**4. New drugs in ongoing clinical trials**

#### **4.1 Anti IgE**

#### *4.1.1 Ligelizumab*

Ligelizumab (QGE031) is a new monoclonal antibody directed against the Cε3 domain of IgE, which in preclinical and in phase I clinical studies demonstrated its 50-fold greater affinity to IgE in vitro and six- to nine-fold greater potency in vivo compared to omalizumab. This affinity difference is caused due to epitope differences between ligelizumab and omalizumab that contribute to their distinct qualitative IgE-receptor profiles. Ligelizumab was superior in its ability to suppress IgE binding to FcεRI, basophil activation, and IgE secretion by B cells [34]. It was also shown that Ligelizumab provided a longer suppression of free and cell-bound IgE [35]. Omalizumab was shown to inhibit the interaction of IgE-FcεRII (CD23) more efficiently than Omalizumb, and this finding might explain the superior anti-asthmatic effect of omalizumb, considering the role of CD23 in lung inflammation [34]. In order to further assess its efficacy in CSU, a phase IIb dose-finding trial was designed for the efficacy and safety of ligelizumab. Doses of 24 mg, 72 mg, and 240 mg every four weeks were compared to the omalizumab standard dose of 300 mg every four weeks and to placebo in 382 adult patients with CSU. Clinical beneficial effects were evaluated by using - UAS7 (Urticaria Activity Score) and HSS7 (Hives Severity Score). The percentage of patients with a complete control of their hives (HSS7:0) and a complete control of their symptoms (UAS7:0) at week 12 was significantly higher in all ligelizumab arms (24 mg, 72 mg, 240 mg) compared with omalizumab (300 mg) and the placebo. The question regarding the low complete response rates with omalizumab was attributed to the high percentage of patients with an autoimmune pattern and angioedema. Adverse events rates were similar in all groups, except for a slightly higher incidence of local reaction at the injection site of ligelizumab 240 mg compared to omalizumab [36]. Patient's follow up in this clinical study revealed that among patients who achieved an UAS7 ≤ 6 at

#### *New Biological Treatment Options in CSU DOI: http://dx.doi.org/10.5772/intechopen.97647*

week 20, the beneficial therapeutic response was maintained for a median of 16, 8 and 8 weeks with ligelizumab 240 mg, 72 mg, and omalizumab, respectively. In addition, a 1-year extension phase of the above clinical study showed that in patients with UAS7 ≥ 12 who received ligelizumab 240 mg every 4 weeks (NCT02649218), the UAS7 ≤ 6 score response was maintained for a median period of 28 weeks [37]. Moreover, the treatment with ligelizumab was superior in other clinical measures when compared with omalizumab, namely, a decrease in the use of rescue medication [38] a greater and sustained efficacy in reducing angioedema at week 12 (the percentage of angioedema-free patients with ligelizumab 72 mg, 240 mg, omalizumab 300 mg, and placebo, was 87.5%, 94.9%, 76.3%, and 68.3%, respectively [39]. Several Phase III clinical trials (NCT03580356, NCT03580369, NCT03437278, NCT04210843) are currently in progress in order to further investigate the efficacy and safety of ligelizumab 72 mg and 120 mg when compared with omalizumab 300 mg and a placebo in CSU adolescent and adult patients up to 52 weeks. In Japan, in adult CSU patients who failed to response to H1-anti-histamines, are part of another phase III, open-label, and single-arm study of ligelizumab that is currently in progress (NCT03907878). It is hopeful that these studies and the extension phase study with ligelizumab will better characterize its usage in re-treatment, and selfadministration, as well as its its benefit as a monotherapy.
