Ensuring CV Safety

By Cyril Clarke, ICON Development Solutions | January 22, 2013

Integrated methodologies for early assessment

Ensuring cardiovascular (CV) safety remains a significant challenge in bringing new molecules to market; issues with CV safety contribute to drug attrition during preclinical and clinical development as well as cause adverse drug reactions. Cardiovascular liability has also been the cause of several high profile post-marketing withdrawals, including Vioxx and Meridia. As these cases indicate, the problem is not limited to drugs developed for specific CV indications. Other well-known examples include Herceptin and several of the kinase inhibitors such as Sutent and Gleevec in oncology.

In the diabetes field, the long-term cardiovascular safety of molecules is a subject of increasing regulatory scrutiny. As more targeted therapies are developed for conditions of chronic inflammation such as rheumatoid arthritis (RA), the regulatory spotlight will be focused in that direction.

The ongoing challenge of monitoring and measuring cardiac safety is implied in the following scenarios:
  • Some oncology agents now confer such good survival from the primary tumor that rising event rates of cardiac failure five or more years post treatment are being increasingly appreciated.
  • Does the fact that joint disease is less active mean that patients with RA will benefit in a reduction in cardiac event rates from their elevated baseline compared to non-RA patients with otherwise matched CV risk factors?
Historically it’s been assumed that emergent hepatoxicity is much more of an issue than emergent cardiotoxicity once molecules enter clinical development. Several groups have looked at this in detail. An excellent integrated  summary is provide by Laverty et al.1 It’s clear that cardiovascular toxicity occurs more frequently than hepatoxicity. This may mean that, from a new chemical entity (NCE) perspective, we have started to develop an  ability to predict structures and intermediate metabolites that raise hepatic ‘flags.’

Incidence of Cardiovascular Toxicity
Data indicate that Phase I clinical trials have a very low incidence of cardiovascular events. This may mean that current preclinical screening is already capable of detecting molecules with a high risk of CV safety liability prior to entering clinical development?

It’s important to note that cardiac safety is not synonymous with QTc issues. This distinction is not to undermine the utility of QTc. The number of molecules either withdrawn or abandoned as a result of QTc issues is testament that it’s important. Its prominence is due to the relative ease of measuring a parameter that we have confidence in interpreting. Many other cardiac safety parameters that we can measure, however, are not readily understood in the context of predicting individual or population-level outcomes.

The Possible Way Forward
Understanding a drug’s effects on the following parameters, at a high level, would allow developers to begin to build a model linking drug exposure to possible undesirable changes in function:
  1. Effects on cardiac contractility: Possible methodologies include the use of MRI and cardiac ultrasound.
  2. Effects on cardiac electrophysiology: Classical ECG/EKG methodologies can be deployed. Their inherent ability to pick up undesired effects relies on our ability to define undesired effects and the relative importance of these in normal subjects and patients.
  3. Effects on vessel walls: This area has received a markedly increased focus and demand for characterization. The “gold standard” for measuring this parameter can include flow-mediated dilation coupled with measurement of endothelial function.
  4. Effects on blood and blood constituents with regard to atherogenic and thrombotic potential: This involves assessing possible platelet activation (using markers such as CD 62 expression or platelet aggregometry in response to specific agonist stimulation) and the overall “integrated coagulability” using techniques such as the various cartridges within the PFA 100 system.
The model that could be developed from understanding a drug’s effects on such parameters would enable greater insight into risks and benefits. A focused analysis of findings in early phase studies will allow optimal design of the later phase cardiac outcome studies. As a result, the industry could do a much better job of predicting — and ultimately preventing — high-risk cardiovascular events that could occur when drugs are chronically administered to large populations.  

  1. “How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?” by HG Laverty, C; Benson, EJ; Cartwright, MJ; Cross,C Garland,T; Hammond,C; Holloway, N; McMahon, J; Milligan, BK; Park, M; Pirmohamed, C; Pollard, J; Radford, N; Roome, P; Sager, S; Singh, T; Suter, W; Suter, A; Trafford, PGA; Volders, R; Wallis, R; Weaver, M; York, JP; Valentin, 2011, British Journal of Pharmacology, p. 163, 675–693, ©2011 The British Pharmacological Society.

Cyril Clarke is vice president Translational Medicine, ICON Development Solutions. He can be reached at cyril.clarke@iconplc.com

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