Biologics in Asthma: A Paradigm Shift in Treatment for Severe Asthma Patients

Case study: Rohan, a 12-year-old boy from Delhi’s urban slums

Rohan, a cheerful and active boy, was first diagnosed with severe persistent asthma at just 8 years of age. Living in one of Delhi’s densely populated slums, he is constantly exposed to toxic levels of air pollution (with PM2.5 levels often exceeding 150 µg/m³), household smoke from open-fire cooking, and seasonal allergens. Although he uses a basic inhaler, his condition remains poorly controlled due to inconsistent access to preventive treatment and limited healthcare awareness in his community. Over the past year, Rohan has endured repeated emergency hospital visits, often struggling to breathe during the night, missing weeks of school, and being unable to play or study like his peers. His condition was underdiagnosed for several years, leading to progressive breathlessness, and he has required multiple intensive care unit admissions.

His story is just one of millions — a clear reflection of the urgent need for structured asthma care, early diagnosis, routine follow-up, and most critically, public health policies that address air quality, access to inhalers, and community awareness.

Current status and challenges

Global Initiative for Asthma (GINA) is a tool which provides evidence-based guidelines for asthma management. The Standard Controller Therapy (steps 3–5) recommended for asthma patients involves low-dose inhaled corticosteroid (ICS), Short-Acting Beta-Agonist (SABA), and Long-Acting Beta-Agonist (LABA) for maintenance and reliever therapy (MART).^[2]

Before considering any step up, the diagnosis is to be confirmed, and common problems evaluated or assessed in adults (Steps 1–2 combined) who were considered by a clinician to have mild asthma, were taking SABA alone, or had controlled asthma on daily low-dose ICS or leukotriene receptor antagonist.^[3] The preferred step 3 treatment is the regimen with low-dose ICS-formoterol as MART. If needed, the maintenance dose of ICS-formoterol can be increased with the number of maintenance inhalations.^[3]

Even though asthma treatments have improved significantly, some patients continue to experience uncontrolled symptoms, frequent exacerbations, and increased hospitalizations.^[4] Recently, there has been an increase in morbidity and mortality, an increase in healthcare expenditure, and a decrease in quality of life as a result of the disease.^[4] For patients with severe asthma, high-dose inhaled or oral steroids are given along with LABA. Drugs such as tiotropium, leukotriene modifiers, and biologics are also considered in addition to MART therapy. Biologics are recommended in the step 5 category for the management of moderate-to-severe asthma.^[5]

They have emerged as an essential element in the management of severe asthma, offering targeted therapies that promise significant improvement in patients with uncontrolled disease. These therapies, which include monoclonal antibodies that block specific molecules involved in the inflammatory processes of asthma, are particularly beneficial for individuals with eosinophilic or allergic asthma who fail to achieve adequate control with standard therapies such as ICSs.

The demand for biologics has increased as the global burden of severe asthma rises, with conventional treatments frequently proving ineffective in controlling symptoms. However, challenges remain in their widespread use. The high cost of biologic therapies is a significant barrier, limiting access for many patients, especially in low- and middle-income countries. In addition, biologics require administration via injection or infusion, which can be inconvenient and may deter patient adherence. There is also a need for further research to better understand which patients will benefit most from biologic therapies and to improve long-term safety.

This comprehensive review article seeks to investigate the function of biologics, modes of action, clinical efficacy, safety profiles, their present role and prospective future in the treatment of uncontrolled severe asthma.

Sensitization and Immune Activation

Allergens such as pollen and dust mites are processed by antigen-presenting cells (APCs), including dendritic or lymphoid cells, in allergic asthma. These APCs present the antigens to T-helper (Th0) cells which then differentiate into Th2 cells. The Th2 cells release cytokines such as IL-4, IL-5, and IL-13, triggering a series of actions that attract eosinophils to the airways and activate B cells to produce IgE. This cascade contributes to airway inflammation, remodeling, fibrosis, and epithelial hyperplasia.^[4,11]

IgE and mast cell activation

Upon subsequent allergen exposure, B cells are stimulated and produce IgE [Figure 1]. It then attaches to receptors on mast cells, sensitizing, and stimulating their degranulation. The degranulation of mast cells releases mediators such as histamine, prostaglandins, and leukotrienes. Histamine leads to bronchoconstriction, increased vascular permeability, and mucus secretion. Leukotrienes such as LTC4, LTD4, and LTE4 are potent inducers of prolonged bronchoconstriction, causing airway edema. Prostaglandins such as PGD2 are mostly responsible for bronchospasm and inflammation. Airway smooth muscle contracts in response to inflammatory mediators such as leukotrienes, histamine, and acetylcholine, reducing airway diameter. This constriction significantly contributes to the symptoms of wheezing and breathlessness.^[12]

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Figure 1:

IgE-mediated allergic pathway in asthma.

