Comparative effectiveness of dupilumab and omalizumab on asthma exacerbations and systemic corticosteroid prescriptions: Real-world US ADVANTAGE study.

BACKGROUND: In the United States, dupilumab is approved for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma, and omalizumab is approved for managing moderate-to-severe allergic asthma uncontrolled by inhaled corticosteroids. However, limited comparative effectiveness data exist for these biologics due to differing patient characteristics and treatment histories. OBJECTIVE: This study assessed the real-world effectiveness of dupilumab and omalizumab for asthma in patients in the United States. METHODS: In this retrospective observational study, TriNetX Dataworks electronic medical record data were used to identify patients with asthma age ≥12 years who initiated (index) dupilumab or omalizumab between November 2018 and September 2020 and who had at least 12 months of pre- and post-index clinical information. Inverse probability of treatment weighting was applied to balance potential confounding in treatment groups. Asthma exacerbation rates and systemic corticosteroid (SCS) prescriptions were compared using a doubly robust negative binomial regression model, adjusting for baseline exacerbation/SCS rates and patient characteristics with ≥10% standardized differences after inverse probability of treatment weighting. RESULTS: All inclusion and exclusion criteria were met by 2138 dupilumab patients and 1313 omalizumab patients. After weighting, the majority of baseline characteristics were balanced (standard difference <10%) between the 2 groups. Dupilumab was associated with a 44% lower asthma exacerbation rate (P < .0001) versus omalizumab. Additionally, dupilumab treatment significantly (P < .05) reduced SCS prescriptions by 28% during the follow-up period compared with omalizumab treatment. CONCLUSIONS: The US ADVANTAGE real-world study demonstrated a significant reduction in severe asthma exacerbations and SCS prescriptions for patients prescribed dupilumab compared with patients prescribed omalizumab during 12 months of follow-up.

Dupilumab sustains efficacy in patients with moderate-to-severe type 2 asthma regardless of inhaled corticosteroids dose.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins-4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long-term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL). METHODS: Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1 ), 5-item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. RESULTS: Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high-dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313-0.494). Improvements in pre-BD FEV1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. CONCLUSIONS: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

[Pharmacoeconomics analysis of using a fixed combination of budesonide/formoterol in patients with asthma in the health care system of the Russian Federation].

AIM: To evaluate the budgetary impact of using budesonide + formoterol (Symbicort Turbuhaler) as maintenance therapy in real clinical practice compared with standard therapy for asthma of varying severity: for mild asthma with on-demand salbutamol; for moderate and severe asthma with the drug salmeterol + fluticasone and salbutamol on demand. MATERIALS AND METHODS: A static mathematical model was built to assess the impact on the budget when introducing the drug budesonide + formoterol (Symbicort Turbuhaler) in the treatment of asthma into clinical practice from the point of view of the state. Demographic data was taken from the official data of the Federal State Statistics Service. Direct medical costs included the cost of medicines, the cost of hospitalization of patients associated with the development of asthma exacerbations, and the cost of scheduled outpatient visits. Indirect costs considered the loss of GDP due to hospitalization of patients against the background of asthma exacerbations. A one-way sensitivity analysis was performed to confirm the robustness of the study results. RESULTS: Assessment of direct costs in the treatment of mild, moderate and severe asthma showed that a gradual increase in the proportion of patients receiving the drug budesonide + formoterol (Symbicort Turbuhaler) over the years to 5.5, 7.7 and 9.7% accordingly, led to an increase in the cost of pharmacotherapy over 3 years by 1.7 billion rubles, while direct non-drug costs associated with the treatment of complications that developed during the treatment of asthma decreased by 8.3 billion rubles. Thus, the reduction in total direct costs amounted to RUB 6.7 billion. At the same time, indirect costs decreased by 6.0 billion rubles. The total reduction in all costs (direct and indirect) when switching patients to budesonide + formoterol (Symbicort Turbuhaler) amounted to 12.5 billion rubles. In addition, the use of the drug budesonide + formoterol (Symbicort Turbuhaler) resulted in a decrease in the number of exacerbations: in the first year by 3137, in the second by 4393 and in the third by 5534 cases. A total of 13 064 asthma exacerbations were prevented over 3 years. CONCLUSION: Increasing the proportion of patients with asthma of varying severity receiving therapy with budesonide + formoterol (Symbicort Turbuhaler) will reduce the financial burden on both the healthcare system and the budgetary system.

