Director, Clinical Pharmacology & Pharmacometrics CSL Behring Raleigh, North Carolina, United States
Disclosure(s):
Venkateswari Y. Muthukrishnan, PhD: No relevant disclosure to display
Objectives: Cardiovascular risk is associated with inflammation mediated by interleukin-6 (IL-6). We evaluated intravenous (IV) clazakizumab, a monoclonal antibody targeting the IL-6 ligand, in a phase 2b trial in adults with cardiovascular disease and/or diabetes receiving maintenance dialysis with high-sensitivity C-reactive protein (hs-CRP) ≥ 2 mg/L at baseline.1 The goal of this work was to develop pharmacokinetic (PK) and longitudinal PK-pharmacodynamic (PK-PD) models to predict the exposure-response of clazakizumab and hs-CRP to inform the recommended phase 3 dose selection.
Methods: Study CSL300_2301 phase 2b (NCT05485961) is a dose-finding portion of the combined phase 2b/3 study. It is a double-blind, randomized, placebo-controlled study with an analysis for dose selection once all subjects in phase 2b completed treatment through at least 12 weeks of clazakizumab. Participants were randomized to receive IV clazakizumab (2.5 mg, 5 mg, or 10 mg, n=32 per dose group) or placebo (n=31) every 4 weeks for up to 24 weeks. Serial blood samples were collected to measure clazakizumab and hs-CRP concentrations in serum using a validated enzyme-linked immunosorbent assay and a validated particle-enhanced immunoturbidimetric assay, respectively. All analyses were performed using the non-linear mixed-effects modeling (NONMEM) software version 7.5.1.
Results: The analysis datasets included: 891 measurable PK observations and 96 participants for popPK analysis; and 1277 measurable hs-CRP observations and 126 participants for PK-PD. The PKs were well characterized by a 2-compartment model with linear elimination. The significant effect of body weight on clazakizumab clearance (CL) and central compartment volume (V1) was described with estimated allometric exponents, and increased levels of baseline free IL-6 were associated with increases in CL. The estimated population typical values were 0.228 L/day for CL and 4.05 L for V1. Longitudinal PK-PD modeling was used to characterize the PK-PD relationship between clazakizumab and hs-CRP levels. PK-PD was best described by an indirect-response inhibitory model with clazakizumab concentrations inhibiting the kin (zero-order rate of production) of hs-CRP. Higher baseline hs-CRP levels were associated with a faster kin. Model-based simulations predicted all clazakizumab doses (2.5, 5, and 10 mg IV every 4 weeks) would result in the majority of subjects experiencing a ≥80% decrease from baseline hs-CRP (80.9%, 83.4%, and 88.1%, respectively) and hs-CRP levels < 2 mg/mL (67.7%, 76.7%, and 82.6%, respectively) at Week 12.
Conclusions: Pharmacometric models adequately described the PK and PD data for clazakizumab and hs-CRP, respectively. These modeling and simulation results, combined with safety data,1 support the dose selection in the phase 3 placebo-controlled trial to evaluate the impact of IL-6 inhibition via clazakizumab administration upon cardiovascular events.
Citations: [1] Chertow, G.M., Chang, A.M., Felker, G.M. et al. IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial. Nat Med 30, 2328–2336 (2024).
