Background/Purpose: GSK3196165 is a high-affinity anti-GM-CSF cytokine IgG mAb currently in development for RA, with reported efficacy using IV dosing. This study evaluated the efficacy and safety of GSK3196165 dose-ranging in RA.

Methods: 222 adult patients with active, moderate-severe RA per ACR 2010 criteria, ≥4 each of swollen and tender joints, DAS28(CRP) ≥3.2 and CRP ≥5.0 mg/L, were randomized equally to placebo or GSK3196165 22.5mg, 45mg, 90mg, 135mg or 180mg SC weekly for 5 injections, then every other week until Week 50 (with blinded/automated escape to the 180mg dose at Weeks 14 and 26 for non-responders). The primary outcome was the proportion of patients who achieved remission (DAS28(CRP) <2.6) at Week 24, with dose selection for further studies at Week 12.

Results: 37 patients were randomised to each treatment group; 150 patients completed the study (Week 62); 86/175 (49.1%) eligible patients were escalated to the 180mg dose after Week 12, and 57/83 (68.7%) patients after Week 24. Patient characteristics were well balanced across the groups. There were more patients in remission at Week 24 in the active groups (e.g. 16% in the 180mg group, p=0.134) than those on placebo group (3%). There was a dose-related treatment effect in change from baseline in DAS28(CRP) at Week 12, which was also reflected in other clinical endpoints with or without acute-phase reactants (see Table below).

The onset of clinical response across most endpoints was seen at Week 1, but the improvement in the GSK3196165 groups appeared to plateau from approximately Week 6 onwards, maintained to Week 52.

Observed PK exposures were lower than anticipated from previous studies. During the 5 weekly doses, maximum pre-dose concentrations were observed at Week 4 with geometric mean of 1,857 ng/mL (CV_b 176%) with the 180mg dose, but concentrations dropped unexpectedly after reducing dosing frequency to dosing every two weeks. At Week 12, pre-dose geometric mean concentration was 680 ng/mL (CV_b 124%), which was below the anticipated threshold based on preclinical data for maximum efficacy.

GSK3196165 was well-tolerated, and adverse events were reported similarly across treatment groups. No drug-related SAEs, significant infections and/or pulmonary events were observed.

Conclusion: GSK3196165 has shown dose-related, clinically-meaningful benefit. Following dosing every two weeks, exposure to GSK3196165 was lower than predicted due to increased apparent clearance. Further studies are now required to confirm the additional clinical benefit expected with increased exposure from weekly dosing of GSK3196165 in patients with RA.

This study (NCT02504671) was funded by GSK.