Nonclinical safety pharmacology studies for siRNA follow a hybrid of the small molecule (SM) guidance and biologics guidance. The Oligonucleotide Safety Working Group (OSWG) has published a series of recommendation papers for oligonucleotides, including recommendations for safety assessment, because development of oligonucleotide-based therapeutics is not addressed by regulations. This is especially true regarding the hERG assay, which is a core assay in ICH S7B for SM. While OSWG states that a hERG study is not necessary for IND submission, all approved siRNAs have submitted hERG data which are necessary for requesting a TQT waiver.
Development of a robust hNaV1.9 high-throughput screening assay on the Sophion Qube384 platform. This is complemented by a suite of ion channel selectivity assays and sensory neuron recordings to create a versatile screening cascade to support NaV1.9 drug discovery programmes.
Optical voltage imaging of human iPSC-derived cardiomyocytes was used to assess electrophysiological effects of compounds beyond hERG inhibition. Action potential waveform analysis revealed compound-specific and concentration-dependent changes, enabling mechanistic differentiation of multichannel activity and demonstrating a human-relevant approach for translational cardiac safety assessment.