Evolocumab Safe, Effective in Mixed Hyperlipidemia: Study

Marlene Busko

May 29, 2015

AMSTERDAM, THE NETHERLANDS — The investigational human monoclonal antibody proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab (Amgen) was safe and effective in patients with mixed hyperlipidemia (elevated triglycerides as well as raised LDL-cholesterol levels) in a pooled analysis of clinical-trial data[1].

"We felt it was important to evaluate the treatment response [to evolocumab] in individuals with higher [>1.7 mmol/L] vs lower [<1.7 mmol/L] triglyceride levels with a background of hypercholesterolemia," Dr Robert Rosenson (Icahn School of Medicine at Mount Sinai, New York) said, presenting study results here at the International Symposium on Atherosclerosis 2015.

After 12 weeks, evolocumab substantially reduced LDL cholesterol—by 67% more than placebo and by 42% more than ezetimibe (Zetia, Merck)—in patients with mixed hypercholesterolemia (all P<0.001); it reduced LDL cholesterol by 65% more than placebo and by 40% more than ezetimibe, for patients in the entire pooled-study population.

It was also "comforting" that there was no signal for worse adverse effects in patients with elevated triglycerides during up to 5 years of follow-up, Rosenson added.

This new class of drugs would "clearly offer significant therapeutic potential for a segment of people who can't be adequately treated at the moment," cochair Dr Allen Sniderman (McGill University, Montreal, Quebec), told heartwire from Medscape. However, since several companies are involved in developing PCSK9 inhibitors and "so many very coherent . . . experts are involved with the companies—which isn't to say they're biased—it's going to be hard to get a disinterested viewpoint" to balance the drug cost vs the incremental patient benefit, he noted. Ongoing trials are investigating cost-effectiveness, Rosenson said earlier in reply to a question by Sniderman.

High Triglycerides Plus High Cholesterol

Patients with mixed hyperlipidemia have high levels of total cholesterol, LDL cholesterol, and triglycerides, often with low levels of HDL cholesterol, and they typically have glucose intolerance and diabetes with an increased production of triglyceride-rich lipoproteins[2].

The effects of PCSK9 inhibition on LDL-C lowering in this subgroup of patients are not well studied, Rosenson said. The researchers compared the efficacy and safety of evolocumab in individuals with and without elevated triglycerides (≥1.70 mmol/L and <1.70 mmol/L, respectively) who participated in phase 2 and phase 3 trials of this drug.

The patients were 18 to 75 years old and had LDL-cholesterol levels above 2 mmol/L and triglyceride levels below 4.5 mmol/L. Compared with other participants, those with high triglycerides were twice as likely to have diabetes and were also more likely to have other cardiovascular risk factors, lower levels of HDL cholesterol, and higher levels of non-HDL cholesterol and apolipoprotein B.

The trial participants had received subcutaneous injections of evolocumab every 2 weeks or every month or placebo or ezetimibe.

The current study looked at pooled efficacy data from four phase 3 trials—MENDEL-2 (monotherapy), LAPLACE-2 (combination therapy), RUTHERFORD-2 (patients with heterozygous familial hypercholesterolemia [FH]), and GAUSS-2 (statin-intolerant patients)—of 1148 individuals with triglycerides >1.7 mmol/L and 1998 individuals with triglycerides <1.7 mmol/L.

At baseline, participants with mixed hyperlipidemia who received evolocumab had a mean LDL-cholesterol level of 3.4 mmol/L, a median triglyceride level of 2.0 mmol/L, and a mean HDL-cholesterol level of 1.2 mmol/L.

"We felt that it was important to look at parameters other than just LDL cholesterol," said Rosenson. In 2008, the American Diabetes Association and the American College of Cardiology identified targets for secondary lipids, and "many organizations, despite the recent ACC/AHA guidelines, still focus on targets for LDL cholesterol and non-HDL cholesterol, and apolipoprotein B, of course, is a very important predictor of risk in individuals who have metabolic syndrome/diabetes," he said.

After 10 or 12 weeks, the participants with mixed hyperlipidemia who received evolocumab had significantly greater reductions in LDL cholesterol, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) than the other participants.

"More individuals treated with this PCSK9 inhibitor [than with placebo or ezetimibe] achieved the targets established by different professional societies for lowering LDL cholesterol <1.8 mmol/L, non-HDL-cholesterol <2.6 mmol/L, and apolipoprotein B <0.8 g/L," Rosenson reported.

To determine the safety of evolocumab, the current study pooled data from 2092 patients in phase 2 and 3 studies and 1485 patients in open-label studies (that lasted up to 5 years) who had elevated baseline triglycerides.

Evolocumab was well tolerated, and rates of serious adverse events or adverse events leading to discontinuation were similar among participants who received the study drug or placebo or ezetimibe.

There were fewer reactions at the injection site using newer delivery devices. There were also more adverse events with longer follow-up, but these were mainly nasopharyngitis, which is not believed to be related to the compound.

When asked who should receive evolocumab, Rosenson replied: "I would say that for individuals with homozygous and heterozygous [familial hypercholesteremia] FH, the PCSK9 inhibitors afford [them] the opportunity for better [lipid] control than they have ever had in their lifetimes," and these new agents may replace medications such as mipomersen (Kynamro, ISIS) and lomitapide (Juxtapid, Aegerion) that are approved for FH. "I think that's a definite population for benefit," he said.

Moreover, evolocumab can also benefit patients with elevated LDL cholesterol who are intolerant to statins. Anecdotally, evolocumab has been life-changing for some patients taking statins who had very severe myalgia.

Ongoing clinical trials of evolocumab are investigating additional LDL-cholesterol lowering in patients who are receiving a maximum statin dose, and "we're all looking forward to that data in years to come," said Rosenson.

The study was funded by Amgen. Rosenson is a consultant for Aegerion Pharmaceuticals, CVS Caremark, Hoffman-La Roche, Janssen Pharmaceuticals, Novartis, Pfizer, Regeneron Pharmaceuticals, and Sanofi. He is on the scientific advisory boards of Amgen, AstraZeneca, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, LipoScience, and Regeneron Pharmaceuticals. He has given industry-sponsored lectures for AstraZeneca and Kowa Pharmaceuticals America.

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