Amgen Announces New FOURIER Analysis Showing Benefit With Repatha® (Evolocumab) In High-Risk Patients With Established Cardiovascular Disease And Chronic Kidney Disease

THOUSAND OAKS, Calif., Oct. 26, 2018 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced a new Repatha cardiovascular outcomes study (FOURIER) analysis evaluating the effects of Repatha^® (evolocumab) in patients with established cardiovascular disease by kidney function. In line with previous FOURIER subgroup analyses, these results further demonstrate Repatha's efficacy in reducing not only low-density lipoprotein cholesterol (LDL-C) levels, but also the relative risk for major cardiovascular events such as heart attack and stroke, in high-risk patients including those with mild-to-moderate chronic kidney disease (CKD).^1-4 In these patients (N=4,443), absolute reductions tended to be greater in the risk for the composite secondary endpoint which included cardiovascular death, heart attack or stroke. Adverse events were similar across patients regardless of CKD stage and consistent with the Repatha known safety profile. The results were presented at the American Society of Nephrology's (ASN) annual Kidney Week in San Diego.  

"Patients with chronic kidney disease are considered a high-risk population due to increased rates of cardiovascular events associated with impaired kidney function," said Robert P. Giugliano, M.D., S.M., Brigham and Women's Hospital, Harvard Medical School and lead investigator. "The results of this analysis demonstrate evolocumab is a safe and effective approach for the reduction of LDL-C and cardiovascular risk in patients with established cardiovascular disease and mild-to-moderate kidney impairment on background lipid-lowering therapies, who require additional treatment options." 

Analysis of the FOURIER subgroup of patients with CKD showed treatment with Repatha resulted in consistent and robust reductions in LDL-C levels across all patients independent of kidney function (58.7 percent LDL-C reduction in patients with stage 3 CKD versus 58.2 percent LDL-C reduction in those with preserved kidney function).⁵

Treatment with Repatha was also associated with significant reductions in the risk for the composite of cardiovascular death, heart attack or stroke across patient subgroups regardless of CKD stage. Patients with more advanced CKD tended to have greater reductions in the absolute risk for cardiovascular events (2.5 percent reduction in absolute risk in patients with ≥ stage 3 CKD compared to 1.7 percent absolute risk reduction in patients with preserved kidney function at year three).⁵

"This subanalysis is the first to report the effects of a PCSK9 inhibitor in patients with CKD and established cardiovascular disease. These results continue to reinforce Repatha's efficacy and safety across a wide range of high-risk patient populations," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "It is vitally important for patients with CKD to have additional treatment options to help manage their LDL-C levels and heightened risk of cardiovascular events."

Early stage CKD, which is often associated with comorbidities such as diabetes, high blood pressure and heart disease, affects an estimated 10 percent of Americans.^6,7 CKD is an independent risk factor for the development of cardiovascular disease, with the frequency and risk for adverse outcomes increasing with worsening kidney function.^7-9 

Repatha Cardiovascular Outcomes (FOURIER) Study Design
FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk), a multinational Phase 3 randomized, double-blind, placebo-controlled trial, is designed to evaluate whether treatment with Repatha in combination with statin therapy compared to placebo plus statin therapy reduces cardiovascular events. The primary endpoint is the time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint is 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 1,300 study locations around the world were randomized to receive Repatha subcutaneous 140 mg every two weeks or 420 mg monthly plus effective statin dose; or placebo subcutaneous every two weeks or monthly plus effective statin dose. Optimized 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 at least 1,630 patients experienced a key secondary endpoint.

About Repatha^® (evolocumab)
Repatha 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 (LDL) 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.¹⁰

Repatha is approved in more than 60 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.

Important U.S. Product Information

Repatha is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody indicated:

• to reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease.
• as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) to reduce low-density lipoprotein cholesterol (LDL-C).
• as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDLC.

The safety and effectiveness of Repatha have not been established in pediatric patients with HoFH who are younger than 13 years old or 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. Serious hypersensitivity reactions including angioedema have occurred in patients treated with Repatha.

Allergic reactions: Hypersensitivity reactions (e.g. angioedema, 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 patients treated with Repatha and occurring more frequently than placebo) were: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site 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.

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%).

