The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study

Abstract

Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection. We also report a first-in-human, randomized, double-blind, placebo-controlled, dose-escalating study of intravenous (IV) or subcutaneous (SC) rozanolixizumab in healthy subjects (NCT02220153). The primary objective was to evaluate safety and tolerability. Secondary objectives were assessment of rozanolixizumab pharmacokinetics and pharmacodynamics, including effects on circulating IgG concentrations. Forty-nine subjects were randomized to receive rozanolixizumab ( = 36) or placebo ( = 13) across six cohorts. The first three cohorts received IV doses, and the subsequent three cohorts received SC doses, of rozanolixizumab 1, 4, or 7 mg/kg ( = 6 for each cohort; plus = 7 or 6 for placebo, respectively). The most frequent treatment-emergent adverse event [TEAE; headache, 14 of 36 (38.9%) subjects] was dose-dependent and more prominent after IV administration. Severe TEAEs occurred in four subjects, all in the highest-dose IV group [headache ( = 3) and back pain ( = 1)]. Rozanolixizumab pharmacokinetics demonstrated nonlinear increases with dose. There were sustained dose-dependent reductions in serum IgG concentrations (IV and SC rozanolixizumab). These data provide clinical evidence for the therapeutic potential of rozanolixizumab.

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

“…These results are consistent with previously published data: two humans with β2m-deficiency (and consequently FcRn-deficient) had plasma IgG concentrations of about 11% and 25% of normal, 51 and FcRn-deficient mice had plasma IgG concentrations of about 11.8% of normal. 45 The extent of plasma IgG reduction achieved in these preclinical investigations and in the clinical study 6 are comparable with the reduction (~ 50–60%) observed following a full course of repeated plasmapheresis procedures in humans, which is one of the current standards of care in autoimmune diseases. 52,53 This suggests that FcRn blockade may not only have clinical efficacy in autoimmune disease, but also that it could be more simply and rapidly administered, and may be more convenient and more specific in its mechanism of action than current treatments.…”

“…Furthermore, the PK/PD studies reported here in transgenic mice and cynomolgus monkeys showed that rozanolixizumab caused no reduction in plasma albumin concentration outside the normal range; an observation also reported in healthy volunteers. 6 The reductions in albumin observed in the 13-week cynomolgus monkey toxicology study were likely attributed to partial steric hindrance at high concentrations of rozanolixizumab; however, it is important to note that in this study, rozanolixizumab was administered at a concentration 100-fold in excess of the planned human exposure level. In cynomolgus monkeys there was no effect of rozanolixizumab or 1519.g57 Fab’PEG on concentrations of IgM and IgA (which are not recycled by FcRn), these data support the results observed in the clinical healthy volunteer study of rozanolixizumab.…”

“…To evaluate any species differences in the potential binding of rozanolixizumab to human and cynomolgus monkey tissues prior to the first-in-human study, 6 a tissue cross-reactivity study was performed using immunohistochemical staining and microscopy of frozen tissue sections. Rozanolixizumab showed specific staining in vascular endothelium, epithelial cells, urothelium, connective tissue, glomerular mesangium, and smooth muscle (see Supplementary Figure 5 for examples of staining).…”

“…Results from this study support the findings of the previously reported 4-week toxicology study. 6 SC (50 and 150 mg/kg) or IV (150 mg/kg) administration of rozanolixizumab every 3 days for 13 weeks and intermittent SC dosing of rozanolixizumab (150 mg/kg) every 3 days in each of Weeks 1, 6 and 10 (Table 3) was well tolerated in cynomolgus monkeys. The no-observed-adverse-effect level (NOAEL) was 150 mg/kg dosed IV or SC every 3 days.…”

“…In a healthy volunteer study (n = 48), dose-dependent reductions in serum IgG were observed, and an acceptable safety profile was demonstrated, with single (subcutaneously [SC] and intravenously [IV] administered) doses of rozanolixizumab. 6 …”