LAUSR

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 1a single ascending-dose study (7-700 mg subcutaneously [SC]) in healthy subjects and a phase 1b multiple ascending-dose study (70-420 mg subcutaneously 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 (AUCinf and AUCtau ) above 51 and 57 days•μg/mL for the single-dose (≥70 mg) and multiple-dose studies (≥70 mg Q2W), respectively. ICOSL receptor occupancy (RO) on circulating B cells, a surrogate PD endpoint 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 2b study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus.