Crenezumab Fails to Slow Clinical Decline in Early Alzheimer Disease

Crenezumab is well tolerated, but it does not reduce clinical decline in patients with early Alzheimer disease.

In patients with prodromal to mild (ie, early) Alzheimer disease (AD), treatment with crenezumab is well tolerated, however, it does not help reduce clinical decline. These are the findings of a study published in JAMA Neurology.

Recognizing the unmet global need in patients with AD, with no fully approved therapeutics to modify disease progression, researchers sought to evaluate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G-quadruplex (G4) antibody targeting amyloid-beta oligomers, in individuals with early AD.

Two global multicenter, phase 3, randomized, double-blind, parallel-group efficacy and safety studies — CREAD ( Identifier: NCT02670083) and CREAD2 ( Identifier: NCT03114657) — were initiated in 2016 and 2017, respectively. CREAD was conducted in 194 sites in 30 countries, whereas CREAD2 was conducted in 209 sites in 27 countries.

The primary efficacy outcome was change from baseline to week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, which measures decline in 6 clinical domains due to cognitive loss (range of scores, 0 to 18, with higher scores indicative of greater impairment). Secondary efficacy measures included cognition evaluated by the 13-item Alzheimer’s Disease Assessment Scale and Mini-Mental State Examination, as well as function evaluated by the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory. Biomarker assessments were performed as well.

CREAD screened a total of 3736 participants; CREAD2 screened a total of 3664 participants. In both studies, researchers enrolled individuals aged between 50 and 85 years with early AD. The exclusion of participants with certain comorbidities and evidence of cerebral infarction, more than 4 microbleeds, or areas of leptomeningeal hemosiderosis on magnetic resonance imaging (MRI) resulted in the exclusion of 2923 and 2858 individuals from CREAD and CREAD2, respectively.

CREAD and CREAD2 phase 3 crenezumab trials were terminated early due to lack of efficacy.

Thus, a total of 813 participants in CREAD and 806 in CREAD2 were randomly assigned, in a 1:1 ratio, to crenezumab or placebo. In the final analysis, the CREAD study included 404 patients in the crenezumab group and 409 individuals in the placebo group, whereas the CREAD2 study included 407 participants in the crenezumab group and 399 participants in the placebo group. All data were analyzed until January 2019 in CREAD and until August 2019 in CREAD2.

Among the 813 participants in CREAD, the mean age was 70.7±8.2 years; 483 women,  330 men. Among the 806 participants in CREAD2, the mean age was 70.9±7.7 years; 456 women, 350 men. Baseline characteristics in both of the studies were well balanced between the placebo and crenezumab groups with respect to sex, age, ethnicity, education, and cognitive and functional scale scores. Overall, 42.6% (346 of 813) and 48.1% (388 of 806) of participants in CREAD and CREAD2, respectively, had prodromal AD, whereas 57.4% (467 of 813) and 51.9% (418 of 806) of participants, respectively, had mild AD.

Both of the studies were discontinued early after a preplanned interim analysis of CREAD showed that the study was not likely to meet the primary endpoint. Overall, 21.3% (173 of 813) participants completed CREAD prior to discontinuation. CREAD2 was discontinued before any of the participants had completed the study.

Between-group differences in mean change from baseline in CDR-SB score (ie, placebo minus crenezumab) was –0.17 (95% CI, –0.86 to 0.53; P =.63) at week 105 in CREAD (86 in the crenezumab group vs 88 in the placebo group).

Compared with prior trials, no new safety signals were identified. Amyloid-related imaging abnormalities with edema were rare, mild, and transient. There were no meaningful changes in AD biomarkers reported.

Limitations of CREAD and CREAD2 warrant mention. Since both studies were terminated early, the data sets were smaller and truncated with respect to longitudinal follow-up, particularly in CREAD2, in which no participants reached week 105. Further, analyses in prodromal vs mild dementia subgroups within the pooled CREAD/CREAD2 data sets were limited by the large overlap in clinical baseline scale scores between both of the groups. With more than 80% of the participants of White ethnicity in both of the studies, limited data are available in ethnically and racially diverse patients.

The researchers concluded that “CREAD and CREAD2 phase 3 crenezumab trials were terminated early due to lack of efficacy.” They added, “No new safety signals were observed.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Ostrowitzki S, Bittner T, Sink KM, et al. Evaluating the safety and efficacy of crenezumab vs placebo in adults with early Alzheimer disease: two phase 3 randomized placebo-controlled trials. JAMA Neurol. Published online September 19, 2022.