Research Points to Potential Novel Treatments for Severe Asthma

Severe asthma is a complex phenotype of asthma that is associated with increased morbidity and characterized by frequent and severe exacerbations. Although the mechanisms of disease severity for this form of asthma are not fully understood, progress has been made in identifying promising targets for potential new treatments.

At the 2014 Annual Meeting of the American Academy of Allergy, Asthma & Immunology, held February 28 — March 4, 2014, in San Diego, CA, Stanley J. Szefler, MD, director of the Pediatric Asthma Research Program at the Breathing Institute at Children’s Hospital Colorado, and professor of pediatrics at the University of Colorado Denver School of Medicine, reviewed the current approach to asthma treatment, discussed several reasons why patients may have an inadequate response to conventional asthma therapy, and outlined examples of novel treatment approaches.

Szefler observed that, over the past 50 years, there have been paradigm shifts in asthma treatment every 10 years or so. Despite this, he noted that “It is sobering that only a 10-15% reduction in asthma-related deaths has been achieved since the 1980s.”

However, he noted that researchers are now looking more closely at better control of the disease by means of prevention and maintenance therapy or early intervention, as opposed to waiting for acute exacerbations and employing intensive treatment under urgent or emergency care conditions.

As in other specialties, asthma treatment is becoming more individualized, with researchers placing greater emphasis on patient characteristics, genetic make-up, and biomarkers. This research is paying off, with new classes of drugs being introduced and under development, including new immunomodulators.

Our understanding of clinically relevant differences between asthma phenotypes has also improved. Szefler drew attention to “Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program,” published in 2010 in the American Journal of Respiratory and Critical Care Medicine, that focused on the identification of asthma phenotypes using cluster analysis as part of the Severe Asthma Research Program. The authors identified five distinct phenotypes of asthma within the study population:

• Mild allergic asthma, characterized by early onset atopic asthma with normal lung function treated with two or fewer controller medications and minimal health care utilization
• Mild-to-moderate allergic asthma, characterized by early-onset atopic asthma and preserved lung function but increased medication requirements and health care utilization
• Moderate-to-severe older onset asthma, characterized by late-onset nonatopic asthma, reduced FEV1, and frequent oral corticosteroid use to manage exacerbations
• Severe allergic asthma, characterized by severe airflow obstruction with bronchodilator responsiveness, but differ in other variable such as age of asthma onset, atopic status, and use of oral corticosteroids
• Severe COPD-like fixed airflow asthma

A key feature of severe asthma is the extent of frequent and severe exacerbations, characterized by an indistinct inflammatory pattern. Szefler noted that the multiple mechanisms of disease severity have not been not fully elucidated, and that inflammatory mediators generated by the disease may lead to corticosteroid resistance associated with Th2 pathways.

Szefler said that some clinicians consider the six-step approach to therapy for severe asthma that has been implemented in the US, which recommends delaying anti-IgE monoclonal antibody administration (currently only omalizumab is FDA-approved) until steps 5 or 6, to be rather conservative. The Inner-City Anti-IgE Therapy for Asthma Mechanistic Study (ICATA) trial showed that treatment with omalizumab significantly reduced the incidence of asthma exacerbations in the spring and fall, which are the worst time of the year for attacks. Szefler said that in his opinion the International ERS/ATS guidelines on the definition, evaluation, and treatment of severe asthma are better defined than the pre-existing WHO and US guidelines.

In addition to the use of anti-IgE agents in adults and teenagers, other potential new treatments include administration of ant-IgE antibodies in children under 12 years of age, tiotropium, anti-IL5, anti-IL4/13 and a re-evaluation of allergen immunotherapy in general.

Szefler concluded by saying that future directions for preventing and managing severe asthma may include the introduction of new immunomodulators targeting Th2 pathways directed at IL5, IL13 and IL4/13, the identification of key patient characteristics and biomarkers associated with treatment response and, lastly, the application of immunomodulators for prevention of exacerbations, disease progression and, as a long-term goal, forestalling the onset of disease.