Oct 232013
 

Dupilumab, an injectable monoclonal antibody that inhibits signaling by interleukin-4 and interleukin-13, reduced asthma exacerbations by almost 90% while also improving asthma symptoms in a randomized trial. Participants had moderate-to-severe asthma that had previously been uncontrolled despite use of inhaled corticosteroids with long-acting beta-agonists.

Twenty five million people in the U.S. -- 8% of the population -- are believed to have asthma. In about 10-20%, their asthma remains less than well-controlled despite use of inhaled corticosteroids and long-acting beta agonists. These patients often require repeated doses of systemic corticosteroids, increasing their risk for long term side effects including obesity, diabetes, and osteoporosis.

No one really understands why some people's asthma doesn't respond to standard therapy (although for some, it's because they don't have asthma). Asthma may occur through multiple poorly understood mechanisms, but about half of people with asthma have aberrant type 2 helper T cell (Th2) immunity. Overactive Th2-pathway activity can result in elevated eosinophil levels, which are partially responsible for asthma pathology and symptoms.

Dupilumab inhibits signaling by IL-4 and IL-13, two cytokines associated with Th2 cells that are known to contribute to asthma and allergies (e.g., IL-4 controls differentiation of Th2-cells, which stimulate eosinophils; IL-13 attracts eosinophils). Sanofi and Regeneron Pharmaceuticals published their results of a phase 2 randomized trial testing dupilumab earlier this year in the New England Journal of Medicine.

What They Did

Sally Wenzel et al enrolled 104 patients at 28 U.S. sites with moderate-to-severe asthma (reversible airflow limitation or positive methacholine challenge) and elevated eosinophils in sputum or blood, with persistent symptoms despite taking inhaled corticosteroids and long-acting beta agonists, and at least one exacerbation in the past 2 years. They were randomized to receive dupilumab 300 mg injected subcutaneously weekly or placebo for 12 weeks. They tapered off the ICS/LABA by week 9 to try to better identify the effect of dupilumab.

What They Found

Dupilumab drastically reduced asthma exacerbations: 3 patients receiving dupilumab and 23 receiving placebo experienced exacerbations (an 86% relative risk reduction, an odds ratio of 0.08). Asthma symptom scores and albuterol use were reduced with dupilumab (they increased with placebo). Asthma biomarkers (FeNO, serum IgE, eotaxin-3, and TARC) also improved favorably with dupilumab. There were no apparent safety events.

What It Means

With dupilumab, Sanofi and Regeneron hope to score another Xolair (omalizumab), a blockbuster injectable anti-IgE asthma treatment costing $1,000 a month that brought in $989 million for Novartis and Genentech in 2010. With the publication of this trial, they look to be on their way.

Dupiluamb's results exceed previous trials of Th2 cytokine inhibiting monoclonal antibody therapies for asthma: both reslizumab and lebrikizumab were shown to improve lung function in severe asthma, but not meaningful clinical outcomes like the number of exacerbations. Unlike dupilumab, those agents act on IL-13, but not IL-4, which has a greater breadth of effects by acting more upstream in signaling cascades.

No word on the phase 3 trial, but rest assured it's coming. Dupilumab is also being studied as a possible treatment for atopic dermatitis.

Sally Wenzel et al. Dupilumab in Persistent Asthma with Elevated Eosinophil Levels. N Engl J Med 2013; 368:2455-2466.

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Dupilumab reduced asthma exacerbations by ~90% in RCT