Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials

Abstract

Importance: Alzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression.

Objective: To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD.

Design, setting, and participants: Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD. CREAD (194 sites in 30 countries) and CREAD2 (209 sites in 27 countries) were global multicenter studies. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. A total of 3736 and 3664 participants were screened in CREAD and CREAD2, respectively. Both trials enrolled individuals aged 50 to 85 years with early AD. Participants with some comorbidities and evidence of cerebral infarction or more than 4 microbleeds or areas of leptomeningeal hemosiderosis on magnetic resonance imaging were excluded. After 2923 and 2858 were excluded, respectively, 813 participants in CREAD and 806 in CREAD2 were randomly assigned in a 1:1 ratio to either placebo or crenezumab. In the final analysis, there were 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. Data were analyzed up until January 2019 and August 2019, respectively.

Interventions: Participants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks.

Main outcomes and measures: The primary outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.

Results: There were 813 participants in CREAD (mean [SD] age, 70.7 [8.2] years; 483 female and 330 male) and 806 in CREAD2 (mean [SD] age, 70.9 [7.7] years; 456 female and 350 male). Baseline characteristics were balanced between both groups. The between-group difference in mean change from baseline in CDR-SB score (placebo minus crenezumab) was -0.17 (95% CI, -0.86 to 0.53; P = .63) at week 105 in the CREAD study (88 placebo; 86 crenezumab). Compared with previous trials, no new safety signals were identified, and amyloid-related imaging abnormalities with edema were rare, mild, and transient. 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 end point.

Conclusions and relevance: Crenezumab was well tolerated but did not reduce clinical decline in participants with early AD.

Trial registration: ClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Ostrowitzki, Bittner, Schneider, Blondeau, and Hu and Ms Smith are full-time employees of F. Hoffmann-La Roche and stockholders in F. Hoffmann-La Roche. Drs Sink, Mackey, Rabe, Hu, Clayton, and Sanabria-Bohórquez; Mr Rabbia, Dr Toth; and Drs Eichenlaub, Honigberg, and Doody are full-time employees of Genentech, part of F. Hoffmann-La Roche, and stockholders in F. Hoffmann-La Roche. Dr Honig reports consultant fees from Cortexyme, Eisai, and Prevail; study research funding from AbbVie, Alector, Biogen, Eisai, Genentech, F. Hoffmann-LaRoche, and Eli Lilly; grants from Roche during the conduct of the study; and grants from Abbvie, Eisai, Alector, Acumen, Genentech, Union Chimique Belge, Vaccinex, Biogen, Aprinoia, Cyclerion, Johnson & Johnson, Transposon, and Neurokine Therapeutics and personal fees from Eisai, Prevail, Cortexyme, and Biogen outside the submitted work. Dr Woodward has received research funding and speaker/consultancy fees from F. Hoffmann-La Roche, Eli Lilly, Johnson & Johnson/Janssen Cilag, AbbVie, Actinogen, Axovant, Anavex, Cognition Therapies, Pfizer, Novartis, Biogen, Nutricia, Mundipharma, Abbott, Merck, Eisai, and GlaxoSmithKline. Dr Boada reports grants from Merck, AbbVie, Araclon, Biogen, Bioibérica, Grifols, Kyowa Hakko Kirin, Eli Lilly; grants and other support from Merck Sharp & Dohme, Nutricia, Oryzon Genomics, Piramal Imaging Limited, and Schwabe Farma Iberica outside the submitted work; and for Caixabank, but does not receive them directly; fees from Servier and Eli Lilly for consulting; from Eli Lilly, Nutricia, Roche, and Schwabe for lectures; from Eli Lilly, Biogen, Roche, Bioiberica, Eisai, and Schwabe for serving on advisory boards; from Grifols, Roche, Biogen Araclon Biotech for consulting, advisory boards, and lectures; from Merck and Zambon for consulting and advisory boards; from Novo-Nordisk and Servier for advisory boards and lectures; grants from Grifols, La Caixa, Ciberned, European Federation of Pharmaceutical Industries and Associations, the EuroNanoMed III program, the Innovative Medicines Initiative Eranet Call 2012, Programa Misiones IA-2021—Spain, the EU Joint Programme – Neurodegenerative Disease Research PRE-ADAPT project, European Marie Sklodowska Curie, Instituto de Salud Carlos III, and Fondo Europeo Desarrollo Regional during the conduct of the study.Dr van Dyck has received recent speaker/consultancy fees from F. Hoffmann-La Roche, Eisai, Ono, and Cerevel and recent study research funding from Biogen, Biohaven, Eisai, Genentech, F. Hoffmann-La Roche, Johnson & Johnson/Janssen, Eli Lilly, Merck, Novartis, Union Chimique Belge, and Cerevel as well as grants from Biogen, Eli Lilly, Biohaven, Janssen, Union Chimique Belge, Roche, Genentech, Eisai, and Cerevel and personal fees from Roche (scientific advisor), Eisai (scientific advisor), Ono (consultant), and Cerevel (consultant) outside the submitted work. Dr Grimmer has received consulting fees from AbbVie,Alector, Anavex, Biogen, Bracket, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia/Quintiles, Life Molecular Imaging, Novartis, Novo Nordisk, Noselab, NuiCare, Roche Pharma, Toyama, and Vivoryon; lecture fees from Actelion, B.Braun, Biogen, Eli Lilly, Life Molecular Imaging, Novartis, Parexel, Roche Diagnostics, Roche Pharma, Schwabe, Toyama, Union Chimique Belge, and Vivoryon; and grants to his institution from Actelion and Novartis. Dr Selkoe is a director and consultant to Prothena Biosciences. Dr Quartino was a full-time employee of Genentech, part of F. Hoffmann-La Roche, at the time of this work and is now a full-time employee of Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Gothenburg, Sweden. Dr Dolton was a full-time employee of Genentech, part of F. Hoffmann-La Roche, at the time of this work and is now a full-time employee of Roche Products and owns stock or stock options in Roche. No other disclosures were reported.

Figures

Figure 1.. Enrollment, Randomization, and Study Completion in CREAD and CREAD2

CREAD indicates A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Crenezumab in Patients With Prodromal to Mild Alzheimer’s Disease. aThe number of participant deaths does not represent the total number of deaths in the studies but only those where the death itself led to study discontinuation. A total of 13 deaths occurred (CREAD: 5 in placebo and 8 in crenezumab; CREAD2: 6 in placebo and 0 in crenezumab).

Figure 2.. Mean Change in Clinical Dementia Rating–Sum of Boxes Scores for CREAD

CREAD indicates A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Crenezumab in Patients With Prodromal to Mild Alzheimer’s Disease.