Biologics and targeted therapy for severe refractory asthma

Toronto – Asthma has entered the era of personalized medicine with therapies that target specific inflammatory pathways in people with severe disease who don’t respond to normal inhaler therapy. According to Asthma Canada, 3.8-million Canadians suffer from this chronic inflammatory condition and estimates 250,000 have severe asthma. About 250 people in Canada die from it each year. But it was only in the late 1990s when it was suggested asthma can be divided into two subtypes based on inflammatory pathways. Since then, more specific inflammatory pathways have been identified, and a number of biologics which target those pathways have been developed. “Biologics are not for every patient, but for the patients where they are indicated … often the changes in quality of life and the change in their asthma control is quite dramatic. They have changed things quite impressively for severe asthmatics,” said Dr. Harold Kim, chief of the division of clinical immunology and allergy at Western University. He has conducted research on the topic and spoke on a panel at the recent annual virtual conference of the Canadian Thoracic Society. When it comes to “dividing it up in terms of management we’ve divided up (asthma types) relatively simplistically into two large groups. One would be the Type-2 (T2) group are who are often (but not always) allergic and/or are patients who have nasal polyps and asthma,” he told the Medical Post in an interview. T2 asthmatics are described as having allergic and non-allergic eosinophilic asthma. Eosinophils are a type of white blood cell that help promote inflammation, but chronic severe asthmatics can have additional types of inflammatory cells contribute to the process as well as high eosinophil counts. The second type of asthma, the non-T2 side is not as well studied or understood, and there is still a lack of good treatments for patients in that category. The majority of patients fall in the T2 side, and within that between 5% to 10% have either difficult-to-control or severe asthma. According to the Global Initiative for Asthma (GINA) guidance, severe asthma is asthma that is “uncontrolled despite adherence with maximal optimized therapy and treatment of contributory factors, or that worsens when high-dose treatment is decreased.” In other words, high dose combination inhalers isn’t enough. Close to 10 years ago, omalizumab was the first biologic approved for use in moderate to severe asthmatics. Since then, four others have been approved, each targeting slightly different pathways. For example, omalizumab is an IgE neutralizing antibody while mepolizumab and reslizumab are anti-interleukin-5 (IL-5) inhibitors. Benralizumab is an IL-5 receptor antagonist and dupilumab is an IL-4/13 antagonist. In the future we may have medications that target thymic stromal lymphopoietin (TSLP), IL-25, IL-33 or other inflammatory cells, according to a recent review of the drugs. Deciding which patients should get which biologic isn’t always straight forward, Dr. Kim said. But lung function testing is vital to help confirm that a patient actually has asthma in the first place as breathing symptoms can be caused by reflux, sinusitis, coronary issues or other conditions. Studies suggest as many as 30% of patients being treated for asthma may not even have asthma, he said. Tests such as spirometry, peak flow expiratory tests and sometimes methacholine challenges are needed. At the same time, it can be a challenge sorting out who has increased symptoms because of poor compliance or adherence to medications. One study which measured non-adherence in difficult-to-control asthmatics who were potentially eligible for biologics, found close to half were nonadherent when it came to using preventor therapies. It also found serum eosinophils were higher in nonadherent patients. Refer poor control But patients who are poor responders to high-dose, combination inhaler therapy, for whatever reason, should be referred to an asthma specialist, Dr. Kim said. After lung function testing, patients can then undergo phenotype testing to measure eosinophil counts, IgE levels and complete allergy skin and blood testing. The eosinophil counts help determine which of the biologics a patient might qualify for as they have different cut-off points. Biologics are not cheap and run about $30,000 per year. “To get the drugs, patients require certain levels of eosinophils and IgE to get them covered by either private or provincial plans,” Dr. Kim said. Most of the biologics are given as subcutaneous injections, except for reslizumab which is given intravenously and is used less frequently than the others for this reason. The injectables are given, depending on the drug, anywhere from once every two weeks to every two months. Patients on biologics should be re-evaluated every three to six months. If a biologic works well, then inhaled steroids or other medications could be decreased. If a patient doesn’t respond well, then a reassessment should be done, and possibly a different biologic or other treatments could be tried. For most patients, the biologics are well tolerated, said Dr. Kim. He noted that omalizumab has a small risk of an allergic reaction, mepolizumab has been associated with shingles in rare instances and dupilumab “has a small risk of eosinophils paradoxically going higher then coming down. Also, some instances of conjunctivitis have been reported with dupilumab when used in patients who also have eczema.”

Biologics and targeted therapy for severe refractory asthma

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