Equivalence of SYN008 versus omalizumab in patients with refractory chronic spontaneous urticaria: A multicenter, randomized, double-blind, parallel-group, active-controlled phase III study

To the Editor: The global prevalence of chronic spontaneous urticaria (CSU) is estimated to be approximately 0.5–1%, with approximately 0.75% in China.[1,2] Second-generation H1-antihistamines (H1AHs) at a standard dose are currently the preferred first-line treatment for CSU. In the case of an inadequate response to H1AHs after 1–2 weeks of treatment, the dose of the same H1AH could be increased to a maximum of 4-fold, or it could be combined with other antihistamines. For patients with CSU who remain intolerant or unresponsive despite 2–4 weeks of treatment with increased doses of antihistamines, omalizumab, a humanized recombinant anti-immunoglobulin E (IgE) monoclonal antibody (300 mg every 4 weeks), is recommended as third-line treatment.[3] SYN008, a biosimilar of omalizumab (Xolair®, Novartis[4]), was developed by CSPC in China. A multicenter, randomized, double-blind, parallel-group, and positive-controlled phase III study in China was conducted to evaluate the equivalence of SYN008 and omalizumab as an add-on to H1AH therapy in the treatment of refractory Chinese adult CSU patients. Written informed consent was obtained from all patients before study initiation. Eligible patients were randomized at a 1:1 ratio to receive 300 mg of either SYN008 or omalizumab subcutaneously every 4 weeks for 12 weeks. Randomization was stratified according to the weekly itch severity score (ISS7) (<13 vs. ≥13) within 7 days prior to randomization. Between July 2021 and February 2023, 440 patients were screened across 32 sites in China. Among them, 343 patients were randomized and allocated to the SYN008 group (n = 171) or omalizumab group (n = 172) [Supplementary Figure 1, https://links.lww.com/CM9/C413]. The demographic and baseline clinical characteristics were comparable between the two groups [Supplementary Table 1, https://links.lww.com/CM9/C413]. In the SYN008 and omalizumab groups, the mean ages were 40.0 and 40.2 years, respectively; 56.5% and 51.2% of the patients were in the 18 to less than 40-year group, and the majority of the patients were females (64.7% and 68.6%, respectively). The mean ISS7 scores were 14.75 and 14.93, with 72.9% and 72.1% of the patients having ISS7 scores ≥13, respectively. The mean weekly urticaria activity score (UAS7) values were 29.61 and 30.02, respectively, and the mean total IgE levels were 247.95 and 241.23 IU/mL, respectively. In the full analysis set (FAS), the trends of changes in the ISS7, UAS7, and the weekly number of hives score (NHS7) from baseline in both groups of patients during the treatment period were generally consistent [Figure 1A–C].Figure 1: (A): The mean changes in ISS7 from baseline during the treatment period (FAS). (B): The mean changes in UAS7 from baseline during the treatment period (FAS). (C): The mean changes in NHS7 from baseline during the treatment period (FAS). (D): Forest plot for subgroups - Between-group differences in ISS7 change from baseline at week 12. CI: confidence interval; FAS: full analysis set; ISS7: weekly itch severity score; NHS7: weekly number of hives score; SD: standard deviations, UAS7: weekly urticaria score.At week 12, the mean change from baseline in the ISS7 (primary endpoint) significantly improved, and the least squares [LS] mean was −11.82 (0.37) in the SYN008 group and −11.03 (standard error [SE]: 0.37) in the omalizumab group. The treatment difference in the LS mean from baseline in the ISS7 was −0.80 (90% confidence interval [CI]: −1.64, 0.05), which lies within the predefined equivalence margin (±2.1) [Supplementary Table 2, https://links.lww.com/CM9/C413]. The results of the per-protocol set (PPS) and sensitivity analyses for the primary endpoint were consistent with those of the primary analysis [Supplementary Tables 3 and 4, Supplementary Figure 2, https://links.lww.com/CM9/C413]. With the exception of the ≥ 65-year subgroup (only 3 patients in each group), the treatment differences for the remaining subgroups in the LS mean in the ISS7 approximately fell into the equivalence interval of ± 2.1 [Figure 1D]. In the SYN008 and omalizumab groups, at week 12, the LS means of changes from baseline in the UAS7 were −24.04 (0.72) and −22.25 (0.72), with an LS mean of the treatment difference −1.79 (95% CI: −3.78, 0.21); the proportions of patients with the UAS7 ≤6 were 64.1% and 57.0%, respectively, and the odds ratio (OR) between the treatment groups was 1.40 (95% CI: 0.90, 2.17). Interestingly, the proportions of patients with the UAS7 = 0 were 47.1% and 39.0%, respectively, and the OR between the treatment groups was 1.41 (95% CI: 0.91, 2.17). Approximately 80% of the patients in both treatment groups achieved the ISS7 minimally important difference (MID) response at week 12 (81.8% vs. 82.0% in the SYN008 and omalizumab groups), with an OR of 0.99 (95% CI: 0.57, 1.74). The median time to the ISS7 MID in the treatment groups was 2.0 weeks, with a hazard ratio of 1.14 (95% CI: 0.91, 1.42) after stratification by ISS7 (<13 vs. ≥13). In the SYN008 and omalizumab groups, at week 12, the LS mean (SE) changes from baseline in the Dermatology Life Quality Index (DLQI) were −11.09 (0.37) and −11.00 (0.37), with an LS mean treatment difference of −0.08 (95% CI: −1.11, 0.95) [Supplementary Table 2, https://links.lww.com/CM9/C413]. Similar efficacy results for the above secondary endpoints in the FAS were observed in the PPS [Supplementary Table 3, https://links.lww.com/CM9/C413]. During the 24-week study period, 118 (69.4%) patients in the SYN008 group and 120 (69.8%) patients in the omalizumab group experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs (≥5%) were upper respiratory tract infection (12.4%), urinary tract infection (5.9%), and cough (5.3%) in the SYN008 group and upper respiratory tract infection (7.6%) and hypertriglyceridemia (5.8%) in the omalizumab group. Most TEAEs were mild or moderate. There were no TEAEs leading to dose reduction, suspension of the study drug, or death [Supplementary Table 5, https://links.lww.com/CM9/C413]. In the SYN008 and omalizumab groups, the incidences of treatment-emergent antidrug antibodies and neutralizing antibodies were 11.9% (20/168) and 2.4% (4/168) vs. 7.7% (13/169) and 0, respectively [Supplementary Table 6, https://links.lww.com/CM9/C413]. In this study, equivalence was demonstrated between SYN008 and omalizumab 300 mg at 4-week intervals in patients with CSU who remained symptomatic after treatment with H1AHs. The 90% CI for the treatment difference in mean changes from baseline in the ISS7 at week 12 was entirely within the predefined equivalence margin of ± 2.1 in the FAS.[5] The results of the PPS, sensitivity, and subgroup analyses were all consistent with those of the FAS, indicating their high robustness. Overall, SYN008 was well tolerated, and its safety profile was comparable to that of omalizumab, with no new or unexpected safety signals. The most frequently reported TEAEs were upper respiratory tract infection, headache, nasopharyngitis, skin and subcutaneous disorders, and gastrointestinal disorders, which are consistent with the findings of a previous study.[5] The main limitation of this phase III study is the short total observation period of 24 weeks, with 12 weeks each for treatment and follow-up durations. Therefore, a long-term observational study in which more CSU patients and more data are available may be needed to further evaluate the efficacy and safety results of this study.