Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects

Abstract

Background: Using a monoclonal antibody with greater affinity for IgE than omalizumab, we examined whether more complete suppression of IgE provided greater pharmacodynamic effects, including suppression of skin prick responses to allergen.

Objective: To explore the pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity humanized monoclonal IgG1κ anti-IgE.

Methods: Preclinical assessments and two randomized, placebo-controlled, double-blind clinical trials were conducted in atopic subjects. The first trial administered single doses of QGE031 (0.1-10 mg/kg) or placebo intravenously, while the second trial administered two to four doses of QGE031 (0.2- 4 mg/kg) or placebo subcutaneously at 2-week intervals. Both trials included an open-label omalizumab arm.

Results: Sixty of 73 (82%) and 96 of 110 (87%) subjects completed the intravenous and subcutaneous studies, respectively. Exposure to QGE031 and its half-life depended on the QGE031 dose and serum IgE level. QGE031 had a biexponential pharmacokinetic profile after intravenous administration and a terminal half-life of approximately 20 days. QGE031 demonstrated dose- and time-dependent suppression of free IgE, basophil FcεRI and basophil surface IgE superior in extent (free IgE and surface IgE) and duration to omalizumab. At Day 85, 6 weeks after the last dose, skin prick wheal responses to allergen were suppressed by > 95% and 41% in subjects treated subcutaneously with QGE031 (2 mg/kg) or omalizumab, respectively (P < 0.001). Urticaria was observed in QGE031- and placebo-treated subjects and was accompanied by systemic symptoms in one subject treated with 10 mg/kg intravenous QGE031. There were no serious adverse events.

Conclusion and clinical relevance: These first clinical data for QGE031, a high-affinity IgG1κ anti-IgE, demonstrate that increased suppression of free IgE compared with omalizumab translated to superior pharmacodynamic effects in atopic subjects, including those with high IgE levels. QGE031 may therefore benefit patients unable to receive, or suboptimally treated with, omalizumab.

Keywords: IgE; QGE031; allergic; anti-IgE; antibody; atopic; ligelizumab; monoclonal.

Figure 1

Subject disposition for (a) the intravenous trial and (b) the subcutaneous trial. *Total approximate numbers are provided. Subjects were excluded because they declined to participate or failed to meet eligibility criteria. ^†The placebo cohort was introduced following a protocol amendment to serve as an expansion of the placebo group at the highest (10 mg/kg) dose level. ^‡Omalizumab was dosed as per the FDA dosing table . ^¶Placebo pooled from Cohorts 2, 3 and 6.

Figure 2

Time course for serum concentrations of QGE031 following (a) single 2-h intravenous infusion and (b) 2-weekly subcutaneous administration on two (0.2 mg/kg) to four occasions (all other cohorts). Data presented are geometric means. Vertical arrows in panel (b) denote the times of administration of QGE031 (except for the 0.2 mg/kg cohort where QGE031 was administered on just the first two instances).

Figure 3

Individual subject serum concentrations of total and free IgE in response to increasing doses of QGE031, placebo or omalizumab following (a) single 2-h intravenous infusion and (b) multiple, 2-weekly subcutaneous administrations. The upper and lower limit of quantification for free IgE was 250 ng/mL and 7.8 ng/mL, respectively, for the intravenous study. The upper and lower limit of quantification for free IgE was 250 ng/mL and 1.95 ng/mL, respectively, for the subcutaneous study. Subjects with high IgE (i.e. > 1000 IU/mL for intravenous study and > 700 IU/mL for subcutaneous study) are plotted in red. The placebo group in subcutaneous study contains all placebo-treated patients in subcutaneous study regardless of cohort. iv, intravenous; sc, subcutaneous.

Figure 4

Individual subject time courses for the expression of basophil surface FcεRI and basophil surface IgE in response to increasing doses of QGE031, placebo or omalizumab in (a) single 2-h intravenous infusion and (b) multiple, 2-weekly subcutaneous administrations. Subjects with high IgE (i.e. > 1000 IU/mL for intravenous study and > 700 IUM/mL for subcutaneous study) are plotted in red. The placebo group in subcutaneous study contains all placebo-treated patients in subcutaneous study regardless of cohort. iv, intravenous; MESF, molecules of equivalent soluble fluorochrome; s, soluble; sc, subcutaneous.

Figure 5

Time courses of changes in allergen-induced skin prick wheal responses: (a) area under the dose–response curve values and (b) threshold 1 : 3 dilution of allergen eliciting a response after subcutaneous administration of QGE031, placebo or omalizumab. Data are presented as mean + standard deviation. Serial threefold dilutions of allergen were applied in skin prick testing. A value of 1 = threefold dilution, 2 = ninefold dilution, etc. A value of 0 was assigned if the threshold concentration eliciting a response was the neat allergen. A value of −1 was assigned if no response was elicited at any concentration. AUC, area under the curve.