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Airway inflammation

Inflammatory cells (eosinophils, mast cells, T cells) infiltrate the airway wall, releasing cytokines and chemokines that perpetuate inflammation. Eosinophils sometimes release granules such as eosinophilic cationic protein and major basic protein, which cause damage to airway epithelial cells, heightening the sensitivity to triggers. Allergens such as cold air and exercise stimulate the nerves innervating the highly sensitive airways, causing airway hyperresponsiveness (AHR). This results in exaggerated bronchoconstriction in response to minimal triggers.^[13]

Airway remodeling

Recurrent allergen exposure causes chronic inflammation of the airways, leading to irreversible structural changes. It causes thickening of airways due to subepithelial fibrosis, which is mediated mostly by transforming growth factor-beta. This thickening further causes hypertrophy and hyperplasia of airway smooth muscle, worsens bronchoconstriction, and causes mucus gland hypertrophy, resulting in permanent loss of lung function.^[14] IL-13 causes proliferation of goblet cells in the airway epithelium, producing excessive mucus. These mucus plugs thicken and obstruct the airways, exacerbating airflow limitation.

Special variants of asthma

Inflammatory mediators are associated with cough-variant asthma, which increases the sensitivity of both C and Aδ fibers by lowering their activation thresholds. It allows these nerves to generate action potentials in response to mild chemical, thermal, or mechanical stimuli that would normally be insufficient to trigger activation of these afferent nerves.

In patients on long-term aspirin, dysregulated arachidonic acid metabolism by enzyme 5-lipoxygenase and cyclooxygenase leads to the generation of leukotrienes, prostaglandins, and thromboxane, which serve as potent bronchoconstrictors.^[12] These patients can suffer from aspirin-exacerbated respiratory disease.

Steroid-resistant asthma, also known as corticosteroid-refractory asthma, is more commonly observed in patients who have been on long-term corticosteroid therapy. This condition occurs when individuals exhibit a poor or diminished response to glucocorticoids, which are typically used to control inflammation in asthma. The resistance may arise due to alterations in glucocorticoid receptor function, increased expression of pro-inflammatory cytokines, or other molecular changes within the immune system that reduce the effectiveness of corticosteroids.^[15] Asthma endotypes can be further categorized based on clinical and inflammatory profiles into eosinophilic, neutrophilic, mixed eosinophilic and neutrophilic, and non-inflammatory (paucigranulocytic) types.^[5,16] Asthma severity can be classified into four categories: intermittent, mild persistent, moderate persistent, and severe persistent. This classification is based on symptom frequency and FEV₁ levels.^[10] Asthma is categorized as childhood-onset or adult-onset depending on the age at which symptoms begin. Childhood-onset asthma is commonly related to allergic triggers and is frequently associated with a pronounced atopic background. On the other hand, adult-onset asthma is non-allergic and is mostly triggered by occupational exposures or infections.^[17]

These classifications help identify the specific type of asthma, enabling tailored treatments and improving disease management. Severe asthma is a heterogeneous condition due to different phenotypes according to the presence of Type 2 inflammation, which is divided according to the presence (“Type 2 high”) or absence (“non-Type 2 high”). TH2 inflammation characterizes both early onset allergic and late onset eosinophilic phenotypes mediated by IL-4, IL-13 and IL-5.^[5,18] Corticosteroids account for almost all types of asthma cases. Biologics are primarily used for eosinophilic asthma, which includes both allergic and non-allergic type 2 (T2) asthma. For T2-low, neutrophilic severe asthma, monoclonal antibodies address cellular and molecular pathways involved in inflammation, releasing IL-4,5, 13 and their receptors as well as cytokines such as thymic stromal lymphopoietin (TSLP), IL-33, which are responsible for T2-high asthma [Figure 2].^[5,18]

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Figure 2:

Key inflammatory pathways in Type-2 asthma and biologic targets.

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Anti-Ig E monoclonal antibodies

Omalizumab binds to free circulating IgE (FcεRI and FcεRII) on two Cε3 or CD23 domains and prevents its interaction with mast cell receptors, thus reducing allergic inflammation.^[5] It inhibits the release of histamine and leukotrienes and decreases the exacerbations of severe asthma.

Some studies, such as the INNOVATE Trial and PROSPERO study, demonstrated that omalizumab significantly reduced asthma exacerbations despite blood eosinophil count and fractional exhaled nitric oxide (FeNo).^[19] Omalizumab also has a definite role in improving lung function after 5–9 years of therapy by increasing FEV1 in 1 s.^[20-22]

IL-5 monoclonal antibodies

Mepolizumab, reslizumab are anti-IL-5 monoclonal antibodies.

