Pharmacokinetics and Pharmacodynamics of LY2599666, a PEG-Linked Antigen Binding Fragment that Targets Soluble Monomer Amyloid-β

Li Li, Eugene Y. Zhen, Rodney L. Decker, Brian A. Willis, David Waters, Peng Liu, Ann Hake, Ronald Bradley Demattos, Mosun Ayan-Oshodi

Research output: Contribution to journalArticle

Abstract

LY2599666 is a humanized, affinity-optimized monoclonal antibody antigen-binding fragment linked to a PEG molecule and targets soluble amyloid-β (Aβ) monomers. This first-in-human dose ascending study assessed pharmacokinetics (PK) (measured as serum free LY2599666 concentration) and pharmacodynamic (PD) effects (measured as plasma total soluble Aβ 40 and Aβ 42) after a single subcutaneous (SC) dose of 10, 25, 100, and 200 mg LY2599666 in healthy subjects. As LY2599666 binds to multiple soluble Aβ monomers, a two-target mediated drug disposition model (TMDD) was developed to simultaneously fit serum LY2599666 concentration and Aβ monomer levels. Four Alzheimer's disease patients completed 25 mg once-weekly dosing of LY2599666 for 12 weeks. In addition, single cerebrospinal fluid samples were collected to assess penetration capability across the blood-brain barrier. PK and PD data collected from the multiple dose cohort aligned with model predictions, suggesting the established TMDD model predicted suppression of soluble Aβ 40 and Aβ 42 in plasma after SC dosing of LY2599666.

Original languageEnglish (US)
Pages (from-to)137-144
Number of pages8
JournalJournal of Alzheimer's Disease
Volume68
Issue number1
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Keywords

  • Alzheimer's disease
  • Aβ monomer
  • pharmacokinetic/pharmacodynamic
  • target-mediated drug disposition

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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