Evolocumab: lowering LDL-C to unprecedented levels did not negatively impact cognition

Amgen announced detailed results from evolocumab cognitive function trial (EBBINGHAUS) evaluating the impact on cognitive function in 1,974 patients enrolled in the evolocumab cardiovascular outcomes study (FOURIER).

The study demonstrated that the effect of evolocumab on the primary endpoint of executive function was non-inferior to placebo. In addition, there was no statistical difference between evolocumab and placebo on the other cognitive domains tested: working memory, memory function and psychomotor speed (secondary endpoints). 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 evolocumab and placebo groups. 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. Secondary endpoint results in the three cognitive domains of working memory, memory function and psychomotor speed were consistent with the primary endpoint result. 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. Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Evolocumab 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, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels. 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.