Emerging Therapies from Novartis for Chronic Spontaneous Urticaria
Ligelizumab is the primary emerging therapy being investigated by Novartis for chronic spontaneous urticaria (CSU), showing superior efficacy to placebo but not to omalizumab in recent Phase 3 trials.
Current Status of Ligelizumab
Ligelizumab is a next-generation, high-affinity humanized anti-IgE monoclonal antibody that has been extensively studied for CSU treatment. The development pathway includes:
Phase 2b trials: Early studies showed promising results with ligelizumab demonstrating potentially superior efficacy compared to omalizumab. At week 12,51% of patients receiving ligelizumab 72 mg achieved complete control of hives versus 26% with omalizumab 1.
Phase 3 PEARL trials: More recent and definitive Phase 3 studies (PEARL-1 and PEARL-2) demonstrated that while ligelizumab (at doses of 72 mg and 120 mg) was superior to placebo in reducing CSU symptoms, it did not show superiority to omalizumab 2.
Long-term safety: A one-year extension study showed that ligelizumab 240 mg was well-tolerated with no new safety signals, and 53.1% of patients achieved complete response after 52 weeks of treatment 3.
Mechanism of Action
Like omalizumab, ligelizumab targets IgE but with different binding characteristics:
- Ligelizumab has a higher binding affinity to IgE compared to omalizumab
- It targets free IgE in serum, preventing it from binding to high-affinity IgE receptors (FcεRI) on mast cells and basophils
- This inhibits mast cell degranulation and subsequent release of inflammatory mediators that cause urticaria symptoms 4
Dosing in Clinical Trials
Ligelizumab has been studied at various doses:
- Phase 2b: 24 mg, 72 mg, 120 mg (single dose), and 240 mg 1
- Phase 3: 72 mg and 120 mg administered subcutaneously every 4 weeks 2
- Extension study: 240 mg administered subcutaneously every 4 weeks 3
Clinical Efficacy
The efficacy of ligelizumab has been measured using standardized tools:
- Weekly Urticaria Activity Score (UAS7): Measures disease activity
- Complete control of hives: Indicated by a weekly hives-severity score of 0
- Complete symptom control: Indicated by a UAS7 score of 0
In the Phase 2b trial, at week 12:
- 51% of patients receiving ligelizumab 72 mg achieved complete control of hives
- 44% achieved complete control of symptoms
- These rates were higher than with omalizumab (26%) 1
However, in the larger and more definitive Phase 3 trials, ligelizumab showed:
- Superior efficacy to placebo (p<0.0001)
- No superiority to omalizumab in reducing UAS7 scores at week 12 2
Safety Profile
The safety profile of ligelizumab appears consistent across studies:
- Most adverse events were mild to moderate in severity
- No new safety signals compared to omalizumab
- Well-tolerated in long-term use (up to 52 weeks) 3, 2
Other Novartis Anti-IgE Approaches
While ligelizumab is the most advanced, Novartis has been involved in developing other anti-IgE approaches:
- UB-221: Another anti-IgE antibody in earlier stages of development 5
- DARPins (Designed Ankyrin Repeat Proteins): Novel protein scaffolds that can be engineered to bind IgE with high specificity 5
Current Treatment Context
It's important to note that omalizumab (Xolair) remains the only FDA-approved anti-IgE therapy for CSU, indicated for:
- Adults and adolescents 12 years and older with CSU
- Patients who remain symptomatic despite H1 antihistamine treatment 6
According to current guidelines, the treatment approach for CSU follows a stepwise algorithm:
- Second-generation H1-antihistamines at standard dose
- Increasing H1-antihistamine dose up to 4 times if needed
- Adding omalizumab for patients who fail to respond to high-dose antihistamines 7, 8
Clinical Implications
For healthcare providers managing patients with CSU:
- Ligelizumab may offer an alternative option for patients with CSU who don't respond adequately to current therapies
- The optimal dose appears to be 72 mg or 120 mg every 4 weeks based on Phase 3 data
- Some preliminary evidence suggests that omalizumab non-responders or partial responders might benefit from ligelizumab 5
Monitoring Response
When these therapies become available, response should be monitored using validated tools such as:
The goal of treatment remains complete control of symptoms, which significantly improves quality of life for patients with this challenging condition.