Ligelizumab treatment for severe asthma: learnings from the clinical development programme

Abstract

Objective: Ligelizumab is a humanised IgG1 anti-IgE antibody that binds IgE with higher affinity than omalizumab. Ligelizumab had greater efficacy than omalizumab on inhaled and skin allergen provocation responses in mild allergic asthma. This multi-centre, randomised, double-blind study was designed to test ligelizumab in severe asthma patients not adequately controlled with high-dose inhaled corticoids plus long-acting β2-agonist.

Methods: Patients received 16 weeks ligelizumab (240 mg q2w), omalizumab or placebo subcutaneously, and ACQ-7 was measured as primary outcome at Week 16. In addition, the study generated dose-ranging data of ligelizumab and safety data.

Results: A total of 471 patients, age 47.4 ± 13.36 years, were included in the study. Treatment with ligelizumab did not significantly improve asthma control (ACQ-7) and exacerbation rates compared to omalizumab and placebo. Therefore, primary and secondary objectives of the study were not met. The compound was well tolerated, and the safety profile showed no new safety findings. Pharmacokinetic data demonstrated faster clearance and lower serum concentrations of ligelizumab than historical omalizumab data, and exploratory in vitro data showed differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds.

Conclusion: Ligelizumab failed to demonstrate superiority over placebo or omalizumab. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high-affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. Therefore, the data suggest that different anti-IgE antibodies might be selectively efficacious for different IgE-mediated diseases.

Keywords: CD23; asthma; biologics; ligelizumab; omalizumab.

Figure 1

(a) Schematic study design, the main comparative component framed in red. (b) Trial profile.

Figure 2

ACQ‐7 change from baseline: There was no notable difference in the change from baseline in the ACQ‐7 score between the ligelizumab 240 mg q2w group (n = 120) and placebo (n = 49). Similarly for other ligelizumab dose groups, no notable differences could be seen compared to placebo.

Figure 3

Time‐to‐first exacerbation: No difference in time‐to‐first exacerbation between ligelizumab (n = 120) and placebo (n = 96) 16 weeks after completion of treatment period in post hoc analysis (combined placebo groups).

Figure 4

(a) Steady state of ligelizumab serum concentration was reached after 6–12 weeks, peaks differing according to dosing. (b) At 12 weeks, total IgE was increased in no apparent dose‐related manner by forming ligelizumab‐IgE complexes with reduced clearance. Mean free IgE was suppressed below the lower level of quantification at all concentrations above 120 mg q2w.

Figure 5

(a) Inhibition of FcεRI‐induced hexosaminidase release from mast cells by ligelizumab (black symbols) and omalizumab (blue symbols). (b) Inhibition of IgE binding to FcεRI (left) or CD23 (right) by omalizumab (blue, n = 5) or ligelizumab (ligelizumab, black, n = 5). Individual IC50 values from repeat experiments and medians (black lines) are shown. CD23 binding data are for RPMI 8866 (circles, n = 4), IM9 (triangles n = 2) and EBV B cells (squares, n = 2). Ligelizumab inhibits IgE binding to FcεRI bearing mast cells more potently than omalizumab, whereas omalizumab is more potent at inhibiting IgE binding to CD23. P‐values from t‐tests for the respective groups are indicated on top.