# Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials

- **DOI:** [10.1016/s0140-6736(23)01684-7](https://doi.org/10.1016/s0140-6736(23)01684-7)
- **Rating:** Strong (4.1 out of 5)
- **Verdict:** Two pivotal trials establish ligelizumab’s efficacy against placebo, but failure to outperform omalizumab limits its clinical differentiation.
- **Framework version:** v5.9
- **Pipeline version:** v0.4
- **Evaluation date:** 2026-09-18
- **Evaluation page:** https://www.nabu.science/paper/10.1016%2Fs0140-6736(23)01684-7

## Key claims

1. Both PEARL-1 and PEARL-2 studies met their primary efficacy endpoint of superiority of ligelizumab in terms of CFB-UAS7 at week 12 versus placebo (p<0·0001), but not versus omalizumab
   - Support: Well-supported
   - Type: Primary finding
   - Basis: prespecified primary comparisons produced concordant estimates in two independently conducted trials
   - Location: Results, p.154; Table 2
2. ligelizumab is a well-tolerated anti-IgE treatment, as effective as omalizumab
   - Support: Tentative
   - Type: Secondary
   - Basis: superiority testing did not formally establish equivalence or non-inferiority against omalizumab
   - Location: Discussion, p.157
3. No new safety signals were identified for ligelizumab or omalizumab
   - Support: Well-supported
   - Type: Secondary
   - Basis: systematic adverse-event ascertainment included serious events, predefined special-interest events, and adjudication
   - Location: Summary; Table 3; Results, pp.155–156
4. Ligelizumab treatment resulted in a significantly higher cumulative number of angioedema-free weeks at week 12 compared with placebo
   - Support: Supported
   - Type: Secondary
   - Basis: prespecified regression analysis supports the placebo comparison, with singleton retention limiting strength
   - Location: Discussion, p.157; Table 2

## Strengths

- **Replicated active-comparator phase 3 evidence** Two independently conducted, identically designed trials produced concordant findings: ligelizumab was superior to placebo but not to omalizumab. This resolves the principal comparative-efficacy question raised by phase 2b results.
  - Dimension: contribution
  - Location: Methods, pp.148–149; Results, p.154; Table 2
- **Strong randomisation and analysis execution** Interactive Response Technology, stratification, maintained masking, assigned-treatment efficacy analysis, repeated-measures modelling, and multiple imputation support the primary comparisons. Baseline characteristics were balanced across treatment groups.
  - Dimension: methodological rigour
  - Location: Methods, pp.149–153; Table 1
- **Systematic and transparent harms reporting** The study reports adverse events, serious events, discontinuations, predefined events of special interest, adjudicated anaphylaxis, and a death. Table 3 and the Results provide treatment-group comparisons rather than only aggregate reassurance.
  - Dimension: methodological rigour
  - Location: Methods, p.150; Results, pp.155–157; Table 3

## Limitations

- **Equality wording exceeds tested design** The final statement that ligelizumab was “as effective as omalizumab” converts failure to demonstrate superiority into an affirmative equality claim. The trials were not designed as formal equivalence or non-inferiority studies.
  - Dimension: reporting
  - Location: Discussion, p.157; Table 2
- **Applicability gaps remain for subgroups** Non-White participants were relatively underrepresented, and adolescent efficacy findings were exploratory and based on small samples. These constraints limit confidence in subgroup transferability despite broad geographic recruitment.
  - Dimension: positioning
  - Location: Results, pp.154–155; Discussion, p.157
- **Sponsor controlled major analytic stages** The funder participated in design, data collection, analysis, interpretation, and report writing, and sponsor employees conducted the statistical and safety analyses. These roles are fully disclosed but limit analytic independence.
  - Dimension: methodological rigour
  - Location: Role of the funding source, p.153; Contributors and Declaration of interests, p.158

## Reliability checks

Caveats (4 of 4 checks).

- **Internal coherence:** Clean. Allocation totals, efficacy and safety denominators, effect estimates, and the primary conclusion are consistent across the Summary, Figure 2, and Tables 1–3. Protocol amendments and the hierarchical testing sequence are also described consistently.
- **Research conduct:** Noted. Ethics, consent, prospective registration, conflicts of interest, and a controlled data-sharing pathway are declared. The funder participated directly in all major stages from design through analysis, interpretation, and report writing, which warrants disclosure-aware interpretation but does not establish unreliability.
- **Reference integrity:** Clean. 31 of 31 checkable references verified
  - 31 references in manuscript
  - 1 reference confirmed by manual review
  - References not verified automatically are resolved manually within 24 hours.

## Post-publication record

- **Status:** Clean
- **Summary:** No retraction or expression of concern found in Crossref (includes Retraction Watch).
- **Last checked:** 2026-10-17