The recent ICH E14/S7B Q&As have provided more clarity on the methodologies that should be employed when conducting a GLP hERG to support and IND filing for a novel clinical compound.

My 12 month industrial placement at Metrion Biosciences was a truly remarkable experience that has helped me grow both personally and professionally. Choosing to complete a placement year was a big decision for me which was made 100% worth it!

Two-pore domain K+ (K2P) channels are a family of four-pass transmembrane K+ channels that dimerise, as homomers or heteromers, to form a functional K+ channel complex capable of regulating membrane potential through a background K+ conductance.

Kv3.1 is a voltage-gated potassium channel encoded by the KCNC1 gene. At the recent SLAS EU meeting, we presented a poster to demonstrate how a cell line expressing the KCNC1 V434L mutation was generated and validated using biophysical and pharmacological methods, then used to screen approximately 6,800 compounds from The Broad Institute Repurposing Hub to identify inhibitors for potential use in the treatment of patients with this rare mutation.

By Alex Pinggera, Senior Scientist II, Metrion Biosciences

To enable the study of ion channels found on the lysosomal membrane we perform the lysosomal patch-clamp technique:

Cells are seeded out at a high density onto Poly-D-Lysine coated coverslips. This ensures that the cells are well adhered to the coverslip, and that they form a vast network, which facilitates easier slicing and extraction of the lysosomes from the cells.

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).