Metrion Biosciences Limited (Metrion), the specialist ion channel CRO and drug discovery company, today announced it has contributed to two new peer-reviewed papers under the U.S. Food and Drug Administration’s (FDA) CiPA (Comprehensive in vitro Proarrhythmia Assay) initiative. The papers, in Nature Scientific Reports1 and Toxicology and Applied Pharmacology2, focus on application of improved cardiac safety testing protocols and recommendations for best practice for the drug discovery industry.
The CiPA Initiative (www.cipaproject.org), which began in July 2013 following a workshop at the US FDA, has the objective to revise and enhance the regulatory framework assessing cardiac safety of new chemical entities. Under current guidelines, new therapeutics undergo initial assessment of proarrhythmic risk by measuring activity against the hERG cardiac ion channel, before progressing to studies in preclinical animal models and ultimately, a Thorough QT interval study in the clinic. The CiPA initiative aims to extend the use of advances in early electrophysiology-based cardiac ion channel screening, in silico predictive modelling, and human induced pluripotent stem cell derived cardiomyocytes to improve the accuracy and reduce the cost of predicting the cardiac liability of new drug candidates. Metrion’s research forms part of the first stage of the proposed harmonisation work, to provide clarity on how to standardise cardiac ion channel assays to ensure they deliver consistent data for in silico models of clinical cardiac arrythmia risk.
The first paper1, published in Nature Scientific Reports on 27th March 2020 by an international group of authors drawn from 20 different commercial and academic laboratories, including Metrion Biosciences, was coordinated by the Health and Environmental Sciences Institute (HESI). It reviews data from a multi-year, multi-site collaboration across industry, academia and the FDA regulatory agency to optimize experimental protocols and reduce experimental variability and bias. The goal of the study was to guide the development of best practices for the use of automated patch clamp technologies in early cardiac safety screening. High quality in vitro cardiac ion channel data is required for accurate and reliable characterisation of the risk of delayed repolarisation and proarrhythmia in the human heart and to guide subsequent clinical studies and regulatory submissions.
The second paper2, to be published formally in Toxicology and Applied Pharmacology paper on 1st May 2020 but currently available online, uses automated patch clamp data from the CiPA consortium to address the lack of statistical quantification of variability, which hinders the use of primary hERG potency data to predict cardiac arrhythmia. The consortium establishes a more systematic approach to estimate hERG block potency and safety margins.
Dr Marc Rogers, CSO, Metrion Biosciences, said: “The Metrion team has been a participant in the international CiPA Initiative since inception and we are now pleased to be able to announce the publication of our data from this global collaborative scientific effort. We believe these projects will make a significant contribution to the eventual revision of cardiac safety testing guidelines by the FDA and other international regulatory agencies. They also contribute to deepening our knowledge of the underlying causes of proarrhythmia, which will help prevent early attrition of potentially promising drugs.”
Contributing organisations to the Nature Scientific Reports CiPA study include: Charles River Laboratories; Bayer AG; Sophion Bioscience A/S; Nanion Technologies; GlaxoSmithKline PLC; Pfizer; Sanofi R&D; Astra Zeneca; B’SYS GmbH; Bristol-Myers Squibb Company; Eurofins Discovery; Merck; Metrion Biosciences Ltd.; Natural and Medical Science Institute at the University of Tübingen; Northwestern Feinberg School of Medicine, Chicago; Roche Innovation Center Basel; Novoheart; Health and Environmental Sciences Institute, Washington, DC; AbbVie.
Contributing organisations to the Toxicology and Applied Pharmacology hERG study include: Center for Drug Evaluation and Research, Food and Drug Administration; Eli Lilly and Company; AstraZeneca; CiPA LAB; NMI-TT GmbH; Sophion Bioscience A/S; B’SYS GmbH; The Ion Channel Company; F. Hoffmann-La Roche AG; Eurofins Discovery; Bristol-Myers Squibb; Merck & Co., Inc; Metrion Biosciences Ltd.; Nanion Technologies; Charles River Laboratories; Bayer AG; University of Nottingham; Université de Lille.
Metrion Biosciences’ comprehensive cardiac safety testing ‘White Paper’ “The changing landscape of cardiac safety” is available to download.