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|Lowering LDL Levels With Repatha® (Evolocumab) Did Not Adversely Affect Cognitive Function In Landmark Phase 3 Study|
"There has long been a debate that low LDL cholesterol levels could lead to negative effects on memory or other cognitive functions," said
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 versus -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
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 -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
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
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 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
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
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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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
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