Exploratory evaluation of relationships between genetic variation and GSK3196165 pharmacokinetics in Studies 205180, 201755 and 204581 and efficacy in Study 201755

Trial description: GSK3196165 is a high-affinity recombinant human monoclonal antibody (mAb) that binds specifically to human GM-CSF and neutralises its biological function by blocking the interaction of GM-CSF with its cell surface receptor. It is currently in clinical development for the treatment of rheumatoid arthritis (RA). GSK3196165 clearance in healthy volunteers (HV) is 3 times higher (0.91, CI: 0.82 - 1.00 L/day) than generally reported for monoclonal antibodies (0.3 L/day) along with lower bioavailability (0.34, CI: 0.26 - 0.42), which may be due to its impaired binding with FcRn (slower dissociation resulting in lower re-circulation into blood) and possible increased interaction with the cell membranes (resulting in enhanced pre-systemic catabolism and lower lymphatic uptake). The apparent clearance (CL/F) after SC administration of GSK3196165 in RA and hand osteoarthritis (HOA) subject is 2.4 and 1.9 times higher, respectively, than healthy volunteers (HV). This resulted in lower trough concentrations as anticipated based on HV bioavailability study (MOR103C104). It is well established that genetic variation can impact PK parameters which may be manifested in variability in patient response to medicines. These analyses are designed to assess the effect of genetic variation on two PK parameters, apparent clearance and steady-state trough concentration at week 12, as well as the effect on week 12 efficacy as measured by DAS28 (CRP) change from baseline. Genetic samples are available from phase IIA and IIB RA studies, 205180 (RENAISSANCE) and 201755 (BAROQUE), respectively. In addition, genetic samples are available from Study 204851, a phase IIA HOA study. While the OA indication has been terminated, the samples have value for the PK analysis. Data for the PK endpoints will be pooled and evaluated in all three studies while efficacy will only be evaluated in the 201755 study.The Genetics PK population comprises all subjects in the intent-to-treat (ITT) population of studies 201755, 205180 and 204851, who provided written informed consent for pharmacogenetic research, were successfully genotyped and have valid apparent clearance and/or week 12 trough concentration data available. The Genetics Efficacy population comprises all subjects in the intent-to-treat (ITT) population of study 201755, who provided written informed consent for pharmacogenetic research, were successfully genotyped and have valid week 12 DAS28 (CRP) data available. The size of the Genetics PK and Genetics Efficacy populations may vary across endpoints as it is dependent upon availability of data.Genetic variation from across the genome and 11 pre-specified candidate gene variants in the target, target receptor and receptors that bind mAbs, will be assessed in the genetics population using linear regression models.