Background
Recent efficacy studies of asthma biologics have included highly enriched patient populations. Using a similar approach, we examined factors that predict response to omalizumab to ...facilitate selection of patients most likely to derive the greatest clinical benefit from therapy.
Methods
Data from two phase III clinical trials of omalizumab in patients with allergic asthma were examined. Differences in rates of asthma exacerbations between omalizumab and placebo groups during the 16‐week inhaled corticosteroid (ICS) dose‐stable phase were evaluated with respect to baseline blood eosinophil counts (eosinophils <300/μL low vs ≥300/μL high) and baseline markers of asthma severity (emergency asthma treatment in prior year, asthma hospitalization in prior year, forced expiratory volume in 1 second FEV1; FEV1 <65% vs ≥65% predicted, inhaled beclomethasone dipropionate dose <600 vs ≥600 μg/day, and long‐acting beta‐agonist LABA use yes/no).
Results
Adults/adolescents (N = 1071) were randomized to receive either omalizumab (n = 542) or placebo (n = 529). In the 16‐week ICS dose‐stable phase, rates of exacerbations requiring ≥3 days of systemic corticosteroid treatment were 0.066 and 0.147 with omalizumab and placebo, respectively, representing a relative rate reduction in omalizumab‐treated patients of 55% (95% CI, 32%‐70%; P = .002). For patients with eosinophils ≥300/μL or with more severe asthma, this rate reduction was significantly more pronounced.
Conclusion
In patients with allergic asthma, baseline blood eosinophil levels and/or clinical markers of asthma severity predict response to omalizumab.
Asthma is one of the most common chronic diseases of childhood. Allergen sensitization and high frequencies of comorbid allergic diseases are characteristic of severe asthma in children. Omalizumab, ...an anti-IgE mAb, is the first targeted biologic therapeutic approved for the treatment of moderate-to-severe persistent allergic asthma (AA) that remains uncontrolled despite high-dose inhaled corticosteroids plus other controller medications. Since its initial licensing for use in adults and adolescents 12 years of age and older, the clinical efficacy, safety, and tolerability of omalizumab have been demonstrated in several published clinical trials in children aged 6 to less than 12 years with moderate-to-severe AA. These studies supported the approval of the pediatric indication (use in children aged ≥6 years) by the European Medicines Agency in 2009 and the US Food and Drug Administration in 2016. After this most recent change in licensing, we review the outcomes from clinical trials in children with persistent AA receiving omalizumab therapy and observational studies from the past 7 years of clinical experience in Europe. Data sources were identified by using PubMed in 2016. Guidelines and management recommendations and materials from the recent US Food and Drug Administration's Pediatric Advisory Committee meeting are also reviewed.
In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate ...the efficacy of DrotAA for adults who had severe sepsis and a low risk of death.
We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation APACHE II score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected.
Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01).
The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.
...party writing assistance was provided by Linda Wagner, PharmD, of Envision Pharma Group (Excel Scientific Solutions, Inc), and funded by Genentech, Inc, and Novartis Pharmaceuticals Corporation. ...Safety AEs of special interest included anaphylactic events, as defined by the National Institute of Allergy and Infectious Disease criteria,E4 related to omalizumab; suspected transmission of an infectious agent by the study drug; and cases of potential drug-induced liver injury. Table E1 Demographic and clinical characteristics of patients participating in the double-blind period Characteristic Omalizumab (n = 81) Placebo (n = 53) At baseline (day 1) Age (y), mean ± SD 43.1 ± 14.7 48.5 ± 13.2 Sex: female, n (%) 60 (74.1) 40 (75.5) Race, n (%) White 68 (84.0) 42 (79.2) Black 6 (7.4) 7 (13.2) Asian 2 (2.5) 3 (5.7) American Indian or Alaska Native 2 (2.5) 0 Other 3 (3.7) 1 (1.9) Body mass index (kg/m2), mean ± SD 29.8 ± 6.3 30.8 ± 7.7 Duration of CIU/CSU symptoms (mo), mean ± SD 77.0 ± 118.8 73.6 ± 67.3 Systemic corticosteroids for symptoms, n (%)∗ 37 (45.7) 23 (43.4) Weekly itch severity score, mean ± SD 15.7 ± 3.6 16.0 ± 3.5 Weekly no. of hives score, mean ± SD 16.7 ± 4.6 16.9 ± 4.5 No. of days with angioedema in the past wk, mean ± SD 1.8 ± 2.6 2.8 ± 3.0 UAS7, mean ± SD 32.4 ± 7.2 32.9 ± 7.0 DLQI score, mean ± SD 14.5 ± 6.7 16.0 ± 7.1 In-clinic UAS, mean ± SD 4.8 ± 1.2 4.8 ± 1.1 Smoker, current or former, n (%) 16 (19.8) 12 (22.6) At randomization (week 24) Weekly itch severity score, mean ± SD 0.4 ± 0.8 0.5 ± 1.1 Weekly no. of hives score, mean ± SD 0.3 ± 0.7 0.3 ± 0.8 No. of days with angioedema in the past wk, mean ± SD 0.0 ± 0.1 0.0 ± 0.2 UAS7, mean ± SD 0.6 ± 1.4 0.9 ± 1.6 DLQI score, mean ± SD 0.7 ± 1.5 1.2 ± 2.8 In-clinic UAS, mean ± SD 0.6 ± 1.3 0.6 ± 1.4 Table E2 TEAEs causally related to the study drug∗ Values given as n (%) unless otherwise noted.TEAE, Treatment-emergent adverse event. Patient Comorbidities History of anaphylaxis Allergies Previous omalizumab exposure Event description All patients (N = 205) 46 y-old woman CIU; angioedema; mild, intermittent asthma; possible viral illness N N N 9 h after first dose developed headache, malaise, worsening of hives, itchy