Background/Purpose: Granulocyte macrophage-colony stimulating factor (GM-CSF) mediates a range of immunological and inflammatory processes, and plays a role in a variety of inflammatory diseases. Namilumab (AMG203), a human immunoglobulin G1 (IgG1) monoclonal antibody with high affinity for the GM-CSF ligand, is under investigation in rheumatoid arthritis (RA) and psoriasis. Selection of an appropriate dosing schedule using modelling and simulation for proof-of-concept (PoC) studies is a key step in drug development. The objective of this analysis was to integrate clinical and non-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to identify an appropriate subcutaneous dosage for namilumab PoC and traditional Phase II studies.

Methods: A range of data was used to build the fundamentals of the analysis. Initially, the effective concentration of 22E9, a surrogate mouse antibody of namilumab, in a collagen-induced arthritis (CIA) mouse model was combined with the outcome of an ex-vivo cellular inhibition assay for namilumab in order to suggest an efficacious concentration range (22E9 and namilumab have similar neutralising potencies against murine and human GM-CSF, respectively). In addition, PK and PD similarities and differences between namilumab and anti-TNF-α antibodies, as well as known cytokine levels in joints of patients with RA, were used to support the predicted efficacy range of namilumab. These concentrations were translated into human doses using a population PK model developed based on data from two Phase I studies of namilumab in healthy volunteers (single ascending intravenous doses up to 8 mg/kg) and patients with mild-to-moderate RA (repeated subcutaneous doses of 150 or 300 mg; PRIORA, NCT01317797).

Results: The EC₅₀ for namilumab was calculated as 11 µg/mL in the CIA mouse model, which was supported by results of the ex-vivo blood assay. In addition, the observation of similar affinities of anti-TNF-α antibodies (12–90 pM) and namilumab (46 pM), in conjunction with target expression in the synovium in similar ranges of magnitude, indicated that targeting clinical concentration ranges seen with anti-TNF-α antibodies should translate into clinical efficacy. Next, a population PK model was applied to translate clinical concentration ranges into dosing schedules. Doses from 20 to 150 mg were selected with the intent to cover low, medium and high efficacious exposures in RA and psoriasis. In addition, a loading dose was suggested for a selected Phase II trial.

Conclusion: Integration of preclinical and clinical PK and PD data for namilumab and combination of these with data from anti-TNF-α antibodies was essential to determine the appropriate namilumab dose schedule for evaluation in Phase II studies.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/dose-selection-of-namilumab-an-anti-gm-csf-monoclonal-antibody-an-integrated-pharmacokinetic-and-pharmacodynamic-approach-for-phase-ii-studies-in-patients-with-rheumatoid-arthritis/