Dupilumab is effective in type 2-high asthma patients receiving high-dose inhaled corticosteroids at baseline.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation. In phase 2b (NCT01854047) and phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200/300 mg every 2 weeks (q2w) reduced severe exacerbations, improved prebronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1 ) and quality of life measures, and it was generally well tolerated in patients with uncontrolled, persistent (phase 2b), or moderate-to-severe (phase 3) asthma. METHODS: In patients on high-dose inhaled corticosteroids (ICS) with type 2-high asthma (subgroups including baseline blood eosinophils ≥150/300 cells/µL and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb), annualized severe exacerbation rates over the treatment period, changes from baseline in pre-BD FEV1 and asthma control (5-item asthma control questionnaire [ACQ-5]) were analyzed. RESULTS: In high-dose ICS type 2-high subgroups, dupilumab 200/300 mg q2w vs placebo in the phase 2b (24 weeks) and phase 3 (52 weeks) studies significantly reduced severe exacerbations by 55%-69%/57%-60% (all P<.05) and 53%-69%/48%-66% (all P < .001), respectively, except in patients with ≥ 300 eosinophils/µL in phase 2b study (24%/50% (P = .52/0.15). Across subgroups, pre-BD FEV1 improved by 0.18-0.22 L/0.19-0.24 L (all P < .05) and 0.23-0.36 L/0.15-0.25 L (all P < .01) and ACQ-5 scores were reduced by 0.46-0.55/0.47-0.85 (all P < .05) and 0.38-0.50/0.24-0.30 (all P < .05), respectively, except dupilumab 200 mg q2w in phase 2b in patients with FeNO ≥ 25 ppb (0.41; P = .09). Dupilumab was also effective in patients taking medium-dose ICS. CONCLUSION: Dupilumab significantly reduced severe exacerbations and improved lung function and asthma control in patients with type 2-high asthma on high-dose ICS at baseline.

Efficacy and safety of omalizumab in children with moderate-to-severe asthma: a meta-analysis.

OBJECTIVE: To assess the efficacy and safety of omalizumab in children with moderate-to-severe asthma. DATA SOURCES: We systematically searched MEDLINE, EMBASE, and Cochrane for randomized controlled trials (RCTs ) (inception to January 2020). STUDY SELECTIONS: All RCTs which were conducted in childhood and adolescence with asthma and compared the efficacy or safety of omalizumab were adopted. RESULTS: Three studies with four publications including 1380 pediatric patients met our criteria. For children with moderate-to-severe asthma, omalizumab decreased asthma exacerbations rate (OR 0.51, 95% CI: 0.44-0.58, p < 0.001) compared with placebo with no evidence of heterogeneity. Omalizumab reduced the rate of asthma exacerbations 0.58) with treatment period ≥30 weeks (p for heterogeneity = 0.03). Omalizumab treated patients had an excellent or good response rate of treatment effectiveness assessed by physicians (2.75, 2.45-3.09) and a bigger reduction in the dosage of inhaled corticosteroid (ICS) at the end of follow-up. For children with severe asthma, omalizumab also reduced the likelihood of asthma exacerbations and increased the odd of treatment effectiveness rated as excellent or good. Patients receiving omalizumab had a lower incidence of severe adverse events (0.36, 0.22-0.57). CONCLUSIONS: These findings suggested that omalizumab had beneficial effects on moderate-to-severe asthma in children. Patients may benefit more from long-term use of omalizumab. In addition, omalizumab reduces the rate of serious adverse events requiring hospitalizations.

Pregnancy outcomes in the omalizumab pregnancy registry and a disease-matched comparator cohort.

BACKGROUND: The Observational Study of the Use and Safety of Xolair (omalizumab) during Pregnancy (EXPECT) pregnancy registry was a prospective observational study established in 2006 to evaluate perinatal outcomes in pregnant women exposed to omalizumab and their infants. OBJECTIVE: This analysis compares EXPECT outcomes with those from a disease-matched population of pregnant women not treated with omalizumab. Data from a substudy of platelet counts among newborns are also presented. METHODS: The EXPECT study enrolled 250 women with asthma exposed to omalizumab during pregnancy. The disease-matched external comparator cohort of women with moderate-to-severe asthma (n = 1153), termed the Quebec External Comparator Cohort (QECC), was created by using data from health care databases in Quebec, Canada. Outcome estimates were age adjusted based on the maternal age distribution of the EXPECT study. RESULTS: Among singleton infants in the EXPECT study, the prevalence of major congenital anomalies was 8.1%, which was similar to the 8.9% seen in the QECC. In the EXPECT study 99.1% of pregnancies resulted in live births, which was similar to 99.3% in the QECC. Premature birth was identified in 15.0% of EXPECT infants and 11.3% in the QECC. Small for gestational age was identified in 9.7% of EXPECT infants and 15.8% in the QECC. CONCLUSION: There was no evidence of an increased risk of major congenital anomalies among pregnant women exposed to omalizumab compared with a disease-matched unexposed cohort. Given the observational nature of this registry, however, an absence of increased risk with omalizumab cannot be definitively established.

Dupilumab efficacy and safety in Japanese patients with uncontrolled, moderate-to-severe asthma in the phase 3 LIBERTY ASTHMA QUEST study.

