Evolocumab

Pharmacologic interventions for PCSK9 Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408

For a review of all PCSK9 inhibitors please click here

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Evolocumab or AMG145 is a fully human monoclonal antibody that binds and inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) a molecule responsible for the degradation of LDL receptors. Pre-clinical studies, and early clinical trials have shown the efficacy and potency of evolocumab in decreasing LDL cholesterol as an add-on agent or as monotherapy. Further trials are needed to evaluate the efficacy of evolocumab in improving cardiovascular outcomes.

Properties

Evolocumab aslo known as AMG145 is a fully human monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that attaches to surface LDL receptors and triggers their degradation. This reduces the ability of hepatocytes to uptake LDL cholesterol and subsequently leads to increased levels of circulating LDL. By binding PCSK9, evolocumab inhibits LDL receptor destruction and increases the endocytosis of LDL from the circulation. Pre-clinical studies, and early clinical trials have shown the efficacy and potency of evolocumab in decreasing LDL cholesterol as an add-on agent or as monotherapy.

Major Trials

Phase II Trials

RUTHERFORD

A multicenter, double-blinded, randomized, placebo-controlled, dose-ranging study to determine the efficacy and safety of evolocumab in heterozygous familial hypercholesterolemia patients. 168 patients receiving statins with or without ezetimibe were randomly assigned to subcutaneous evolocumab 350 mg, 420 mg, or placebo administered every 4 weeks. At 12 weeks, LDL cholesterol was lowered by 43% and 55% with evolocumab 350 mg and 420 mg, respectively, compared with a 1% increase in the placebo group.

GAUSS

Based on the fact that approximately 10% to 20% of patients cannot tolerate statins, the GAUSS trial was designed to assess the efficacy and tolerability of evolocumab in patients with statin intolerance due to muscle-related side effects. 160 patients with statin intolerance were randomized equally into 5 different groups: evolocumab alone at 280 mg, 350 mg, or 420 mg doses; evolocumab at 420 mg plus 10 mg of ezetimibe and 10 mg of ezetimibe plus placebo - all given subcutaneously. At week 12, mean LDL cholesterol levels were lowered by 41% in the lowest dose group, 51% in the highest dose group, and 63% in the high dose group of evolocumab combined with ezetimive. In comparison, 15 the placebo/ezetimibe group demonstrated a 15% decrease in LDL cholesterol. Four serious adverse events were reported with evolocumab which were coronary artery disease, acute pancreatitis, hip fracture, syncope. Myalgia was also the most common treatment-emergent adverse effect observed during the study.

LAPLACE-TIMI 57

LAPLACE-TIMI 57 was designed to assess the efficacy, safety and tolerability to a range of doses of evolocumab in hypercholesterolemic patients. 631 patients on a stable dose of a statin (with or without ezetimibe) were randomly assigned to evolocumab at 70, 105, or 140 mg or placebo every two weeks or evolocumab at 280, 350, or 420 mg or placebo every four weeks. At week 12, mean LDL-C concentrations in the 2-week-dosing group was reduced from 42% to 66 % compared to a 42% to 50% reduction in the 4-week-dosing group. No serious or life-threatening events was observed.

MENDEL

The MENDEL trial was designed to assess the efficacy, safety and tolerability of evolocumab as monotherapy for hypercholesterolemia. 406 untreated hypercholesterolemic patients were assigned to similar groups as in the LAPLACE-TIMI 57 study and after 12 weeks, similar results with the prior studies were obtained (39 to 51% reduction in LDL cholesterol).