In eosinophilic asthma, IL-5 cytokine has a major role in activation and recruitment. Mepolizumab works by binding to IL-5, preventing it from attaching to receptors on eosinophils or blocking its activity.^[13,23] On the other hand, benralizumab targets the IL-5 alpha receptor on eosinophils and induces apoptosis through antibody-dependent cellular cytotoxicity. Hence, mepolizumab and benralizumab are the most commonly preferred drugs in eosinophilic asthma with blood eosinophil count >150 cells/µL).^[24]

Like omalizumab, it also reduces exacerbation rate up to 50–70% in patients and also helps in reducing the maintenance dose of oral corticosteroids by 50% as compared to placebo (DREAM Trial).^[4,6,13,25]

Eger et al. and some RCT studies showed that subsequent treatment with anti-IL-5 therapy for years can make patients super-responders.^[26] It can also reduce exacerbation rate up to 70% despite having a lower count of ≥500 cells/µL in 2 RCT studies. The SIROCCO and CALIMA trials have demonstrated more rapid eosinophil depletion with reslizumab than benralizumab in eosinophilic asthma.^[27] The OSMEX and BORA study confirmed the sustained efficacy with long-term safety of continuous mepolizumab and Benralizumab treatment.^[24]

Omalizumab and mepolizumab have shown marked improvement in eosinophilic asthma, but they have a very small role in decreasing AHR as compared to etanercept, which is an anti-tumor necrosis factor antibody. Etanercept also has a significant role in refractory asthma, showing improvement of lung function.^[28]

Anti-IL-4 and IL-13 monoclonal antibodies

IL-4/IL-4 Receptor alpha and IL-13 are involved in TH-2 inflammation and play a crucial role in asthma. IL-13 has similar effects to IL-4 primarily affecting structural cells such as epithelial cells, smooth muscle cells, and fibroblasts. It also reduces airway hyperresponsiveness and limits mucus production.^[13] Dupilumab has shown effectiveness in various phenotypes by blocking IL-4/13 receptors. Pascolizumab is another humanized antibody directed against IL-4 receptor, but failed to show efficacy in symptomatic, corticosteroidnaïve asthma patients.^[29]

The LIBERTY Quest and venture trial showed a 50% reduction in the exacerbations rate in steroid-dependent asthma patients. It also improves lung function in asthma patients.^[6,30]

Anti-IL-17 monoclonal antibodies

Bordalumab inhibits the IL-17 signaling pathway associated with neutrophilic inflammation.^[5]

The choice of biologic therapy should be tailored to the individual patient’s asthma phenotype, biomarker profile, and clinical history.

Novel biological targets

It includes novel cytokines, receptors, and signaling molecules that may offer additional therapeutic options for patients with different asthma phenotypes.

Safety profiles

The safety profile of biologics in asthma is generally favorable, but like all medications, they are not without potential risks. However, patients should be monitored closely for any signs of susceptible reactions, infections, or other potential side effects while on biologic treatment. They should also be educated and sensitized about the adverse events and how to seek immediate medical attention if such a reaction occurs.

Biologics are designed to be more targeted by acting on distinct inflammatory pathways that contribute to the progression of asthma, and are potentially safer than conventional systemic therapies such as oral corticosteroids. However, consideration should be given to the potential adverse effects associated with each biologic class.

Mostly, mild-to-moderate injection site reactions (e.g., redness, itching, and swelling) are found with biologics. Although anaphylaxis can occur with patients receiving omalizumab, it is rare. Parasitosis and giardiasis are also associated with omalizumab.^[36,39] Dupilumab and brodalumab are most commonly responsible for adverse drug reactions such as nasopharyngitis (common cold) and headaches in patients.^[40] Some cases of inflammatory bowel disease have also been reported with brodalumab use. Healthcare providers must thoroughly evaluate a patient’s medical history, including comorbidities, potential drug interactions, before initiating biologic therapy. Patients should also maintain open communication with their healthcare providers, sharing any side effects or concerns that arise during treatment. By carefully considering patient characteristics and potential risks, healthcare providers can make informed decisions to ensure the safety and efficacy of biologic treatments for asthma. In addition, regular monitoring of patients on biologics is crucial to identify any potential adverse effects early on.

Predictive biomarkers and personalized medicine

It has emerged as a key component of asthma management, particularly in the context of biologic therapies.

Predictive biomarkers

Predictive biomarkers are measurable indicators that provide information about a patient’s response to a specific treatment.

Advantages

The integration of predictive biomarkers and personalized medicine in asthma management offers several other advantages. It enables the selection of therapies according to patient profile, increases the likelihood of a positive treatment response, helps in cost reduction, and reduces the risk of unnecessary drug exposure.

Accessibility

Other guidelines and recommendations of biologics

Other guidelines, such as those from ATS and ERS, state that mepolizumab, reslizumab, or benralizumab should be considered for patients with severe eosinophilic asthma who have elevated blood eosinophil levels (≥150 cells/µL) on at least two occasions within a year. The National Institute for Health and Care Excellence guidelines in the United Kingdom and the Canadian Thoracic Society recommend these drugs when blood eosinophils are ≥300 cells/µL on continuous oral corticosteroids.^[41-43]

The future of biologics in asthma management holds significant promise, with ongoing research and developments aimed at further improving patient outcomes and expanding treatment options. Some biologics initially approved for specific asthma phenotypes are showing efficacy in other asthma subtypes or related respiratory conditions.