No need to bypass a full cardiac profile
testing the cardiac safety of drug candidates more fully - thanks
to a new addition to Millipore's services.
Through a license deal with Merck & Co, Millipore has added the human L-type calcium channel to the range of cell lines offered in its CardiacProfiler service - used to test a drug candidate for potentially fatal heart side effects. Although the US Food and Drug Administration (FDA) only describes testing drugs to see if they delay heart repolarisation as a 'non binding recommendation', most pharma firms see it as crucial to gaining approval, according to Millipore. Tests such as this also prevent the companies wasting money on drugs that probably won't receive approval, even if they prove effective. As such, the earlier a company can test a drug candidate, the better - ideally in preclinical testing, explained Dr Jeffrey Till, group product manager of drug discovery at Millipore, in an interview. Other companies, such as MDS Pharma Services, also produce these types of cell. However, Millipore claim to be the first to be able to provide the human version with the main alpha-1 subunit and also the alpha-2, beta and delta subunits. Dr Till said that although ion channels are popular targets in drug discovery, what brought them to the forefront was the discovery that they are also responsible for some dangerous side effects - they are "anti-targets," he said. Specifically, the hERG channel (named after the Ether-a-go-go gene in fruit flies), is critical in repolarising the heart and maintaining cardiac rhythm. Blocking the effect of this protein can cause arrhythmia and lead to heart attacks. The effect is diagnosed by an increased QT interval (the time it takes for the heart muscle to contract and relax) on an electrocardiogram (ECG). This discovery led to the FDA recommendations and an estimated 10 to 20 approved drugs were withdrawn from the market, including the blockbuster allergy therapy, Seldane (terfenadine). However, hERG is only one of the ion channels found in the heart. Millipore already offered six of these channels, and the L-type calcium channel is now the seventh. The others are Nav1.5, KCNQ1/minK, Kv1.5, Kv4.3/KChIP1 and HCN4. According to Millipore, when developing a non-cardiac drug, it could be important to also test the calcium channel. Although Dr Till admitted it is still unclear how many of the seven will be required in a standard drug liability test, he described the CardiacProfiler as "a comprehensive view of cardiac liability." "Also, you can have a safe drug that inhibits hERG, if you also inhibit the L-type calcium channel," he continued. This is because hERG is a potassium channel and so the negative effects of blocking it could be effectively cancelled out by blocking the calcium channel. Dr Till noted that Millipore's test could help establish a ratio of how much a drug can block hERG and still be safe, if the calcium channel is also blocked. An example of a drug that blocks both is verapamil, which is used to treat hypertension, angina and irregular heart beats. Dr Till explained that the company had been developing the cell line for "a couple of years" because the number of subunits made it a difficult target to produce. Selecting the correct functional cell clone from the hundreds of possibilities also took time, he said.
