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Biopharmaceuticals Cardiology Regulatory

 News Release - February 22, 2017

Repatha(R) (Evolocumab) Receives European Commission Approval For New 420 mg Single-Dose Delivery Option

THOUSAND OAKS, Calif., Feb. 21, 2017 -- (Healthcare Sales & Marketing Network) -- Amgen (AMGN) today announced that the European Commission (EC) has adopted a decision to change the RepathaŽ (evolocumab) marketing authorization, approving a new single-dose delivery option. The new automated mini-doser (AMD) with a pre-filled cartridge is a hands-free device that provides 420 mg of Repatha in a single injection per administration. Repatha is the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor in Europe with the option of a single monthly injection. Repatha is a human monoclonal antibody that blocks a protein called PCSK9, which inhibits the body's natural system for eliminating "bad" cholesterol (low-density lipoprotein cholesterol or LDL-C) from the blood.1

"Amgen is committed to advancing care and improving the lives of patients with cardiovascular disease," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "We are proud to bring this dosing alternative to patients in Europe, providing another option for them to incorporate Repatha into their cardiovascular care, with less frequent and hands-free administration."

Approval from the EC grants a change to the centralized marketing authorization with unified labeling in the 28 countries that are members of the European Union (EU). Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions on the basis of the decision of the EC. The Repatha AMD will be available in Europe this year depending on reimbursement requirements.

In 2015, Repatha was the first PCSK9 inhibitor to gain marketing authorization in Europe as an every-two-week or monthly dosing regimen. In Europe, Repatha is approved as an adjunct to diet for the treatment of high cholesterol in combination with statins or other lipid-lowering therapies in patients unable to control their LDL-C with maximally tolerated statin doses, or alone or in combination with other lipid-lowering therapies in patients who are statin intolerant or for whom a statin is contraindicated. Repatha is also approved in combination with other lipid-lowering agents in patients with homozygous familial hypercholesterolemia (age 12 and over). The effect of Repatha on cardiovascular morbidity and mortality has not yet been determined.

The U.S. Food and Drug Administration approved the single 420 mg monthly injection option on July 11, 2016, as the Pushtronex™ system for use with Repatha (on-body infusor with prefilled cartridge).

About RepathaŽ (evolocumab)

RepathaŽ (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.1

The Repatha cardiovascular outcomes trial (FOURIER) is designed to evaluate whether treatment with Repatha in combination with statin therapy, compared to placebo plus statin therapy, reduces the risk of cardiovascular events in patients with high cholesterol and clinically evident cardiovascular disease, and completed patient enrollment in June 2015. Top-line results from the approximately 27,500-patient event-driven Repatha cardiovascular outcomes study were announced by Amgen in February 2017. Detailed results from the Repatha cardiovascular outcomes study will be presented at the American College of Cardiology 66th Annual Scientific Session (ACC.17) in Washington, D.C., March 17-19, 2017.

Repatha is approved in more than 40 countries, including the U.S., Japan, Canada and in all 28 countries that are members of the EU. Applications in other countries are pending.

Important EU Product Information

In Europe Repatha is approved for use in:

Hypercholesterolemia and mixed dyslipidemia

Repatha is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet:
  • in combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
  • alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.
Homozygous familial hypercholesterolemia Repatha is indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia in combination with other lipid-lowering therapies.

The effect of Repatha on cardiovascular morbidity and mortality has not yet been determined.

Posology

Primary hypercholesterolemia and mixed dyslipidemia in adults

The recommended dose of Repatha is either 140 mg every two weeks or 420 mg once monthly; both doses are clinically equivalent.

Homozygous familial hypercholesterolemia in adults and adolescents aged 12 years and over The initial recommended dose is 420 mg once monthly. After 12 weeks of treatment, dose frequency can be up-titrated to 420 mg once every 2 weeks if a clinically meaningful response is not achieved. Patients on apheresis may initiate treatment with 420 mg every two weeks to correspond with their apheresis schedule.

Important Safety Information This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Contraindications: Hypersensitivity to the active substance or to any of the excipients.

