ARTICLE OPEN ACCESS CLASS OF EVIDENCE ABBY A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease Jeffrey L. Cummings, MD, ScD, Sharon Cohen, MD, Christopher H. van Dyck, MD, Mark Brody, MD, Correspondence Craig Curtis, MD, William Cho, MD, Michael Ward, PhD, Michel Friesenhahn, MA, Christina Rabe, PhD, Dr. Cummings Flavia Brunstein, MD, PhD, Angelica Quartino, PhD, Lee A. Honigberg, PhD, Reina N. Fuji, VMD, PhD, [email protected] David Clayton, PhD, Deborah Mortensen, PhD, Carole Ho, MD, and Robert Paul, MD Neurology® 2018;90:e1889-e1897. doi:10.1212/WNL.0000000000005550 Abstract CME Course Objective NPub.org/cmelist To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). MORE ONLINE Class of Evidence Methods Criteria for rating In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were therapeutic and diagnostic randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab studies 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or NPub.org/coe placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical De- mentia Rating–Sum of Boxes scores from baseline to week 73. Podcast Dr. Jeff Burns talks with ff Results Dr. Je rey Cummings about results from the The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a re- ABBY trial. duction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached NPub.org/wt43vt statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both fi β groups, there was a signi cant increase in CSF -amyloid1-42 levels that correlated with cren- ezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. Conclusions Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of cren- ezumab treatment at even higher doses in patients with early AD. Clinicaltrials.gov identifier NCT 01343966. Classification of evidence This study provides Class II evidence that, for people with AD, crenezumab does not signifi- cantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study. From the Cleveland Clinic Lou Ruvo Center for Brain Health (J.L.C.), Las Vegas, NV; Toronto Memory Program (S.C.), ON, Canada; Alzheimer’s Disease Research Unit (C.H.v.D.), Yale University School of Medicine, New Haven, CT; Brain Matters Research Inc (M.B.), Delray Beach, FL; Compass Research, LLC (C.C.), Orlando, FL; Genentech (W.C., M.W., M.F., F.B., A.Q., L.A.H., R.N.F., D.C., D.M., C.H., R.P.), South San Francisco, CA; and Roche Diagnostics (C.R.), Penzberg, Germany. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Roche Pharmaceuticals. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e1889 Glossary Aβ = β-amyloid; AD = Alzheimer disease; ADAS-Cog = Alzheimer’s Disease Assessment Scale–Cognitive Subscale; ADCS- ADL = Alzheimer’s Disease Cooperative Study–Activities of Daily Living; AE = adverse event; ARIA = amyloid-related imaging abnormalities; ARIA-E = amyloid-related imaging abnormalities indicative of vasogenic edema or effusions; ARIA-H = amyloid- related imaging abnormalities indicative of microhemorrhage and siderosis; CDR-SB = Clinical Dementia Rating–Sum of Boxes; CREAD = A Study of Crenezumab Versus Placebo to Evaluate the Efficacy and Safety in Participants With Prodromal to Mild Alzheimer’s Disease; FcγR = Fc-gamma receptor; MMSE = Mini-Mental State Examination; SAE = serious adverse event. Alzheimer disease (AD) is the most common form of de- Patients mentia1 and is characterized by deposition of amyloid plaques Eligible patients were 50 to 80 years old, met the criteria for mild in the brain composed primarily of β-amyloid (Aβ) peptides.2 to moderate probable AD according to the National Institute Aβ peptides may accumulate as soluble monomers and aggre- of Neurologic and Communicative Disorders and Stroke— gate as oligomers and insoluble fibrils,1 but soluble oligomers Alzheimer’s Disease and Related Disorders Association criteria14 – are suggested to be a major driver of neurotoxicity.3 5 and had a Mini-Mental State Examination (MMSE) score of 18 to 26 points.15 Additional inclusion criteria were a Geriatric Crenezumab, a fully humanized immunoglobulin isotype G4 Depression Scale score of <6, a Clinical Dementia Rating–Sum – monoclonal antibody, binds to monomers and aggregated forms of Boxes (CDR-SB) score of ≥0.5,16 18 and an Alzheimer’s of Aβ with a 10-fold–higher affinity for