives were reported affected, according to an autosomal dominant transmission.
TC-8831, a nicotinic acetylcholine receptor agonist, reduces L-DOPA-induced dyskinesia in the MPTP macaque. [2013]Long-term L-DOPA treatment for Parkinson's disease (PD) is limited by motor complications, particularly L-DOPA-induced dyskinesia (LID). A therapy with the ability to ameliorate LID without reducing anti-parkinsonian benefit would be of great value. We assessed the ability of TC-8831, an agonist at nicotinic acetylcholine receptors (nAChR) containing α6β2/α4β2 subunit combinations, to provide such benefits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) lesioned macaques with established LID. Animals were treated orally for consecutive 14-day periods with twice-daily vehicle (weeks 1-2) or TC-8831 (0.03, 0.1 or 0.3 mg/kg, weeks 3-8). L-DOPA was also administered, once-daily, (weeks 1-12, median-dose 30 mg/kg, p.o.). For the following two-weeks (weeks 9-10), TC-8831 was washed out, while once-daily L-DOPA treatment was maintained. The effects of once-daily amantadine (3 mg/kg, p.o.) were then assessed over weeks 11-12. LID, parkinsonism, duration and quality of ON-time were assessed weekly by a neurologist blinded to treatment. TC-8831 reduced the duration of 'bad' ON-time (ON-time with disabling dyskinesia) by up to 62% and decreased LID severity (median score 18 cf. 34 (vehicle), 0.1 mg/kg, 1-3 h period). TC-8831 also significantly reduced choreiform and dystonic dyskinesia (median scores 6 and 31 cf. 19 and 31 respectively (vehicle), both 0.03 mg/kg, 1-3 h). At no time did TC-8831 treatment result in a reduction in anti-parkinsonian benefit of L-DOPA. By comparison, amantadine also significantly reduced dyskinesia and decreased 'bad' ON-time (up to 61%) but at the expense of total ON-time (reduced by up to 23%). TC-8831 displayed robust anti-dyskinetic actions and improved the quality of ON-time evoked by L-DOPA without any reduction in anti-parkinsonian benefit.
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.
Age-Related Changes of 14-3-3 Isoforms in Midbrain of A53T-SNCA Overexpressing Mice. [2015]Parkinson's disease (PD) is characterized by loss of midbrain dopaminergic neurons, which are affected by cytoplasmic inclusions, named Lewy pathology. The main component is alpha-synuclein (SNCA), a protein modulating SNARE-complex dependent neurotransmission. SNCA mutations trigger dominantly inherited PD variants and sporadic cases of PD via aggregation and transmission. SNCA and isoforms of the 14-3-3 family show sequence homology, protein interaction and joint aggregation, so 14-3-3 s may be key molecules of pathogenesis.
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.
Pulmonary Safety and Tolerability of Inhaled Levodopa (CVT-301) Administered to Patients with Parkinson's Disease. [2019]CVT-301, an inhaled levodopa (LD) formulation, is under development for relief of OFF periods in Parkinson's disease (PD). Previously, we reported that CVT-301 improved OFF symptoms relative to placebo. In this study, we evaluate pulmonary function in patients treated with a single dose of CVT-301 or placebo for 3 hours, or received multiple doses/day for 4 weeks.
Novel ATP13A2 and PINK1 variants identified in Chinese patients with Parkinson's disease by whole-exome sequencing. [2022]Genetic factors are considered to play a critical role in patients with early-onset Parkinson's disease (EOPD). The genetic spectrum of EOPD patients has been extensively investigated in Caucasian populations but rarely in the Chinese population. In this study, a total of 21 unrelated Chinese EOPD patients were enrolled. Multiplex ligation-dependent probe amplification assay and whole-exome sequencing were performed, followed by Sanger sequencing. Detailed clinical features were presented. Two novel likely pathogenic variants (p.Q648X in ATP13A2 and p.N521fs in PINK1) and 10 previously reported Parkin pathogenic variations (exon 2 deletion, exon 3-4 deletion, exon 4 deletion, exon 6-7 deletion, exon 7 deletion; p.G284R, p.G329 V, p.R366W, p.N428fs, p.M458 L) were identified in 9 out of 21 (42.86%) patients. The frequency (33.33%) of Parkin variations is much higher in our cohort than that in the East Asian population. The patient carrying the ATP13A2 variant showed no response to levodopa treatment. Our findings broaden the genetic spectrum and clinical features of EOPD patients.
Characterization of Recessive Parkinson Disease in a Large Multicenter Study. [2022]Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.
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.
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.
Inhaled Levodopa (CVT-301) for the Treatment of Parkinson Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials. [2023]To investigate the efficacy and safety of CVT-301 in treating motor fluctuation in patients with Parkinson disease (PD).
Parkin Maintains Robust Pacemaking in Human Induced Pluripotent Stem Cell-Derived A9 Dopaminergic Neurons. [2023]The degeneration of nigral (A9) dopaminergic (DA) neurons results in cardinal motor symptoms that define Parkinson's disease (PD). Loss-of-function mutations in parkin are linked to a rare form of early-onset PD that is inherited recessively.
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.