Background/Purpose: To characterize the exposure-response (ER) relationship between systemic exposure to sirukumab (an anti- interleukin-6 [IL-6] human monoclonal antibody) and the occurrence of selected safety events in patients with active rheumatoid arthritis (RA). The safety events of interests include serious infection, clinical laboratory abnormalities (neutropenia, thrombocytopenia, elevations of alanine aminotransferase [ALT], triglyceride, total cholesterol, low-density lipoprotein (LDL) or bilirubin, and abnormal high-density lipoprotein [HDL]), major adverse cardiovascular events (MACE), malignancy, and death.

Methods: Serious infection and laboratory abnormalities were assessed based on pooled data from 4 phase 3 trials of sirukumab (ie, data through Week 52 from SIRROUND-D and -M, and data through Week 24 from SIRROUND-T and -H). MACE, malignancy, and death were assessed through the BLA safety data cut (September 2016) to leverage as much data available as possible due to lower incidence of events. Established population PK model of sirukumab was used to generate empirical Bayesian estimates of exposure metrics for individual patients using actual dosing records, including cumulative area under the curve (AUC), maximum (C_max), minimum (C_min) and average (C_ave) concentrations at steady-state. For serious infection and laboratory abnormalities, two analyses were performed, quartile analysis where the proportion of patients with events were assessed by 4 PK quartile subgroups and the distribution of PK exposure versus the occurrence of events or laboratory abnormality toxicity grade reached (worst grade experienced over the assessment period). For MACE, malignancy and death, distribution plots of PK exposure versus events were generated.

Results: Based on the distribution plots and/or the quantile analysis of pooled data, there was no trend of increasing occurrence of events with higher sirukumab exposures for MACE, malignancy, death, serious infection, triglyceride elevation or thrombocytopenia. Weak correlations were observed between sirukumab exposure and neutropenia, ALT elevation, LDL elevation, total cholesterol elevation, abnormal HDL or bilirubin elevation, where patients who had higher exposure to sirukumab tended to have more abnormal laboratory measures.

Conclusion: No apparent correlation was identified between sirukumab exposure and MACE, malignancy, and death in RA patients receiving up to 5 years of SC sirukumab treatment. Small ER trends were observed for neutropenia, ALT elevation and abnormal lipid parameters, which were consistent with the known modulation effects of anti-IL6 agents as reported for other anti-IL-6 biologics in patients with RA.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/correlation-analysis-between-sirukumab-exposure-and-selected-safety-events-following-subcutaneous-administration-using-pooled-phase-3-data-in-rheumatoid-arthritis/