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Evolocumab Demonstrates Long-Term Efficacy for Hyperlipidemia
Results from the DESCARTES (Durable Effect of PCSK9 Antibody Compared with Placebo Study) trial found that the investigational PCSK9 inhibitor, evolocumab, for the treatment of hyperlipidemia significantly reduced low-density lipoprotein (LDL) cholesterol levels in patients with a wide range of cardiovascular risks who were receiving guideline-recommended lipid lowering therapy. To date, DESCARTES is the longest and largest study involving the monoclonal antibody, evolocumab [N Engl J Med. 2014;370(19):1809-1819].
PCSK9, a serine protease that is produced predominantly in the liver, is secreted into the plasma and plays a crucial role in regulating LDL cholesterol levels by binding to hepatic LDL receptors and promoting their degradation.
In the randomized, double-blind, placebo-controlled, phase 3 DESCARTES trial, conducted between January 2012 and November 2013, researchers sought to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. Patients with hyperlipidemia were stratified according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. Based on this classification, patients were put through a lipid stabilization phase with combinations of diet alone, diet plus atorvastatin, and diet, atorvastatin, and ezetimibe for a run-in period of 4 to 12 weeks.
Of the 2120 patients who were screened, 901 received at least 1 dose of a study drug, and 800 completed 52 weeks of treatment. Of the 901 patients who received a study drug, 111 received background lipid-lowering therapy with diet alone, 383 received 10 mg of atorvastatin daily, 218 received 80 mg of atorvastatin daily, and 189 received 80 mg of atorvastatin plus 10 mg of ezetimibe daily. As anticipated, the prevalence of cardiovascular disease and cardiovascular risk factors were higher in the groups receiving more intensive background lipid-lowering therapy.
Patients with LDL cholesterol of ≥75 mg/dL were then randomized in a 2:1 ratio to receive 420 mg of evolocumab or placebo subcutaneously every 4 weeks for 48 weeks. The monthly injections could be split (eg, two 3 mL doses or three 2 mL doses). Study visits were conducted every 4 weeks, with additional visits at weeks 13 and 37. The primary end point was percent change from baseline in LDL cholesterol level at week 52.
The researchers found that the reduction of LDL levels at 12 weeks was consistent with levels at 52 weeks, demonstrating long-term efficacy. At week 52, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57%±2.1% and 57.5%±1.6% at week 12. Compared with placebo, the mean LDL cholesterol reductions from baseline with evolocumab at week 52 were 55.7%±4.2% in the diet-alone group, 61.1%±2.6% in the group with diet changes and atorvastatin 10 mg, 56.8%±5.3% in the group with diet and atorvastatin 80 mg, and 48.5%±5.2% in the group with diet and atorvastatin at 80 mg plus ezetimibe 10 mg. Evolocumab treatment also significantly reduced levels of apolipoprotein B, nonhigh-density lipoprotein cholesterol, lipoprotein(a), and triglycerides.
The overall incidence of adverse events occurring during treatment was similar in the evolocumab group and placebo group, with 448 of 599 patients and 224 of 302 patients, respectively, experiencing an adverse event. The most common adverse events in the evolocumab group were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. There were more reports of myalgia and elevated creatine kinase levels among patients receiving evolocumab compared to patients receiving placebo (4% and 1.2%, respectively).
The investigators noted that the study’s findings take into account the run-in period of lipid-lowering therapy that was determined by each patient’s LDL cholesterol goals. The results were also similar to the relative reduction of 52% in LDL cholesterol levels reported in the first year of OSLER (Open-Label Study of Long-Term Evaluation against LDL-C) study.
