Phase 3b Study Confirms Ligelizumab’s Consistent CSU Control

Chronic spontaneous urticaria (CSU) remains a challenging condition for a subset of patients who do not achieve adequate control with standard H1-antihistamines. Anti-IgE therapies have expanded treatment options, and ligelizumab, an investigational high-affinity anti-IgE monoclonal antibody, has been evaluated across multiple phase 2 and phase 3 trials.¹ The phase 3b extension study summarized here provides long-term data on ligelizumab re-treatment and self-administration in patients who previously completed one of several ligelizumab clinical programs.²

This multicenter trial used an initial 12-week double-blind period followed by open-label treatment extending up to 2 years, although the study was ultimately stopped early for strategic reasons. As the authors note, “the study sponsor made a strategic decision to discontinue further clinical development of ligelizumab in chronic urticaria…not based on any safety concerns with ligelizumab.” Because many patients discontinued after the early termination announcement, later-period sample sizes were smaller than planned.

Study Population and Design

A total of 1371 patients entered the study, drawn from prior phase 3 (PEARL-1, PEARL-2), phase 2b adolescent, and Japanese open-label safety studies. Eligible patients had relapsed CSU, defined as a UAS7 ≥16 during screening despite ongoing antihistamine therapy. Participants were assigned to receive ligelizumab 72 mg or 120 mg every 4 weeks.

The study’s co-primary objectives focused on re-treatment efficacy in adults previously enrolled in the PEARL trials, specifically the proportion achieving well-controlled disease (UAS7 ≤6) at week 12. Secondary outcomes included itch and hive severity scores, complete response rates (UAS7 = 0), angioedema-free weeks, and dermatology-specific quality of life (DLQI 0–1). Safety was assessed throughout all study phases.

Efficacy Findings

Re-treatment with ligelizumab reproduced clinically meaningful reductions in disease activity. By week 12:

• 53.5% of patients receiving 72 mg and 57.5% receiving 120 mg reached UAS7 ≤6.
• Among prior responders from the PEARL studies, approximately 82% again achieved UAS7 ≤6, regardless of dose.

Complete response (UAS7 = 0) occurred in 37% of patients on 72 mg and 41% on 120 mg. Improvements in itch (ISS7) and hive (HSS7) scores were comparable across groups, and patients averaged roughly 9–10 angioedema-free weeks during the 12-week assessment period. Quality-of-life improvement was notable: 45.6% of patients on 72 mg and 55.8% on 120 mg achieved DLQI 0–1.

These outcomes suggest meaningful clinical benefit with either dose, with modest numerical advantages for 120 mg in some secondary endpoints.

Self-Administration Outcomes

A major objective of the extension was assessing whether ligelizumab could be effectively self-administered using a prefilled syringe. Patients who transitioned to self-administration maintained high response rates. At week 24 to 12 weeks after beginning self-administration—approximately 69% of patients across both dose groups achieved UAS7 ≤6, and this response was sustained through week 52.

Pharmacokinetic analyses showed comparable drug exposure between self-administered and healthcare-provider–administered dosing. Importantly, the authors report that “the ligelizumab prefilled syringe can be used effectively for self-administration by patients (or by caregivers), with outcomes comparable to those when administered by HCPs.”

Safety

Ligelizumab exhibited a consistent and acceptable safety profile, similar to earlier clinical phases. Most treatment-emergent adverse events (TEAEs) were mild or moderate. Injection-site reactions—including erythema, wheals, and urticaria—were the most common treatment-related events but rarely led to discontinuation.

Serious adverse events (SAEs) were infrequent, with COVID-19 representing the most frequent SAE. Three deaths occurred during the study, none judged related to treatment. Two adjudicated cases of anaphylaxis were identified; only one was considered treatment-related. No new safety signals emerged in cardiovascular, hematologic, or infectious AESIs, and the overall safety profile aligned with earlier Phase 2b and Phase 3 trial data.

Conclusion

Although the development program for ligelizumab in CSU has been discontinued for non-safety reasons, this phase 3b extension provides valuable long-term data. Re-treatment reliably restored disease control in prior responders as well as in the broader relapsed population. Self-administration proved feasible and effective, offering flexibility that may matter in real-world practice. Overall, ligelizumab demonstrated robust symptom control and a consistent safety profile in patients with antihistamine-refractory CSU.

References

1. Kolkhir P, Fok JS, Kocatürk E, Li PH, Okas TL, Marcelino J, Metz M. Update on the treatment of chronic spontaneous urticaria. Drugs. 2025 Apr;85(4):475-486. doi: 10.1007/s40265-025-02170-4.
2. Gimenez-Arnau A, Maurer M, Reich A, et al. Long-term efficacy and safety of ligelizumab as re-treatment in patients with chronic spontaneous urticaria. Allergy. 2025. doi: 10.1111/all.70181.