Asthma Biologics

Asthma is a condition that impacts millions globally, affecting over 339 million people, according to the World Health Organization. It’s a long-term condition that triggers inflammation and tightening of the airways, causing symptoms like wheezing, difficulty breathing, chest tightness, and coughing.

Many people control their asthma with inhaled corticosteroids and bronchodilators, but some still face challenges with severe asthma even on high doses. For these individuals, biologics offer the potential for long-term relief.

Biologics represent a significant leap forward in asthma treatment. Unlike traditional medications that work broadly, biologics focus on the specific biological processes causing the disease. In this article, we’ll explore biologics for asthma, how they work, and how they offer hope for those with severe asthma who haven’t found relief from conventional therapies.

How the Immune System Plays a Role in Asthma

Asthma is driven by inflammation in the airways, which may be set off by allergens, irritants, or respiratory infections. The immune system, specifically T-helper cells, eosinophils, and immunoglobulin E (IgE), overreacts, leading to chronic inflammation.

This response causes the airways to become overly sensitive, producing excessive mucus and narrowing the airways further.

Research has identified several cytokines (proteins that regulate immune responses) as key players in asthma. These include:

• • Interleukin-4 (IL-4)
  • Interleukin-5 (IL-5),
  • Interleukin-13 (IL-13)

The development of biologics has enabled us to target and block these cytokines, offering a more precise way to treat asthma.

What Are Biologics?

Biologics are a class of medications derived from living organisms. Unlike conventional asthma treatments that address symptoms broadly, biologics are designed to target specific components of the immune system that drive asthma.

These drugs, often monoclonal antibodies, block proteins like IgE and cytokines to reduce inflammation in a more targeted manner.

Monoclonal Antibodies Explained

Monoclonal antibodies are lab-made proteins that mimic the immune system’s ability to fight off harmful pathogens, like viruses and bacteria. These antibodies target and bind to a specific substance (called an antigen) in the body, such as a protein involved in disease processes.

Types of Asthma Targeted by Biologics

Biologics are used to treat specific types of asthma, particularly those that are more severe or difficult to control with standard treatments like inhaled corticosteroids. The types of asthma that biologics commonly target include:

• • Severe Eosinophilic Asthma: This type of asthma is characterized by high levels of eosinophils (a type of white blood cell) and leads to persistent inflammation in the airways. Patients with this condition often suffer from more severe symptoms and frequent exacerbations.

• • Severe Allergic Asthma: This form of asthma is driven by IgE, which plays a central role in allergic reactions. Patients with elevated IgE levels often experience frequent asthma attacks triggered by allergens like pollen, dust, or pet dander.

Additionally, some patients with asthma require high doses of oral corticosteroids to manage symptoms. Biologics can help reduce the need for steroids by targeting specific inflammatory pathways.

Approved Biologics for Asthma Treatment

Regulatory agencies have approved several biologics for treating severe asthma. These biologics have undergone rigorous clinical trials to demonstrate their efficacy and safety in reducing asthma symptoms and exacerbations.

Here are some of the FDA-approved biologics for asthma treatment:

Omalizumab, an anti-IgE antibody, was the first biologic treatment for asthma approved in the US and Europe. It works by stopping IgE from attaching to receptors on certain immune cells, like mast cells and basophils.

This process helps reduce the release of inflammatory chemicals and weakens the body’s allergic response. It also lowers the number of IgE receptors on mast cells, which further reduces inflammation.

Earlier studies confirmed that omalizumab is both safe and effective. In 2022, a study followed patients for 16 years to assess the long-term safety and effectiveness of the drug in real-world use.

Here are the results:

• • Patients experienced fewer attacks, averaging 0.88 per year, compared to 3.6 asthma attacks per year before.
  • There were no hospitalizations for asthma-related issues during the entire 16-year period, compared to 0.3 hospitalizations per patient before.
  • Patients’ lung function improved significantly over time.
  • Patient-reported outcomes such as asthma-related quality of life (AQLQ) and asthma control test (ACT) scores improved from the start of the study and remained high, especially during the first 9 years.
  • Patients were able to reduce their asthma medications, particularly oral corticosteroids (OCS).

Additionally, omalizumab is generally well tolerated and has a low risk of severe allergic reactions (anaphylaxis), which is estimated at 0.1% to 0.2%. Despite this low risk, the FDA has issued a black box warning for omalizumab.

Mepolizumab has been studied in patients with uncontrolled eosinophilic asthma. Research shows that mepolizumab reduces asthma flare-ups, improves lung function, enhances asthma control, and decreases the need for OCS in multiple clinical trials.

In the SIRIUS trial, mepolizumab treatment allowed a 50% reduction in OCS doses for patients with eosinophilic asthma who were on long-term OCS therapy. This benefit occurred while still reducing asthma flare-ups by 32% and improving asthma control by 43%.

However, its effect on lung function has been mixed. Some trials showed improved FEV1, a key indicator of lung health, while the DREAM trial (one of the largest trials) found no significant FEV1 changes with mepolizumab.

IMPORTANT NOTE:

To reduce the risk of herpes zoster infections, it is recommended that individuals aged 50 and older receive a zoster vaccination (preferably recombinant, not live virus) four weeks before starting treatment.

