Tezepelumab in Adults and Adolescents With Severe, Uncontrolled Asthma

Nathan L. Boyer, MD – Uniformed Services University of the Health Sciences

DISCLOSURES March 04, 2022

The U.S. Food and Drug Administration (FDA) has approved the first-in-class biologic tezepelumab-ekko as an add-on maintenance treatment to standard therapy for severe asthma in adults and children aged 12 years and older. The approval is based on results from the PATHFINDER clinical trial program, including the randomized, phase 3, double-blinded, placebo-controlled NAVIGATOR trial.

Key Takeaways:

Patients with severe asthma who have nonallergic or non-eosinophilic phenotypes are not candidates for many current monoclonal antibody therapies.

Because of this, new monoclonal antibodies are being developed including tezepelumab, which is a human monoclonal antibody that blocks thymic stromal lymphopoietin or TSLP.

TSLP has been implicated in type 2 inflammation in asthma including airway obstruction, disease severity, and glucocorticoid resistance.

Use of tezepelumab resulted in fewer asthma exacerbations in high-risk patients compared to placebo and may be a therapeutic option for patients with severe asthma including those with nonallergic or non-eosinophilic phenotypes.

This transcript has been edited for clarity.

For patients with severe uncontrolled asthma, many current biologic agents are unsuitable, particularly those with nonallergic or non-eosinophilic phenotypes. Thus, there remains an unmet need for new therapies, which are effective in a broader population of patients. Recent studies have evaluated thymic stromal lymphopoietin as a target for a novel biologic agent.[2] Not everyone has heard of this target, so let’s discuss thymic stromal lymphopoietin or TSLP.

TSLP is an epithelial cell-derived cytokine implicated in multiple downstream processes involved in asthma. It has been correlated with airway obstruction, disease severity, and glucocorticoid resistance. TSLP is known to also play a role in type 2 inflammation in asthma—affecting interleukin 5, mast cell activation, eosinophilic activation, and serum IgE (Immunoglobulin E) levels. Basically, TSLP is involved with signaling related to asthma pathways, including type 2 and non–type 2 inflammation.

The drug tezepelumab is a human monoclonal antibody that blocks TSLP.[3] A prior phase 2B trial, PATHWAY,[4] showed a 71% lower rate of asthma exacerbations using this therapy versus placebo. With this result, the NAVIGATOR study[5] was created to further evaluate tezepelumab therapy. The study was a phase 3 multicenter, double-blind, randomized, placebo-controlled trial with sites throughout the world. Each group, placebo or tezepelumab, consisted of approximately 530 patients with severe asthma, defined as having at least two asthma exacerbations in the last 12 months on at least moderate-dose inhaled corticosteroid therapy, and with 50% of the group having a blood eosinophil count of greater than 300 cells/mL.

Patients were administered 210 mg of tezepelumab versus placebo subcutaneously every 4 weeks. Primary outcomes for exacerbations at 1 year, which was also subdivided based upon eosinophil count. Secondary outcomes included change from pre-bronchodilator, FEV1 (forced expiratory volume in 1 second), asthma control, and quality of life assessed via questionnaires.

Tezepelumab was found to reduce the annual rate of asthma exacerbations 0.93 compared to placebo at 2.10, which was less pronounced in the group with eosinophil counts less than 300, 1.02 versus 1.73, although both findings were statistically significant. The absolute risk reduction of asthma exacerbations was approximately 16% for the tezepelumab group. Pre-bronchodilator FEV1 improved by 0.23 L in the tezepelumab group and by 0.09 L in the placebo group. Asthma control and quality of life were also better in the tezepelumab group.

FeNO, or the fractional secretion of nitric oxide, and blood eosinophil counts were also monitored and were improved in the tezepelumab group versus placebo. Interestingly, FEV1, FeNO, and blood eosinophil counts all improved within 2 weeks and remained stable throughout the study. Adverse events, rates of study withdrawal, and complications were about the same in the two groups. Tezepelumab therapy is an effective monoclonal antibody against TSLP for [patients with] severe, uncontrolled asthma, including those with nonallergic or non-eosinophilic disease.