Lowering LDL Levels with Repatha(R) (evolocumab) Did Not Adversely Affect Cognitive Function in Land

- Repatha Cognitive Function Trial Evaluated Subset of Patients From Cardiovascular Outcomes Trial

- No Signal for Worsening Cognitive Function Observed Even in Patients Who Reached LDL Cholesterol Below 25 mg/dL

- Detailed Results From One of the Largest Randomized, Controlled Studies of Cognitive Function Presented at a Late-Breaking Clinical Trials Session at ACC.17

Amgen (NASDAQ:AMGN) announced detailed results from the Repatha® (evolocumab) cognitive function trial (EBBINGHAUS) evaluating the impact on cognitive function in 1,974 patients enrolled in the Repatha cardiovascular outcomes study (FOURIER). The study demonstrated that the effect of Repatha on the primary endpoint of executive function was non-inferior to placebo. In addition, there was no statistical difference between Repatha and placebo on the other cognitive domains tested: working memory, memory function and psychomotor speed (secondary endpoints). The detailed results from EBBINGHAUS were presented at a Late-Breaking Clinical Trials Session at the American College of Cardiology 66th Annual Scientific Session (ACC.17) in Washington, D.C.

"There has long been a debate that low LDL cholesterol levels could lead to negative effects on memory or other cognitive functions," said Robert P. Giugliano, M.D., S.M., Brigham and Women's Hospital, Boston and lead study investigator. "We did not find evidence for a decline in neurocognitive function after nearly two years of treatment with evolocumab using a dedicated series of neuropsychologic tests. We also asked patients and their physicians to provide their assessments and found no differences between evolocumab and placebo. These findings provide strong support for the safety of reducing LDL with evolocumab to levels well below current treatment targets."

In the primary cohort of 1,204 patients, followed for a median of 19 months, the change from baseline raw score of spatial working memory strategy index of executive function was similar in the Repatha and placebo groups (mean baseline score 17.8; mean change from baseline ‑0.2 vs. -0.3, respectively). The primary endpoint was below the pre-specified margin, demonstrating non-inferiority. The primary endpoint was assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory strategy index of executive function, an established language- and culture-independent computerized, tablet-based cognitive assessment tool.

"These results, from one of the largest randomized controlled trials on cognitive function, clearly demonstrated that lowering LDL-C to unprecedented levels with Repatha did not negatively impact cognition," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "These results further support the safety of Repatha as an effective LDL-lowering therapy with no observed negative effects on memory or other cognitive functions."

Secondary endpoint results in the three cognitive domains of working memory, memory function and psychomotor speed were consistent with the primary endpoint result. Patients treated with Repatha experienced change from baseline similar to placebo in all three cognitive domains tested: spatial working memory between-errors score (baseline 21.0, Repatha -0.5 versus placebo -0.9), paired associates learning total errors adjusted (baseline 25.8, change with Repatha -1.5 versus with -1.5 with placebo), RTI median five-choice reaction time (baseline 355.9, 5.2 milliseconds change with Repatha versus 0.9 milliseconds with placebo). Changes from baseline in the global composite score were similar between treatment arms (baseline -0.008, changes with Repatha 0.03 versus 0.06 with placebo). Results in the full cohort were consistent with those in the primary cohort.

In an exploratory analysis, these results were consistent regardless of achieved low-density lipoprotein cholesterol (LDL-C) levels, including 661 patients with the lowest LDL-C level (<25 mg/dL).

In the EBBINGHAUS study, neurocognitive adverse event rates were similar between treatment arms. In the full cohort, 19 (1.9 percent) neurocognitive adverse events were reported in the Repatha group compared to 16 (1.6 percent) events in the placebo group. In the 27,564-patient Repatha cardiovascular outcomes trial (FOURIER), neurocognitive adverse events were reported in 1.6 percent in the Repatha group compared to 1.5 percent in the placebo group. The adverse events identified in EBBINGHAUS were consistent with the adverse events identified in FOURIER.

Repatha Cognitive Function (EBBINGHAUS) Study Design

EBBINGHAUS (Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in high cardiovascUlar risk Subjects) is a double-blind, placebo-controlled randomized non-inferiority trial involving of 1,974 patients with clinically evident atherosclerotic cardiovascular disease enrolled in the Repatha cardiovascular outcomes trial (FOURIER). The primary non-inferiority assessment of the primary endpoint spatial working memory strategy index of executive function (assessing executive function, or high-level thinking and decision making) was performed on the primary cohort of 1,204 patients who enrolled on or before the first dose of investigational product and had at least one post-baseline CANTAB assessment. The full cohort (1,974 patients) included all randomized patients. The primary endpoint was assessed by comparing the 95 percent confidence interval (CI) with the pre-specified non-inferiority margin for the treatment difference between Repatha and placebo. Secondary endpoints were the CANTAB Spatial Working Memory between-errors score (assessing working memory, or the ability to hold material in mind while that material is being actively processed); the CANTAB Paired Associates Learning Total Errors Adjusted (assessing memory function, or the ability to store and retrieve information by associating an event with a time and place); and the CANTAB Reaction Time Five-Choice Median Reaction Time (assessing psychomotor speed, which is responsible for detecting and responding to a stimulus). For all three secondary endpoints, the 95 percent CI for the estimated treatment difference between Repatha and placebo spanned equivalence.

Primary and secondary endpoints were assessed using a tablet-based tool at baseline, weeks 24, yearly, and at study end. The primary analysis compared the mean change from baseline in patients who had a baseline cognitive assessment on or prior to the first day of study drug.

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 hard major adverse cardiovascular event (MACE) composite endpoint is the time to cardiovascular death, myocardial infarction or stroke (key secondary endpoint). The extended MACE composite endpoint is the time to cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (primary endpoint).

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® (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

Repatha is approved in more than 40 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®. 

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.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.

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REFERENCES

Repatha® U.S. Prescribing Information. Amgen.

World Health Organization. Cardiovascular diseases (CVDs) fact sheet. Accessed February 2017.