Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease

Abstract

ImportanceAlzheimer 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.ObjectiveTo 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 ParticipantsTwo 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.InterventionsParticipants received placebo or 60 mg/kg crenezumab intravenously every 4 weeks for up to 100 weeks.Main Outcomes and MeasuresThe primary outcome was change from baseline to week 105 in Clinical Dementia Rating–Sum of Boxes (CDR-SB) score.ResultsThere 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 RelevanceCrenezumab was well tolerated but did not reduce clinical decline in participants with early AD.Trial RegistrationClinicalTrials.gov Identifiers: CREAD, NCT02670083; CREAD2, NCT03114657

Fc effector of anti-Aβ antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model

“…Although they decreased the incidence of ADCC, CDC, vasogenic edema, and microhemorrhage, these antibodies still did not demonstrate adequate therapeutic efficacy. 13,14 These findings indicate that merely reducing the risk of inappropriate proinflammatory response do not increase therapeutic efficacy, and other mechanisms may underlie clinical failures. In our present study, we showed that an IgG4 subtype Aβ-targeting antibody, A16I4, activated the complement system and increased microglial synapse elimination (Supplementary Figs.…”

“…10,11 To overcome the side effects of immunotherapies, antibodies targeting Aβ N-terminus (such as bapineuzumab), or IgG4 and IgG2 subtypes such as crenezumab and ponezumab were applied in clinical trials. [12][13][14] However, these antibodies still failed to rescue cognitive deficits in AD patients although some side effects significantly reduced. Recently, antibodies targeting Aβ aggregates such as aducanumab and lecanemab showed some beneficial effects in rescuing cognitive deficits, but they still exhibited low efficacy.…”

Alzheimer’s Disease: A Brief History of Immunotherapies Targeting Amyloid β

“…It is a human IgG1 antibody, targeting Aβ fibrils ( Figure 2 ), and it comprises both N-terminal and central amino acids of Aβ [ 57 ] In a recent press release, Roche declared, that the phase III Graduate studies with their mAb failed the primary endpoints of slowing clinical decline in patients with early, prodromal to mild AD [ 58 ]. Additionally for Crenezumab (AC Immune SA, Lausanne, Switzerland; Genentech, South San Francisco, CA, USA; Hoffmann-La Roche), a humanized IgG4 targeting Aβ oligomers as well as fibrils [ 59 ], the clinical phase III placebo-controlled study was not successful in reducing the clinical decline in participants with early AD [ 60 ]. Solanezumab (Eli Lilly & Co., Indianapolis, IN, USA), a humanized form of the murine monoclonal antibody m266 generated against Aβ13-28 has similar binding qualities as Crezenumab [ 61 ] and finalized its phase III trial in 2014 for mild to moderate AD.…”

Lecanemab for Alzheimer's disease: new hope or another false dawn?

“…Over the past 15 years, much of this research has focussed on developing monoclonal antibodies as potential disease modifying treatments (DMTs) targeting Aβ. 4 However, a number of trials of similar molecules did not meet the primary endpoint or were pulled midway after interim futility analyses, [5][6][7] leading to questions about whether this was the right approach given the complex and multifactorial pathogenesis of AD.…”