Rushing to abandon tQT


Drug discovery always involves the continuous reassessment of the benefit-risk balance: from the first target identification all the way to the choice of patient population most suited to a new drug.
This paper (BioCentury (2013) Vol. 21,No.30 Page A1-A4) considers the call by the FDA and key Pharma stakeholders for the fine tuning of the benefit-risk evaluation during the cardiovascular safety de-risking of molecules: in particular with regards to QT signal prolongation, proarrhythmia and Torsades de Pointes (TdP) risk.
Following the withdrawal of eight drugs from the US market in the 1990s, a link between the inhibition of the hERG potassium channel, prolongation of the QT signal and elevated risk of TdP was made. Now, identification of pharmacological selectivity over inhibition of the hERG channel is standard in drug discovery programs. Further preclinical evaluation in animals and ultimately costly thorough QT trials (tQT) are employed to further clarify the risk / safety margins of development compounds.
It is now considered that information regarding QT prolongation, alone, is an insufficient predictor of TdP. Currently a 5-15 millisecond prolongation of the QT signal is considered a clinical risk, with >15 millisecond prolongation considered a serious clinical concern. The journal suggests that the focus of QT prolongation under the current FDA guidelines may have ‘killed’ development compounds that do not cause fatal arrhythmia.
The FDA, in consultation with pharma companies, clinicians and academics, want to abandon tQT studies by 2015, replacing them with a preclinical assay suite better able to detect proarrhythmia side effects than existing assays. The proposed suite would be:
• Functional Voltage clamp studies on several cardiac ion channels including hERG, Na1.5, CaV1.2, KvLQT1 and Kir2.1.
• Human stem cell derived ventricular cardiomyocytes, to look at the repolarization effects of a compound.
• Computational modelling of cardiomyocytes, based on input from the studies above, to predict early afterdepolarisation and action potential duration, both now considered predictors of the risk of a compound triggering arrhythmias.
The deadline is laudable, however achieving industry wide consensus by 2015 as to the assay suite’s format and interpretation of results may prove challenging. Replacing tQT would no doubt save money and resource for late stage preclinical and early clinical development. It will be important that the latest scientific understanding of repolarisation gives rise to clear guidelines to the discovery scientist. If research groups opt to prosecute molecules with a known hERG and QT prolongation liability, what ‘blend’ of pharmacology in the other ion channels is acceptable? Voltage clamp studies may still prove costly and resource consuming in an early drug discovery setting. For those hoping that the new assay suite and guidelines will significantly expedite and broaden drug discovery, choosing to sail close to the guidelines and navigating through them may take longer than anticipated.

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One thought on “Rushing to abandon tQT

  1. Unfortunately, I don’t seem to have access to the journal article you mention, but thank you for this interesting and succinct article. There’s been some interesting work in this area on the computational modelling side of things. The prolongation of action potential in single-cell computational models caused by simulated drug actions on the hERG, Na1.5, and CaV1.2 channels has been found to be a better predictor of TdP risk than hERG alone. (http://www.ncbi.nlm.nih.gov/pubmed/21300721), and to be a suitable replacement for QT prolongation assays on rabbit hearts (http://www.ncbi.nlm.nih.gov/pubmed/23624022).

    There is some evidence to suggest that non-typical currents, such as the late sodium current, which is caused by single-molecule opening events of the Na1.5 channel, might be important in pro-arrhythmia (http://heart.bmj.com/content/92/suppl_4/iv1.abstract), which is interesting, because some drugs (such as ranolazine) are strong hERG blockers but don’t cause TdP.

    Modelling might be ultimately more predictive than QT assays if the mechanistic link between single channel block and TdP can be explored. This paper tries to link events at the cellular level (namely, early afterdepolarisations) and TdP risk:
    http://www.sciencedirect.com/science/article/pii/S1734114013714865?_rdoc=1&_fmt=high&_origin=ihub&_docanchor=&md5=9ffa87934275edd7180b52f5e973f002. All in all, a very exciting field to be in!

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