Dataset Information

Phase II Dose Selection for Alpha Synuclein-Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain.

ABSTRACT: This modeling and simulation analysis was aimed at selecting doses of cinpanemab (BIIB054), a monoclonal antibody targeting aggregated ?-synuclein, for a phase II study in Parkinson's disease (PD). Doses and regimens were proposed based on anticipated target concentration in brain interstitial fluid (ISF); in vitro/in vivo data on the affinity of monoclonal antibodies to the target protein; and safety, tolerability, and pharmacokinetic data (1-135 mg/kg intravenous administration) from a phase I single ascending dose (SAD) study. A population pharmacokinetic modeling approach was used to select intravenous doses of 250, 1,250, and 3,500 mg every 4 weeks, to maintain 50%, 90%, and > 90% of target binding in ISF of PD participants. A favorable safety profile from the SAD study-which showed that cinpanemab was generally well-tolerated at doses up to 90 mg/kg, supported by modeling and simulations of the anticipated safety margins-allowed implementation of a fixed-dose approach.

SUBMITTER: Kuchimanchi M

PROVIDER: S-EPMC7499191 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Phase II Dose Selection for Alpha Synuclein-Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain.

Kuchimanchi Mita M Monine Michael M Kandadi Muralidharan Kumar K Woodward Caroline C Penner Natalia N

CPT: pharmacometrics & systems pharmacology 20200819 9

This modeling and simulation analysis was aimed at selecting doses of cinpanemab (BIIB054), a monoclonal antibody targeting aggregated α-synuclein, for a phase II study in Parkinson's disease (PD). Doses and regimens were proposed based on anticipated target concentration in brain interstitial fluid (ISF); in vitro/in vivo data on the affinity of monoclonal antibodies to the target protein; and safety, tolerability, and pharmacokinetic data (1-135 mg/kg intravenous administration) from a phase I ...[more]

PMID: 32613752

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Project description:The selective Bruton tyrosine kinase (BTK) inhibitor poseltinib has been shown to inhibit the BCR signal transduction pathway and cytokine production in B cells (Park et al. Arthritis Res. Ther. 18, 91, https://doi.org/10.1186/s13075-016-0988-z , 2016). This study describes the translation of nonclinical research studies to a phase I clinical trial in healthy volunteers in which pharmacokinetics (PKs) and pharmacodynamics (PDs) were evaluated for dose determination. The BTK protein kinase inhibitory effects of poseltinib in human peripheral blood mononuclear cells (PBMCs) and in rats with collagen-induced arthritis (CIA) were evaluated. High-dimensional phosphorylation analysis was conducted on human immune cells such as B cells, CD8 + memory cells, CD4 + memory cells, NK cells, neutrophils, and monocytes, to map the impact of poseltinib on BTK/PLC and AKT signaling pathways. PK and PD profiles were evaluated in a first-in-human study in healthy donors, and a PK/PD model was established based on BTK occupancy. Poseltinib bound to the BTK protein and modulated BTK phosphorylation in human PBMCs. High-dimensional phosphorylation analysis of 94 nodes showed that poseltinib had the highest impact on anti-IgM + CD40L stimulated B cells, however, lower impacts on anti-CD3/CD-28 stimulated T cells, IL-2 stimulated CD4 + T cells and NK cells, M-CSF stimulated monocytes, or LPS-induced granulocytes. In anti-IgM + CD40L stimulated B cells, poseltinib inhibited the phosphorylation of BTK, AKT, and PLCγ2. Moreover, poseltinib dose dependently improved arthritis disease severity in CIA rat model. In a clinical phase I trial for healthy volunteers, poseltinib exhibited dose-dependent and persistent BTK occupancy in PBMCs of all poseltinib-administrated patients in the study. More than 80% of BTK occupancy at 40 mg dosing was maintained for up to 48 h after the first dose. A first-in-human healthy volunteer study of poseltinib established target engagement with circulating BTK protein. Desirable PK and PD properties were observed, and a modeling approach was used for rational dose selection for subsequent trials. Poseltinib was confirmed as a potential BTK inhibitor for the treatment of autoimmune diseases.Trial registration: This article includes the results of a clinical intervention on human participants [NCT01765478].

Dataset Information

Phase II Dose Selection for Alpha Synuclein-Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain.

Publications

Phase II Dose Selection for Alpha Synuclein-Targeting Antibody Cinpanemab (BIIB054) Based on Target Protein Binding Levels in the Brain.

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