CHICAGO – Bempedoic acid, a novel oral lipid-lowering agent, reduced LDL cholesterol by 21% and high-sensitivity C-reactive protein by 24% with a side-effect profile similar to placebo in statin-intolerant hypercholesterolemic patients with or at high risk for atherosclerotic cardiovascular disease in the pivotal phase 3 CLEAR Serenity trial, Ulrich Laufs, MD, PhD, reported at the American Heart Association scientific sessions.
CLEAR Serenity is one of five pivotal phase 3 trials of bempedoic acid. The others evaluated bempedoic acid as add-on therapy to obtain additional lipid lowering in patients already on a maximum-dose statin, and in combination with ezetimibe (Zetia) as a single pill, also in patients on full-dose statin therapy. All of these trials met their efficacy and safety endpoints. The drug’s developer, Esperion Therapeutics, has announced plans to file for marketing approval of bempedoic acid and for the bempedoic acid/ezetimibe combo pill with the Food and Drug Administration and the European Medicines Agency in the first months of 2019.
CLEAR Serenity was a 24-week, double-blind, placebo-controlled trial conducted at 67 North American sites. The 345 statin-intolerant participants were randomized 2:1 to bempedoic acid at 180 mg once daily or placebo.
“I think the specific contribution of this study is, importantly, that myalgia and other muscle-related symptoms were not increased with bempedoic acid versus placebo in this population that’s statin intolerant, more than 90% of whom complained of statin-related muscle symptoms,” said Dr. Laufs, professor and chair of the department of cardiology at the University of Leipzig (Germany).
Rates of major adverse cardiovascular events were too low in this relatively short-term, modest-size trial to be informative, but the results of the previously presented CLEAR Harmony trial are reassuring in this regard, according to the cardiologist. CLEAR Harmony was a 52-week study that included 2,230 patients with atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia whose LDL was inadequately controlled despite high-intensity statin therapy. They were randomized to add-on bempedoic acid or placebo. The adjudicated major adverse cardiovascular event rate was 4.6% in the bempedoic acid group and not significantly different at 5.7% in controls.
Definitive data on the effect of bempedoic acid on cardiovascular morbidity and mortality event rates will eventually be provided by an ongoing global randomized, double-blind, placebo-controlled trial expected to enroll more than 12,000 patients.
Rates of various types of adverse events were closely similar in the bempedoic acid and placebo groups in CLEAR Serenity, with a couple of intriguing exceptions, according to Dr. Laufs. For example, the rate of new-onset or worsening diabetes was 2.1% in the bempedoic acid group, compared with 4.5% in controls.
“This is consistent with results in the other studies in the overall bempedoic acid program. It will be something of great interest to follow up in the ongoing outcomes trial,” he said. “At this point I would feel comfortable in saying that there is no deterioration of glucose tolerance, unlike with statins. Whether there is an actual improvement or not needs to be characterized a little better.”
The other difference in the safety profile between the two study arms in CLEAR Serenity was a trend for higher uric acid levels and an increased risk of developing gout in the bempedoic acid group. Gout occurred in 1.7% of the bempedoic acid group and 0.9% of placebo-treated controls. A similar signal has been seen in the other pivotal trials, but a definitive answer as to gout risk must await the large ongoing outcomes trial, Dr. Laufs continued.
Bempedoic acid is a first-in-class oral inhibitor of ATP citrate lyase, an enzyme that is inactive in skeletal muscle – thus, the lack of myalgia complaints – and lies upstream of HMG-CoA reductase in cholesterol synthesis. When combined in a single pill with ezetimibe, which lowers LDL by stimulating the LDL receptor, the lipid-lowering impact is magnified over that of either drug alone. In the phase 3 program, the combination pill resulted in a further 35% reduction in LDL when added to a maximally tolerated statin and a 43% reduction in LDL when used as monotherapy.
Session cochair Robert H. Eckel, MD, commented that bempedoic acid appears to be poised to address a significant unmet need in preventive cardiology.
“We clearly need alternative therapies in patients with statin intolerance. We see a lot of these patients in referral centers. This drug looks safe and very effective at modifying LDL, about as much so as ezetimibe and maybe a little bit more,” said Dr. Eckel, professor of medicine and director of the lipid clinic at University of Colorado Hospital, Aurora.
Dr. Laufs reported serving as a paid consultant to Esperion Therapeutics, the study sponsor, as well as to Amgen and Sanofi.