"We now have additional evidence of the benefit of evolocumab in reducing cardiovascular event risk, even in patients starting with LDL-C levels below the most aggressive current guideline targets and in patients already on maximum-intensity statin therapy," said
The two analyses compared clinical outcomes in patients stratified by baseline LDL-C above and below 70 mg/dL and in patients on maximum-intensity statin therapy, defined as atorvastatin 80 mg or rosuvastatin 40 mg daily, versus patients on less intense statin therapy.
"These results provide further evidence for patients with established cardiovascular disease who would otherwise be considered as being successfully managed to the most stringent treatment targets," said
Baseline LDL-C Analysis
In patients with a baseline LDL-C below 70 mg/dL (n=2,034), Repatha reduced the median baseline LDL-C from 65.5 mg/dL to 21.0 mg/dL. Repatha consistently reduced the risk of the composite primary endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death, regardless of whether baseline LDL-C was below or above 70 mg/dL (20 percent in patients with baseline <70 mg/dL; 14 percent in patients with baseline ≥70 mg/dL, P-interaction=0.65). The results were also consistent for the more robust, secondary composite endpoint of heart attack, stroke or cardiovascular death where patients with a baseline LDL-C less than 70 mg/dL experienced a 30 percent reduction in cardiovascular events and patients with a baseline LDL-C greater than or equal to 70 mg/dL experienced a 19 percent reduction in cardiovascular events (P-interaction=0.44).
Background Statin Analysis
In patients on maximum-intensity statins (n=7,533), Repatha reduced the median baseline LDL-C from 93 mg/dL to 32 mg/dL. Additionally, Repatha consistently reduced the risk of major cardiovascular events in patients on maximum-intensity and less intense statin therapy in both the composite primary endpoint (14 percent in patients on maximum-intensity statin therapy; 15 percent in patients on less intense statin therapy, P-interaction=0.88) and the composite secondary endpoint (22 percent in patients on maximum-intensity statin therapy; 19 percent in patients on less intense statin therapy, P-interaction=0.71).
In the two analyses, there were no differences in the rates of adverse events leading to discontinuation between treatment groups in patients who had a baseline LDL-C below 70 mg/dL (4.4 percent Repatha; 4.6 percent placebo) or in patients on maximum-intensity statin therapy (3.9 percent Repatha; 3.7 percent placebo).
Results from the primary analysis of the 27,564-patient Repatha cardiovascular outcomes study were also presented at the meeting. The study was statistically powered around the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death (key secondary composite endpoint) and found that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent (p<0.001) reduction in these events. The study also found a statistically significant 15 percent reduction (p<0.001) in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death.
No new safety concerns were identified in this large clinical trial with roughly 60,000 patient-years of follow-up; this included the assessment of patients who achieved very low levels of LDL-C. The detailed results from the Repatha cardiovascular outcomes study were initially presented during a Late-Breaking Clinical Trials Session at the
Repatha Cardiovascular Outcomes (FOURIER) Study Design
The 27,564-patient Repatha cardiovascular outcomes study, FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), was a multinational Phase 3 randomized, double-blind, placebo-controlled trial, designed to evaluate whether treatment with Repatha in combination with statin therapy compared to placebo plus statin therapy reduces cardiovascular events. The primary endpoint was time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint was the time to cardiovascular death, myocardial infarction or stroke.
Eligible patients with high cholesterol (LDL-C ≥70 mg/dL or non-high-density lipoprotein cholesterol [non-HDL-C] ≥100 mg/dL) and clinically evident atherosclerotic cardiovascular disease at more than 1,200 study locations around the world were randomized to receive Repatha subcutaneous 140 mg every two weeks or 420 mg monthly plus optimized statin dose; or placebo subcutaneous every two weeks or monthly plus effective statin dose. Effective statin therapy was defined as at least atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved. The study was event driven and continued until 1,630 patients experienced a key secondary endpoint.
About Repatha® (evolocumab)
Repatha® (evolocumab) is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Repatha binds to PCSK9 and inhibits circulating PCSK9 from binding to the low-density lipoprotein receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Repatha increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.1
Repatha is approved in more than 50 countries, including the U.S., Japan, Canada and in all 28 countries that are members of the European Union. Applications in other countries are pending.
U.S. Repatha Indication:
Repatha® is indicated as an adjunct to diet and:
The effect of Repatha® on cardiovascular morbidity and mortality has not been determined.
The safety and effectiveness of Repatha® have not been established in pediatric patients with HoFH who are younger than 13 years old.
The safety and effectiveness of Repatha® have not been established in pediatric patients with primary hyperlipidemia or HeFH.
Important U.S. Safety Information
Contraindication: Repatha® is contraindicated in patients with a history of a serious hypersensitivity reaction to Repatha®.
Allergic reactions: Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients treated with Repatha®, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with Repatha®, treat according to the standard of care, and monitor until signs and symptoms resolve.
Adverse reactions: The most common adverse reactions (>5% of Repatha®-treated patients and more common than placebo) were: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions.
In a 52-week trial, adverse reactions led to discontinuation of treatment in 2.2% of Repatha®-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to Repatha® treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for Repatha® and placebo, respectively).
Adverse reactions from a pool of the 52-week trial and seven 12-week trials:
Local injection site reactions occurred in 3.2% and 3.0% of Repatha®-treated and placebo-treated patients, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportions of patients who discontinued treatment due to local injection site reactions in Repatha® -treated patients and placebo-treated patients were 0.1% and 0%, respectively.
Allergic reactions occurred in 5.1% and 4.7% of Repatha®-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for Repatha® and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).
Neurocognitive events were reported in less than or equal to 0.2% in Repatha®-treated and placebo-treated patients.
In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1,988 patients treated with Repatha® had at least one LDL-C value <25 mg/dL. Changes to background lipid-altering therapy were not made in response to low LDL-C values, and Repatha® dosing was not modified or interrupted on this basis. Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by Repatha® are unknown.
Musculoskeletal adverse reactions were reported in 14.3% of Repatha® -treated patients and 12.8% of placebo-treated patients. The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for Repatha® and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
Homozygous Familial Hypercholesterolemia (HoFH): In 49 patients with homozygous familial hypercholesterolemia studied in a 12-week, double-blind, randomized, placebo-controlled trial, 33 patients received 420 mg of Repatha® subcutaneously once monthly. The adverse reactions that occurred in at least 2 (6.1%) Repatha®-treated patients and more frequently than in placebo-treated patients, included upper respiratory tract infection (9.1% versus 6.3%), influenza (9.1% versus 0%), gastroenteritis (6.1% versus 0%), and nasopharyngitis (6.1% versus 0%).
Immunogenicity: Repatha® is a human monoclonal antibody. As with all therapeutic proteins, there is a potential for immunogenicity with Repatha®.
Please contact Amgen Medinfo at 800-77-AMGEN (800-772-6436) or 844-REPATHA (844-737-2842) regarding Repatha® availability or find more information, including full Prescribing Information at www.amgen.com and www.Repatha.com.
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