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By Charles Bankhead, Staff Writer, MedPage Today Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this randomized, controlled trial demonstrated strong efficacy of the IL-4 antagonist dupilumab in preventing asthma exacerbations among highly selected subjects with asthma.Be aware that the study protocol required all subjects to taper off their inhaled steroids and beta-agonists; this is not really a comparison of dupilumab versus conventional therapy.PHILADELPHIA -- Asthma exacerbations decreased by 87% in patients treated with an investigational agent that targets the interleukin-4 (IL-4) receptor, results of a placebo-controlled phase II trial showed.
Dupilumab was associated with an exacerbation rate of 6% compared with 44% in the placebo group.
Measures of lung function and asthma control also improved significantly in the dupilumab arm, and treatment with the monoclonal antibody was associated with a reduction in biomarkers of Th2-driven inflammation.
The drug was generally well tolerated; the most common adverse events were injection-site reactions, nasopharyngitis, nausea, and headache, as reported online in the New England Journal of Medicine and simultaneously at the American Thoracic Society meeting.
"This study targeted those individuals who, on the basis of eosinophil levels in their blood, seemed to have evidence for Th2-type asthma," principal investigator Sally Wenzel, MD, of the University of Pittsburgh, told MedPage Today. "By using this drug that blocks this pathway, we observed a really robust response compared with placebo in patients with moderate to severe asthma."
"The drug improved exacerbations, improved lung function, improved symptoms, and improved asthma control."
About half of patients with asthma have inflammation associated with type 2 helper T-cell (Th2) activation. The Th2-related cytokines IL-4 and IL-13 have been implicated in asthma and atopic diseases. The cytokines signal through overlapping receptors that have an alpha subunit of IL-4 receptor, the authors noted in their introduction.
Antibodies that target the IL-4 receptor alpha subunit potentially could inhibit downstream pathways used by both IL-4 and IL-13. Dupilumab targets the alpha subunit and has been shown to inhibit signaling by IL-4 and IL-13.
Wenzel and colleagues reported findings from a randomized, placebo-controlled trial of dupilumab in adults with moderate to severe asthma and elevated eosinophil levels. Eligible patients had persistent, poorly controlled asthma of at least moderate intensity and elevated blood eosinophil count (=300 cells/mL) or elevated sputum eosinophil level (=3%).
Eligibility criteria also included an asthma diagnosis for at least 12 months, forced expiratory volume at 1 second (FEV1) =50% of predicted, a score of 1.5 to 3.0 (of a possible 0 to 6) on the Asthma Control Questionnaire (ACQ5), and one or more asthma exacerbations in the 2 years before enrollment.
Investigators at 28 sites in the U.S. randomized 104 patients to once-weekly injections of dupilumab 300 mg or placebo. Randomized treatment continued for 12 weeks or until occurrence of an asthma exacerbation. Patients also received fluticasone and salmeterol twice a day for 4 weeks. Use of inhaled steroids was tapered and discontinued during weeks 6 through 9.
The primary endpoint was asthma exacerbation during the 12-week treatment period. Secondary endpoints included time to an asthma exacerbation and change from baseline to week 12 in FEV1, morning and evening peak expiratory flow (PEF), morning and evening asthma symptom score, nocturnal awakenings, and number of daily inhalations of a short-acting beta-agonist.
The authors reported that 87% of patients in the dupilumab arm completed the study compared with 67% in the placebo group. The most common reason for discontinuation was lack of efficacy (11 with placebo versus one with dupilumab).
Overall, 26 patients had asthma exacerbations during the trial, three in the dupilumab group and 23 in the placebo group. The difference translated into an odds ratio of 0.08 in favor of dupilumab treatment (P<0.001).
With respect to secondary endpoints, analysis of time to exacerbation showed a significant advantage in favor of dupilumab (HR 0.10, P<0.001). Patients treated with dupilumab had significant improvement (P=0.05 to P<0.001) in all but one secondary outcome, change in evening PEF (4.3 versus -18.4 L/min, P=0.06).
A similar proportion of patients in each group reported adverse events, which were generally nonspecific and mild or moderate in intensity. Three patients in each group discontinued because of adverse events.
The most common adverse events in the dupilumab group were injection-site reactions (in 15 patients), nasopharyngitis (seven), upper respiratory infection (seven), and headache (six). The most common adverse events in the placebo group were upper respiratory infection (nine), sinusitis (five), and injection-site reactions (five).
The proof-of-principle trial produced compelling data but only for a limited group of patients with asthma, Michael E. Wechsler, MD, of National Jewish Health in Denver, said in an editorial. He noted that only 1 in 5 patients screened for the study met entry criteria.
"We do not know whether dupilumab will be effective in other patient populations, such as the much larger population of patients who use inhaled glucocorticoids and long-acting beta-agonists and do not have eosinophilia," Wechsler wrote.
"Furthermore, although this therapy appeared to be effective in reducing exacerbations as LABAs and inhaled glucocorticoids were withdrawn, in clinical practice, physicians do not withdraw therapy to induce exacerbations.
"Thus, the apparent reduction in deleterious asthma outcomes as therapies were withdrawn only serves to tell us that this biologic therapy appears to work ... but may not be advantageous in a 'real world' situation, and thus the finding offers little direction for clinical practitioners."
The study was supported by Sanofi and Regeneron Pharmaceuticals.
Wenzel disclosed relationships with Sanofi, Merck, Array BioPharma, Genentech, GlaxoSmithKline, Regeneron, Actelion, Gilead, and Teva. Co-authors disclosed relationships with Amgen, Array BioPharma, Boehringer Ingelheim, Cephalon, Cerecor, Circassia, Cytos Biotechnology, Forest Laboratories, Genentech, GlaxoSmithKline, Hoffmann-LaRoche, Johnson & Johnson, Meda, Medimmune, Merck, Novartis, Pfizer, Rigel, Sanofi, Shionogi, Sunovion, Teva, Vectura, Sunovion, AstraZeneca, Hycor, KaloBios, Johnson & Johnson, Mylan, Revalesio, Roxane Laboratories, Boston Scientific, and Merck. Investigators included current and former employees of Sanofi and Regeneron.
Wechsler disclosed relationships with GlaxoSmithKline, Novartis, Cephalon/Teva, Sepracor/Sunovion, NKT Therapeutics, Asthmatx/Boston Scientific, Genzyme, MapPharma, Genentech, Boehringer Ingelheim, Merck, Cytos, and Medimmune.
Charles Bankhead
Staff Writer
Working from Houston, home to one of the world's largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.
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