Theodore A. Omachi

A randomized multicenter study evaluating Xolair persistence of response after long-term therapy

Background Few data are available to assist clinicians with decisions regarding long‐term use of asthma therapies, including omalizumab. Objective We sought to evaluate the benefit and persistence of response in subjects continuing or withdrawing from long‐term omalizumab treatment. Methods Evaluating the Xolair Persistency Of Response After Long‐Term Therapy (XPORT) was a randomized, double‐blind, placebo‐controlled withdrawal study that included subjects with moderate‐to‐severe persistent asthma receiving long‐term omalizumab. Subjects were randomized by using a hierarchical dynamic randomization scheme to continue their same dose of omalizumab or withdraw to placebo and were then followed every 4 weeks for 1 year. The primary outcome was any protocol‐defined severe asthma exacerbation. The secondary outcome was time to first protocol‐defined severe asthma exacerbation. Exploratory outcomes included changes in Asthma Control Questionnaire and Asthma Control Test scores. Results Significantly more subjects in the omalizumab group (67%) had no protocol‐defined exacerbation than in the placebo group (47.7%); an absolute difference of 19.3% (95% CI, 5.0%, 33.6%) represents a 40.1% relative difference. Time to first protocol‐defined exacerbation analysis revealed a significantly different between‐group exacerbation pattern that was consistent with the primary analysis. Subjects continuing omalizumab had significantly better asthma control (mean [SD] change from baseline to week 52: Asthma Control Test score, −1.16 [4.14] vs placebo, −2.88 [5.38], P = .0188; Asthma Control Questionnaire score, 0.22 [0.66] vs placebo, 0.63 [1.13], P = .0039). Discontinuation of omalizumab was associated with an increase in free IgE levels and an increase in basophil expression of the high‐affinity IgE receptor. No safety concerns were noted. Conclusion Continuation of omalizumab after long‐term treatment results in continued benefit, as evidenced by improved symptom control and reduced exacerbation risk.

Risk of corticosteroid-related adverse events in asthma patients with high oral corticosteroid use.

BACKGROUND Oral corticosteroids (OCS) are a mainstay of asthma treatment. Their use increases the risk of various corticosteroid-related adverse events, but the extent of risk is poorly characterized. OBJECTIVE To determine the incremental risk of possible corticosteroid-related adverse events (AE) in asthma among patients with high OCS use compared with patients who do not use OCS. METHODS Patients with asthma in a commercial health care claims data base who were high-OCS users (≥30 days of OCS use annually) were matched to no-OCS users by age, sex, and geographic region, and the presence or absence of chronic obstructive pulmonary disease (COPD) as a comorbidity. We examined bone-related conditions, pneumonia, opportunistic infections, diabetes mellitus, and other disorders as potential AEs by using χ(2) tests to compare potential AE prevalence between the cohorts, with and without stratification by a COPD diagnosis. We controlled for the number of inhaled steroids (ICS) canisters filled. RESULTS A total of 3604 patients with asthma and high OCS use were matched to 3604 patients who did not use OCS (mean age, 54.4; 68.1% female; 44.9% with COPD). Patients with high OCS use had statistically significantly higher rates of any potential AE compared with patients who did not use OCS (83.5% versus 78.1%), (p < 0.001). Rates of individual potential AEs were also higher in patients who used higher doses of OCS. Patterns of AEs were similar in patients with and those without COPD, with statistically significantly higher overall AE risk and individual risks in high-OCS users. The number of ICS canisters filled was not a significant predictor of AE. CONCLUSION Patients with asthma who were treated with OCS for ≥30 days per year have a greater overall risk of possible corticosteroid-related AEs compared with those patients with no OCS use, whether or not they had COPD.

Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study in moderate to severe asthma

Background: EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long‐term safety of omalizumab in an observational setting, focusing predominantly on malignancies. Objective: The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. Methods: Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. Results: At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non‐omalizumab group (50% vs 23%). Omalizumab‐treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non–omalizumab‐treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non‐omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91–1.91). Conclusion: This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non‐omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded.

