HERG Assays

In our experience, it is crucial for a project team to be aware of hERG inhibition as the main LQT risk factor during the early phases of drug discovery and to have easy access to training materials and internal experts if consultation is needed. During lead selection, use of appropriate hERG assays and early LQT risk assessments must be done in the context of a lead series represented by at least ten compounds (Figure 16.5). 

With the transfer of most biopharmaceutical INDs from CBER to CDER in 2003, there has been an increased tendency to apply the small-molecule paradigm for evaluation of QT liability to biopharmaceutical product candidates, and to request information on hERG assays or plans for definitive clinical QT studies. This does not seem reasonable based on the postmarketing safety data for biopharmaceuticals, nor on scientific grounds as discussed above. If these investigations become routinely required, they will only add significant time and costs to the process of biopharmaceutical product evaluation and have little ultimate impact on patient safety. 

Bridgland-Taylor, M.H. et al. 2006. Optimization and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks HT. J. Pharmacol. Toxicol. Meth. 54, 189-199. 

Brimecombe JC, Kirsch GE, Brown AM. Test article concentrations in the hERG assay Losses through the perfusion, solubility and stability. / Pharmacol Toxicol Methods. 2009 59(l) 29-34. 

To facilitate easy and quick generation of local QSARs, an in-house QSAR tool has been developed within Hoffman-La Roche. This tool allows all project teams to build a local model. Local SARs have been developed for several projects using hERG assay data and the in vitro screen for chromosomal damage in mammalian cells. These local SARs can also be applied in a more general sense. 

J. Ducroq, R. Printemps, S. Gudbof J. Gardette, C. Salvetat, M. Le Grand, Action potential experiments complete hERG assay and QT-interval measurements in cardiac preclinical studies. J Pharmacol Toxicol Methods 56,159-170 (2007). 

QT liability hERG assay QTc assay (non-rodent) QTc assay (non-rodent)... 

The in vitro hERG assay that is routinely conducted as part of the precUnical cardiovascular safety testing for small molecule pharmaceuticals is not appropriate for monoclonal antibodies because they have very low potential to interact with the extracellular or intracellular (pore) domains on the hERG channel (Vargas et al. 2008). In addition, their large size would preclude them from being able to access and block the inner pore of the hERG channel where many small molecule pharmaceuticals bind. 

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