Published Online: August 3, 2012
Although increasing evidence suggests that asthma is a heterogeneous disease, guidelines for standard-of-care asthma therapy have relied on an empirical and clinically defined, rather than biologically defined, approach. Many pharmaceutical companies are developing targeted therapies for patients with severe asthma that does not respond well to standard treatments. However, these new therapies may not work in all patients with severe asthma. To optimize treatment efficacy, it is important both to treat patients most likely to benefit from a therapy as well as to identify patients unlikely to benefit from the therapy. One subset of asthma patients predicted most likely to benefit from specific anti-inflammatory therapies is characterized by increased numbers of eosinophils in their airways. Specialized pulmonary clinics are equipped to sample the airways via induced sputum or invasive bronchoscopies to determine whether a patient has eosinophilic asthma. However, these techniques have not been proven to be beneficial additions to the existing standard of care. There are many biological and technical reasons for this, including a lack of consensus on thresholds for eosinophil-guided treatment and sampling methods that are labor intensive, time consuming, expensive, not standardized, and have not been widely adopted by medical practices that treat asthma patients. A simple blood test that identifies asthma patients with eosinophilic airway disease could accelerate the process of drug development for new targeted therapies and would represent an important step toward “personalized medicine” for severe asthma.
In a new paper published in The Journal of Allergy and Clinical Immunology (JACI), Jia and colleagues at Genentech conducted a study to identify biomarkers of eosinophilic airway inflammation in severe asthma. The work included samples from subjects participating in an observational study, called “BOBCAT,” which was conducted in collaboration with more than 15 academic centers. BOBCAT enrolled patients with poorly controlled asthma despite high-dose inhaled corticosteroid (ICS) treatment. Samples were collected from blood and from the airways via induced sputum and bronchoscopy. Previously, the Genentech group, in collaboration with researchers at the University of California, San Francisco (UCSF), identified a gene signature present in bronchial samples of asthma patients with elevated airway eosinophils and expression of interleukin (IL)13 (Woodruff et al, 2009 Am J Respir Crit Care Med. 180(5):388-95 and Choy et al, 2011 J Immunol 186(3):1861-9). A goal of the present work was to determine whether any of the genes in the previously identified gene signature encoded soluble proteins that might be detectable at elevated levels in the peripheral blood of severe asthmatics with eosinophilic airway inflammation. One promising candidate was periostin, a protein secreted from bronchial epithelial cells in response to IL13 stimulation. Genentech has recently published the outcome of a phase 2 randomized placebo-controlled clinical trial of lebrikizumab, a monoclonal antibody against IL13. In that trial, patients were subdivided according to pre-treatment serum periostin levels. “Periostin-high” patients experienced significantly greater placebo-adjusted lung function improvement from lebrikizumab than “periostin-low” patients (Corren et al, 2011 N Engl J Med 365(12):1088-98).
Jia et al developed a highly sensitive and specific assay capable of detecting all of the major known variants of periostin in serum. In the BOBCAT study, patients exhibited a distribution of airway eosinophilia both in induced sputum and in bronchial tissue. Patients with elevated sputum or tissue eosinophilia had elevated serum periostin levels relative to patients with lower sputum or tissue eosinophilia. Patients with elevated eosinophils in both sputum and bronchial tissue had the highest levels of serum periostin. In a statistical model comparing periostin with other candidate biomarkers of eosinophilic airway inflammation including immunoglobulin (Ig)E, fractional exhaled nitric oxide (FeNO), and blood eosinophils, serum periostin was the single best predictor of airway eosinophilia in severe asthma.
Recognition that not all patients with asthma may benefit from the same therapeutic approach is a critical step toward developing new therapies that target specific subsets of patients. Pulmonary specialty clinics are equipped to identify subsets of asthma patients using sophisticated airway sampling techniques, but simpler diagnostic tests will be needed to enable successful multi-center clinical trials, regulatory approval, and ultimately the broad application of targeted asthma therapy. While confirmation of preliminary results in larger phase 3 trials will be carried out, serum periostin appears to be a promising biomarker to identify the subset of asthma patients most likely to benefit from therapies targeting IL13.
The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.