Current and Future Biologics for Severe Allergic Asthma in Children Over 6 Years
- Improved understanding of asthma endotypes, reflecting pathological processes that underlie asthma phenotypes, has informed the development of add-on biologic therapies for severe, treatment-resistant allergic asthma in children.
- Diligent history-taking and careful diagnosis remain crucial in the process of selecting medical treatment for severe asthma in young patients.
- Age, diagnostic biomarkers, dosing schedule preferences, body weight, and comorbidities are several of the patient variables to be considered for biologic drug selection in children with severe asthma.
- Important questions for future research include whether biologics have a role in prevention of asthma in children, and whether biologics for allergic asthma can be administered on a seasonal basis.
Between 0.23% to 0.5% of children and adolescents have severe, uncontrolled asthma, which is typically defined as persistent or recurring asthmatic symptoms or acute asthma attacks that are insufficiently controlled by maximal standard treatment such as inhaled corticosteroid (ICS) therapy, long-acting beta-2 agonists (LABA), leukotriene receptor antagonists (LTRA), and other therapies.1 As the prevalence of asthma has grown globally over the last several decades,2 asthma in children similarly has become more prevalent, with considerable negative effects on a range of physical, social, and emotional outcomes, as well as quality of life. Of particular concern, while mortality due to severe asthma has decreased across patient groups aged older than 15, the mortality rate in children has not decreased similarly.3 Furthermore, there are persistent disparities in the prevalence of asthma in the United States across racial, sex, geographic, and age factors. In particular, asthma attacks and presentation for emergency care are more common in children aged 12 to 17 and in racial and ethnic groups other than non-Hispanic White and Asian Americans.4 The considerable expenses spent on health care utilization among asthma patients may also be unequally distributed; school-aged children with asthma are more likely to come from underserved or disadvantaged populations and poorer families and have more chronic comorbidities than their peers without asthma.5
Treatment options for addressing treatment-resistant, allergic-type severe asthma have advanced in recent years, as research has begun to uncover the pathological processes, known as endotypes, that underlie asthma phenotypes. In children, the most common endotype, T2-high, features excessive activity of T-helper 2 (T2) lymphocytes. These lymphocytes predominantly secrete cytokines interleukin (IL)-4, IL-5, IL-9, and IL-13, which cause airway inflammation.6,7 Immunoglobulin E (IgE)-mediated inflammation further aggravates this hypersensitivity reaction in some patients with T2-high asthma.
Our improved understanding of these pathological processes now allows clinicians to tailor treatment decisions and monitor outcomes in allergic asthma in young patients based on disease endotype. The potential for personalized medical care brought about by these advances has been exemplified by the development of a range of biologic drugs and their approval as add-on therapies for severe asthma. Omalizumab was the first biologic approved for patients aged 12 and older with moderate to severe persistent asthma in 2003.8 In subsequent years, 4 other biologics for treatment-resistant asthma received approval: mepolizumab in 2015,9 benralizumab in 2017,10 dupilumab in 2018,11 and tezepelumab in 202112; 2 of these biologics later received expanded approved for the treatment of asthma in patients aged 6 and older: omalizumab in 201613 and dupilumab in 2021.14
The mechanism of action among these biologics varies, reflecting our increasingly nuanced understanding of asthma endotypes. Omalizumab causes IgE blockade, whereas mepolizumab and benralizumab are both IL-5 blockers. Dupilumab inhibits signaling of both IL-4 and IL-13; tezepelumab differs by targeting the thymic stromal lymphopoietin (TSLP), an airway epithelial cytokine, and has demonstrated benefit in both the T2-high and T2-low asthma subtypes.15
While the advent of biologics for severe asthma has dramatically expanded treatment options, we still have much to learn regarding how to optimize and personalize pediatric asthma treatment. For example, treatment selection requires consideration of patient age, asthma phenotype, moderate vs severe disease status, therapeutic goals, symptom triggers, side effect risks, patient preferences, and relevant comorbidities (eg, atopic dermatitis).7 However, in pediatric patients, outcomes research to guide and prioritize these considerations is still in its early stages. Early reports indicate that these biologic therapies are generally well tolerated, with a low rate of adverse effects requiring discontinuation.6 However, conclusions such as these are extrapolated in part from literature on adult patients.
Long-term outcome studies focused on children are needed, particularly in children aged younger than 12, children of lower socioeconomic status, and children from racial and ethnic minorities. Future studies are also needed to identify novel predictive biomarkers and help clinicians determine the optimal choice for patients who are eligible for multiple treatment options.16 Such research will help clarify the appropriate durations of treatment with biologics for severe allergic asthma.
