Affiliations: Eli Lilly and Company, Indianapolis, IN, USA
Correspondence:
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Correspondence to: Li Li, Drop Code 0734, Lilly Corporate Center, Indianapolis, IN 46285, USA. Tel.: +1 317 651 4141; Fax: +1 317 433 3287; E-mail: [email protected].
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 Aβ40 and Aβ42) 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 Aβ40 and Aβ42 in plasma after SC dosing of LY2599666.
Keywords: Aβ monomer, Alzheimer’s disease, pharmacokinetic/pharmacodynamic, target-mediated drug disposition
