Ligelizumab Immunogenicity and Impact on Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety in Patients With Chronic Spontaneous Urticaria.

Ligelizumab is a highly potent, humanized IgG1 anti-IgE monoclonal antibody that was developed to treat chronic spontaneous urticaria (CSU). The immunogenicity of ligelizumab and its clinical impact were investigated in CSU patients following subcutaneous administration of 72 or 120 mg ligelizumab once every 4 weeks based on pooled data from two pivotal phase 3 clinical trials (PEARL-1 and PEARL-2). Across the 72 mg ligelizumab, 120 mg ligelizumab and placebo transitioned 120 mg ligelizumab arms, treatment-emergent anti-drug antibodies (TE-ADAs) were observed in 20.0%-22.6% of patients, out of whom 78.0%-81.7% developed neutralizing antibodies. The majority (> 99%) of patients with TE-ADAs had treatment-induced ADAs and 74.0%-90.0% developed a persistent ADA response. ADA titers became detectable in Week 12 after start of ligelizumab treatment and reached plateau around Week 20, with the median ADA onset at 143-147 days. In the 72 and 120 mg ligelizumab arms, the geometric mean steady-state trough concentration of ligelizumab was 52% and 41% lower, and the pharmacodynamic marker total IgE (% change from baseline) was 71% and 66% lower in ADA-positive than in ADA-negative patients, respectively. However, primary efficacy endpoint (change from baseline in Urticaria Activity Score 7) and key safety endpoints (incidence of treatment-emergent hypersensitivity and injection-site reactions) did not show clinically meaningful difference between ADA-positive and ADA-negative patients. This comprehensive analysis is the first report characterizing the immunogenicity profile of ligelizumab. The results indicate that ADAs reduced ligelizumab pharmacokinetic exposure and target engagement but had no clinically relevant impact on efficacy or safety in patients with CSU.