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

Abstract

BackgroundUsing 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.ObjectiveTo explore the pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity humanized monoclonal IgG1κ anti-IgE.MethodsPreclinical 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.ResultsSixty 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 RelevanceThese 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.

Anti-IgE treatment, airway inflammation and remodelling in severe allergic asthma: current knowledge and future perspectives

“…Lumiliximab (IDEC-152) is a primatised monoclonal antibody against FcεRII that has already been shown to block IgE synthesis in human B-cells and reduce serum IgE levels [39,40]. Ligelizumab (QGE031), a humanised monoclonal IgG1κ antibody with a high avidity for IgE, was also recently evaluated regarding its pharmacokinetics, pharmacodynamics and safety [41]. Monoclonal antibody-12 is another promising anti-human IgE antibody that may prove useful for the extracorporeal depletion of IgE and IgE-bearing cells from peripheral blood [42].…”

Anti IgE Therapy in Chronic Urticaria

“…It also afords more and longer suppression of free IgE and IgE on the surface of circulating basophils compared to omalizumab [44].…”

Justification for IgE as a therapeutic target in chronic spontaneous urticaria

“…The optimal duration of the treatment and its long-term safety have not been established. In the future, the effects of additional anti-IgE monoclonal antibodies, for example Ligelizumab, which show greater affinity for IgE than omalizumab, will be investigated in patients with chronic urticaria (60). A recent trial with Quilizumab, a humanized, afucosylated monoclonal IgG 1 antibody that binds membrane IgE at the M1-prime segment, which is absent in soluble IgE, has been published.…”