Biomarkers
THE SOONER THE BETTER utilising biomarkers to eliminate drug candidates with cardiotoxicity in preclinical development
The rapidly escalating costs of drug development is causing the biopharmaceutical industry to focus its R&D efforts on identifying new technologies and methods that can predict the safety and efficacy of new compounds as early as possible in the drug development process. Today, only one in 11 compounds advance from first-in-man studies to regulatory approval and these late-stage failures – mainly caused by safety issues – exact a heavy toll on the biopharmaceutical industry as the cost of clinical trials is extremely expensive, legal liability is of concern and companies are under great scrutiny by investors
C
ardiotoxicity, or drug-induced cardiac injury, is one of the leading causes of drug withdrawals (eg, rofecoxib
(Vioxx®), terfenadine), labelling changes restricting drug use ((rosiglitazone (Avandia®), delays in regulatory approval and late-stage com- pound failures. Drugs that cause heart muscle or valve damage or potentially fatal arrhythmias in patients have been implicated in 28% of drug withdrawals in the United States over the past 30 years. The discovery of drug-induced cardiotoxi- city holds enormous consequences for pharma- ceutical companies: if cardiotoxicity is discov- ered during drug development, then the pro- gramme will be terminated; if discovered after launch, then the drug may be withdrawn or restricted, and the companies can possibly be sued for negligence.
The growing concern surrounding cardiotoxici- ty is not restricted to a specific therapeutic area. Almost every therapeutic class of drugs has pro- duced unanticipated cardiotoxicities (eg, torsade de pointe, progressive cardiomyopathy), including
Drug Discovery World Summer 2011
anthracyclines and other anticancer agents, anti- retrovirals, antibacterials, antifungals, psy- chotropics and antihistamines. A recent high-pro- file case of drug-induced cardiotoxicity is trastuzumab (Herceptin®), which has been suc- cessfully used for the treatment of advanced breast carcinoma with overexpression of the HER2 pro- tein. Trastuzumab did not reveal cardiotoxicity in preclinical animal studies; however, this antibody demonstrated an unexpectedly high incidence of left ventricular (LV) dysfunction in subsequent clinical trials. Although the cardiac damage is reversible, it frequently results in discontinuation of treatment.
Cardiotoxicity is becoming particularly concern- ing for chronically administered drugs such as neu- rologic/psychiatric agents and chemotherapeutic agents because toxicity may only become evident after long-term accumulation of the drug or its metabolites in the heart. Additionally, some car- diac events may be so rare that they can only be identified many years post-launch and only after many thousands or millions of patients have been
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By Dr Federica Crivellente
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