Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid

Ting Yang, Yifan Dang, Beth Ostaszewski, David Mengel, Verena Steffen, Christina Rabe, Tobias Bittner, Dominic M. Walsh, Dennis J. Selkoe

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Objective: Oligomeric forms of amyloid β protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), but it is not known whether anti-Aβ antibodies are capable of lowering oAβ levels in humans. Methods: We developed an ultrasensitive immunoassay and used it to measure oAβ in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-Aβ antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oAβ levels, and these were compared to levels at week 69 in placebo (n = 28), SC (n = 35), and IV (n = 35) treated patients. Results: Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oAβ at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p = 0.0035 for SC and p = 0.01 for IV crenezumab versus placebo. The median percentage change was −48% in the SC arm and −43% in the IV arm. No systematic change was observed in the placebo group, with a median change of −13% and equivalent portions with negative and positive change. Interpretation: Crenezumab lowered CSF oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti-Aβ agents. ANN NEUROL 2019;86:215–224.

Original languageEnglish (US)
Pages (from-to)215-224
Number of pages10
JournalAnnals of Neurology
Volume86
Issue number2
DOIs
StatePublished - Aug 2019
Externally publishedYes

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Amyloid
Cerebrospinal Fluid
Placebos
Alzheimer Disease
Anti-Idiotypic Antibodies
Amyloidogenic Proteins
Immunoassay
crenezumab
Biomarkers

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Yang, T., Dang, Y., Ostaszewski, B., Mengel, D., Steffen, V., Rabe, C., ... Selkoe, D. J. (2019). Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. Annals of Neurology, 86(2), 215-224. https://doi.org/10.1002/ana.25513

Target engagement in an alzheimer trial : Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. / Yang, Ting; Dang, Yifan; Ostaszewski, Beth; Mengel, David; Steffen, Verena; Rabe, Christina; Bittner, Tobias; Walsh, Dominic M.; Selkoe, Dennis J.

In: Annals of Neurology, Vol. 86, No. 2, 08.2019, p. 215-224.

Research output: Contribution to journalArticle

Yang, T, Dang, Y, Ostaszewski, B, Mengel, D, Steffen, V, Rabe, C, Bittner, T, Walsh, DM & Selkoe, DJ 2019, 'Target engagement in an alzheimer trial: Crenezumab lowers amyloid β oligomers in cerebrospinal fluid', Annals of Neurology, vol. 86, no. 2, pp. 215-224. https://doi.org/10.1002/ana.25513
Yang, Ting ; Dang, Yifan ; Ostaszewski, Beth ; Mengel, David ; Steffen, Verena ; Rabe, Christina ; Bittner, Tobias ; Walsh, Dominic M. ; Selkoe, Dennis J. / Target engagement in an alzheimer trial : Crenezumab lowers amyloid β oligomers in cerebrospinal fluid. In: Annals of Neurology. 2019 ; Vol. 86, No. 2. pp. 215-224.
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AB - Objective: Oligomeric forms of amyloid β protein (oAβ) are believed to be principally responsible for neurotoxicity in Alzheimer disease (AD), but it is not known whether anti-Aβ antibodies are capable of lowering oAβ levels in humans. Methods: We developed an ultrasensitive immunoassay and used it to measure oAβ in cerebrospinal fluid (CSF) from 104 AD subjects participating in the ABBY and BLAZE phase 2 trials of the anti-Aβ antibody crenezumab. Patients received subcutaneous (SC) crenezumab (300mg) or placebo every 2 weeks, or intravenous (IV) crenezumab (15mg/kg) or placebo every 4 weeks for 68 weeks. Ninety-eight of the 104 patients had measurable baseline oAβ levels, and these were compared to levels at week 69 in placebo (n = 28), SC (n = 35), and IV (n = 35) treated patients. Results: Among those receiving crenezumab, 89% of SC and 86% of IV patients had lower levels of oAβ at week 69 versus baseline. The difference in the proportion of patients with decreasing levels was significant for both treatment arms: p = 0.0035 for SC and p = 0.01 for IV crenezumab versus placebo. The median percentage change was −48% in the SC arm and −43% in the IV arm. No systematic change was observed in the placebo group, with a median change of −13% and equivalent portions with negative and positive change. Interpretation: Crenezumab lowered CSF oAβ levels in the large majority of treated patients tested. These results support engagement of the principal pathobiological target in AD and identify CSF oAβ as a novel pharmacodynamic biomarker for use in trials of anti-Aβ agents. ANN NEUROL 2019;86:215–224.

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