Meyer Kattan, MD, professor of pediatrics at Columbia University Irving Medical Center, New York, and director of the Pediatric Pulmonary Division at New York-Presbyterian/Morgan Stanley Children’s Hospital, has a multi-decade record of performing research on asthma in children funded by the National Institutes of Health. In this article, Dr Kattan discusses state-of-the-art treatments for severe allergic asthma in children and future directions for research.
A subset of children with severe, persistent allergic asthma do not achieve adequate disease control with inhaled corticosteroids. Among those over 6 years of age, treatment options have changed considerably over the past several years and now include biologic therapies. Would you give an overview of how this new era of biologic therapies evolved in the past several years?
Asthma is a heterogeneous disease characterized by chronic inflammation. Over the last 3 decades, we have usually treated it with ICS, but not every patient responds to this therapy. The question is, what is different about those who respond to steroids and those who do not?
In this regard, with an improved understanding of cellular mechanisms and transcriptional factors within the cell, we have been able to study cellular pathways and cytokines that were making the inflammation worse. That is, we gained insights into what type of cell receptor is being activated, or what pathways are being activated by a certain receptor in a certain individual. For example, the majority of patients with severe asthma are T2-high, which is characterized by eosinophils in the blood.
What we learned is that although the clinical presentation of asthma — the phenotype — may be similar across many patients, we needed to target particular cellular and molecular pathways, which we call endotypes. The current biologics were developed to counteract the effects of these inflammatory mediators within a pathway such as T2. Furthermore, each biologic has been developed to target a different part of a given pathway.
To date, 5 biologics have been approved for the treatment of moderate to severe asthma in children. Of those, 3 are approved for children aged 6 years and older: omalizumab, mepolizumab, and dupilumab. The other 2, benralizumab and tezepelumab, are approved for children aged 12 years and older. Again, each biologic affects different signaling pathways within the inflammatory cascade.
In deciding when and whether to initiate biologic therapy in this patient group, what factors or considerations do you prioritize for optimal outcomes?
The first thing to prioritize is the patient’s history, which is more important than anything else. As I mentioned, we are considering a patient who is not responding to therapy, but via looking into their history we ask the question, why are they not responding to therapy? Is it because they are not taking the medicine properly? Is it because they are not taking the medicine at all? We really have to ask the right questions and sometimes do a little detective work. For example, you may be able to check the patient’s refills via the electronic health record and see whether they have actually been filling their medication. Also, you can easily determine whether the patient’s inhalation technique is correct during a visit. I had a patient who showed me his inhaler and showed me how he took it, but when I asked him what the number was on the readout of how many puffs were left, it was 0. We really have to rule out that sort of problem.
But supposing you have established that the patient really has failed to respond to high-dose steroid therapy, you do not want to keep increasing the steroid dose if they are not responding, especially in children, even though inhaled steroids are generally safe. So that patient may be a candidate for a biologic, especially if their asthma is allergic-type. But how do we know that they have allergic asthma? We look for comorbidities, such as eczema and allergic rhinitis, that may suggest atopy; we look for a high blood eosinophil count, which is a marker of allergy; and we test exhaled nitric oxide (FeNO), which is an indicator of allergic inflammation. If the patient confirms that they feel the medication they are using is not working, even at the right doses, then they may be an excellent candidate for biologics.
A caveat is that we have to confirm the diagnosis of asthma; it is possible that a patient who does not respond to high-dose steroids actually does not have asthma. A very common missed diagnosis is vocal cord dysfunction, such as exercise induced laryngeal obstruction (EILO).17 Respiratory noises in a child with EILO may sound like asthma, but they are actually from the upper airway. Other conditions in children that may produce respiratory symptoms like chronic cough, but are not really asthma, include cystic fibrosis, primary ciliary dyskinesia, and perhaps reflux.18 Thus, make sure the patient is taking the medicine correctly, and make sure you have the right diagnosis. Given those confirmations, if the patient is not responding well to medication, a biologic may be indicated.
How do you select among the options for biologic therapy in this patient population?
Treatment selection is driven by the patient’s clinical and endotype characteristics, and also according to the specific indications for each agent, because each biologic targets a different pathway. The unique properties of each biologic make them especially appealing for precision medicine. The relevant biomarkers need to be evaluated: usually blood eosinophils, skin prick testing, and serum IgE. As mentioned earlier, we can measure the degree of inflammation in the airways with FeNO, which tells us in a nonspecific manner that there is some allergic type of inflammation.
As an example of treatment considerations for these patients, omalizumab is a biologic that has been available for over a decade, and there is a lot of experience with it in children. It is an anti-IgE biologic, so the patient must have a somewhat elevated IgE for this drug to be indicated,19 although it should not be too high because then the needed dose probably would be too high for it to be recommended. Regardless, omalizumab has a good track record in those children and it has been shown that, in many of these patients, we do not even have to give that medication all year long.20 This is particularly true for patients whose symptoms are induced by viruses, which often starts occurring in autumn between September and January. So if that therapy starts in August, right before the viral season and before the patients start school, it is very effective. An interesting question this raises is, why does an anti-allergy drug help viral-induced exacerbations? This could be because people who are allergic have a diminished interferon response to the virus,21 and there is some evidence that omalizumab affects the interferon response.22,23
Again, that is just 1 type of patient, and there are limitations to using omalizumab. Omalizumab is dosed for asthma according to an algorithm based on weight and serum IgE level,19 so a patient who is obese and has an excessively high IgE probably is not eligible for omalizumab.
Dupilumab, in addition to being a very good asthma medication, happens to be excellent for eczema and is actually approved for the treatment of eczema in children aged as young as 6 months old.24 In a child with both eczema and asthma, dupilumab can be used to treat both at once. Patients with a somewhat elevated eosinophil count — an absolute count of at least 150 or 200 — are eligible for this biologic. Mepolizumab is also an excellent biologic; it can be given once a month,25 whereas dupilumab has to be given every 2 weeks. It also depends on what is acceptable to the patient. Eligibility and dosing for tezepelumab, on the other hand, do not depend on a high eosinophil count.26 Hence, if a patient aged 12 or older is not doing well on ICS and does not have a high eosinophil count, that may be a treatment option.
These drugs all work well in the right patient, and you have to decide which is best for that particular patient based on their history and lab values.
Historically, medical treatment of children has sometimes been driven by evidence from trials that were carried out mainly in adults. For the treatment of severe allergic asthma in children, what evidence base now exists from studies carried out with patients aged younger than 18? What population-specific research is still needed to maximize safety and help predict treatment responses?
As a condition of drug approval, the US Food and Drug Administration (FDA) typically requires studies of new drugs to be conducted in patients aged 12 and older. Accordingly, those studies do include children aged between 12 and 17 as participants, but often in very small numbers. Therefore, there is less data in children for many drugs; historically, a lot of drugs that we use in children have not been approved for children. But having said that, there are studies in children with these biologics. First of all, there are studies in children with omalizumab,27 and there has been plenty of real-life clinical experience in using omalizumab in children over the years. To summarize that research and experience: it has a good safety profile and it has been effective.28
With the newer biologics, there is not as much real-life experience yet, but studies likewise have been conducted in children.29 Furthermore, some of that research has been conducted in minority populations, including Black and Hispanic populations.30 However, we do need more data, and there certainly is not as much data in children as there is in adults. In dupilumab, there have been studies in children aged as young as 6 months for eczema, but not for asthma.
Still, as a result of studying the effects of a given drug in multiple diseases, more and more data are accumulating specific to children. These drugs seem to be quite safe, demonstrate very few side effects, and may have a steroid-sparing effect.13 The most common side effects with all these biologics are allergic reactions such as hives. With dupilumab, another side effect is conjunctivitis, which is treatable but can be severe.31 Anaphylaxis is mentioned in the package inserts, but that is very rare.32
What future therapeutic pathways and outstanding questions are on your mind regarding severe allergic asthma in children?
There are certainly other mediators that could be future targets in asthma. Tezepelumab was a good example of a biologic that targets a different cytokine, TLSP. That made it a bit different from the other currently approved biologics. As a potential example for the future, IL-6 has been associated with asthma33; there are anti-IL-6 drugs available for rheumatic diseases.34 Perhaps some of those agents, or new agents derived from those, could be helpful for asthma.
In the meantime, an important question is, do any of these biologics help prevent asthma? Some children at high risk for asthma wheeze; not all children who wheeze end up with asthma, but if a patient wheezes, has a family history of asthma, and also has eczema, that is a high-risk child. Can we prevent asthma with these biologics? In fact, there is an ongoing study posing this question, a trial of omalizumab in young children (aged 2 to 3) who have not yet been diagnosed with asthma but are at high risk.35
Another important question is, do you have to give these biologic therapies year-round? Or can young patients take a treatment holiday, similarly to how we pause inhaled steroids in the summer for many children? As mentioned earlier, we showed (at least with omalizumab) that we do not have to give it all the time. Rather, we can administer it for 4 months starting just before and continuing through the viral season, which cuts the cost considerably. However, with the other biologics, we do not yet know whether it is okay to pause them during the summer; we need to learn the answer to that question.
This Q&A was edited for clarity and length.
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Reviewed February 2023