By Steve Jenkinson, VP Drug Discovery and Safety Assessment, Metrion Biosciences

Our webinar 'In Vitro Assessment of Cardiac Risk in Drug Discovery' enabled attendees to learn how an hiPSC-CM model can help provide clear decision-making data for their project team, avoiding costly issues related to QTc and QRS cardiac liabilities in the clinic.

Prior to joining Metrion I had the privilege of co-chairing the Secondary Pharmacology Working Group under the auspice of the IQ DruSafe Consortium. This team consisted of a collaborative group of colleagues from across industry including members from Sanofi, GSK, UCB, Novartis, Vertex, Janssen, Takeda, Merck, AbbVie, Roche as well as others.

The team conducted an extensive survey to highlight similarities and differences in screening strategies and target panels across the pharmaceutical industry and as a result we identified a number of opportunities for further optimisation within the secondary pharmacology assessment of novel compounds.

Currently, only 10% of the drugs that enter Phase I receive marketing approval from the U.S. Food and Drug Administration (FDA), with unmanageable toxicity accounting for approximately 30% of the clinical failures for investigational new drugs (INDs). Safety-based discontinuation of INDs is mainly associated with cardiotoxicity (which is also one of the most common reasons for the withdrawal of marketed drugs).

Last year we worked alongside authors from Amgen and published data in support of refining the hERG testing strategy for silencing RNA (siRNA). In accordance with the ICH S7B guidelines, an in vitro assay targeting the hERG channel forms a crucial component of the integrated risk assessment for delayed ventricular repolarization. The function of hERG may be influenced by either direct (acute) mechanisms or indirect (chronic) mechanisms. While some approved oligonucleotide therapeutics have submitted hERG data to regulatory bodies, gathered using protocols akin to small-molecule testing (with an incubation time <20 min, indicative of acute effects), oligonucleotides operate via distinct mechanisms and timelines (notably indirect effects).

This year’s Cambridge Ion Channel Forum (CICF) took place at AstraZeneca’s new world class facilities at The Discovery Centre (DISC) at the Biomedical Campus in Cambridge, UK. Upon arrival representatives from academia, biotech, pharma and contract research organisations were all catching up with old friends and making new connections, while enjoying lunch and an interesting selection of posters.

We generated a stable cell line expressing the lysosomal channel TRPML1 at the cell surface. First we validated this on manual patch-clamp and went on to develop robust assays for our higher throughput screening platforms, Qube 384 and FLIPR Penta, which are capable of detecting TRPML1 modulators for drug discovery.