throat, stomach cramps, wheezing, and cough, which escalated Self-injected epinephrine and went to the ED TEAE, n 8 1 7 16 1 A. Kaplan, D. Ledford, M. Ashby, J. Canvin, J.L. Zazzali, E. Conner, J Allergy Clin Immunol, Vol. 132, 2013, 101-109 2 M. Maurer, K. Rosén, H.J. Hsieh, S. Saini, C. Grattan, A. Gimenéz-Arnau, Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria, N Engl J Med, Vol. 368, 2013, 924-935 3 S.S. Saini, C. Bindslev-Jensen, M. Maurer, J.J. Grob, E. Bülbül Baskan, M.S. Bradley, 1, antihistamines: a randomized, placebo-controlled study, J Invest Dermatol, Vol. 135, 2015, 925 4 S.D. Mathias, E.A. Tschosik, J.L. Zazzali, Adaptation and validation of the Urticaria Patient Daily Diary for adolescents, Allergy Asthma Proc, Vol. 33, 2012, 186-190 5 S.D. Mathias, S.C. Dreskin, A. Kaplan, S.S. Saini, S. Spector, K.E. Rosén, Development of a daily diary for patients with chronic idiopathic urticaria, Ann Allergy Asthma Immunol, Vol. 105, 2010, 142-148 6 A.Y. Finlay, G.K. Khan, Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use, Clin Exp Dermatol, Vol. 19, 1994, 210-216
The human genome is extensively folded into 3-dimensional organization. However, the detailed 3D chromatin folding structures have not been fully visualized due to the lack of robust and ...ultra-resolution imaging capability. Here, we report the development of an electron microscopy method that combines serial block-face scanning electron microscopy with in situ hybridization (3D-EMISH) to visualize 3D chromatin folding at targeted genomic regions with ultra-resolution (5 × 5 × 30 nm in xyz dimensions) that is superior to the current super-resolution by fluorescence light microscopy. We apply 3D-EMISH to human lymphoblastoid cells at a 1.7 Mb segment of the genome and visualize a large number of distinctive 3D chromatin folding structures in ultra-resolution. We further quantitatively characterize the reconstituted chromatin folding structures by identifying sub-domains, and uncover a high level heterogeneity of chromatin folding ultrastructures in individual nuclei, suggestive of extensive dynamic fluidity in 3D chromatin states.
For patients with moderate-to-severe persistent allergic asthma, omalizumab is approved for subcutaneous administration according to a recommended dosing table based on weight and total ...immunoglobulin E (IgE) level. The aim of this analysis was to assess asthma outcomes including quality of life in patients with allergic asthma initiated on omalizumab in the PROSPERO trial; patients were stratified by where their IgE and body weight fell on the approved dosing table. Patient groups were defined as Inside Dosing Table: patients whose IgE and weight fell within the approved dosing table (n = 506); Insufficient Data to Recommend a Dose: patients who fell into the section of the approved dosing table where not enough clinical data were available to make dosing recommendations (n = 72); and Outside Dosing Table: patients who fell outside the approved dosing table due to baseline IgE and/or weight (n = 209). Overall, asthma and quality of life outcomes were improved after omalizumab initiation for both patients who fall within the recommended dosing table or those who fall outside the recommended dosing table. Our results suggest that omalizumab treatment may be effective in a wide range of patients with moderate-to-severe allergic asthma.
ClinicalTrials.gov identifier NCT01922037.
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•Omalizumab is approved for the treatment of moderate-to-severe allergic asthma.•In the US, omalizumab is given by a dosing table based on IgE levels and weight.•We found omalizumab improved asthma for patients inside or outside the dosing table.•Therefore, omalizumab may help a wide range of patients with asthma.
Omalizumab has demonstrated efficacy in clinical trials of patients with asthma, but real-world data are needed.
To assess outcomes after omalizumab initiation in patients with asthma in a real-world ...setting.
Patients aged 12 years and older with allergic asthma who were candidates for omalizumab on the basis of physician-assessed need were enrolled in a US-based, prospective, single-arm, 48-week multicenter study, the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab. Monthly assessments included exacerbations, health care utilization, asthma control test (ACT), and adverse events. At baseline, 6 months, and end of study, biomarkers (blood eosinophils and fractional exhaled nitric oxide) were collected and spirometry performed.
Of 806 enrollees, 801 (99.4%) received omalizumab and 622 (77.2%) completed the study. The exacerbation rate significantly improved from a mean of 3.00 ± 3.28 in the 12 months before baseline to 0.78 ± 1.37 through month 12 (P < .001) and was similar in adults and adolescents; there was a reduction of 81.9% in the percentage of patients with 1 or more hospitalizations. Lung function remained generally unchanged. A mean improvement of 4.4 ± 4.9 in ACT scores was observed. Eighty-seven percent of patients were responders on the basis of clinical improvement in exacerbations, lung function, or ACT scores. Baseline biomarker status was associated with ACT scores and lung function improvement, but the magnitude of this improvement was not clinically relevant. No new safety signals emerged.
Omalizumab initiation in patients with asthma resulted in improved exacerbation rates, reduced hospitalizations, and improved ACT scores compared with pretreatment values, regardless of biomarker status.
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