In Vitro Assessment of Cardiac Risk in Drug Discovery

Opportunities to Leverage Non-clinical Data in a Regulatory Integrated QTc Assessment

A Clinically Translatable hIPSC Cardiomyocyte Model to Predict QTc and QRS Cardiac Risk

This presentation will focus on the opportunities a sponsor now has available to increase the efficiency and effectiveness of QTc assessment by leveraging the ICH S7B core assays. There will also be times when the already conducted core hERG and in vivo assays do not meet the new expected ‘best practice’. The talk will address how gaps in best practice or limitations in tested exposures could be mitigated.

Derek Leishman, Vice President Translational and Quantitative Toxicology, Eli Lilly and Company

Dr Leishman’s experience which is most relevant to this presentation has been gained as PhRMA Topic Leader and past Rapporteur of the ICH E14/S7B Implementation Working Group.  In that capacity Dr Leishman will be sharing on the opportunities presented by the new ICH E14/S7B Q&As.  Dr Leishman is also a past president of the Safety Pharmacology Society and has spent a 32 year pharmaceutical industry career primarily focused on cardiovascular safety and PKPD modeling.

Derisking the potential for cardiac liability of novel compounds early in drug discovery is key to ensuring the development of high-quality clinical candidates. Indeed, this led to regulatory agencies developing specific guidelines (ICH S7B) to ensure appropriate safety studies are conducted at the preclinical stage. Evaluation of hERG liability is one key component in such an assessment. However, given the complex interplay between ion channels involved in the generation of the cardiac action potential, assessment of this target alone may result in the omission of other important mechanisms that can deleteriously affect cardiac function. Human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) models have been positioned as more complex, holistic cellular models that can integrate the myriad of inputs that contribute to the generation and maintenance of cardiac function. Indeed, the most recent ICH S7B guidance update includes hiPSC-CMs as a suitable derisking model.

In this presentation, I will describe a model utilizing iCell2 hiPSC-CMs¹ loaded with a voltage sensitive dye in combination with a fast capture rate plate reader to generate high quality action potential recordings in a 96 well based format.² Moreover, using an extensive and robust reference data set, the translation of key endpoints from this assay allows the prediction of compound plasma exposures in the clinic that will be associated with a 10 ms change in QTc for novel preclinical compounds, as well as provide an insight into the probability of potential QRS liabilities. In addition, data from this assay can also be used as part of the integrated risk assessment described in ICH S7B when seeking a Thorough QT (TQT) waiver from the regulatory authorities.

1. https://www.fujifilmcdi.com/products/cardiac-cells/icell-cardiomyocytes-2
2. https://lumencor.com/products/volta-scanner

Steve Jenkinson, Vice President, Drug Discovery and Safety, Metrion Biosciences

Steve Jenkinson is a thought leader in his field with a strong background in drug discovery and secondary pharmacology. He has managed drug discovery programmes across multiple therapeutic areas and stages, ranging from target identification to the nomination of candidates for preclinical development.

He has over 25 years leading discovery projects within GSK and Tanabe Research Laboratories and  joins Metrion from Pfizer where, as Senior Director, he established, developed and led the in vitro secondary pharmacology team. Additionally, Steve was co-chair of the IQ DruSafe Secondary Pharmacology Working Group and was a member of the FDA’s HESI Pro-Arrhythmia Group.

Steve completed two Postdoctoral research fellowships, at the Scripps Institute in La Jolla and the Neurosciences Institute in San Diego, before returning to the UK to begin his drug discovery career at Pfizer, Sandwich. Steve received his undergraduate degree in Pharmacology from the University of Glasgow and PhD in Molecular Pharmacology from the University of Leicester.