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Cholesterol-lowering medication Evolocumab, a PCSK9 inhibitor: safety analysis


One-year data from prespecified exploratory endpoints of adjudicated cardiovascular events in the phase 2 ( OSLER-1 ) and phase 3 ( OSLER-2 ) open-label extension studies of Evolocumab ( Repatha ), a novel investigational low-density lipoprotein cholesterol ( LDL-C )-lowering medication, were presented at the American College of Cardiology's 64th Annual Scientific Session ( ACC.15 ) and published in the New England Journal of Medicine ( NEJM ).
A two-year analysis of Evolocumab safety and tolerability data from the longest proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) inhibitor trial to date ( OSLER-1 ) was also presented.

Data from prespecified exploratory endpoints in the ongoing open-label OSLER-1 and OSLER-2 studies showed Evolocumab plus standard of care ( SOC ) treatment reduced adjudicated cardiovascular events ( 0.95% Evolocumab plus standard of care; 2.18% standard of care ) over a one-year analysis period.
Adverse events ( greater than or equal to 1% in the Evolocumab plus SOC group and more frequent in the Evolocumab plus SOC group by at least 1% ) included arthralgia, headache, pain in extremity and fatigue.
The cardiovascular events analysis comprises exploratory findings from the ongoing open-label OSLER studies.
Evolocumab plus SOC treatment reduced LDL cholesterol by 61% compared to SOC.

The OSLER-1 and OSLER-2 trials are ongoing open-label extension studies designed to characterize long-term effects of Evolocumab. The trials enrolled 4,465 patients who had completed one of 12 phase 2 and 3 Evolocumab studies, 2,976 of whom were randomized to subcutaneous Evolocumab 140 mg every two weeks or 420 mg monthly plus SOC therapy and 1,489 were randomized to SOC alone over one year.
The median LDL cholesterol was 120 mg/dL at parent study baseline; approximately 70% of patients were on a statin at the start of the extension studies.
Compared to SOC alone, Evolocumab plus SOC reduced adjudicated cardiovascular events ( death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke and transient ischemic attack or heart failure requiring hospitalization ) compared to SOC alone ( 0.95% Evolocumab plus SOC vs 2.18% SOC over one year ), with a consistent effect on death, coronary and cerebrovascular events as well as by subgroups ( e.g., age, sex, baseline LDL cholesterol, statin use, National Cholesterol Education Program [ NCEP ] risk ).

Adverse events with a frequency of at least 1% in the Evolocumab plus SOC arm and that were more frequent with Evolocumab plus SOC by at least 1% included arthralgia ( 4.6% Evolocumab plus SOC; 3.2% SOC ), headache ( 3.6% Evolocumab plus SOC; 2.1% SOC ), pain in extremity ( 3.3% Evolocumab plus SOC; 2.1% SOC ) and fatigue ( 2.8% Evolocumab plus SOC; 1.0 percent SOC ).
Adverse events of interest included muscle-related adverse reactions ( 6.4% Evolocumab plus SOC; 6.0% SOC ), injection site reactions ( 4.3% Evolocumab plus SOC; N/A SOC ) and neurocognitive events ( 0.9% Evolocumab plus SOC; 0.3% SOC ). Compared to SOC alone, Evolocumab plus SOC reduced LDL cholesterol by 61% to a median of 48 mg/dL.
In this analysis, median study exposure for the first year of the extension studies was 11.1 months.

Data from the OSLER-1 study showed Evolocumab maintained its efficacy over a two-year period and no safety risk was identified.
The study, which began in October 2011, randomized 1,104 patients who completed short-term, double-blind, controlled Evolocumab studies to receive SOC ( n=370 ) or SOC plus open-label Evolocumab 420 mg monthly ( n=734 ) for one year.
After the first year, all patients received monthly Evolocumab plus SOC.
At the end of year two, 590 patients were still receiving Evolocumab, showing a persistence rate of 80%. Of the patients on Evolocumab over the entire two-year period, 33 patients ( 4.5% ) discontinued use due to an adverse effects.
Safety and tolerability were comparable regardless of achieved LDL cholesterol level.
Low-density lipoprotein cholesterol-lowering was sustained for more than two years, with a reduction of 54% at week 52 and 52% at week 124.

Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 ( PCSK9 ). PCSK9 is a protein that targets LDL receptors for degradation and thereby reduces the liver's ability to remove LDL cholesterol from the blood.
Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL cholesterol from the blood. ( Xagena )

Source: Amgen, 2015

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