Background/Purpose: Olokizumab (OKZ) is an anti-interleukin-6 (IL-6) monoclonal antibody in development for the treatment of rheumatoid arthritis (RA). In phase 2 studies, treatment with OKZ+methotrexate (MTX) resulted in significant improvements in disease activity compared to placebo (PBO)+MTX.^1,2 Here, we use dose-response modeling based on phase 2 efficacy and safety data to determine the optimal OKZ doses for phase 3 development. This modeling approach utilizes all available data to reach a scientifically-based decision.

Methods: The nonparametric Jonkheere-Terpstra (JT) test was fitted to DAS28(CRP) data from two phase 2, double-blind, randomized, dose-ranging (60 to 480 mg 4-week [wk] cumulative dose [cd]) studies (RA0056 [NCT01242488] and RA0083 [NCT01463059]) to test for a monotonic dose-response curve with no assumptions on curve shape. The JT test indicated that a dose-response model was statistically significant, allowing the Hill parametric model to be used, with study as a categorical covariate that affected both the ED₅₀ and E_max parameters. Mean and 95% confidence intervals for response were calculated. The Hill model fitted the data adequately, allowing estimation of the response curves using all available information. To select an appropriate dose, a balance between both safety and efficacy must be achieved. Thus a dose-response model for the incidence of adverse events (AEs) was also required. A logistic regression model was fitted to the 17 most commonly observed preferred terms across pooled phase 2 data.

Results: The JT test indicated a statistically significant monotonic dose-response relationship: p<0.005 for all dosing regimens (every 2 wks [Q2W] and every 4 wks [Q4W]) in each study, and across pooled data from the two studies. Categorical DAS28(CRP) endpoints also indicated a monotonic dose-response relationship (Table). A parametric dose-response curve fitted using a Hill model³ to combined data from the studies (Figure) adequately described the data, with an inflection point of 120 mg 4-wk cd. This is the smallest dose that attains a response near the maximum. Dosing frequency had a small, non-statistically significant effect on categorical DAS28(CRP) response. Logistic regression analysis of AEs did not indicate a dose-related increase in AEs vs PBO+MTX, with the exception of injection site reaction.

Conclusion: Efficacy increased with dose without an increase in safety events, and plateaued at approximately 120 mg 4-wk cd. Modeling data were robust, with comparable results for individual studies vs pooled data, and continuous vs categorical responses. Thus a dose at the inflection point (128 mg 4-wk cd, given as 64 mg Q2W) and a dose below the inflection point (64 mg 4-wk cd) were selected for inclusion in the phase 3 program. References: 1. Genovese M. Ann Rheum Dis 2014;73(9):1607–15; 2. Takeuchi T. Mod Rheum 2016;26(1):15–23; 3. Reeve R. 2013. J Biopharm Stat 2013;23(3):648–61

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/dose-response-modeling-is-a-useful-tool-to-determine-doses-for-phase-3-experience-from-olokizumab/