Ligelizumab for Chronic Spontaneous Urticaria Maurer, Marcus; Giménez-Arnau, Ana M; Sussman, Gordon ...
The New England journal of medicine,
10/2019, Letnik:
381, Številka:
14
Journal Article
Recenzirano
Odprti dostop
This dose–response trial of ligelizumab showed that approximately half the patients treated with 240 mg of ligelizumab had complete resolution of hives, as compared with only approximately one ...quarter of the patients treated with the recommended dose of omalizumab.
Objective
Ligelizumab is a humanised IgG1 anti‐IgE antibody that binds IgE with higher affinity than omalizumab. Ligelizumab had greater efficacy than omalizumab on inhaled and skin allergen ...provocation responses in mild allergic asthma. This multi‐centre, randomised, double‐blind study was designed to test ligelizumab in severe asthma patients not adequately controlled with high‐dose inhaled corticoids plus long‐acting β2‐agonist.
Methods
Patients received 16 weeks ligelizumab (240 mg q2w), omalizumab or placebo subcutaneously, and ACQ‐7 was measured as primary outcome at Week 16. In addition, the study generated dose‐ranging data of ligelizumab and safety data.
Results
A total of 471 patients, age 47.4 ± 13.36 years, were included in the study. Treatment with ligelizumab did not significantly improve asthma control (ACQ‐7) and exacerbation rates compared to omalizumab and placebo. Therefore, primary and secondary objectives of the study were not met. The compound was well tolerated, and the safety profile showed no new safety findings. Pharmacokinetic data demonstrated faster clearance and lower serum concentrations of ligelizumab than historical omalizumab data, and exploratory in vitro data showed differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds.
Conclusion
Ligelizumab failed to demonstrate superiority over placebo or omalizumab. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high‐affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. Therefore, the data suggest that different anti‐IgE antibodies might be selectively efficacious for different IgE‐mediated diseases.
In this multi‐centre, randomised, double‐blind study, 471 severe asthmatics were treated with the high‐affinity anti‐IgE antibody ligelizumab. Treatment did not significantly improve asthma control and exacerbations compared to omalizumab and placebo. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high‐affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds, potentially blunting the effect in asthma.
Background
Chronic spontaneous urticaria (CSU) negatively impacts patients' sleep, thereby reducing health‐related quality of life (HRQoL). Half of patients with inadequately controlled CSU report ...sleep interference often or every night, which can lead to depression, anxiety, social, and work‐related problems.
Methods
This randomized, double‐blind, placebo‐controlled Phase 2b core study (NCT02477332) included adult patients ≥18 years with moderate to severe CSU inadequately controlled with H1‐antihistamines. The current analysis includes patients randomized to receive ligelizumab 72 or 240 mg, omalizumab 300 mg or placebo every 4 weeks (q4w) for five injections over 20 weeks with treatment‐free follow‐up for 24 weeks. Patients could enter the open‐label extension study (NCT02649218) from Week 32 onwards if their weekly urticaria activity score was ≥12, which included an open‐label treatment (52 weeks of ligelizumab 240 mg q4w) and a 48‐week post‐treatment follow‐up. Weekly Sleep Interference Scores (SIS7, range 0 no interference–21 substantial interference), Weekly Activity Interference Score (AIS7), Dermatology Life Quality Index (DLQI) scores, and Overall Work Impairment were assessed.
Results
Mean baseline SIS7 scores were balanced between the treatment arms for ligelizumab 72 mg (n = 84) and 240 mg (n = 85), omalizumab 300 mg (n = 85), and placebo (n = 43). By Week 12, patients experienced large improvements in sleep interference, with least square mean (standard error) changes from baseline (CFB) in SIS7 of −7.84 (0.58), −7.55 (0.61), −6.98 (0.60), and −5.85 (0.81), respectively. By Week 12, CFB in AIS7 were −8.25 (0.57), −8.25 (0.59), −7.30 (0.60), and −5.62 (0.79), DLQI scores were −9.79 (0.77), −9.93 (0.81), −8.35 (0.79), and −6.99 (1.11), and Overall Work Impairment scores were −28.96 (3.73), −30.76 (3.71), −25.74 (3.91), and −20.13 (5.10) for ligelizumab 72 and 240 mg, omalizumab 300 mg and placebo, respectively. Improvements in each patient‐reported outcome were sustained with ligelizumab 240 mg treatment during the extension study.
Conclusions
Ligelizumab showed effective and sustained responses in managing sleep interference in patients with CSU, and numerically higher responses than with omalizumab and placebo. Treating the symptoms of CSU with ligelizumab improved disease burden, HRQoL, and markedly improved sleep quality.
Ligelizumab for Chronic Spontaneous Urticaria Maurer, Marcus; Giménez-Arnau, Ana M.; Sussman, Gordon ...
New England journal of medicine/The New England journal of medicine,
10/2019, Letnik:
381, Številka:
14
Journal Article
Two pivotal, randomized, double-blind studies in a chronic dermatology disease were ongoing when the COVID-19 pandemic broke out. The trials had identical design, with four parallel treatment arms: ...two doses of active drug, an active comparator and placebo. When recruitment was temporarily halted due to the pandemic, both trials had already achieved over 80% of the targeted sample size. The unprecedented and unpredictable dynamic of the pandemic caused concerns about potential risks to data integrity and interpretability, which needed to be addressed. In this article, we describe some of these challenges and mitigation strategies. In particular, the complex confirmatory situation involving multiple active doses, endpoints and comparators led to a careful modification of the testing scheme to maintain the power of key endpoints and comparisons while still controlling the relevant Type I error rates. Specifically, the strategy was adjusted to perform some lower-level statistical tests in the hierarchy on the pool of both studies, taking advantage of the replicate study design. Primary endpoint comparisons against placebo and active control remained separately by study. In this article, we share our ideas and experiences in devising this risk mitigation proposal for the statistical methodology of these pivotal trials during the COVID-19 pandemic.
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.
A total of 226 patients received ligelizumab 240 mg for 52 weeks. Overall, 84.1% of patients experienced at least one TEAE. After 52 weeks of treatment, 53.1% of patients had a complete response and 75.8% of patients had cumulative complete responses. The long‐term safety profile of ligelizumab 240 mg in patients was consistent with the core study and re‐treatment efficacy was shown.Abbreviations: BAS, basophil; CSU, chronic spontaneous urticaria; FcεRI, Fc epsilon receptor 1; IgE, immunoglobulin E; MC, mast cell; MoA, mechanism of action; TEAE, treatment‐emergent adverse event; UAS7, weekly urticaria activity score; UAS7 = 0, complete response; UAS7 ≤ 6, minimal disease activity
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