Most heart disease drugs are aimed at reducing "bad" low-density lipoprotein (LDL) cholesterol. But AstraZeneca figures that strategy alone still leaves patients with a meaningful risk of suffering major cardiovascular events.
So, scientists at the British pharma are working on boosting "good" high-density lipoprotein cholesterol (HDL-C) as a strategy for reducing the risk of heart disease.
Now, the company has early data showing an experimental antibody drug increases HDL-C in monkeys and people. Combining the drug with a PCSK9 inhibitor appears to have a synergistic effect.
The drug, dubbed MEDI5884, is designed to neutralize a circulating enzyme called endothelial lipase. The protein regulates HDL in the blood by breaking down lipids called phospholipids. Previous studies have found increased endothelial lipase levels in people with obesity and coronary artery disease.
In monkeys, blocking endothelial lipase with MEDI5884 increased plasma HDL-C in a dose-dependent manner, the AZ team reported in a study published in Science Translational Medicine. At the highest dose tested, researchers recorded a roughly twofold increase in HDL-C within two weeks. The effect lasted throughout the two-month study.
The AZ team also tested the drug in a small group of healthy volunteers in a phase 1 study. The treatment increased HDL-C—though to a lesser extent than it had in the monkeys—without causing any major side effects, the researchers said. The drug also increased the size and number of HDL particles.
Oddly, the researchers also observed a concurrent increase in bad cholesterol in both monkeys and humans. So they decided to combine MEDI5884 with an anti-PCSK9 antibody drug. The FDA has approved two PCSK9 inhibitors to lower LDL-C and reduce CV risks: Sanofi and Regeneron’s Praluent and Amgen’s Repatha.
In monkeys pretreated with a PCSK9 inhibitor, MEDI5884 raised HDL-C to a similar degree while the magnitude of the increase in LDL-C was reduced, according to the team.
PCSK9 drugs once carried megablockbuster potential thanks to their strong LDL-lowering effects, but neither Praluent nor Repatha has lived up to expectations. Payer pressure and an ongoing price war haven't helped either player in the market.
The AZ team suggested combining endothelial lipase inhibition with a PCSK9 blockade could enhance the efficacy of each component. “[I]t is intriguing to consider dual inhibition of EL and PCSK9 and the potential for synergy that may arise from combined action of the two complementary mechanisms, both targeting different aspects of [reverse cholesterol transport],” the scientists wrote in the study.