OSLER

OSLER was an open label study that included patients from any of the 4 phase II trials of evolocumab. It was designed to assess the efficacy and safety of longer-term (52-weeks) administration of evolocumab in patients with hypercholesterolemia. Of the initial patients enrolled in previous trials, 1104 patients (81%) elected to enroll into the OSLER study. Irrespective of initial treatment group, patients were randomized 2:1 to receive either standard of care with evolocumab 420 mg every 4 weeks or standard of care alone. Patients who received evolocumab demonstarted a 52.3% reduction in LDL choleterol levels, while patients who discontinued evolocumab and received standard of care in this trial had a return to baseline LDL levels by 12 weeks with no rebound effect. Adverse events occurred in 73.1% of patients in the standard of care arm compared to 81.4% of patients in the evolocumab arm.

Phase III Trials

DESCARTES

DESCARTES compared evolocumab treatment to placebo in patients with dyslipidemia for a total duration of 52 weeks. Evolocumab or a matching placebo were administered following a run-in period of 4-12 weeks of one of four standard of care lipid-lowering therapy regimens (diet alone, diet plus 10 mg atorvastatin daily, 80 mg of atorvastatin daily, or 80 mg of atorvastatin plus 10 mg of ezetimibe daily). In total, 905 patients underwent randomization. Treatment with 420 mg of evolocumab every 4 weeks was associated with a significant reduction in LDL cholesterol levels (57% greater than placebo group). Depending on background therapy, the reductions ranged between 48.5% with 80 mg atorvastatin and ezetimibe pretreatment to 61.6% in with 10 mg atorvastatin pretreatment. Adverse events during treatment were comparable in the evolocumab group and the placebo group. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain.

LAPLACE-2

LAPLACE-2 was designed to evaluate the efficacy and tolerability of evolocumab vs. ezetimibe when used in combination with a moderate- vs high-intensity statin. Patients (n=2067) were randomized to 1 of 24 different treatment combinations for a total duration of 12 weeks. Evolocumab was associated with a 66% to 75% reduction in LDL-C levels every 2 weeks, and a 63% to 75% reduction every monthly compared to placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups. Adverse events were reported in 36% of patients treated with evolocumab, compared to 40% and 39% in patients administered ezetimibe and placebo, respectively. The most common adverse events in the evolocumab treatment group were headache, back pain, muscle spasms, arthralgia, and extremity pain.

MENDEL-2

MENDEL-2 randomized 614 patients to 1 of 6 combinations: oral placebo and subcutaneous (SC) placebo biweekly; oral placebo and SC placebo monthly; ezetimibe and SC placebo biweekly; ezetimibe and SC placebo monthly; oral placebo and evolocumab 140 mg biweekly; or oral placebo and evolocumab 420 mg monthly. Treatment with evolocumab led to a significant reduction in LDL-C from baseline values, on average by 55%-57% greater than placebo and by 38%-40% greater than ezetimibe. Adverse events were comparable across all treatment groups.

GAUSS-2

GAUSS-2 evaluated the efficacy and safety of evolocumab compared to ezetimibe in patients with hypercholesterolemia who cannot tolerate recommended statin doses. Patients enrolled (n=307) were randomized 2:2:1:1 to evolocumab 140 mg every 2 weeks, evolocumab 420 mg once monthly, both with oral placebo, or daily oral ezetimibe with subcutaneous placebo every 2 weeks or every month. Evolocumab treatment resulted in a 53% to 56% reduction in LDL-C, compared to 37% to 39% reduction in the ezetimibe group. Adverse events led to drug discontinuation in 8% of the evolocumab-treated patients and 13% of the ezetimibe-treated patients. Myalgia occured much less often in the evolocumab treatment arms.

RUTHERFORD-2

Although results from the RUTHERFORD trial have not yet been published, initial findings were presented in ACC 2014. A total of 331 patients with heterozygous familial hypercholesterolemia unable to achieve target LDL cholesterol on statin with or without ezetimibe, were randomized to evolocumab 140 mg once every 2 weeks or placebo vs. evolocumab 420 mg once monthly or matching placebo for a total duration of 12 weeks. At 12 weeks, both doses of evolocumab achieved similar reductions in LDL-C, 61% and 56%, respectively.

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