Randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm: RESTORE SR

Piccini, Jonathan P.; Pritchett, Edward L.C.; Davison, Beth A.; Cotter, Gad; Wiener, Laura Elizabeth; Koch, Gary G.; Feld, Gregory K.; Waldo, Albert L.; Gelder, Isabelle C. Van; Camm, A. John; Kowey, Peter R.; Iwashita, Julie; Dittrich, Howard C.

doi:10.1016/j.hrthm.2016.04.012

Cited by 28 publications

(18 citation statements)

References 18 publications

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“…In contrast, the development of 400 mg vanoxerine in the treatment of atrial fibrillation had to be discontinued because of unacceptably high prevalence of TdP (Piccini et al, ). Its IC 50 value for hERG channel was just over ninefold greater than that for the late I Na current (9.3 and 85.2 nM, respectively; Obejero‐Paz et al, ).…”

Section: Discussionmentioning

confidence: 99%

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies

Ligneau

Shah

Berrebi-Bertrand

et al. 2017

British J Pharmacology

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Background and PurposeWe evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.Experimental ApproachNonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro‐arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell‐derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology. ICH S7B‐recommended assays included in vitro hERG (KV11.1) channels, in vivo dog studies with follow‐up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro‐arrhythmia model.Key ResultsBoth sets of nonclinical data consistently excluded pitolisant from having clinically relevant QT‐liability or pro‐arrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late INa reducing activities at high concentrations, which resulted in pitolisant reducing dofetilide‐induced early after‐depolarizations (EADs) in the ICH S7B studies. Studies in stem cell‐derived human cardiomyocytes with dofetilide or E‐4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the ion channel effects measured are consistent with results from both the stem cell‐derived cardiomyocytes and rabbit Purkinje fibres and categorized pitolisant as a drug with low torsadogenic potential. Results from the two sets of nonclinical studies correlated well with those from two clinical QT studies.Conclusions and ImplicationsOur findings support the CiPA initiative but suggest that sponsors should consider investigating drug effects on EADs and the use of pro‐arrhythmia models when the results from CiPA studies are ambiguous.

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Section: Discussionmentioning

confidence: 99%

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies

Ligneau

Shah

Berrebi-Bertrand

et al. 2017

British J Pharmacology

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“…In a phase II doseranging COR-ART study, vanoxerine was highly effective in converting atrial brillation and atrial utter (AF/AFL) to sinus rhythm without evidence of proarrhythmia [68]. However, this drug was eventually terminated from development due to occurrence of cardiac arrhythmias including torsade de pointes (TdP) in patients with structural heart disease [69].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Vanoxerine Dihydrochloride as a CDK2 / 4 / 6 Triple-Inhibitor for the Treatment of Human Hepatocellular Carcinoma

Zhu

Xia

et al. 2021

Preprint

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Background: Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods: We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC.Results: We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxic drug in human HCC QGY7703 and Huh7 cells (IC50: 3.79μM for QGY7703and 4.04μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1‑arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40mg/kg, i.p.) injection for 21 days produced significant anti‑tumor activity (p<0.05), which was comparable to that achieved by 5-Fu (10mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerine dihydrochloride treatment group.Conclusions: The present study is the first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

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“…Subsequently, a randomized, double-blinded study confirmed vanoxerine superior efficacy to placebo (70% vs. 20%). However, the study was terminated early due to the occurrence of ventricular arrhythmias and torsades de pointes in the treatment group (Piccini et al, 2016). This concerning finding regarding vanorexine safety profile was in contrast to an earlier phase 2B clinical trial, the Safety and Efficacy of Vanoxerine for Conversion of Atrial Fibrillation or Flutter to Normal Sinus Rhythm (COR-ART) trial, which found vanoxerine to have high conversion rate (84%), to be well tolerated, and to cause no ventricular arrhythmias (Dittrich et al, 2015).…”

Section: Vanoxerine (Gbr-12909)mentioning

confidence: 99%

“…TASK-3, the closest relative of TASK-1, expresses prominently in human right auricles. Interestingly, human atrial TASK-1 and TASK-3 can form heterodimers ( Rinné et al, 2015 ).…”

Section: Emerging Antiarrhythmic Drugs For Rhythm Controlmentioning

confidence: 99%

Revisiting Antiarrhythmic Drug Therapy for Atrial Fibrillation: Reviewing Lessons Learned and Redefining Therapeutic Paradigms

2020

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Randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm: RESTORE SR

Cited by 28 publications

References 18 publications

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies

Discovery of Vanoxerine Dihydrochloride as a CDK2 / 4 / 6 Triple-Inhibitor for the Treatment of Human Hepatocellular Carcinoma

Revisiting Antiarrhythmic Drug Therapy for Atrial Fibrillation: Reviewing Lessons Learned and Redefining Therapeutic Paradigms

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