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

the distribution of immune cells in children after spontaneous natural birth (Fig 2, D). No direct significant association was observed between gestational age and cord blood immune cell frequencies (data not shown). Collectively, the profile of circulating innate and adaptive immune cells was observed to differ between neonates delivered by prelabor C-section and natural birth. To our knowledge, this is the first study to identify gestational age to be inversely correlated to the C-section–associated immune cell distribution within prelabor C-section–delivered newborns. This gestational age– associated immune cell pattern implies that factors relating to pregnancy affect the fetal immune cell profile in a gradual manner during the final weeks of pregnancy, and this suggests the occurrence of immune programming alongside the onset of labor in term children. The link between C-section and increased risk of immune-mediated diseases is generally thought to be due to different bacterial colonization patterns dependent on the route of delivery. On the basis of our results, we propose that absence of labor-related in utero immune programming in prelabor C-section–born children may be a contributing factor to the reported association between C-section and immune-mediated diseases. Further understanding of these processes may help to understand and prevent unwanted effects of C-section in relation to disease programming of the child.

Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE)

Background: Interleukin (IL)‐13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). Objective: We investigated the efficacy and safety of lebrikizumab, an IL‐13 monoclonal antibody, as an add‐on to topical corticosteroid (TCS) treatment. Methods: A randomized, placebo‐controlled, double‐blind, phase 2 study. Adults with moderate‐to‐severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2‐week TCS run‐in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)‐50 at week 12. Results: In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI‐50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI‐50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate. Limitations: Protocol‐mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long‐term efficacy or safety evaluations. Conclusion: When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate‐to‐severe AD.

Response to omalizumab using patient enrichment criteria from trials of novel biologics in asthma

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.

Health care resource use and costs associated with possible side effects of high oral corticosteroid use in asthma: a claims-based analysis.

Background The objective of this study was to estimate the prevalence of possible oral corticosteroid (OCS)-related side effects and health care resource use and costs in patients with asthma. Methods This was a cross-sectional, matched-cohort, retrospective study using a commercial claims database. Adults with asthma diagnosis codes and evidence of asthma medication use were studied. Patients with high OCS use (≥30 days of OCS annually) were divided into those who did versus those who did not experience OCS-related possible side effects. Their health care resource use and costs were compared using linear regression or negative binomial regression models, adjusting for age, sex, geographic region, Charlson Comorbidity Index score, and chronic obstructive pulmonary disease status. Results After adjustment, high OCS users with possible side effects were more likely to have office visits (23.0 vs 19.6; P<0.001) and hospitalizations (0.44 vs 0.22; P<0.001) than those without possible side effects. Emergency department visits were similar between the groups. High OCS users with possible side effects had higher adjusted total annual mean health care costs (

Corticosteroid-related toxicity in patients with chronic idiopathic urticaria‐chronic spontaneous urticaria

25,168) than those without such side effects (

Developing drugs for treatment of atopic dermatitis in children (≥3 months to <18 years of age): Draft guidance for industry

21,882; P=0.009). Conclusion Among high OCS users, patients with possible OCS-related side effects are more likely to use health care services than those without such side effects. Although OCS may help control asthma and manage exacerbations, OCS side effects may result in additional health care resource use and costs, highlighting the need for OCS-sparing asthma therapies.

Timing and duration of omalizumab response in patients with chronic idiopathic/spontaneous urticaria

BACKGROUND Treatments for patients with chronic idiopathic urticaria (CIU)-chronic spontaneous urticaria (CSU) who were unresponsive to antihistamines include oral corticosteroids (OCS). Risks of OCS-related side effects in these patients have not been described quantitatively. OBJECTIVE To investigate the relationship between OCS use and the risk of developing side effects possibly attributable to OCS and associated health care costs in privately insured patients with CIU/CSU. METHODS This retrospective cohort study analyzed a commercial claims data base from January 1, 2008, to December 31, 2012. Patients with CIU/CSU were identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes via a validated algorithm. Possible OCS-related side effects included the following: diabetes mellitus, hypertension, lipid disorders, cataracts, depression or mania, osteoporosis or fractures, and infectious diseases. A time-dependent Cox regression (adjusted for age, sex, Charlson Comorbidity Index, and immunomodulator use) was used to separately model cumulative oral prednisone-equivalent exposure and the risk of side effects. Incremental total adjusted health care costs were compared in patients with versus patients without possible OCS-related side effects. RESULTS Among 12,647 patients with CIU/CSU, 55.4% used OCS. An additional 1 g of prednisone-equivalent exposure was associated with a 7% increase in the likelihood of developing a possible side effect (hazard ratio, 1.07 [95% confidence interval, 1.05-1.08]). From the period before to the period after OCS initiation, the total mean adjusted annual health care costs increased by