The most common adverse reactions in the Cardiovascular Outcomes Trial (>5% of patients treated with Repatha and occurring more frequently than placebo) were: diabetes mellitus (8.8% Repatha, 8.2% placebo), nasopharyngitis (7.8% Repatha, 7.4% placebo), and upper respiratory tract infection (5.1% Repatha, 4.8% placebo).    

Among the 16,676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the trial was 8.1% in patients assigned to Repatha compared with 7.7% in those assigned to placebo.  

Homozygous Familial Hypercholesterolemia (HoFH): The adverse reactions that occurred in at least two patients treated with Repatha and more frequently than placebo were: upper respiratory tract infection, influenza, gastroenteritis, and nasopharyngitis.

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.

About Amgen in the Cardiovascular Therapeutic Area
Building on more than three decades of experience in developing biotechnology medicines for patients with serious illnesses, Amgen is dedicated to addressing important scientific questions to advance care and improve the lives of patients with cardiovascular disease, the leading cause of morbidity and mortality worldwide.¹¹ Amgen's research into cardiovascular disease, and potential treatment options, is part of a growing competency at Amgen that utilizes human genetics to identify and validate certain drug targets. Through its own research and development efforts, as well as partnerships, Amgen is building a robust cardiovascular portfolio consisting of several approved and investigational molecules in an effort to address a number of today's important unmet patient needs, such as high cholesterol and heart failure.

About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be the world's largest independent biotechnology company, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential. 

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

Forward-Looking Statements 
This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission reports filed by Amgen, including our most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and Form 8-K. Unless otherwise noted, Amgen is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.

No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Our results may be affected by our ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing our products and global economic conditions. In addition, sales of our products are affected by pricing pressure, political and public scrutiny and reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment. Furthermore, our research, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. We or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and product liability claims. In addition, our business may be impacted by the adoption of new tax legislation or exposure to additional tax liabilities. Further, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors, or we may fail to prevail in present and future intellectual property litigation. We perform a substantial amount of our commercial manufacturing activities at a few key facilities and also depend on third parties for a portion of our manufacturing activities, and limits on supply may constrain sales of certain of our current products and product candidate development. In addition, we compete with other companies with respect to many of our marketed products as well as for the discovery and development of new products. Discovery or identification of new product candidates cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate will be successful and become a commercial product. Further, some raw materials, medical devices and component parts for our products are supplied by sole third-party suppliers. Certain of our distributors, customers and payers have substantial purchasing leverage in their dealings with us. The discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations. Our efforts to acquire other companies or products and to integrate the operations of companies we have acquired may not be successful. A breakdown, cyberattack or information security breach could compromise the confidentiality, integrity and availability of our systems and our data. Our stock price is volatile and may be affected by a number of events. Our business performance could affect or limit the ability of our Board of Directors to declare a dividend or our ability to pay a dividend or repurchase our common stock. We may not be able to access the capital and credit markets on terms that are favorable to us, or at all.

CONTACT: Amgen, Thousand Oaks
Kristen Davis, 805-447-3008 (Media)
Kristen Neese, 805-313-8267 (Media)
Arvind Sood, 805-447-1060 (Investors)

References

1. Bonaca, M.P., et al. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 137, 338-350 (2018).
2. Sabatine, M.S., et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 5, 941-950 (2017).
3. Sabatine, M.S., et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 376, 1713-1722 (2017).
4. Sabatine, M.S., et al. Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: An Analysis from FOURIER. Circulation (2018).
5. Charytan, D.M. & Sabatine, M.S. Towards Better Medication Usage in Patients with CKD.  Presented at: American Society of Nephrology Annual Conference (San Diego, CA, 2018).
6. CDC, Chronic Kidney Disease Surveillance System—United States. http://www.cdc.gov/ckd. Accessed: October 25, 2018.
7. Subbiah, A.K., Chhabra, Y.K. & Mahajan, S. Cardiovascular disease in patients with chronic kidney disease: a neglected subgroup. Heart Asia 8, 56-61 (2016).
8. Pinkau, T., Hilgers, K.F., Veelken, R. & Mann, J.F. How does minor renal dysfunction influence cardiovascular risk and the management of cardiovascular disease? J Am Soc Nephrol 15, 517-523 (2004).
9. Jellinger, P.S., et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. Endocr Pract 23, 1-87 (2017).
10. Repatha Prescribing Information.  (Amgen, Thousand Oaks, CA, 2017).
11. W.H.O., Cardiovascular diseases (CVDs) fact sheet. http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed: October 25, 2018

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