oligomers.6 The im- Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) munoglobulin isotype G4 backbone confers reduced activation DelayedWordRecallscoreof≥5.19 Treatment with approved of Fc-gamma receptors (FcγRs) and minimizes the FcγR- AD drugs such as acetylcholinesterase inhibitors or memantine mediated inflammatory activation of microglia, hypothesized was permitted if initiated ≥3 months and stabilized ≥2months to contribute to neurotoxicity,7,8 while preserving FcγR- before randomization. mediated microglial phagocytosis and removal of Aβ oligomers.6 Study design and treatment Amyloid-related imaging abnormalities (ARIA) indicative of The study was conducted in 2 overlapping parts (figure e-1, vasogenic edema or effusions (ARIA-E) and microhemorrhage links.lww.com/WNL/A461). Patients were randomly and siderosis (ARIA-H) have been reported recently with assigned in a 2:1 ratio to receive crenezumab 300 mg SC every monoclonal antibodies that bind aggregated forms of Aβ and 2 weeks (the low-dose cohort) or placebo in part 1 and to have immunoglobulin isotype G1 backbones with fully FcγR- crenezumab 15 mg/kg IV every 4 weeks (the high-dose co- mediated effector function, limiting the dose levels that could hort) or placebo in part 2. Randomization into the 2 parts was – be safely administered.9 11 Crenezumab was designed on the independent and sequential. Enrollment in part 2 of the study basis of the hypothesis that an antibody with reduced effector began only when randomization in part 1 and the safety run-in function would have a lower risk of inducing ARIA-E/H.12,13 (described below) were complete. Randomization was man- aged by a central IxRS vendor using dynamic hierarchical randomization based on 3 factors: APOE e4 genotype, MMSE Methods score (<22 vs ≥22), and study site. Primary research question To assess the potential for using a higher dose of crenezumab This phase 2, multicenter, randomized, double-blind, placebo- compared to phase 1, part 2 of the phase 2 study was preceded controlled, parallel-group study was designed to evaluate the by a safety run-in period that was conducted in parallel with safety and efficacy of crenezumab in patients with mild to part 1 and consisted of at least 2 monthly IV administrations moderate AD that was conducted from April 25, 2011, to of 15 mg/kg crenezumab in 13 patients (11 active: 2 placebo). February 18, 2014, at 72 sites in North America and Europe. On the basis of the available safety data, the 15-mg/kg dose Class II evidence is provided here. was selected for the high-dose IV cohort of the study. Patients from this cohort were not included in the primary efficacy Standard protocol approvals, registrations, analysis. and participant consents The study protocol was approved by the local institutional Outcomes review board at each site. Written informed consent was The primary efficacy outcome measures were changes in obtained from each patient (or legally authorized representa- the 12-item ADAS-Cog (ADAS-Cog12) and CDR-SB tive) before entry into the study (ClinicalTrials.gov identifier scores from baseline to week 73.20,21 The secondary effi- NCT01343966). The study was conducted in accordance with cacy outcome measure, the Alzheimer’sDiseaseCo- the Declaration of Helsinki and the International Conference operative Study–Activities of Daily Living (ADCS-ADL) on Harmonisation Consolidated Guidelines on Good Clinical score, was analyzed in the same manner as the primary Practice. efficacy outcome measures.22 e1890 Neurology | Volume 90, Number 21 | May 22, 2018 Neurology.org/N To assess the exploratory outcome of crenezumab pharma- Cohorts from part 1 (low-dose 300 mg SC cohort) and part 2 cokinetics, blood samples were collected to measure serum (high-dose 15 mg/kg IV cohort) were analyzed separately, crenezumab concentrations and analyzed with a validated reflecting their independent and sequential randomization. ELISA (limit of detection 50 ng/mL). Three subpopulations determined by baseline MMSE score were analyzed: MMSE score of 18 to 26 (all patients), MMSE CSF collection was conducted as an optional procedure at score of 20 to 26 (mild AD), and MMSE score of 22 to 26 week 1 (day 1/baseline) and before study drug administration (very mild AD).