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Novel agent lowers LDL more than ezetimibe


 

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SAN DIEGO– ETC-1002, an oral LDL-lowering drug with a novel mechanism of action, decreased LDL by up to 30% more than did ezetimibe in a large phase IIb study.

The 348-patient trial also showed that ETC-1002 and ezetimibe are additive in their LDL-lowering effects, with the combination reducing LDL levels by up to 48%, compared with baseline, Dr. Paul Thompson reported at the annual meeting of the American College of Cardiology.

Dr. Paul Thompson Bruce Jancin/Frontline Medical News

Dr. Paul Thompson

Importantly, the investigational drug and ezetimibe, which is marketed in the United States as Zetia, showed similarly favorable safety and tolerability profiles. And ETC-1002 proved equally effective at LDL-lowering in statin-intolerant and -tolerant patients, noted Dr. Thompson, director of cardiology at Hartford (Conn.) Hospital and professor of medicine at the University of Connecticut, Storrs.

ETC-1002 is a first-in-class oral modulator of the enzymes adenosine triphosphate citrate lyase and adenosine monophosphate–activated protein kinase. These dual mechanisms of action cause the liver to take up LDL cholesterol from the blood.

Asked how he sees the drug potentially fitting into the dyslipidemia treatment landscape, which could soon include the eagerly anticipated, super-potent LDL-lowering proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, Dr. Thompson pointed out that there have been no cardiovascular outcome studies of ETC-1002.

“Without outcomes data in terms of survival, I’d say ETC-1002 will be an additional drug in our armamentarium for treating high cholesterol levels. And so far, we’ve generally seen that reductions in LDL cholesterol result in reductions in clinical events. I would think that this drug would be a way to treat statin-intolerant or -tolerant patients in combination with ezetimibe or alone. And where it fits in will depend somewhat on the cost of the medication,” he said.

The double-blind, phase IIb study randomized 177 hypercholesterolemic patients with muscle-related statin intolerance and 171 without statin intolerance to 12 weeks of once-daily ETC-1002 at 120 mg or 180 mg, ezetimibe at 10 mg, the combination of ETC-1002 at 120 mg plus ezetimibe 10 mg, or ETC-1002 at 180 and ezetimibe 10 mg.

ETC-1002 at the lower dose reduced LDL by a mean of 27% from a baseline of 165 mg/dL. The 180-mg dose decreased LDL by 30%. In contrast, ezetimibe monotherapy lowered LDL by 21%, a significantly lesser effect than with either dose of ETC-1002. The effects of combination therapy were additive: ETC-1002 at 120 mg plus ezetimibe reduced LDL by 43%, compared with baseline, while ETC-1002 at 180 mg plus ezetimibe 10 mg lowered LDL by 48%.

ETC-1002 also improved other atherogenic lipids and markers of systemic inflammation. For example, apolipoprotein B decreased by 30% with ETC-1002 at 120 mg, 40% with ETC-1002 at 180 mg, and 10% with ezetimibe at 10 mg. Similarly, C-reactive protein levels fell by 30% and 40% with low- and higher-dose ETC-1002, compared with a 10% reduction with ezetimibe.

Muscle-related complaints were several-fold more common in the group with a history of statin intolerance as defined by the Food and Drug Administration – namely, muscle-related intolerance to at least two statins, including one at the lowest approved dose. However, rates of discontinuation from drug-related adverse events were similarly low at 3%-8% across the five treatment arms.

“I think the take-home message is that the safety profile of the drug looks good,” the cardiologist said.

No significant changes were seen in body weight, blood glucose levels, or blood pressure during the 12-week study.

Dr. Thompson reported receiving a research grant from Esperion Therapeutics, the study sponsor. He serves as a consultant to AstraZeneca, Merck, and Sanofi-Aventis.

bjancin@frontlinemedcom.com

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