Another Bench-to-Bedside Story in the Treatment of Asthma

Posted by Rachel Wolfson • June 26th, 2013

In the early 20th century, the physician’s toolbox for asthma included adrenergic stimulants and belladonna alkaloids derived from the thorn-apple plant. Fifty years later, corticosteroids were added to the repertoire. (See the NEJM 200th anniversary review article on asthma.) But the next 50 years witnessed much more accelerated changes as basic science advances inspired the development of targeted therapies for asthma, such as leukotriene modifiers, antibodies against IgE, and mast cell stabilizers. The ranks of targeted therapies continue to grow in this week’s issue of NEJM, in which Wenzel and colleagues report on the efficacy of a novel biologic agent to treat asthma.

Evidence of type 2 helper T-cell (Th2) activation is present in approximately half of patients with asthma. Interleukin-4 (IL-4) and interleukin-13 (IL-13) are two of the major cytokines that mediate the Th2 inflammatory response, and there has been growing interest in targeting these cytokines to treat asthma. Dupilumab is a monoclonal antibody against the alpha subunit of the IL-4 receptor, which is common to both the IL-4 and IL-13 receptors. Thus, dupilumab effectively inhibits both IL-4 and IL-13 signaling and downregulates Th2 mediated inflammation.

Inspired by dupilumab’s potential to disrupt the pathogenesis of asthma, Wenzel and colleagues conducted a randomized, double-blind phase 2A study that compared dupilumab to placebo. In this 14 week trial, 104 patients with moderate-to-severe asthma and elevated eosinophil levels while on inhaled glucocorticosteroids, were enrolled: 52 patients received weekly subcutaneous injections of dupilumab, and the other half received placebo injections. All patients started the trial with moderate asthma symptoms while being treated with long-acting beta agonists, which were discontinued after 4 weeks, and inhaled glucocorticoids, which were tapered off and discontinued between weeks 6 and 9. The primary end point, asthma exacerbations, occurred in 3 patients receiving dupilumab (6%) and 23 receiving placebo (44%), corresponding to a relative risk reduction of 87%. In terms of secondary end points, all week-12 measurements favored dupilumab. For example, at week 2 there was a statistically significant increase in FEV1 from baseline in the dupilumab treatment group, which continued through week 12. In addition, levels of Th2 associated biomarkers, including TARC, eotaxin-3, and IgE, all decreased at week 1 and remained decreased through week 12 in the dupilumab group. Adverse effects, including injection-site reactions, nasopharyngitis, nausea, and headaches, occurred more frequently with dupilumab. In addition, one patient experienced a papular rash, utricaria and edema after treatment with dupilumab.

This trial is yet another exciting example of how understanding pathophysiology can guide meaningful drug development. In an accompanying editorial, however, Michael Wechsler, MD, cautions against jumping to the conclusion that dupilumab is a magic bullet for asthma. First, he points out that this trial likely only applies to a subgroup of asthma patients, given that only 21% of the screened patients fit the inclusion criteria. In addition, he notes that dupilumab was most effective at reducing exacerbations only after standard therapy was withdrawn. Thus, although the trial was an important proof of principle, dupilumab may not change clinical practice.

Despite these shortcomings, Wenzel and colleagues show convincingly that dupilumab can modify both the clinical course and lung function in a subset of asthma patients, another great example of bench-to-bedside research. Along with leukotriene modifiers, anti-IgE antibodies, and mast cell stabilizers, dupilumab can be added to the list of drugs that work by targeting the underlying pathophysiology of asthma.

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