A quantitative method to estimate free interleukin-6 among patients treated with the interleukin-6 ligand inhibitor ziltivekimab: comparison to C-reactive protein with implications for the ZEUS, HERMES, and ARTEMIS cardiovascular outcomes trials.

BACKGROUND AND AIMS: Ziltivekimab, a monoclonal antibody targeting the interleukin 6 (IL-6) ligand, is being tested in multiple cardiovascular outcome trials. However, because conventional assays for IL-6 cannot distinguish free IL-6 from ziltivekimab-bound IL-6, measured IL-6 levels do not accurately reflect the reduction of biologically active IL-6 among individuals treated with ziltivekimab. Thus, we developed a quantitative model to estimate free IL-6 levels after ziltivekimab treatment.

METHODS

Using data on total concentrations of IL-6 and ziltivekimab following drug administration, a quantitative model based on a target-mediated drug disposition framework was developed to predict free IL-6 concentrations over time. Predicted free IL-6 levels were then compared to directly measured hsCRP levels in the RESCUE trial.

RESULTS

Using average values from weeks 8-12 in the RESCUE study, estimated free IL-6 concentrations decreased by 72%, 82%, and 90% from baseline to week 12 for those treated with ziltivekimab at doses of 7.5, 15, or 30 mg, respectively. These proportional predicted percent reductions in estimated free IL-6 closely matched the proportional reductions in directly measured hsCRP, an inflammatory biomarker induced by IL-6.

CONCLUSIONS

Predicted reductions in estimated free IL-6 following ziltivekimab closely parallel directly measured levels of downstream hsCRP. Estimated free IL-6 decreased immediately after the first dose, was dose-dependent, and mirrored the timing of hsCRP reduction. These data support ziltivekimab's targeted anti-inflammatory effect through free IL-6 reduction and affirm hsCRP as the most clinically actionable biomarker of direct IL-6 pathway inhibition, findings relevant for the ongoing ZEUS, HERMES, and ARTEMIS phase 3 trials.