What is the difference in mechanism of action between Ligelizumab and Omalizumab (anti-IgE antibodies) in treating Chronic Spontaneous Urticaria (CSU)?

Difference Between Ligelizumab and Omalizumab in Mechanism of Action for CSU Treatment

Ligelizumab has a higher binding affinity to IgE compared to omalizumab, but recent phase 3 trials show it is not superior to omalizumab in treating chronic spontaneous urticaria despite earlier promising results.

Mechanism of Action Differences

Omalizumab

• Selectively binds to free circulating IgE
• Decreases expression of IgE receptors (FcεRI) on mast cells, basophils, and dendritic cells
• Interferes with activation of these effector cells 1
• Binds to the Cε3 domain of the IgE heavy chain, preventing it from binding to its high-affinity receptor FcεRI 2

Ligelizumab

• Next-generation non-triggering fully human monoclonal antibody
• Has significantly higher affinity to IgE compared to omalizumab 3
• More potent in suppressing free IgE levels
• Targets the same Cε3 domain of IgE but with stronger binding properties

Efficacy Comparison

Earlier Studies

• Phase 2b dose-finding trial showed promising results for ligelizumab:
  • At week 12,51% of patients receiving 72 mg ligelizumab achieved complete control of hives versus 26% with omalizumab 4
  • Complete symptom control was achieved in 44% of patients with 72 mg ligelizumab versus 26% with omalizumab 4

Recent Phase 3 Evidence

• The PEARL-1 and PEARL-2 phase 3 trials (2024) demonstrated:
  • Both ligelizumab doses (72 mg and 120 mg) were superior to placebo (p<0.0001)
  • Neither dose of ligelizumab was superior to omalizumab in reducing UAS7 scores 5
  • Estimated treatment differences in mean change-from-baseline UAS7 for ligelizumab vs omalizumab were not statistically significant 5

Safety Profile

• Both medications have similar safety profiles 3, 5
• Most common side effects of ligelizumab are injection site reactions 3
• Compared to ligelizumab, omalizumab has fewer injection site reactions and erythema 6
• No new safety signals were identified for either medication in recent trials 5

Clinical Implications

• Both medications are effective for antihistamine-refractory CSU
• Omalizumab is currently approved for CSU treatment at 300mg subcutaneously every 4 weeks 7
• Approximately 65-87% of CSU patients respond to omalizumab therapy 7
• Despite higher binding affinity to IgE, ligelizumab did not demonstrate superior efficacy to omalizumab in phase 3 trials 5

Treatment Algorithm for CSU

1. Start with standard dose second-generation H1 antihistamines
2. Increase antihistamine dose up to 4 times if needed
3. Add omalizumab 300mg subcutaneously every 4 weeks for refractory cases
4. Consider ligelizumab as an alternative if/when approved, recognizing it has similar efficacy to omalizumab despite higher IgE binding affinity

Important Considerations

• Biomarkers like IgG-anti-TPO to total IgE ratio may help predict response to anti-IgE therapy 7
• Monitor treatment response using validated tools such as UAS7 and UCT 7
• Despite theoretical advantages of ligelizumab's higher binding affinity, clinical outcomes appear similar to omalizumab in large phase 3 trials

In conclusion, while ligelizumab was initially thought to potentially outperform omalizumab due to its higher binding affinity to IgE, the most recent and highest quality evidence from phase 3 trials indicates comparable efficacy between the two medications in treating chronic spontaneous urticaria.