Sustained safety and efficacy of ligelizumab in patients with chronic spontaneous urticaria: A one‐year extension study

Background: Ligelizumab, a next-generation, humanized anti-immunoglobulin E (IgE) monoclonal antibody is in development as a treatment for patients with chronic spontaneous urticaria, whose symptoms are inadequately controlled with standard-of-care therapy. Objective: To evaluate the long-term safety and re-treatment efficacy of ligelizumab 240 mg in patients who completed the core study and extension study. Methods: This open-label, single-arm, long-term Phase 2b extension study was designed to assess patients who were previously administered various doses of ligelizumab, omalizumab or placebo in the Phase 2b, dose-finding core study and who presented with active disease after Week 32. In the extension study, patients received ligelizumab 240 mg subcutaneously every 4 weeks, for 52 weeks and were monitored post-treatment for 48 weeks. Results: Overall, ligelizumab was well-tolerated with no newly identified safety signals. A total of 95.4% (226/237) screened patients received ligelizumab 240 mg in the extension study; 84.1% (190/226) of patients experienced at least one treatment-emergent adverse event. Most reported events were mild (41.6%) or moderate (35.8%) and mostly unrelated to the study treatment. At Week 12, 46.5% of patients had a complete response increasing to 53.1% after 52 weeks. Following 52 weeks of extension study treatment, 75.8% (95% confidence interval, 69.9, 81.3) of patients had cumulative complete responses. The median time to relapse in complete responders was 38 weeks. Conclusion: The long-term safety profile of ligelizumab 240 mg in patients with chronic spontaneous urticaria was consistent with the core study and re-treatment efficacy was shown. Trial registration: ClinicalTrials.gov Identifier: NCT02477332 and NCT02649218

Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety

PurposeThe GALLIUM study (ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101;G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P;CHOP);CVP;or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety.Patients and Methods: A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m(2) on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression.Results: Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68;95% CI, 0.54 to 0.87;P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63;95% CI, 0.46 to 0.88;CHOP: HR, 0.72;95% CI, 0.48 to 1.10;CVP: HR, 0.79;95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles.Conclusion: Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation

Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety

Purpose; The GALLIUM study (ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods: A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter $ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m2 on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results: Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P= .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion: Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation

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

Background: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. Methods: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. Findings: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, –8·0 (95% CI –10·6 to –5·4; PEARL-1), –10·0 (–12·6 to –7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (–1·2 to 2·5; PEARL-1), 0·4 (–1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo –8·0 (–10·5 to –5·4; PEARL-1), –11·1 (–13·7 to –8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (–1·1 to 2·5; PEARL-1), –0·7 (–2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. Interpretation: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. Funding: Novartis Pharma