Background Patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) often continue to experience symptoms despite receiving standard-of-care therapy with H1 -antihistamines ...along with 1 or more add-on therapies. Objectives We sought to evaluate the safety and efficacy of 24 weeks of treatment with omalizumab in patients with persistent CIU/CSU despite treatment with H1 -antihistamines at up to 4 times the approved dose plus H2 -antihistamines, leukotriene receptor antagonists, or both. Methods In this phase III study patients were randomized to receive 6 subcutaneous injections at 4-week intervals of either 300 mg of omalizumab or placebo, followed by a 16-week observation period. The primary objective of the study was to evaluate the overall safety of omalizumab compared with placebo. Efficacy (itch severity, hive, and urticaria activity scores) was evaluated at weeks 12 and 24. Results The overall incidence and severity of adverse events and serious adverse events were similar between omalizumab and placebo recipients; the safety profile was consistent with omalizumab in patients with allergic asthma. At week 12, the mean change from baseline in weekly itch severity score was −8.6 (95% CI, −9.3 to −7.8) in the omalizumab group compared with −4.0 (95% CI, −5.3 to −2.7) in the placebo group ( P < .001). Significant improvements were seen for additional efficacy end points at week 12; these benefits were sustained to week 24. Conclusion Omalizumab was well tolerated and reduced the signs and symptoms of CIU/CSU in patients who remained symptomatic despite the use of H1 -antihistamines (up to 4 times the approved dose) plus H2 -antihistamines, leukotriene receptor antagonists, or both.
Background Proof-of-concept studies with omalizumab in patients with chronic idiopathic urticaria (CIU) have shown significant decreases in mean urticaria activity scores (UASs). Objective We sought ...to evaluate the efficacy and safety of omalizumab in patients with CIU who remain symptomatic despite concomitant H1 -antihistamine therapy. Methods This phase II, prospective, double-blind, placebo-controlled, dose-ranging study investigated omalizumab in patients aged 12 to 75 years in the United States and 18 to 75 years in Germany with a UAS over 7 days (UAS7) of 12 or greater despite antihistamine therapy. Patients were randomized 1:1:1:1 to receive a single subcutaneous dose of 75, 300, or 600 mg of omalizumab or placebo added to a stable dose of H1 -antihistamine. The primary efficacy outcome was change from baseline to week 4 in UAS7. Patients were followed for an additional 12 weeks to monitor safety. Results Ninety patients from the United States or Germany were enrolled. Both the 300-mg omalizumab group (−19.9 vs −6.9, P < .001) and the 600-mg omalizumab group (−14.6 vs −6.9, P = .047) showed greater improvement versus the placebo group in UAS7. No meaningful difference was observed for the 75-mg omalizumab group. Similar results were seen for key secondary end points of weekly hive and itch scores. Onset of effect occurred after 1 to 2 weeks. Omalizumab was well tolerated, and the incidence of adverse events was similar across treatment groups. Conclusion This study demonstrated that a fixed dose of 300 or 600 mg of omalizumab provides rapid and effective treatment of CIU in patients who are symptomatic despite treatment with H1 -antihistamines.
In vivo clearance mechanisms of therapeutic monoclonal antibodies (mAbs) encompass both target-mediated and target-independent processes. Two distinct determinants of overall mAb clearance largely ...separate of target-mediated influences are non-specific cellular endocytosis and subsequent pH-dependent mAb recycling mediated by the neonatal Fc receptor (FcRn), where inter-mAb variability in the efficiency of both processes is observed. Here, we implemented a functional cell-based FcRn recycling assay via Madin-Darby canine kidney type II cells stably co-transfected with human FcRn and its light chain β2-microglobulin. Next, a series of pH-dependent internalization studies using a model antibody demonstrated proper function of the human FcRn complex. We then applied our cellular assays to assess the contribution of both FcRn and non-specific interactions in the cellular turnover for a panel of 8 clinically relevant mAbs exhibiting variable human pharmacokinetic behavior. Our results demonstrate that the interplay of non-specific endocytosis rates, pH-dependent non-specific interactions, and engagement with FcRn all contribute to the overall recycling efficiency of therapeutic monoclonal antibodies. The predictive capacity of our assay approach was highlighted by successful identification of all mAbs within our panel possessing clearance in humans greater than 5 mL/day/kg. These results demonstrate that a combination of cell-based in vitro assays can properly resolve individual mechanisms underlying the overall in vivo recycling efficiency and non-target mediated clearance of therapeutic mAbs.
