Background/Purpose: GSK3196165 is an anti-GM-CSF mAb being developed for RA. In a phase IIb dose-finding study (NCT02504671), RA patients with inadequate response to methotrexate were administered placebo or GSK3196165 (22.5, 45, 90, 135 and 180 mg SC 5 weekly doses followed by administration every other week for 50 weeks) with background methotrexate therapy. The study results are reported in a separate abstract.This analysis aimed to characterize exposure-efficacy relationship for DAS28(CRP), ACR20 and ACR50, and describe the time course of change in DAS28(CRP).

Methods: All available PK data from 222 randomized patients and PK data from previous studies were used to develop a population PK model. ACR data at Week 12 and time-course DAS28(CRP) were used for exposure-response analyses and analysed using both graphically and model-based approaches.

Change from baseline in DAS28(CRP) and proportion of ACR20/50 responders were plotted for placebo group and quartiles of GSK3196165 steady-state trough concentrations. Longitudinal data for DAS28(CRP) was modelled using an indirect response model to describe the treatment effect, placebo effect was described by an exponential decline. Exposure-efficacy relationship for ACR20 and ACR50 at Week 12 was analysed using logistic regression analysis. PK/PD models for DAS28(CRP) and ACR20/50 were utilized to inform optimal dose and regimen for subsequent clinical trials.

Results: GSK3196165 exhibited linear PK over the tested dose range with a mean systemic clearance (CL) of 0.93 L/day and bioavailability (F) of 0.35 in healthy volunteers which is significantly higher CL and lower F than a typical monoclonal antibody. The apparent clearance in RA patients (CL/F) was 2.5 times faster than predicted, resulting in significantly lower trough levels at steady-state. The elimination half-life in RA population was estimated to be 10 days.

At Week 12, higher response for both DAS28(CRP) and ACR20/50 was associated with higher exposures of GSK3196165. The highest quartile showed a median change from baseline of 1.63 points over placebo for DAS28(CRP), while ACR20 and ACR50 showed 59% and 34% response, respectively (12% and 9% in the placebo group). Using population PK and PK/PD models, a dose of 150 mg weekly is predicted to achieve a steady state trough concentration of 2,500 ng/mL, DAS28(CRP) change from baseline of 1.67 over placebo, and ACR50 response rate of 44%.

Conclusion: GSK3196165 has high CL/F compared to typical monoclonal antibody against soluble cytokines. A clear exposure-response relationship was observed with a greater efficacy achieved at higher trough concentration. The predictions suggest that weekly SC administration of 150 mg GSK3196165 can be associated with the clinically-meaningfully higher response rate in both DAS28(CRP) and ACR50 compared with the observed data in study NCT02504671. Further studies are now required to confirm the expected clinical benefit of increased exposure with weekly dosing of GSK3196165 in patients with RA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/exposure-efficacy-analysis-in-dmard-inadequate-response-rheumatoid-arthritis-patients-treated-with-gsk3196165-along-with-methotrexate/