Background Chronic spontaneous urticaria (CSU) is defined by itchy hives, angioedema, or both for at least 6 weeks. Omalizumab, an anti-IgE antibody that affects mast cell and basophil function, is a ...promising new treatment option. As of now, however, the efficacy and safety of different doses of omalizumab used in clinical trials for CSU have not been systematically analyzed and summarized. Objective We sought to assess the efficacy and safety of different doses of omalizumab for the treatment of CSU in a meta-analysis of clinical trial results. Methods Suitable trials were identified by searching PubMed, Medline, Embase, and Web of Science databases and with the help of omalizumab's manufacturers. Only double-blind, randomized, placebo-controlled studies with omalizumab-treated versus placebo-treated patients with CSU were included in this analysis. Results We identified 7 randomized, placebo-controlled studies with 1312 patients with CSU. Patients treated with omalizumab (75-600 mg every 4 weeks) had significantly reduced weekly itch and weekly wheal scores compared with the placebo group. Omalizumab's effects were dose dependent, with the strongest reduction in weekly itch and weekly wheal scores observed with 300 mg. Rates of complete response were significantly higher in the omalizumab group (relative risk, 4.55; P < .00001) and dose dependent, with the highest rates in the 300-mg group. Rates of patients with adverse events were similar in the omalizumab and placebo groups. Conclusion This meta-analysis provides high-quality evidence for the efficacy and safety of omalizumab in patients with CSU and for treating these patients with 300 mg of omalizumab every 4 weeks.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with ...CRSwNP and comorbid asthma previously.
Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2).
Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events.
Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, –1.08 versus 0.06 (P < .0001) and –0.90 versus –0.31 (P = .0140); Nasal Congestion Score, –0.89 versus –0.35 (P = .0004) and –0.70 versus –0.20 (P = .0017); and SNOT-22 score, –24.7 versus –8.6 (P < .0001) and –21.6 versus –6.6 (P < .0001). Adverse events were similar between groups.
Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.
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Background
Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes.
Objective
To assess if patients eligible for both biologics but not optimally controlled ...with omalizumab experience improved asthma control when switched directly to mepolizumab.
Methods
OSMO was a multicenter, open‐label, single‐arm, 32‐week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high‐dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)‐5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ‐5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ‐5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period.
Results
At Week 32 (intent‐to‐treat population n = 145), the least squares (LS) mean changes (standard error SE) in ACQ‐5 and SGRQ total scores were −1.45 (0.107) and −19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ‐5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials.
Conclusion
After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported.
Minimal clinically important difference for improvement in asthma control questionnaire‐5 and St. George's Respiratory Questionnaire total scores was achieved by 77% and 79% of patients, respectively. Annualized rate of clinically significant exacerbations was reduced from 3.26 to 1.18 events/year. Safety and immunogenicity profiles of mepolizumab were consistent with previous placebo‐controlled trials in severe eosinophilic asthma.
Immunoglobulin E and its interactions with receptors FcɛRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between ...IgE and FcɛRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cɛ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cɛ3 domains that inhibit the interaction with FcɛRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cɛ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcɛRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcɛRI, exploiting the intrinsic flexibility and allosteric potential of IgE.
Allergic inflammation has been linked to increased susceptibility to viral illnesses, but it is unclear whether this association is causal.
To test whether omalizumab treatment to reduce IgE would ...shorten the frequency and duration of rhinovirus (RV) illnesses in children with allergic asthma.
In the PROSE (Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations) study, we examined children with allergic asthma (aged 6-17 yr; n = 478) from low-income census tracts in eight U.S. cities, and we analyzed virology for the groups randomized to treatment with guidelines-based asthma care (n = 89) or add-on omalizumab (n = 259). Weekly nasal mucus samples were analyzed for RVs, and respiratory symptoms and asthma exacerbations were recorded over a 90-day period during the fall seasons of 2012 or 2013. Adjusted illness rates (illnesses per sample) by treatment arm were calculated using Poisson regression.
RVs were detected in 97 (57%) of 171 exacerbation samples and 2,150 (36%) of 5,959 nonexacerbation samples (OR, 2.32; P < 0.001). Exacerbations were significantly associated with detection of rhinovirus C (OR, 2.85; P < 0.001) and rhinovirus A (OR, 2.92; P < 0.001), as well as, to a lesser extent, rhinovirus B (OR, 1.98; P = 0.019). Omalizumab decreased the duration of RV infection (11.2 d vs. 12.4 d; P = 0.03) and reduced peak RV shedding by 0.4 log units (95% confidence interval, -0.77 to -0.02; P = 0.04). Finally, omalizumab decreased the frequency of RV illnesses (risk ratio, 0.64; 95% confidence interval, 0.49-0.84).
