Dupilumab reduced exacerbations of moderate to severe asthma by 87% in adults with poorly controlled disease, and induced rapid and sustained improvements in numerous other measures of asthma severity in an industry-sponsored phase II study published online May 21 in the New England Journal of Medicine.
Dupilumab, a monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling, "showed substantial efficacy with regard to both objective and patient-reported end points" when it was used concomitantly with inhaled glucocorticoids and long-acting beta-agonists (LABAs), as well as when those background therapies were withdrawn, reported Dr. Sally Wenzel of the University of Pittsburgh and her associates.
"The magnitude and breadth of efficacy that we observed exceed those in other studies of Th2 [type 2 helper T-cell] cytokine inhibition," the researchers noted in the online report, which was presented simultaneously at the annual meeting of the American Thoracic Society.
Dr. Sally Wenzel
Dupilumab currently is being assessed for the treatment of several diseases mediated by Th2 pathways. The goal of this phase II trial was to evaluate its safety and efficacy in adults with persistent moderate to severe asthma and elevated eosinophil levels whose symptoms were not well controlled with medium- to high-dose inhaled glucocorticoids plus LABAs (usually fluticasone and salmeterol).
The 104 participants were treated at 28 sites across the United States for 12 weeks, and then followed for another 8 weeks. During the intervention phase of the study, approximately half were randomized to receive once-weekly subcutaneous injections of dupilumab (300 mg) and half to receive matching placebo injections, in addition to the background asthma medications.
At week 4, the study subjects discontinued LABAs, and at weeks 6-9 they tapered off inhaled glucocorticoids. "This approach enabled us to observe the effects of dupilumab when added to background therapy, after LABA discontinuation, during the tapering of inhaled glucocorticoids, and as monotherapy," the researchers said.
The primary endpoint of the study was an asthma exacerbation during the 12-week intervention period. Exacerbations occurred in 3 patients receiving dupilumab (6%), compared with 23 receiving placebo (44%), a highly significant difference.
In addition, the time to an asthma exacerbation was significantly longer with dupilumab than placebo. And forced expiratory volume in 1 second (FEV1) "improved by more than 200 mL when dupilumab, as compared with placebo, was added to inhaled glucocorticoids and LABAs, an increase sustained during their tapering and discontinuation," the researchers noted (N. Engl. J. Med. 2013 May 21 [doi: 10.1056/NEJMoa1304048]).
Several other secondary endpoints also favored dupilumab over placebo, including morning peak expiratory flow values, scores on the Asthma Control Questionnaire (ACQ5), morning and evening asthma symptom scores, and the number of albuterol or levalbuterol inhalations needed per day. These measures improved at the beginning of the intervention in both study groups, then quickly returned to baseline levels in the placebo group while remaining constant in the dupilumab group.
The percentage of patients reporting adverse events was similar between the dupilumab and placebo groups (81% vs. 77%). These events tended to be nonspecific and mild, and included nasopharyngitis, nausea, and headache. One patient developed a progressive papular rash, urticaria, and edema after his ninth injection of dupilumab, which responded to nonurgent treatment of the symptoms and did not recur once the drug was withdrawn.
No serious adverse events were attributed to the study drug, and no patient showed clinically significant changes in vital signs, findings on physical examination, laboratory tests, or ECGs.
"Further studies are needed to confirm these observations and better define the target population, dosing regimen, and long-term efficacy and safety," Dr. Wenzel noted.
However, the study findings support the theory that the Th2 cytokines interleukin-4 and interleukin-13 play a pathogenic role in persistent, moderate-to-severe asthma, she added.
This study was funded by Sanofi and Regeneron Pharmaceuticals. Dr. Wenzel reported ties to Sanofi, Regeneron, Amgen, Merck, and other companies. Her associates reported ties to numerous industry sources.