Special Warnings and Precautions: Renal impairment: Patients with severe renal impairment (defined as eGFR < 30 mL/min/1.73 m2) have not been studied. Repatha should be used with caution in patients with severe renal impairment. Hepatic impairment: In patients with moderate hepatic impairment, a reduction in total evolocumab exposure was observed that may lead to a reduced effect on LDL-C reduction. Therefore, close monitoring may be warranted in these patients. Patients with severe hepatic impairment (Child-Pugh C) have not been studied. Repatha should be used with caution in patients with severe hepatic impairment. Dry natural rubber: The needle cover of the glass pre-filled syringe and of the pre-filled pen is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. Sodium content: Repatha contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 'sodium-free'.

Interactions: No formal drug-drug interaction studies have been conducted for Repatha. No studies on pharmacokinetic and pharmacodynamics interaction between Repatha and lipid-lowering drugs other than statins and ezetimibe have been conducted.

Fertility, Pregnancy and Lactation: There are no or limited amount of data from the use of Repatha in pregnant women. Repatha should not be used during pregnancy unless the clinical condition of the woman requires treatment with evolocumab. It is unknown whether evolocumab is excreted in human milk. A risk to breastfed newborns/infants cannot be excluded. No data on the effect of evolocumab on human fertility are available.

Undesirable Effects: The following common (> 1/100 to < 1/10) adverse reactions have been reported in pivotal, controlled clinical studies: influenza, nasopharyngitis, upper respiratory tract infection, rash, nausea, back pain, arthralgia, injection site reactions. Please consult the SmPC for a full description of undesirable effects.

Pharmaceutical Precautions: Store in a refrigerator (2 degrees C – 8 degrees C). Do not freeze. Keep the pre-filled syringe or the pre-filled pen in the original carton in order to protect from light. If removed from the refrigerator, Repatha may be stored at room temperature (up to 25 degrees C) in the original carton and must be used within 1 month.

Important U.S. Product Information RepathaŽ 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 RepathaŽ on cardiovascular morbidity and mortality has not been determined.

The safety and effectiveness of RepathaŽ have not been established in pediatric patients with HoFH who are younger than 13 years old.

The safety and effectiveness of RepathaŽ have not been established in pediatric patients with primary hyperlipidemia or HeFH.

Important U.S. Safety Information

Contraindication: RepathaŽ is contraindicated in patients with a history of a serious hypersensitivity reaction to RepathaŽ.

Allergic reactions: Hypersensitivity reactions (e.g. rash, urticaria) have been reported in patients treated with RepathaŽ, including some that led to discontinuation of therapy. If signs or symptoms of serious allergic reactions occur, discontinue treatment with RepathaŽ, treat according to the standard of care, and monitor until signs and symptoms resolve.

Adverse reactions: The most common adverse reactions (>5% of RepathaŽ-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 RepathaŽ-treated patients and 1% of placebo-treated patients. The most common adverse reaction that led to RepathaŽ treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for RepathaŽ 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 RepathaŽ-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 RepathaŽ-treated patients and placebo-treated patients were 0.1% and 0%, respectively.

Allergic reactions occurred in 5.1% and 4.7% of RepathaŽ-treated and placebo-treated patients, respectively. The most common allergic reactions were rash (1.0% versus 0.5% for RepathaŽ 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 RepathaŽ-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 RepathaŽ 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 RepathaŽ 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 RepathaŽ are unknown.

Musculoskeletal adverse reactions were reported in 14.3% of RepathaŽ-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 RepathaŽ 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 RepathaŽ subcutaneously once monthly. The adverse reactions that occurred in at least 2 (6.1%) RepathaŽ-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: RepathaŽ is a human monoclonal antibody. As with all therapeutic proteins, there is a potential for immunogenicity with RepathaŽ.

Please contact Amgen Medinfo at 800-77-AMGEN (800-772-6436) or 844-REPATHA (844-737-2842) regarding RepathaŽ availability or find more information, including full Prescribing Information, at www.amgen.com and www.Repatha.com.

About Amgen Cardiovascular

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.2 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. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. Even when clinical trials are successful, regulatory authorities may question the sufficiency for approval of the trial endpoints we have selected. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market.

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. 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.

References
  1. RepathaŽ European Commission Summary of Product Characteristics.
  2. World Health Organization. Cardiovascular diseases (CVDs) fact sheet. http://www.who.int/mediacentre/factsheets/fs317/en/. Accessed November 2016.


Source: Amgen

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