There has been an important shift in the approach to the treatment of severe asthma over the last few decades. Traditionally, there has been a one-size-fits-all treatment plan focused solely on using oral steroids, with no other therapeutic options. It is now possible to differentiate among individuals with asthma by using biomarkers that help identify different behaviors and responses to asthma treatment. This has created the opportunity to treat severe asthma with new medications called biologics, or biopharmaceuticals.
As the term suggests, these medicines are derived from biological sources and they are designed to target specific receptors or proteins. In the case of severe asthma, the goal of treatment is to reduce inflammatory processes and these medicines will only be effective in people who have the specific biomarkers. The use of these medicines marks a true breakthrough in severe asthma treatment.
Biological medicine for allergies
One of the first biological agents to pass clinical trials, Xolair (omazilumab), is an injectable medicine that targets the immunoglobulin E (IgE) receptor. IgE is the antibody associated with instigating allergy symptoms. By determining the concentration of IgE after exposure to elements such as grasses, trees, pollens or foods, a doctor can identify the specific triggers initiating allergy symptoms.
Omazilumab’s use in asthma is reserved for people who have elevated IgE levels. Contrary to popular belief, only a minority of asthmatics have this type of allergic basis to their severe asthma. This group is more resistant to treatment and would therefore benefit from biological medicine because it specifically targets and counteracts the effect of those IgE antibodies.
What’s especially interesting is that the outcomes from use of this biological agent in clinical practice are better than results shown in the clinical trials used to get the drug approved by the FDA. How is this possible? The best explanation is that in these clinical settings there is a better effort in patient selection. It is this optimization of treatment, based on patient selection that seems to be the key to better success, in the treatment of severe asthma.
Newer biological medications for asthma
The next biological approved by the FDA is Nucala (mepolizumab). This agent is an especially effective agent in those asthmatics who have elevated levels of white blood cells (wbcs) called eosinophils. Individuals with elevation in levels of these eosinophilic cells have been the subject of study and interest. There is still not full agreement as to whether the elevation of eosinophils is a sign of disease or a sign of a robust response to an underlying disease.
In fact, much debate in clinical science has been devoted to the discussion of whether the eosinophil is a “good guy, bad guy, or innocent bystander.” Besides asthma, there are many other diseases characterized by elevation of eosinophils with different manifestations of disease. This includes infections by parasites, a reaction to a fungus called aspergillus, allergic reactions to medications, and not to be ignored, a subset of people with COPD who also behave differently (to treatments) compared to other people with COPD. There are also some experts who are specifically looking at the similarities shared by people with asthma and people with COPD.
Understanding subtypes and endotypes of asthma
Asthma that is driven by eosinophils stimulating interleukins is now referred to as type 2 inflammation and this includes subtypes (high and low airway inflammation).
Nucala, when used in asthmatics with high levels of eosinophils, does not target those cells. The biological agent targets substances of inflammation called interleukins (Il’s). In asthma, Mepozilumab targets interleukin 5 (Il-5) specifically.
It’s also possible to define other specific types of asthmatics, called endotypes by defining different interleukins aside from Il-5. This opens the possibility for creating other biologicals. Specific interleukins involved in inflammation in asthma) are Il-4, Il-5, and Il-13.
Some of the newer biologicals are Cinqair (reslizumab) and Fasenra (benralizumab), which target Il-5, and a new agent called Dupixent (dupilumab) which targets Il-13.
Efforts to further identify other asthma phenotypes and endotypes use new testing methods. For example, a test has been developed to measure a new protein called periostin, which is induced by Il-13 eosinophilic action, by using exhaled nitric oxide. Traditionally, blood testing was used in identifying endotypes of asthma.
Other factors that affect severe asthma treatment
When treating severe asthma, further optimization of treatment comes when the comorbidities - allergic rhinitis, gastroesophageal reflux which cause daytime symptoms and obesity, with resulting obstructive sleep apnea and night symptoms - are addressed.
It’s also important to take into account the life style of each individual including living quarters, family dynamics, and occupation when treating severe asthma. That plus control of environmental circumstances will further improve outcomes of asthma without the use of strong medications.
The phase III trials of the biologicals that the pharmaceutical companies spearheaded to get these drugs approved did not include all of these variables when subjects for the testing were chosen. The measures used for subject selection were more simplified and focused on the number of exacerbations or pulmonary function test results. Again, this may be why the more precise selection of individuals by doctors, using more selective criteria, may have resulted in better outcomes once the biologics were used in the actual clinical setting.
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Eli Hendel, M.D., is a board-certified internist/pulmonary specialist with board certification in Sleep Medicine. An Assistant Clinical Professor of Medicine at Keck-University of Southern California School of Medicine, and Qualified Medical Examiner for the State of California Department of Industrial Relations, his areas include asthma, COPD, sleep disorders, obstructive sleep apnea, and occupational lung diseases. Favorite hobby? Playing jazz music. Find him on Twitter @Lung_doctor.