Phase Ib, multicentre, open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered mosunetuzumab in participants with systemic lupus erythematosus

To determine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneously administered mosunetuzumab, a CD20xCD3 T-cell-engaging bispecific antibody, in participants with systemic lupus erythematosus (SLE). This phase Ib, multicentre, open-label, dose-escalation study enrolled 15 participants diagnosed with active autoantibody-positive SLE, demonstrated by an SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥4 at screening. The study included two fixed-dosing dose-finding cohorts (1.6 mg or 5 mg of mosunetuzumab on day 1) and three step-up dose-escalation cohorts (day 1 dose of mosunetuzumab established by dose finding, followed by 15 mg, 45 mg or 60 mg of mosunetuzumab on day 8). The primary objective was evaluation of safety; other key objectives were evaluating the PK and PD of mosunetuzumab. Peripheral B-cell counts and T-cell phenotyping were performed using flow cytometry. Fifteen participants were enrolled from January 2022 through December 2023. Two participants discontinued treatment due to treatment-emergent adverse events (AEs). No immune effector cell-associated neurotoxicity syndrome events or high-grade cytokine release syndrome events were reported. The frequency of grade ≥3 AEs and serious AEs was 13.3% and 6.7%, respectively. Mosunetuzumab depleted peripheral B cells below the lower limit of quantification (0.441 cells/µL) in a dose-dependent manner. CD4+ and CD8+ T-cell activation occurred across all tested doses. SLEDAI-2K scores improved, especially among participants with higher baseline SLEDAI-2K scores and those receiving higher doses. The PK profile of mosunetuzumab was consistent with that observed in the relapsed or refractory follicular lymphoma population. Mosunetuzumab demonstrated dose-dependent peripheral B-cell depletion and a safety profile consistent with prior studies in follicular lymphoma. Based on these data, mosunetuzumab is currently being evaluated in a phase II study in severe SLE (NCT07598396). NCT05155345.