Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with ...uncontrolled asthma.
We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV
) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV
in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.
The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval CI, 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV
had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo.
In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).
Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in ...patients with severe asthma while maintaining asthma control is unknown.
We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV
) before bronchodilator use were also assessed.
The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval CI, 37 to 74) lower than that in the placebo group and resulted in an FEV
that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%).
In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV
. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).
Background
Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared ...receptor component for interleukin‐4 and interleukin‐13, key and central drivers of type 2 inflammation.
Objective
Assessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE).
Methods
Data were extracted from three randomized placebo‐controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation‐regulated chemokine (TARC), plasma eotaxin‐3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count.
Results
Dupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin‐3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from −24.8% to −88.6% (placebo +2.6% to −53.6%); −38.2% to −51.5% (placebo +8.3% to −0.16%) in eotaxin‐3; −24.8% to −76.7% (placebo +8.3% to −4.4%) in total IgE; and −13.6% to −41.1% (placebo +10.1% to −6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% 95% CI: −15.8, 0); transient increases followed by decreases to below‐baseline levels in asthma (−14.6% −20.0, −7.7) and CRSwNP (−29.4% −40.0, −16.3); and significant decreases in EoE (−50.0% −50.0, −33.3).
Conclusion and clinical relevance
Dupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.
This analysis assessed dupilumab effect on biomarkers of type 2 inflammation in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis. Dupilumab vs. placebo suppressed thymus and activation‐regulated chemokine, total immunoglobulin E, periostin, and eotaxin‐3 in all studies/indications where assessed; blood eosinophil responses varied by disease. Dupilumab may affect a shared pathophysiological mechanism fundamental to type 2 inflammatory diseases.
Forced expiratory volume in one second (FEV1) is a critical parameter for the assessment of lung function for both clinical care and research in patients with asthma. While asthma is defined by ...variable airflow obstruction, FEV1 is typically assessed during clinic visits. Mobile spirometry (mSpirometry) allows more frequent measurements of FEV1, resulting in a more continuous assessment of lung function over time and its variability. Twelve patients with moderate asthma were recruited in a single‐center study and were instructed to perform pulmonary function tests at home twice daily for 28 days and weekly in the clinic. Daily and mean subject compliances were summarized. The agreement between clinic and mobile FEV1 was assessed using correlation and Bland‐Altman analyses. The test‐retest reliability for clinic and mSpirometry was assessed by interclass correlation coefficient (ICC). Simulation was conducted to explore if mSpirometry could improve statistical power over clinic counterparts. The mean subject compliance with mSpirometry was 70% for twice‐daily and 85% for at least once‐daily. The mSpirometry FEV1 were highly correlated and agreed with clinic ones from the same morning (r = 0.993) and the same afternoon (r = 0.988) with smaller mean difference for the afternoon (0.0019 L) than morning (0.0126 L) measurements. The test‐retest reliability of mobile (ICC = 0.932) and clinic (ICC = 0.942) spirometry were comparable. Our simulation analysis indicated greater power using dense mSpirometry than sparse clinic measurements. Overall, we have demonstrated good compliance for repeated at‐home mSpirometry, high agreement and comparable test‐retest reliability with clinic counterparts, greater statistical power, suggesting a potential for use in asthma clinical research.
Abstract Interleukin‐33 (IL‐33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for ...IL‐33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL‐33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies—a dose‐ranging itepekimab monotherapy study (NCT03738423) and a proof‐of‐concept study of itepekimab alone and in combination with dupilumab (NCT03736967)—were conducted in patients with moderate‐to‐severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof‐of‐concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose‐proportional pharmacokinetics. Pharmacodynamics of total IL‐33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration–time profiles of itepekimab and total IL‐33 were similar for itepekimab with or without dupilumab, and between East Asian and non‐East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL‐33 may not be a key pathogenic driver in moderate‐to‐severe AD.
Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. In the phase 3 LIBERTY ASTHMA QUEST trial ...(NCT02414854) in patients with uncontrolled, moderate-to-severe asthma, add-on dupilumab 200 mg or 300 mg every 2 weeks reduced exacerbations and improved forced expiratory volume in 1 s (FEV
) and quality of life over 52 weeks. This analysis evaluates dupilimab's effect on lung function in the overall population, and subgroups with baseline elevated type 2 inflammatory biomarkers.
Patients were randomised to 52 weeks of subcutaneous dupilumab 200 mg every 2 weeks, 300 mg every 2 weeks, or matched-volume placebos. Lung function outcomes were analysed in the overall population, in patients with ≥150 eosinophils·µL
, ≥300 eosinophils·µL
, ≥25 ppb fractional exhaled nitric oxide (
), and both ≥150 eosinophils·µL
and ≥25 ppb
, at baseline.
Dupilumab treatment (200 mg and 300 mg every 2 weeks) resulted in significant improvements
placebo after 52 weeks in pre-bronchodilator FEV
(0.20 and 0.13 L, respectively,
placebo) and post-bronchodilator FEV
(0.19 and 0.13 L, respectively), forced vital capacity (FVC) (0.20 and 0.14 L, respectively), forced expiratory flow (0.19 and 0.13 L·s
, respectively) and pre-bronchodilator FEV
/FVC ratio (1.75% and 1.61%, respectively) in the overall population (p<0.001). Difference
placebo in post-bronchodilator FEV
slope of change (weeks 4-52) was significant (0.04 L·year
; p<0.05). Greater improvements were achieved in patients with elevated baseline blood eosinophil and/or
levels for most outcomes.
Dupilumab improves lung function outcomes, including large and small airway measurements and fixed airway obstruction, in patients with uncontrolled, moderate-to-severe asthma; particularly in patients with elevated biomarkers of type 2 inflammation.
Use of glucocorticoids for anti-inflammatory efficacy is limited by their side effects. This study examined, in the same individuals, prednisone's acute, dose-dependent effects on inflammation as ...well as biomarkers of glucose regulation and bone homeostasis.
In this randomized, double-blind, parallel-design trial of healthy adults demonstrating cutaneous allergen-induced hypersensitivity, patients received placebo or prednisone 10, 25 or 60 mg daily for 7 days.
Effects on peripheral white blood cell (WBC) count, ex vivo whole blood lipopolysaccharide (LPS)-stimulated TNF-α release and response to cutaneous allergen challenge were assessed concurrently with biomarkers for glucose tolerance and bone turnover.
Differential peripheral WBC counts changed significantly within hours of prednisone administration. Ex vivo, LPS-stimulated TNF-α was significantly reduced by all prednisone doses on days 1 and 7. The late phase cutaneous allergen reaction was significantly reduced with prednisone 60 mg vs placebo on days 1 and 7. Oral glucose tolerance tests revealed significant increases in glycaemic excursion on days 1 and 7, whereas increases in insulin and C-peptide excursions were more notable on day 7 with all doses of prednisone. The bone formation markers osteocalcin, and procollagen I N- and C-terminal peptides decreased significantly on days 1 and 7 vs placebo.
In healthy young adults after single doses as low as 10 mg, prednisone treatment has significant effects on glucose tolerance and bone formation markers within hours of treatment, in parallel with anti-inflammatory effects.
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