FDA Grants Priority Review For Amgen's Supplemental Biologics License Application For Repatha® (evolocumab) To Include Data On Reducing Risk Of Cardiovascular Events

THOUSAND OAKS, Calif., July 27, 2017 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced that the U.S. Food and Drug Administration (FDA) has granted priority review for Amgen's supplemental Biologics License Application (sBLA) for Repatha^® (evolocumab), a PCSK9 inhibitor. If approved by the FDA, the U.S. Prescribing Information for Repatha will be updated to include risk reduction of major cardiovascular events based on data from the large cardiovascular outcomes study (FOURIER). The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of Dec. 2, 2017.

"The FDA's decision to grant priority review for the Repatha cardiovascular outcomes data highlights the urgency to address the need to reduce heart attacks and strokes in high-risk patients who struggle to lower their LDL cholesterol," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We look forward to working with the FDA to update the label for Repatha enabling us to more broadly educate physicians and patients of the proven impact of Repatha to reduce cardiovascular events."

Priority review is assigned to applications for drugs that treat serious conditions and would, if approved, provide significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions.

A second application seeking to expand the lipid-lowering indication to include additional patient populations studied was also accepted by the FDA.

The 27,564-patient Repatha cardiovascular outcomes study (FOURIER) demonstrated that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent (p<0.001) reduction in hard major adverse cardiovascular events (MACE) represented in the composite (secondary) endpoint of time to first heart attack, stroke or cardiovascular death. The study 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.

The magnitude of risk reduction in both the primary and secondary composite endpoints grew over time, with the robust benefit starting as early as six months and accruing through the median 2.2 years of the study. For the secondary composite endpoint, an exploratory analysis showed a reduction in risk of 16 percent in the first year and 25 percent beyond the first year.

Patients on Repatha experienced a reduction in the risk of heart attack (27 percent, nominal p<0.001), stroke (21 percent, nominal p=0.01) and coronary revascularization (22 percent, nominal p<0.001). Consistent with recent trials of more intensive LDL lowering, there was no observed effect on cardiovascular mortality.^1-5 Similarly, there was no observed effect on hospitalization for unstable angina.

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. In particular, there were no notable differences seen between treatment arms in the overall rate of adverse events, serious adverse events or adverse events leading to study drug discontinuation. These results were presented during a Late-Breaking Clinical Trials Session at the American College of Cardiology 66th Annual Scientific Session (ACC.17) and simultaneously published in the New England Journal of Medicine.⁶

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 optimized 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 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 (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.⁷

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:

• Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of low-density lipoprotein cholesterol (LDL-C)
• Other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C

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.

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.⁸ 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 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 one of the world's leading independent biotechnology companies, 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. If we fail to meet the compliance obligations in the corporate integrity agreement between us and the U.S. government, we could become subject to significant sanctions. 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. We may not be able to access the capital and credit markets on terms that are favorable to us, or at all. We are increasingly dependent on information technology systems, infrastructure and data security. 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.

The scientific information discussed in this news release relating to new indications is preliminary and investigative and is not part of the labeling approved by the U.S. Food and Drug Administration or European Commission for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses.

CONTACT: Amgen, Thousand Oaks
Trish Hawkins, 805-447-5631 (Media)
Kristen Davis, 805-447-3008 (Media)
Arvind Sood, 805-447-1060 (Investors)

REFERENCES

1. Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.
2. LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.
3. Pederson TR, et al. JAMA. 2005;294:2437-2445.
4. Search Collaborative Group Lancet 2010;376:1658–69.
5. Cannon CP, et al. N Engl J Med. 2015;372:2387-2397.
6. Sabatine MS, et al. N Engl J Med. 2017;376:1713-1722.
7. Repatha^® U.S. Prescribing Information. Amgen.
8. World Health Organization. Cardiovascular diseases (CVDs) fact sheet. http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed March 2017.

SOURCE Amgen

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