BACKGROUND: In the LIBERTY ASTHMA QUEST (ClinicalTrials.gov: NCT02414854) study, dupilumab 200 mg and 300 mg every 2 weeks vs matched-volume placebo reduced severe asthma exacerbations and improved lung function (FEV1), asthma control, and quality of life in patients with uncontrolled, moderate-to-severe asthma (N = 1902). Here, we examine the safety and efficacy of dupilumab in the subpopulation of Japanese patients who participated in QUEST (n = 114; 6%). METHODS: Endpoints assessed were annualized severe exacerbation rates and the effect of treatment over the 52-week treatment period on FEV1, asthma control, asthma-related quality of life, and markers of type 2 inflammation. RESULTS: In Japanese patients, dupilumab 200 and 300 mg every 2 weeks vs matched placebo reduced severe asthma exacerbation rates by 44% (P = 0.33) and 75% (P = 0.03), respectively, and improved FEV1 at Week 12 by 0.20 L (P = 0.05) and 0.17 L (P = 0.12). FEV1 improvements were rapid (by Week 2) and sustained throughout treatment. Significant and/or numerical improvements vs placebo in asthma control and quality of life were also observed throughout treatment. For each endpoint, greater efficacy was observed in patients with elevated baseline levels of type 2 inflammatory biomarkers (blood eosinophils or FeNO). Dupilumab treatment significantly reduced levels of FeNO and total IgE, but not blood eosinophils. CONCLUSIONS: In this subanalysis of QUEST, the efficacy and safety of dupilumab in Japanese patients was comparable to that observed in the overall intention-to-treat population, suggesting no variability in efficacy on the basis of Japanese ethnicity. (Funded by Sanofi and Regeneron Pharmaceuticals, Inc.; ClinicalTrials.gov number: NCT02414854).

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.

Efficacy and safety of ipratropium bromide/albuterol compared with albuterol in patients with moderate-to-severe asthma: a randomized controlled trial.

BACKGROUND: Many patients with asthma require frequent rescue medication for acute symptoms despite appropriate controller therapies. Thus, determining the most effective relief regimen is important in the management of more severe asthma. This study's objective was to evaluate whether ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks. METHODS: In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were randomized to two sequences of study medication "as needed" for symptom relief (1-7 day washout before second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence, 6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV1 area under the curve (AUC0-6) and peak (post-dose) forced expiratory volume in 1 s (FEV1) response (change from test day baseline) after 4 weeks. The effects of "as needed" treatment with ALB-HFA/CVT-MDI were analyzed using mixed effect model repeated measures (MMRM). RESULTS: A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit of CVT-MDI versus ALB-HFA. FEV1 AUC0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI (p <0.0001); peak FEV1 response was 357 ml for ALB-HFA, 434 ml for CVT-MDI (p <0.0001). Adverse events were comparable across groups. CONCLUSIONS: CVT-MDI significantly improved acute bronchodilation over ALB-HFA alone after 4 weeks of "as-needed" use for symptom relief, with a similar safety profile. This suggests additive bronchodilator effects of ß2-agonist and anticholinergic treatment in moderate-to-severe, symptomatic asthma. TRIAL REGISTRATION: ClinicalTrials.gov No.: NCT00818454 ; Registered November 16, 2009.

Optimal step-down approach for pediatric asthma controlled by salmeterol/fluticasone: A randomized, controlled trial (OSCAR study).

BACKGROUND: Several guidelines, including the Japanese Pediatric Guideline for the Treatment and Management of Asthma (JPGL), recommend salmeterol/fluticasone combination therapy (SFC) as step 3 to 4 treatment for moderate to severe asthma. However, the optimal step-down approach to SFC remains unclear. In the current study, we examined step-down approaches in asthmatic children whose symptoms had been stabilized by SFC 100/200 µg/day. METHODS: This randomized, multicenter, open-label, parallel-group study was conducted over 12 weeks. For step-down therapy, subjects aged 5-15 years were randomly assigned to an SFC group (25/50 µg b.i.d.) or an FP group (100 µg b.i.d.), and treated for 12 weeks. Childhood Asthma Control Test (C-ACT) scores, lung function, and exhaled nitric oxide (FeNO) levels were monitored. RESULTS: Of 131 enrolled subjects, 128 completed the study and were included in the analysis. Decreases in % peak expiratory flow rate and % forced expiratory flow at 50% of vital capacity (V50) were observed in the FP group at each time point. There was a significant difference between the two groups for the change in %V50 from its previous value at each time point. There were no significant changes in FeNO levels (range 15-20 ppb) or C-ACT scores (∼26 points) within or between groups. CONCLUSIONS: A high level of asthma control was maintained with both approaches. The use of SFC step-down resulted in somewhat better respiratory function, with no worsening of airway inflammation. However, halving the dose of SFC and switching to FP alone are both optimal step-down approaches.