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Crenezumab Does Not Reduce Clinical Decline in Adults With Early Alzheimer Disease

In 2 phase 3 randomized placebo-controlled trials, findings showed that although crenezumab was well tolerated, it did not reduce clinical decline in participants with early Alzheimer disease.

News from 2 phase 3 randomized placebo-controlled trials, CREAD (NCT02670083) and CREAD2 (NCT03114657), showed in their findings that intervention with crenezumab (AC Immune SA; Genentech/Hoffmann-La Roche) was tolerable, however there was no reduction in clinical decline in participants with early Alzheimer disease (AD).1 Both trials were discontinued early due to lack of efficacy as no new safety signals were observed and followed a preplanned interim analysis that indicated CREAD was unlikely to meet the primary end point.

In the CREAD study (placebo, n = 88; crenezumab, n = 86), the between-group difference in mean change from baseline in Clinical Dementia Rating–Sum of Boxes (CDR-SB) score resulted in a change of −0.17 (95% CI, −0.86 to 0.53; P = .63) at week 105. Both groups had balanced baseline characteristics and no meaningful changes in AD biomarkers were identified. In general, AD is an unmet medical need and has no fully approved therapeutics to modify the disease progression.

Senior investigator Rachelle S. Doody, MD, PhD, global head, Neurodegeneration, and franchise head, Alzheimer’s Disease Neurodegeneration, Roche/Genentech, and colleagues wrote, “Early termination and lack of efficacy observed in the CREAD trials may be due to a variety of causes.” There have been demonstrated results of antiamyloid antibody treatments investigated in late-phase clinical trials in AD,2,3 though there is remaining uncertainty around the importance of amyloid-β (Aβ) as a driver of disease pathophysiology across disease stages, as well as the need to target particular Aβ species, and the impact of reduced effector function of the antibody. Challenges have also persisted around choosing a sufficiently high dose or long enough duration treatment, the group noted.

CREAD and CREAD2 were conducted between 2016 and 2017, and were global multicenter studies. CREAD included 194 sites in 300 countries while CREAD2 included 209 sites in 27 countries. Overall, participants were screened in CREAD (n = 3736) and CREAD2 (n = 3664), respectively.

CREAD and CREAD2 had enrolled individuals who were aged 50 to 85 years with early AD. Participants were excluded (CREAD, n = 2923; CREAD2, n = 2858) if they had some comorbidities and evidence of cerebral infarction, more than 4 microbleeds, or areas of leptomeningeal hemosiderosis on magnetic resonance imaging. The final participant groups in CREAD (n = 813) and in CREAD2 (n = 806) were then randomly assigned in a 1:1 ratio to either placebo or crenezumab. For the final analysis, participants in CREAD (placebo, n = 409; crenezumab, n = 404) and in CREAD2 (placebo, n = 399; crenezumab, n = 407) were observed.

The analysis of the data went until January 2019 and August 2019 in CREAD and CREAD2, respectively. The participants in CREAD had a mean age of 70.7 years (SD, 8.2), and included 483 women and 330 men. The CREAD2 trial participants had a mean age of 70.9 years (SD, 7.7) years, and included 456 women and 350 men.1 Participants in both trials received either a placebo or 60 mg/kg crenezumab intravenously every 4 weeks until 100 weeks. The change from baseline to week 105 in the CDR-SB score was the primary outcome.

Ostrowitzki et al noted, “Crenezumab serum exposure in CREAD was, as expected, 4 times higher than that achieved in the Study to Evaluate the Efficacy and Safety of Crenezumab in Participants With Mild to Moderate AD (ABBY [NCT01343966]) and the Study to Evaluate the Impact of Crenezumab on Brain Amyloid Load and Related Biomarkers in Participants With Mild to Moderate AD (BLAZE [NCT01397578]).”4,5

Some limitations of these trials, in addition to their early termination, were that the outcome data sets were smaller and truncated in terms of longitudinal follow-up, in particular with CREAD2 as no participants reached week 105. The large overlap between both groups for clinical baseline scale scores meant that the analyses in prodromal versus mild dementia subgroup within the pooled CREAD/CREAD2 data sets were also limited. Another limitation is the little amount of data in ethnically and racially diverse patients, as more than 80% of participants in both studies were White.

“The CSF/plasma ratio of 60 mg/kg of crenezumab evaluated in CREAD was consistent with observations from previous studies of lower doses and supports the notion that drug penetration into the central nervous system was not saturated at this higher dose,” Ostrowitzki et al wrote.

REFERENCES
1. 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. doi:10.1001/jamaneurol.2022.2909
2. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15(2):73-88. doi:10.1038/s41582-018-0116-6
3. Penninkilampi R, Brothers HM, Eslick GD. Safety and Efficacy of Anti-Amyloid-β Immunotherapy in Alzheimer's Disease: A Systematic Review and Meta-Analysis. J Neuroimmune Pharmacol. 2017;12(1):194-203. doi:10.1007/s11481-016-9722-5
4. Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018;90(21):e1889-e1897. doi:10.1212/WNL.0000000000005550
5. Salloway S, Honigberg LA, Cho W, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer's disease (BLAZE). Alzheimers Res Ther. 2018;10(1):96. Published 2018 Sep 19. doi:10.1186/s13195-018-0424-5