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Intravenous Crenezumab Ineffective Against Decline in Alzheimer Disease
While well tolerated, intravenous crenezumab (60 mg/kg IV Q4W) did not reduce clinical decline in patients with prodromal to mild Alzheimer disease (AD), according to recent randomized double-blind placebo-controlled parallel-group phase 3 studies. Researchers published their findings from the CREAD and CREAD 2 studies in JAMA Neurology.
Crenezumab (RO5490245) is a humanized anti-amyloid-β (Aβ) monoclonal immunoglobulin G4 antibody that binds monomeric and aggregated Aβ, with higher affinity for oligomeric Aβ.
“No meaningful changes in AD biomarkers were observed. Both studies were discontinued following a preplanned interim analysis indicating that CREAD was unlikely to meet the primary endpoint,” researchers wrote in the study. The primary endpoint was defined as a change in Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores from baseline to week 105 (week 77 for CREAD 2 at the aforementioned interim analysis).
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CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. Participants were excluded if they met the following criteria: their medical history included other conditions causing neurological deficit; cancer; or cardiovascular, hepatic, immune, or metabolic disorders; presence of evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis (ARIA-hemosiderosis) on magnetic resonance imaging (MRI).
Participants in CREAD (N=813; 483 female and 330 male) and CREAD2 (N=806; 456 female and 350 male) were randomly assigned in a 1:1 ratio to either placebo or crenezumab. Final analysis included 409 participants in the placebo group and 404 in the crenezumab group in CREAD and 399 in the placebo group and 407 in the crenezumab group in CREAD2.
“Observed small differences between treatment arms in both studies lacked consistency across endpoints and between studies and were consistent with random variation around the null hypothesis,” researchers wrote.
“Crenezumab was designed to target Aβ oligomers, which have been hypothesized to be a primary mediator of neurotoxicity; crenezumab also binds to Aβ monomers, albeit with approximately 10-fold lower affinity…Demonstrating target engagement in the central compartment early in development, preferably corroborated by disease-relevant downstream biomarkers, is an important consideration to help exclude lack of sufficient target engagement as a reason for lack of efficacy.”
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