As Esperion Therapeutics awaited the US Food and Drug Administration’s decision on its first-in-class drug, slated for 21 February, cardiologists welcomed trial evidence that the drug significantly reduces low-density lipoprotein cholesterol (LDL-C) in patients at high risk of cardiovascular disease. Esperion and investigators reported in JAMA the results from a phase 3 trial in 779 patients with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia. At 12 weeks, the experimental drug bempedoic acid added to maximally tolerated statins lowered LDL-C by 15.1% from baseline, whereas in the control group of patients on background lipid-lowering therapy LDL-C level increased by 2.4%. In a pooled analysis of four pivotal trials, reported in November at the American Heart Association (AHA) meeting, bempedoic acid lowered LDL-C by 18% compared with placebo in patients on background statin therapy, and by 25% compared with placebo in statin-intolerant patients not on statin background therapy. A cardiovascular outcomes trial is ongoing, with results anticipated by 2022.
Bempedoic acid is an inhibitor of adenosine-citrate lyase, an enzyme in the lipid biosynthesis pathway that acts upstream of HMG-CoA reductase, the target of statins. It is under review with the FDA both as a monotherapy and as a combination tablet with generic lipid-lowering agent ezetimibe, for patients with elevated LDL-C. Should it be approved, the oral drug will face a crowded market, dominated by cheap, convenient, generic statins. Esperion’s agent will also compete with two approved subcutaneously injected PCSK9-targeted antibodies, which facilitate the clearance of LDL cholesterol from the blood. Sales of these antibodies have disappointed to date, in part due to their high cost. But Novartis acquired The Medicines Company in November over hopes for a PCSK9-directed siRNA drug, currently under review at the FDA. An orally available bempedoic acid could shake things up further, especially if priced below PCSK9 modulators. Novartis and Akcea Therapeutics are also recruiting patients into a phase 3 trial of TQJ230, an antisense candidate that cuts lipoprotein(a) levels.