Geoff Kerchner, MD, PhD: Phase III Trials of Crenezumab in Treatment of Prodromal to Mild Alzheimer

“Crenezumab is actually the leading investigational therapy that directly targets that toxic form of Aβ."

Geoff Kerchner, MD, PhD, Senior Medical Director of Neuroscience at Genentech, sat down with NeurologyLive at the 2018 Alzheimer Association International Conference in Chicago, Illinois, to discuss the characteristics from CREAD 1 and CREAD 2, 2 global, randomized, double-blind, placebo-controlled, parallel-group phase III studies testing the safety and efficacy of crenezumab 60 mg/kg in subjects with prodromal to mild Alzheimer disease.

Crenezumab, a humanized Aβ monoclonal IgG4 antibody, binds to multiple forms of Aβ with a high affinity for oligomers, blocking oligomer-induced neurotoxicity and with low risk of amyloid-related imaging abnormalities. Despite the co-primary endpoints of the phase II trial not being met, exploratory analyses suggest that crenezumab should be tested at a higher dose and earlier disease stage for clinically meaningful efficacy. Data from the phase Ib study which investigated the safety and tolerability of higher doses of crenezumab back a 4-fold higher phase III dose than previously used in phase II.

CREAD 1 and CREAD 2 will test whether clinically meaningful efficacy can be achieved without the associated safety findings that are reported with other passive anti-amyloid immunotherapies targeting fibrillar amyloid in Alzheimer disease.

Primary and secondary endpoints of CREAD 1 and CREAD 2 include change from baseline in CDR-SB, ADAS-cog-13 and ADCS-ADL scores over 105 weeks, and exploratory objectives include assessing treatment effects on CSF biomarkers and amyloid- and tau-Pet. The study has completed recruitment with 813 patients enrolled.

Kerchner also discussed the progress that has been made and his excitement for the future, emphasizing that previous trials have allowed researchers to learn that treating at a high dose and treating early are critical. He mentioned that there’s a wealth of knowledge that has helped to improve the design of clinical trials, maximizing the chances to show benefit for patients.