In children with allergic asthma, treatment with omalizumab decreased the duration of RV infections, viral shedding, and the risk of RV illnesses. These findings provide direct evidence that blocking IgE decreases susceptibility to RV infections and illness. Clinical trial registered with www.clinicaltrials.gov (NCT01430403).
We reviewed 24 ‘real‐life’ effectiveness studies of omalizumab in the treatment of severe allergic asthma that included 4117 unique patients from 32 countries with significant heterogeneity in ...patients, clinicians and settings. The evidence underscores the short‐ and long‐term benefit of anti‐IgE therapy in terms of the following: improving lung function; achieving asthma control and reducing symptomatology, severe exacerbations and associated work/school days lost; reducing healthcare resource utilizations, in particular hospitalizations, hospital lengths of stay and accident specialist or emergency department visits; reducing or discontinuing other asthma medications; and improving quality of life – thus confirming, complementing and extending evidence from randomized trials. Thus, omalizumab therapy is associated with signal improvements across the full objective and subjective burden of illness chain of severe allergic asthma. Benefits of omalizumab may extend up to 2–4 years, and the majority of omalizumab‐treated patients may benefit for many years. Omalizumab has positive short‐ and long‐term safety profiles similar to what is known from randomized clinical trials. Initiated patients should be monitored for treatment response at 16 weeks. Those showing positive response at that time are highly likely to show sustained treatment response and benefit in terms of clinical, quality of life and health resource utilization outcomes.
Background
Chronic spontaneous urticaria (CSU) severely impacts quality of life (QoL), especially in patients with wheals and angioedema. Omalizumab is approved as add‐on therapy for CSU patients; ...however, its effect on patients who are double‐positive for wheals and angioedema has not been systematically studied.
Objective
The primary objective was to evaluate the efficacy of omalizumab vs placebo at week 28 using the Chronic Urticaria Quality of Life (CU‐Q2oL) questionnaire. Number of angioedema‐burdened days, time interval between successive angioedema episodes, disease activity, angioedema‐specific and overall QoL impairment were secondary objectives.
Methods
X‐ACT was a phase III, randomized, double‐blind study conducted in 24 centres (Germany), which selectively included CSU patients with angioedema and wheals. Patients were randomized (1 : 1) to omalizumab 300 mg or placebo (every 4 weeks up to week 24) (ClinicalTrials.gov number: NCT01723072).
Results
Of the 91 patients randomized to omalizumab (n = 44) or placebo (n = 47) at baseline, 68 completed the 28‐week treatment phase (omalizumab, 35; placebo, 33). Omalizumab was superior to placebo in improving CU‐Q2oL scores at week 28 (P < 0.001). There was a threefold improvement in angioedema‐burdened days/week with omalizumab (0.3) vs placebo (1.1). The median time to first recurrence of angioedema was 57–63 days with omalizumab and <5 days with placebo. Omalizumab significantly improved angioedema‐specific QoL (P < 0.001). The adverse events reported are in line with the established safety profile of omalizumab.
Conclusion
Omalizumab was an effective treatment option for patients with moderate‐to‐severe CSU symptoms and angioedema unresponsive to high doses of antihistamine treatment.
Background Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure. Objective We sought to compare (1) omalizumab with placebo and (2) ...omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school. Methods A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations ( clincaltrials.gov # NCT01430403 ). Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined. Results Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio OR, 0.48; 95% CI, 0.25-0.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33-1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02-0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002-0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88). Adverse events were rare and similar among arms. Conclusions Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.
Background
Patients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator‐related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment ...in other MC‐driven diseases, but experiences in SM are limited.
Objective
To assess the efficacy and safety of omalizumab in SM.
Methods
In our patient cohort, we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow‐up. Quality of life was assessed by visual analogue scale. S‐tryptase and KIT D816V allele burden were monitored.
Results
A total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM, and 1 ASM‐AHN) received omalizumab with a median duration of 17 months (range: 1‐73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients, we observed a significant reduction in symptoms, with complete symptom control in five (38.5%), major response in three (23.1%), and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side‐effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. Patient‐reported quality of life showed significant improvement. No significant changes in s‐tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded.
Conclusions
Omalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator‐related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings.
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