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Crenezumab Phase 3 CREAD Trials in Alzheimer Disease Discontinued By Roche

The Independent Monitoring Committee’s interim analysis suggested that the treatment was unlikely to meet the trials’ primary end point of change from baseline in Clinical Dementia Rating-Sum of Boxes score.

Sandra Horning, MD

Roche has announced that it will be discontinuing its CREAD 1 and CREAD 2 clinical trials in prodromal to mild sporadic Alzheimer disease, which were assessing its investigational anti-amyloid-beta (Aß) molecule, crenezumab.1

The decision to terminate the phase 3 trials was based on the results of a pre-planned interim analysis of crenezumab’s efficacy and safety conducted by an Independent Monitoring Committee. The committee’s analysis suggested that the treatment was unlikely to meet the trials’ primary end point of change from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.

"While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer disease," said Sandra Horning, MD, the chief medical officer and head of Global Product Development at Roche, in a statement. "We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program. We remain dedicated to the Alzheimer community and will continue our Phase III GRADUATE trials with gantenerumab and Phase II TAURIEL trial with the anti-tau molecule RG6100, as well as our imaging and fluid-based diagnostic solutions."

No safety signals were observed in the interim analysis, and the overall safety profile was similar to what’s been seen in past trials. Roche announced that the data from CREAD 1 (NCT02670083) and CREAD 2 (NCT03114657) will be shared at an upcoming medical meeting, with the hope that the findings will help inform future research programs and trial design.

CREAD 1 was planned to be a double-blind, placebo-controlled, parallel group study, which randomized participants 1:1 to receive either intravenous infusion of crenezumab or placebo every 4 weeks for 100 weeks. The final efficacy and safety assessments were to be performed 52 weeks after the last crenezumab dose.

Likewise, CREAD 2 was also planned to randomize patients 1:1 to receive either intravenous infusion of crenezumab or placebo every 4 weeks for 100 weeks, though the primary efficacy assessment was to be conducted at 105 weeks, and patients would either enter an open-label extension or entered into long-term follow-up for an additional 52 weeks.

Previously, crenezumab was investigated in the phase 2 ABBY and BLAZE trials, after which Investigators used an ultrasensitive in-house immunoassay to measure Aß oligomer levels in the cerebrospinal fluid from 104 subjects before and after treatment with either subcutaneous 300-mg crenezumab or placebo every 2 weeks, or intravenous crenezumab (15 mg/kg) or placebo every 4 weeks, for 68 weeks.

The results showed that treatment with crenezumab was associated with a consistent decrease in Aβ oligomer levels in the cerebrospinal fluid. In total, 86% of those treated intravenously and 89% of those treated subcutaneously had lower levels of Aβ oligomeric levels at week 69 than baseline. The difference in proportions of subjects with decreasing levels was significant for both subcutaneous (P = .001) and intravenous (P = .01) crenezumab.2

Dennis Selkoe, MD, the Coates Professor of Neurologic Diseases at Harvard Medical School and co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Health Center, told NeurologyLive when the results were presented at the 2018 Alzheimer’s Association International Conference that this was the first time direct evidence of target engagement of toxic forms of amyloid in humans had been shown. The results, he said, strongly suggested target engagement and recommended assaying cerebrospinal fluid Aβ oligomers in future trials.

The monoclonal antibody is designed to preferentially bind to and promote removal of neurotoxic oligomers. Crenezumab has an antibody backbone (IgG4) designed to decrease the inflammatory response in the brain, which may result in a lower risk of amyloid-related imaging abnormalities. It was discovered by Swiss biotechnology company AC Immune SA.

The treatment is still being assessed as part of the Banner Alzheimer’s Institute's Alzheimer’s Prevention Initiative (API). It is the focus of the phase 2 Autosomal Dominant Alzheimer's Disease, or ADAD, trial (NCT01998841), which is assessing the treatment versus placebo in individuals who carry the PSEN1 E280A autosomal-dominant mutation and do not meet the criteria for mild cognitive impairment due to Alzheimer or dementia due to Alzheimer, meaning they are in a preclinical phase.3

Participants in the ADAD trial will be randomized in a 1:1 ratio to receive either crenezumab or placebo subcutaneously every 2 weeks, or intravenously every 4 weeks for at least 260 weeks. The switch to the intravenous dose will be optional as a participant decision. Additionally, the study will include a cohort of PSEN1 E280A mutation non-carriers who will be dosed with placebo only.


1. Roche to discontinue Phase III CREAD 1 and 2 clinical studies of crenezumab in early Alzheimer's disease (AD) - other company programmes in AD continue [press release]. Basel, Switzerland: Roche; Published January 30, 2019. globenewswire.com/news-release/2019/01/30/1707331/0/en/Roche-to-discontinue-Phase-III-CREAD-1-and-2-clinical-studies-of-crenezumab-in-early-Alzheimer-s-disease-AD-other-company-programmes-in-AD-continue.html. Accessed January 30, 2019.

2. Selkoe D. Crenezumab Significantly Reduces Aβ Oligomers in CSF. NeurologyLive website. Published August 7, 2018. neurologylive.com/conferences/aaic-2018/dennis-selkoe-crenezumab-significantly-reduces-amyloid-beta-oligomers-csf. Accessed January 30, 2019.

3. Alzheimer’s Prevention Initiative. Banner Alzheimer’s Institute website. banneralz.org/research-clinical-trials/types-of-research-studies/alzheimer%E2%80%99s-prevention-initiative.aspx. Accessed January 30, 2019.