The Ups and Downs of Omalizumab for Severe Asthma with Bill Busse, MD

William Busse, MD

A recent study released at the annual meeting of the American College of Asthma, Allergy and Immunology (ACAAI) in Seattle, Washington, suggested that omalizumab (Xolair, Genentech) reduced the frequency of fall, winter, and spring exacerbations versus placebo in adolescents and adult patients with severe asthma, and paralleled results from the ICATA study in children.

Why should physicians consider omalizumab for cases of severe or seasonal asthma?

We asked Bill Busse, MD, professor of medicine in the Division of Allergy, Pulmonary and Critical Care Medicine at the University of Wisconsin School of Medicine and Public Health to explain how the therapy can be used to help patients who experience seasonal asthma exacerbations.As a background for this, we’ve published 2 papers. First of all, you certainly know about the seasonal variation in asthma exacerbations that has been reported out of Canada. It's called the “September epidemic of asthma exacerbations,” and it's been described since around 1990.

Within about 2 weeks of kids going back to school in early September, emergency room visits for asthma increase significantly. The thought behind this is 2-fold. Number 1 is that when kids go back to school, rhinovirus infections get spread around, so we have worsening of their disease. The second idea is that this is the time of the year when allergy symptoms are intensified.

So you have these two factors coming together during this time, and it puts the kids — and I think to some degree the adults – at greater risk for having an asthma exacerbation.

We reported in 2010 or 2011 in the New England Journal of Medicine a study the inner-city asthma consortium, which was sponsored by the National Institutes of Allergy and Infectious Disease with omalizumab. These are children living in inner cities across the country who are at high risk for having asthma exacerbations, and they're all very likely to be allergic as far as the disease characteristics are concerned.

What we found is that omalizumab significantly reduced the frequency with which these kids had exacerbations. But when we looked at the data and mapped it out over a monthly basis, what you see is that the differences are noticed in the ability of omalizumab to reduce asthma flares, which occur in the spring and fall — this is when kids come back from their vacation breaks and also the time when rhinovirus infections are more likely to occur.

The importance of this observation from my perspective is that it really showed that the allergic antibody IgE is involved as a risk factor for asthma exacerbations when kids get a cold.

We then did a second publication, which was published I think in 2015 or 2014 in the Journal of Allergy and Clinical Immunology the study was on the preseasonal treatment of asthma with either omalizumab or a small boost in inhaled corticosteroids. And the study was designed to look at the seasonal flairs that kids had. We started treatment one month before they went back to school in September and continued it for the first 3 months that they were in school, so it was 4 months of treatment during this high risk period of time. We found that it significantly reduced the risk of asthma exacerbations, indicating that the seasonality aspect is important.

So those were the observations we had, and that's why these abstracts have been looked — to try to put together whether or not 2 aspects – and I think only one of them can be addressed – whether blocking the IgE pathway can be associated with some improvement in lung function.

Why is it important to have omalizumab as an additional treatment option?

We're seeing data that omalizumab does improve lung function in children and in some degree in adults. This is an observation which suggests that by reducing inflammation through the use of this monoclonal antibody, we get some reduction in airway inflammation.There are a number of reasons, and I'd like to encompass this broadly with all the biologics that we now have available, because most of them are hitting the T2 pathway of allergic inflammation. I think that having these 3 classes a biologics provides an option: the anti IgE; the anti-aisle 5 pathway; and the anti 413 pathway with dupilumab.

Why is this important? From my perspective — and I think the epidemiological data supports this –asthma exacerbations are the major cause of burden and risk to patients with asthma. They’re expensive, they compromise their lifestyles, and there are data to suggest that repetitive episodes of asthma exacerbations lead to a greater likelihood of loss of lung function over a period of time.

The other aspect is that standard treatment at the present time is with systemic corticosteroids, and again, we're getting good data to suggest that using multiple courses of systemic corticosteroids in a short period of time is not a benign situation. It really leads to increased risk for other consequential diseases such as hypertension, diabetes, osteoporosis, et cetera, and alterations in growth levels in kids.

What are the best practices for prescribing omalizumab in the clinic?

More importantly, these biologics may have greater target specificity for the events that lead to an asthma exacerbation than do systemic corticosteroids. The kids and adults that are at risk for these exacerbations are on high levels of treatment, and the treatments are not preventing them from the major risk factor of asthma exacerbations. Therefore, having available a treatment, which I think has greater specificity, and where the mechanistic events that lead to an asthma exacerbation, becomes extremely important. Both in terms of improving disease control, and also in minimizing the likelihood that these individuals are going to have side effects from taking high doses of asthma medications, which may not be all that efficacious for their disease.First of all we have to ask ourselves: Is the person having severe disease? Are they at the level of a GINA 4 or 5? If they are, these are potential candidates for omalizumab. The second thing one needs to define is whether they are meeting the criteria for severe disease because they have severe disease or because possibly they've either got coexisting diseases, or they're not taking their medications, or they don't even have asthma. So I think we need to look into those things quickly.

The other thing that we need to start to do is to profile these individuals. With omalizumab, it's prescribed primarily in individuals that have evidence of emerging IgE sensitization. This was the criteria that was established 20 years ago, and again those are the prescribing habits.

There are data that are emerging in the literature to suggest that elevation on IgE, whether or not is associated with allergic sensitization, may also be a criteria for omalizumab. But the prescribing habits require that they have allergic sensitization to at least 1 allergen.

My thought also would be to look at other markers such as levels of eosinophilia in the peripheral blood, and also exhaled nitric oxide. A publication in the American Journal of Respiratory Critical Care a few years ago looked at data from the EXTRA trial, and what it showed was that in an adult population, those individuals that had higher than the median level of peripheral blood eosinophils — and the cut off was 260 cells per cubic millimeter or higher than the median value for exhaled nitric oxide (19.5 parts per billion) – these are the individuals that are going to respond to a greater degree with omalizumab. So I think not only do you want to look at the standard recommendations (allergic sensitization), but again, do they have other markers which suggest that they are more in the type 2 classification of airway inflammation. So I think that those are the factors that every physician who is considering a biologic, including omalizumab, should be considering.