Globally, cardiovascular disease is responsible for more deaths than cancer. It is the world’s most common cause of death. Generations of researchers have put their efforts into discovering safer and more effective drug treatments. However, it takes over 20 years to progress from chemical compound to clinical trials and market entry. Even then, only 10% of drug candidates pass clinical trials and get marketing authorisation. Too many effective drugs are lost to cardiac safety issues. Most of them fail because of drug-induced torsades de pointes (TdP).
What should we do with effective drugs that have a high risk of adverse effects? If we simply withdraw and discard them, it is a waste of resources. The benefit/risk balance is unique for each drug, but regulatory agency guidelines focus mostly on risk. Therefore, developing an agent that could counteract adverse effects such as TdP could save many drugs and 20 years of development time.
LUF7244 is just such an agent. It binds to an allosteric site on the hERG channel and thereby modulates the channel’s binding affinity for other ligands. By protecting hERG from unintentional drug binding, side effects decrease and only the intended effect remains. In our in vivo experiment, TdP events decreased from 100% to 29%, and 5 out of 7 dogs were saved from TdP after dofetilide infusion (an effective I
Kr blocker). Interestingly, the QTc duration didn’t change in response to LUF7244. LUF7244 also suppressed early afterdepolarization in isolated dog cardiomyocytes.
LUF7244 may give us a novel therapeutic strategy. Combining LUF7244 with high-risk drugs could result in safer, and even cheaper, treatments. Developing new drugs to treat diseases that affect a small population is a huge investment for pharmaceutical companies, but if LUF7244 were to become available, drugs that might once have been abandoned in development might reach the market and save lives.
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