Reslizumab is another IL-5 antagonist that works similarly to mepolizumab but is administered intravenously. It is the only biologic delivered intravenously using weight-based dosing, which may offer a distinct advantage over fixed doses.

Researchers evaluated the real-world effectiveness of reslizumab in 134 adults in a Dutch asthma registry. They found that reslizumab significantly reduced asthma flare-ups by 90% and lowered the need for OCS.

The treatment was effective for both biologic-naive patients and those switching from another biologic, with similar reductions in exacerbations and OCS use. Additionally, 59.2% of patients experienced a “good” or “excellent” response to reslizumab.

Benralizumab is an IL-5 receptor antagonist that directly depletes eosinophils through apoptosis (programmed cell death). Unlike mepolizumab and reslizumab, which primarily block IL-5, benralizumab also stops eosinophils from multiplying and becoming activated.

A recent study evaluated the long-term impact of benralizumab over 96 weeks. The treatment significantly reduced asthma flare-ups, with a 94.9% decrease in overall exacerbations and a 96.9% decrease in severe cases.

Lung function also saw notable improvement, and asthma control scores improved to 23. Additionally, 60% of patients were able to stop using OCS, and their blood eosinophil levels were nearly eliminated.

Both patients new to biologics and those with previous biologic experience showed similar benefits. Exacerbation rates dropped by 95.9% in biologic-naive patients and by 92.4% in those with prior biologic use. These results remained stable or continued to improve over time, confirming that benralizumab provides long-lasting and progressive benefits for asthma control.

Dupilumab is a monoclonal antibody that targets the IL-4? receptor, blocking the signaling of both IL-4 and IL-13. Studies have shown that dupilumab was effective in several ways for patients with moderate-to-severe asthma:

• • It significantly reduced the number of adverse events.
  • The use of OCS was decreased, indicating that patients needed fewer steroids to manage their asthma.
  • Dupilumab lowered levels of Type 2 (T2) inflammation markers, which are indicators of asthma severity.
  • Rapidly improved lung function, helping patients breathe better in a short amount of time.

Additionally, dupilumab has shown significant improvement in patients with chronic rhinosinusitis and nasal polyps, making it a strong option for asthma patients with these related conditions.

Tezspire, first approved by the FDA in December 2021, stands as the only biologic treatment for severe asthma that does not have limitations based on asthma type (such as eosinophilic or allergic asthma) or specific biomarkers. This means it can be used to treat a broad range of severe asthma patients.

It’s designed to target the main source of inflammation in asthma, which is the airway epithelium (the tissue lining the airways). This area is the first to be affected by viruses, allergens, pollutants, and other environmental triggers.

When the airway epithelium is exposed to asthma triggers, it releases TSLP, which activates multiple inflammatory pathways. Tezepelumab works by blocking TSLP, which can prevent immune cells from releasing other inflammatory proteins. By doing so, tezepelumab can reduce asthma flare-ups and help improve overall asthma control.

In the Phase III trial, tezepelumab reduced asthma exacerbations by 56%, with an annual rate of 0.93 compared to 2.10 for placebo. Tezepelumab also improved lung function (FEV1 increased by 0.23 liters vs. 0.09 liters with placebo) and led to better scores in asthma control and quality of life.

Who Can Benefit from Biologics?

Biologics are not intended for all asthma patients. These therapies are typically reserved for individuals with moderate to severe asthma who meet specific criteria, such as:

• High levels of eosinophils: Patients with eosinophilic asthma who have elevated blood eosinophil counts are prime candidates for IL-5-targeting biologics like mepolizumab and benralizumab.
• Elevated IgE levels: Patients with allergic asthma who have high IgE levels and are not responsive to inhaled corticosteroids may benefit from omalizumab.
• High FeNO levels: FeNO is a biomarker of airway inflammation, and patients with elevated FeNO may respond well to dupilumab.

In addition to these biomarkers, candidates for biologic therapy are typically individuals who experience frequent exacerbations, require high doses of corticosteroids, or have difficulty controlling their asthma with standard treatments.

The Future of Biologics in Asthma Treatment

With a clearer understanding of asthma’s underlying causes, new pathways for treatment have been discovered, leading to the development of additional biologic therapies. While current FDA-approved biologics mainly target later stages (downstream) of Type 2 (T2) inflammation, researchers are now looking at earlier stages (upstream targets) like IL-25, IL-33, and TSLP.

Drugs like tezepelumab, which targets upstream pathways, may offer new treatment options for patients with noneosinophilic asthma. Other therapies, like small-molecule drugs targeting the Janus kinase pathways, which act later in the T2 process, are also in development.

Researchers are also exploring new ways to deliver these biologics. Traditional methods like subcutaneous or intravenous injections can result in high concentrations in the blood but lower levels in the lungs, where they are needed most. To solve this, nebulized biologic therapies are being tested.

An animal study using a nebulizer to deliver small fragments of anti–IL-13 monoclonal antibodies showed a reduction in allergic airway responses and was well tolerated. This method could provide more targeted and safer asthma treatments in the future.

Final Thoughts

Biologics represent a significant advancement in the treatment of severe asthma, offering targeted therapies that address the underlying immune mechanisms driving the disease.

As research continues and new biologics are developed, these advanced therapies will likely play an increasingly central role in the management of asthma, bringing lasting relief to millions of individuals worldwide.

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