Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical Trials

Rozibafusp alfa (AMG 570) is a first‐in‐class bispecific IgG2‐peptide fusion designed to inhibit inducible T‐cell costimulator ligand (ICOSL) and B‐cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo‐controlled clinical studies: a phase Ia single ascending‐dose study (7–700 mg subcutaneously (s.c.)) in healthy subjects and a phase Ib multiple ascending‐dose study (70–420 mg s.c. every 2 weeks (q2w)) in patients with rheumatoid arthritis. Rozibafusp alfa exhibited nonlinear PK and dose‐related and reversible dual‐target engagement. Maximal reduction of naïve B cells from baseline (> 40%), reflective of BAFF inhibition, was achieved with rozibafusp alfa exposure (area under the concentration‐time curve from time 0 to time infinity (AUC inf ) and AUC within a dosing interval from day 0 to day 14 (AUC tau )) above 51 and 57 days•μg/mL for the single‐dose (≥ 70 mg) and multiple‐dose studies (≥ 70 mg q2w), respectively. ICOSL receptor occupancy on circulating B cells, a surrogate PD end point for ICOSL inhibition, was directly related to drug concentration. PK/PD analysis showed > 90% RO at rozibafusp alfa ≥ 22.2 μg/mL (≥ 420‐mg single dose or ≥ 210 mg q2w multiple dose), with saturation occurring at higher drug concentrations. These results informed the design and dose selection of a phase IIb study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus.