Asthma is one of the most common diseases affecting children. It is a main cause of morbidity and mortality in pediatric patients, and it represents a severe disease burden for patients and families. Asthma is an inflammatory disease of the airways, and it can be caused by many factors. Patients can have edema, bronchospasms, and increased mucus production as a result of this inflammatory reaction. All of this impairs the ability of the patients to breathe. Lack of oxygen throughout the body can quickly turn fatal for some patients. Patients and their caregivers always worry about what would trigger a patients’ asthma, what they can do to avoid this trigger, if they have a rescue inhaler on their person, and what the nearest emergency room is just in case of a flare up. There are many patients who do not respond well to the standard treatment, which has been recently updated to include inhaled corticosteroids replacing or working in addition to short-acting beta agonists. With routine use, short-acting beta agonists have been associated with increased morbidity and mortality. They have been shown to increase the number and severity of asthma exacerbations. With all that is changing in terms of routine asthma care, patients with moderate to severe asthma are often left with limited treatment options. Oral corticosteroids are used to treat exacerbations, but the long-term effects of oral corticosteroids in children are well-documented.(1)
Dupilumab is a monoclonal antibody marketed by Regeneron and Sanofi Genzyme. It is a revolutionary medication taking the type 2 inflammatory disease treatment to new heights. It is approved for many indications, and it is being investigated for other type 2 inflammatory diseases. Dupilumab is currently approved for moderate to severe asthma in adults, atopic dermatitis, and rhinosinusitis with nasal polyps. Dupilumab was recently approved for the treatment of moderate to severe asthma in patients 6-11 years old. The trial that granted this approval was a 52-week, phase 3, randomized, double-blind, placebo-controlled clinical trial. The primary endpoint of the trial was the annualized rate of severe asthma exacerbations. Patients who were given subcutaneous dupilumab had an annualized rate of 0.31 as compared to 0.75 in the placebo arm. When discussing life-threatening clinical asthma exacerbations, this difference is clinically and statistically significant. In terms of overall asthma control, patients in the dupilumab group had better asthma control when compared to placebo. Dupilumab is also quite helpful for patients with an eosinophilic asthma type. Interestingly enough, the amount of adverse events was similar between the two groups. This indicates a significant breakthrough and a new option for patients with moderate to severe asthma which cannot be controlled using other measures.(2)
In patients who fail conventional therapy, the options can be limited. This challenge for patients, families, and caregivers can be quite daunting. With a new agent on the market for these children, the amount of asthma exacerbations and associated healthcare costs is less. Although a new monoclonal antibody is a pricy therapy, the amount that could be saved due to less hospitalizations can be a significant help for the healthcare system overall.
References:
Lizzo JM, Cortes S. Pediatric Asthma. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551631/
Bacharier LB, Maspero JF, Katelaris CH et al. Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma. N Engl J Med. 2021 Dec 9;385(24):2230-2240.
Asthma is a chronic inflammatory condition of the respiratory system, marked by recurring symptoms such as shortness of breath, coughing, and wheezing. Diagnosing asthma involves observing persistent respiratory symptoms and detecting variable airflow obstruction via spirometry. Healthcare providers focus on managing symptoms and preventing future flare-ups through personalized treatment plans. These plans are based on the frequency and severity of symptoms, as well as potential risks, following a step-by-step approach. Early detection and treatment of asthma attacks are vital to avoid the condition escalating to severe, potentially life-threatening levels.
Asthma exacerbation includes two phases; the early phase and the late phase. The early phase is initiated by IgE antibodies that are sensitized and released by plasma cells. These antibodies respond to environmental risk factors such as house dust mites, animal allergens, mold, and farm animals. IgE antibodies then bind to high-affinity mast cells and basophils. When pollutants or risk factors get inhaled, the mast cells release cytokines which eventually de-granulate. Mast cells release histamine, prostaglandins, and leukotrienes, which then contract the smooth muscle and cause airway tightening. Th2 lymphocytes are crucial as they produce interleukins (IL-4, IL-5, IL-13) and GM-CSF, which facilitate cell communication and maintain inflammation. IL-3 and IL-5 support the survival of eosinophils and basophils, while IL-13 contributes to remodeling, fibrosis, and hyperplasia. During the late phase, eosinophils, basophils, neutrophils, memory helper T-cells all confine to the lungs resulting in bronchoconstriction and inflammation. Because of this inflammation and bronchoconstriction, there is an intermittent airflow obstruction, which leads to an increased work of breathing.
Severe asthma is an uncommon condition, affecting less than 5% of children with asthma. However, this small group is responsible for approximately 50% of the healthcare costs associated with pediatric asthma. In the United States, around 75,000 children aged 6 to 11 suffer from uncontrolled moderate-to-severe asthma, with even higher numbers globally. Despite using standard treatments like inhaled corticosteroids and bronchodilators, these children often continue to experience severe symptoms, including coughing, wheezing, and difficulty breathing. Additionally, they may need frequent courses of systemic corticosteroids, which pose significant health risks.
In 2021, the U.S Food and Drug Administration (FDA) approved Dupixent (dupilumab) as an add-on maintenance treatment for patients aged 6 to 11 years with moderate-to-severe asthma either characterized by an eosinophilic phenotype or dependent on oral corticosteroids. The FDA’s 2021 approval of Dupixent for children aged 6 to 11 with moderate-to-severe asthma is based on a phase 3 randomized, double-blind, placebo-controlled trial. This study assessed Dupixent’s efficacy and safety alongside standard treatments in children with uncontrolled moderate-to-severe asthma, with over 90% of participants having at least one concurrent type 2 inflammatory condition. Dupixent is a fully human monoclonal antibody of the immunoglobulin G4 subclass, designed to block interleukin-4 (IL-4) and interleukin-13 (IL-13) receptors. By acting as an IL-4Rα antagonist, it inhibits the receptor signaling of pro-inflammatory cytokines through the JAK-STAT pathway, thereby reducing inflammatory and immunological responses in various conditions.
Among children with high eosinophil levels (≥300 cells/μl, n=259), those receiving Dupixent (100 mg or 200 mg biweekly, based on weight) with standard care experienced a significant reduction in severe asthma attacks, averaging a 65% decrease over one year compared to placebo (0.24 events per year for Dupixent vs. 0.57 for placebo), improved lung function as early as two weeks, sustained for up to 52 weeks, measured by percent predicted pre-bronchodilator FEV1 (FEV1pp). Moreover, at 12 weeks lung function improved by 5.32 percentage points compared to placebo. Lastly, results indicated enhanced asthma control at 24 weeks with 81% of Dupixent patients reporting a clinically meaningful improvement in disease symptoms and impact, compared to 64% of placebo patients, as measured by a >0.5 improvement on a 7-point scale.
Safety results were consistent with Dupixent’s known profile for patients aged 12 and older, though helminth infections were reported in 2.2% of Dupixent patients versus 0.7% of placebo patients. Overall adverse event rates were 83% for Dupixent and 80% for placebo, with more frequent occurrences of injection site reactions (18% Dupixent vs 13% placebo), viral upper respiratory tract infections (12% Dupixent vs 10% placebo), and eosinophilia (6% Dupixent vs. 1% placebo).Asthma can cause significant distress for patients and their families, impacting daily life and overall well-being. However, effective medications are available that provide adequate control and relief from symptoms. Additionally, patients can manage their asthma by identifying and avoiding triggers, maintaining regular physical activity, eliminating smoking, and following a healthy diet. Some individuals also explore alternative treatments, such as herbal medicine, acupuncture, and homeopathy, to further alleviate their symptoms.
Gade, A. (2024, February 28). Dupilumab. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK585114/
Ferrante, G., Tenero, L., Piazza, M., & Piacentini, G. (2022, November 22). Severe pediatric asthma therapy: Dupilumab. Frontiers in pediatrics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9723147/#:~:text=One%20of%20these%20biological%20agents%20is%20dupilumab%2C%20a,is%20approved%20for%20pediatric%20severe%20type%202%20asthma.
FDA expands approval of Dupixent® (dupilumab) to include children aged 6 to 11 years with moderate-to-severe asthma. Sanofi. (n.d.). https://www.sanofi.com/en/media-room/press-releases/2021/2021-10-20-21-30-00-2317854
Sinyor, B. (2023, June 24). Pathophysiology of asthma. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK551579/
Hashmi, M. F. (2024, May 3). Asthma. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK430901/
Blake, K. V., & Moon, J. Y. (n.d.). Chapter 44: Asthma . Shibboleth authentication request. https://accesspharmacy-mhmedical-com.jerome.stjohns.edu/content.aspx?sectionid=270715064&bookid=3097&Resultclick=2#1205562137
Dupilumab for Pediatric Asthma
Asthma is a disease of the airway characterized by hyperresponsiveness to allergens and other environmental factors. Asthma exacerbations, or attacks, occur in two phases. The early phase is activation of the IgE mediated response mechanism, causing mast cell degranulation, smooth muscle contraction, and airway tightening. The late phase can occur hours later, when immune cells localize in the lung tissue and promote bronchoconstriction and inflammation (Sinyor B).
Asthma treatment relies on nonpharmacological interventions such as avoidance of triggers, as well as pharmacological management. The GINA guidelines provide treatment recommendations for patients with asthma, from pediatrics to adult patients with comorbidities. The cornerstones of asthma treatment include inhaled beta- agonists as well as inhaled corticosteroids. Based on the severity of the asthma, which is classified by the number of exacerbations per week and symptom control on a regimen. Common medication regimens include a short- acting bronchodilator (SABA) for as needed relief and a controller medication that consists of a long- acting beta agonist (LABA) in combination with an inhaled corticosteroid (ICS). Use of these medications are first- line and patients often adequately control their symptoms with these therapies. In pediatric patients, ICS are first line maintenance in combination with a SABA for relief. However, if pediatric patients continue to remain uncontrolled after escalating therapy to a combination LABA with ICS, then biologic agents may be considered in these patients (Levy M).
Dupilumab is a monoclonal antibody injectable medication that targets interleukin (IL) 4 and IL-3. Dupilumab blocks the allergic inflammatory cascade that is mediated by CD8+ cells and natural killer cells. This medication, under the trade name Dupixent, is approved for allergic asthma, atopic dermatitis, allergic rhinitis and chronic rhinosinusitis, and eosinophilic esophagitis (Dupilumab).
Dupilumab is indicated in pediatric patients ages 6 to 11 that still remain uncontrolled after continued escalation of therapy. To be considered for add- on use of dupilumab, phenotypic assessment is needed. For example, patients with eosinophilic asthma may have greater beneficial outcomes with dupilumab (Levy M).
Dupilumab is received once every two weeks as a maintenance injection. Dosing is dependent on the patient’s weight. Additionally, patients over the age of 12 should receive a loading dose. There are no hepatic or renal dose adjustments with this medication. This medication is given as a subcutaneous injection into the thigh or lower abdomen. The injection site should be rotated each time. This medication is kept in the refrigerator until it is time to receive the injection. The medication should sit for 45 minutes until it reaches room temperature. The solution inside the prefilled syringe should be clear and colorless. If it is discolored or yellow in color, the medication should be discarded because it cannot be used. Side effects include hypersensitivity reactions such as angioedema, facial redness, and immune thrombocytopenia. Additionally, patients can experience injection site reactions and upper respiratory tract infections. Monitoring for dupilumab includes for signs and symptoms of allergic reactions such as angioedema and arthralgias, symptom control, exacerbation quantity, and pulmonary function tests (Dupilumab).
Citations:
Dupilumab, ln. Lexidrugs Online [Internet Database]. Hudson, OH. Lexi-Comp, Inc. Updated 20 Apr 2024.
Levy M, Bacharier L, Bateman E. et al. Key recommendations for primary care from the 2022 Global Initiative for Asthma (GINA) update. npj Prim. Care Respir. Med.33, 7 (2023). https://doi.org/10.1038/s41533-023-00330-1
Sinyor B, Concepcion Perez L. Pathophysiology Of Asthma. [Updated 2023 Jun 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551579/