Amgen has announced detailed results from the evolocumab (Repatha) 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). The detailed results from EBBINGHAUS were presented at the American College of Cardiology 66th Annual Scientific Session (ACC; 17-19 March, Washington, DC, USA).
“There has long been a debate that low low-density lipoprotein cholesterol (LDL-C) levels could lead to negative effects on memory or other cognitive functions,” says Robert P Giugliano, Brigham and Women’s Hospital, Boston, USA, 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 LDLs 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 evolocumab 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 computerised, 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. Patients treated with evolocumab experienced change from baseline similar to placebo in all three cognitive domains tested: spatial working memory between-errors score (baseline 21.0, evolocumab -0.5 versus placebo -0.9), paired associates learning total errors adjusted (baseline 25.8, change with evolocumab -1.5 versus -1.5 with placebo), RTI median five-choice reaction time (baseline 355.9, 5.2 milliseconds change with evolocumab versus 0.9 milliseconds with placebo). Changes from baseline in the global composite score were similar between treatment arms (baseline -0.008, changes with evolocumab 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 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%) neurocognitive adverse events were reported in the evolocumab group compared to 16 (1.6%) events in the placebo group. In the 27,564-patient evolocumab cardiovascular outcomes trial (FOURIER), neurocognitive adverse events were reported in 1.6% in the evolocumab group compared to 1.5% in the placebo group. The adverse events identified in EBBINGHAUS were consistent with the adverse events identified in FOURIER.