Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


A Randomised, Single-Blind, Placebo-Controlled Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of a Single Intravenous Infusion of GSK315234 in Healthy Volunteers

Baker1,  Mark B., Bendit2,  Marina, Campanile2,  Andrea M., Feeney3,  Maria, Hodsman4,  Peter, Toso2,  John F.

GlaxoSmithKline, London, United Kingdom
GlaxoSmithKline, King of Prussia, PA
GlaxoSmithKline, Stevenage, United Kingdom
Nucleus Network, Melbourne, Australia

Purpose:

GSK315234 is a humanised IgG1 monoclonal antibody (mAb) against human Oncostatin M (OSM) and is being developed for the treatment of rheumatoid arthritis (RA). GSK315234 blocks the interaction of OSM with its cell surface signaling receptor, gp130. Oncostatin M is a member of the interleukin (IL)-6 family of secreted cytokines and is present in the inflamed synovium and blood of patients with RA. Preclinical data indicated that OSM drives pro-inflammatory responses and induces the production of acute phase reactants. OSM also drives cartilage degradation. This study will provide baseline safety, tolerability, pharmacodynamic and pharmacokinetic information in a healthy volunteer population which will enable the identification of well tolerated effective doses to be used in subsequent clinical studies.

Method:

This was a single-blind, placebo-controlled, dose-escalation study in healthy volunteers (males and females of non childbearing potential). Single ascending intravenous doses of GSK315234 (0.003–30 mg/kg) were administered. Assessments included safety/tolerability, pharmacokinetics and pharmacodynamics.

Results:

Seventy two subjects were dosed (48 with active and 24 with placebo) and 66 completed the study. There were no remarkable vital signs, electrocardiogram (ECG), hematology and chemistry changes or infusion reactions. There were clinically observed effects on platelets that matched the predictions of models of the preclinical data. A dose response relationship was observed indicating a maximal effect of a 23% reduction in platelets at the highest exposure of GSK315234. A pharmacodynamic analysis showed that the total OSM levels had a non-linear relationship to drug concentrations and could be modeled using an indirect response model (IC50 for the relationship to be 5 mg/mL and t1/2~30min). The pharmacokinetics of GSK315234 was as expected and similar to other monoclonal antibodies of the same class (clearance 3.5mL/day/kg).

Conclusion:

GSK315234 showed to be safe and well tolerated in healthy volunteers. Observation of platelet pharmacology clearly defines a broad therapeutic interval allowing a choice of doses that can be determined to cause no haematological adverse effects. It also provides proof that the binding of OSM and the elevation of total OSM has downstream consequences on OSM mediated pharmacology. The low clearance of GSK315234 would allow infrequent dosing and regimes similar to other mAbs in the clinic. This data, in combination with preclinical data, confirms OSM blockade by GSK315234 as a rheumatoid arthritis therapy worthy of further investigation.

To cite this abstract, please use the following information:
Baker, Mark B., Bendit, Marina, Campanile, Andrea M., Feeney, Maria, Hodsman, Peter, Toso, John F.; A Randomised, Single-Blind, Placebo-Controlled Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of a Single Intravenous Infusion of GSK315234 in Healthy Volunteers [abstract]. Arthritis Rheum 2009;60 Suppl 10 :427
DOI: 10.1002/art.25510

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