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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.

Pregabalin increased distension sensory thresholds to normal levels in IBS patients with rectal hypersensitivity. A concomitant increase in rectal compliance appeared to be unrelated to the reduction in sensitivity. These data suggest that alpha(2)delta ligands are worthy of further investigation in the treatment of visceral pain disorders, including IBS.

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The proof-of-concept (PoC) decision is a key milestone in the clinical development of an experimental treatment. A decision is taken on whether the experimental treatment is further developed (GO), whether its development is stopped (NO-GO), or whether further information is needed to make a decision. The PoC decision is typically based on a PoC clinical trial in patients comparing the experimental treatment with a control treatment. It is important that the PoC trial be designed such that a GO/NO-GO decision can be made. The present work develops a generic, Bayesian framework for defining quantitative PoC criteria, against which the PoC trial results can be assessed. It is argued that PoC criteria based solely on significance testing versus the control are not appropriate in this decision context. A dual PoC criterion is proposed that includes assessment of superiority over the control and relevance of the effect size and hence better matches clinical decision making. The approach is illustrated for 2 PoC trials in cystic fibrosis and psoriasis.