Amgen announced that the New England Journal of Medicine (NEJM) published results from the Repatha (evolocumab) cognitive function trial (EBBINGHAUS), which was conducted in a subset of patients enrolled in the randomized, placebo-controlled Repatha cardiovascular outcomes study (FOURIER). The study demonstrated that Repatha was non-inferior to placebo, with no significant difference in cognitive function between the Repatha and placebo-treated groups.
“In the first prospectively designed study of cognitive function with a PCSK9 inhibitor using validated instruments, we showed that there were no significant differences between patients taking evolocumab and those on placebo,” said Robert P. Giugliano, M.D., S.M., Brigham and Women’s Hospital, Boston and lead study investigator. “These findings are reassuring for both physicians and patients because they show that LDL cholesterol levels can be lowered with evolocumab to levels well below current treatment targets, with no negative effects on memory or other cognitive domains.”
The effect of Repatha on executive function (primary endpoint) was non-inferior to placebo, and there was no statistical difference between Repatha and placebo on the other cognitive domains tested: working memory, memory function and psychomotor speed (secondary endpoints).
“Historically, the clinical cardiology community has had concerns that low LDL-C levels may impact cognitive function,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “Across our comprehensive clinical trial program, thousands of patients have been treated with Repatha, which has demonstrated a consistent safety profile, even at very low LDL cholesterol levels. These findings add to the body of evidence supporting the safety of LDL-lowering with Repatha in patients with established cardiovascular disease who need more than statin therapy alone.”
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 -0.21 versus -0.29, 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. CANTAB is an established, language- and culture-independent, computerized, tablet-based cognitive assessment tool that uses touchscreen neuropsychological tests of cognition specifically designed to assess central nervous system disorders and cognitive function across a range of domains, including episodic and working memory, executive function, psychomotor speed and attention.
Secondary endpoint results in the three cognitive domains of working memory, memory function and psychomotor speed were consistent with the primary endpoint result, and patients treated with Repatha experienced changes from baseline similar to placebo in all three cognitive domains tested. Changes from baseline in the global composite score were also similar between treatment arms.
In an exploratory analysis, results were consistent regardless of achieved low-density lipoprotein cholesterol (LDL-C) levels and did not show an association between LDL-C level and adverse cognitive outcomes, including in the 661 patients with the lowest-achieved LDL-C level (<25 mg/dL).
In the EBBINGHAUS study, neurocognitive adverse event rates were similar between treatment arms (1.9 percent Repatha; 1.3 percent placebo). The adverse events identified in EBBINGHAUS were consistent with the adverse events identified in the 27,564-patient Repatha cardiovascular outcomes study FOURIER.
Filed Under: Drug Discovery