First Biologic Targeting TSLP Approved For Severe Asthma

FDA Approval

On December 17, 2021, the U.S. Food and Drug Administration (FDA) approved Tezspire (tezepelumab-ekko) injection as a maintenance treatment to improve severe asthma symptoms when used as an add-on with a patient’s current asthma therapy. Tezepelumab is labeled for adults and children aged 12 years and older with severe asthma not controlled by their current asthma medicine. It is the first asthma medication targeting TSLP, a molecule involved in airway inflammation. It is also the first biologic for severe asthma that is not labeled for a specific type of severe asthma such as eosinophilic or allergic, or for a specific biomarker level.ⁱ

Biologics for severe asthma

Monoclonal antibody (MAB) treatments (referred to here as biologics) have been heralded by some as a giant leap forward for severe asthma management.ⁱⁱ Until now, the biologics available for severe asthma have all been indicated for Type-2 (T2) high (eosinophilic or allergic) asthma, and thus require some measurement of biomarkers such as eosinophils in blood or sputum, fractional exhaled nitric oxide (FeNO) and specific immunoglobulin (Ig)E of clinical relevance. For example, one definition of T2 inflammation includes blood eosinophils ≥150/μL, and/or FeNO ≥20 ppb, and/or sputum eosinophils ≥2%, and/or asthma that is clinically allergen-driven.ⁱⁱⁱ

Previously, five biologics were approved for severe asthma (in alphabetical order): benralizumab (Fasenra), dupilumab (Dupixent), mepolizumab (Nucala), omalizumab (XOLAIR), and reslizumab (CINQAIR). These treatments all target specific inflammatory pathways that activate the T2 immune responses that lead to airway inflammation. Benralizumab, mepolizumab, and reslizumab target the interleukin (IL)-5 pathway, while omalizumab targets IgE, and dupilumab targets IL-4 and IL-13. Because they target these specific pathways, omalizumab is indicated only for allergic asthma (positive skin test or in vitro reactivity to aeroallergen); dupilumab for eosinophilic or corticosteroid-dependent severe asthma; and the remaining three for severe eosinophilic asthma.

The recently approved biologic Tezepelumab blocks TSLP, a critical epithelial cytokine that induces T2 inflammation.^iv Acting at an upstream pathogenic level, TSLP triggers complex cascades of downstream pro-inflammatory pathways.^v Tezepelumab was shown to be effective in Phase III randomized clinical trials including the NAVIGATOR trial that assessed patients with a broad range of severe asthma phenotypes, including those with low blood eosinophil counts.^vi Thus, the FDA approved tezepelumab without an indication for a specific type of severe asthma such as eosinophilic or allergic, and without a specific biomarker level.

Potential Impact

By blocking TSLP, tezepelumab may enact broader effects on airway inflammation than are achieved with other biologic treatments owing to its position at the top of the inflammatory cascade, from which it controls several downstream processes that drive eosinophilic and neutrophilic inflammation, as well as structural changes to the airway.^vii Tezepelumab may become a more effective treatment for a broad range of people with severe asthma. Specifically, non-eosinophilic, neutrophilic asthma may be as common as T2 eosinophilic asthma but is less well understood. Tezepelumab has demonstrated its efficacy in severe uncontrolled asthma without regard to baseline eosinophil counts.^viii

Looking to the future

While tezepelumab is the first biologic targeting TSLP to be approved by the FDA, there are additional biologics in the pipeline. Another anti-TSLP treatment under study is CSJ117, a fully human neutralizing antibody antigen-binding fragment (Fab) from Novartis. Unlike the subcutaneously injectable tezepelumab, CSJ117 is being created as an inhaled formulation, possibly offering greater convenience to patients.^ix Additional new biologics that don’t target TSLP are also undergoing testing. For example, a phase IIb clinical trial of Roche’s MSTT1041A, an anti-ST2 (IgG2) human MAB was recently completed but no results have been published. Other possible future treatments for severe asthma could target the kinases (eg, JAK and Pi3K) and PGD2 (acts as a pro-inflammatory mediator).^x Undoubtedly, many more innovative biologic treatments for severe asthma will be developed in the future.

About severe asthma

Asthma is a heterogenous, chronic disease affecting adults and children in which the airways in the lungs narrow and swell, causing a variety of symptoms including labored breathing, wheezing, chest tightness, and cough. According to the World Health Organization, asthma affected an estimated 262 million people in 2019 and caused 461,000 deaths. Asthma is the leading chronic disease in children.^xi

The Global Initiative for Asthma (GINA) provided the following definition of severe asthma in their 2021 report. “Severe asthma is asthma that is uncontrolled despite high dose inhaled corticosteroids-long-acting beta agonist (ICS-LABA), or that requires high dose ICS-LABA to remain controlled.”^xii Similarly, the ATS/ERS criteria defines severe asthma as asthma requiring escalation to step 5 treatment (meaning high-dose ICS in combination with a second controller and/or additional systemic corticosteroid therapy) to maintain asthma control or asthma that remains uncontrolled despite such therapy. While only 5% to 10% of asthma patients meet the criteria for severe asthma, more than 80% of the total asthma healthcare costs can be attributed to them.^xiii Uncontrolled, severe asthma constitutes a considerable burden on patients, families, and healthcare systems.