CAMBRIDGE, U.K.—Metrion Biosciences Ltd., a specialist ion channel contract research organization and drug discovery company, 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. Published in Nature Scientific Reports and Toxicology and Applied Pharmacology, the papers focus on the application of improved cardiac safety testing protocols and recommendations for best practices for the drug discovery industry.
Beginning in July 2013 after a workshop at the FDA, the CiPA Initiative has attempted to revise and enhance the regulatory framework assessing the 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 hERG gene codes for a protein that is the alpha subunit of a potassium ion channel best known for its contribution to the electrical activity of the heart, mediating the repolarizing current in the cardiac action potential to help to coordinate the heart's beating.
The CiPA initiative is designed to extend the use of advances in early electrophysiology-based cardiac ion channel screening, in-silico predictive modeling and human induced pluripotent stem cell-derived cardiomyocytes. The objective is to improve the accuracy and reduce the cost of predicting the cardiac liability of new drug candidates. Metrion’s research is part of the first stage of the proposed harmonization work: to show how to standardize cardiac ion channel assays to ascertain that they deliver consistent data for in-silico models of clinical cardiac arrhythmia risk.
One paper, published in Nature Scientific Reports on March 27 by an international group of authors from 20 different commercial and academic laboratories, reviews data from a multiyear, multisite collaboration across industry, academia and the FDA regulatory agency to optimize experimental protocols and reduce experimental variability and bias. The objective was to guide the development of best practices for the use of automated patch clamp (APC) technologies in early cardiac safety screening. High-quality in-vitro cardiac ion channel data is required for accurate and reliable characterization of the risk of delayed repolarization and proarrhythmia in the human heart, and to guide subsequent clinical studies and regulatory submissions.
APC instruments “enable efficient evaluation of electrophysiologic effects of drugs on human cardiac currents in heterologous expression systems,” according to the paper. Differences in experimental protocols, instruments and dissimilar site procedures affect the variability of values that characterize drug block potency, affecting the usefulness of APC platforms for determining a drug’s cardiac safety margin. The researchers determined variability of APC data from multiple sites that measured the blocking potency of 12 blinded drugs with recommended protocols using five APC platforms across 17 sites. “Adoption of best practices would ensure less variable Apc datasets and improved safety margins and proarrhythmic risk assessments,” the authors argued.
The other paper, which was published in Toxicology and Applied Pharmacology on May 1, uses automated patch clamp data from the CiPA consortium to discuss the lack of statistical quantification of variability that hampers the use of primary hERG potency data to predict cardiac arrhythmia. The consortium offers a more systematic approach to estimate hERG block potency and safety margins.
As the article explains, hERG potency/safety margin is a widely used nonclinical cardiac safety strategy. While a new regulatory paradigm promotes the integration of nonclinical and clinical data, the lack of uncertainty in quantification made it difficult to use hERG potency in the new paradigm. A systematic method was established to address this limitation. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored, based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest that any potency estimate is specific to the protocol used. Analysis supports using different safety margin thresholds in different context.
Dr. Marc Rogers, chief scientific officer at Metrion, concluded, “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.”