Moving Upstream in the PATHWAY for Persistent Uncontrolled Asthma: Anti-TSLP Tezepelumab

Published - Written by Bhavna Seth

A 20-year-old woman, Ms. Karini, visits your clinic after a recent hospital discharge. She was admitted to the ICU and intubated for an asthma exacerbation; her fourth admission for asthma this year. She is tearful, claiming that she has been adherent to her multiple inhalers (glucocorticoids and long-acting bronchodilators), uses good inhaler technique, avoids triggers, and yet continues to have severe exacerbations. A previous trial of omalizumab failed and a workup for secondary causes that may contribute to her asthma was unrevealing. What further therapeutic options might help Ms. Karini?

Despite our best efforts, up to 15% of patients with asthma have poor responses to standard therapy with inhaled glucocorticoids and long-acting bronchodilators. This heterogeneous response to asthma therapy has been attributed to differences in airway inflammation and immune-cell activation patterns, resulting in various asthma phenotypes including eosinophilic (allergic and nonallergic) asthma and noneosinophilic asthma. In addition to omalizumab, an antibody to IgE, two anti-interleukin-5 monoclonal antibodies for eosinophilic asthma are available — mepolizumab and reslizumab. However, these treatments are not effective in patients with asthma activated by other pathways. Tezepelumab, a directed antibody to thymic stromal lymphopoietin (TSLP), is an upstream type-2 helper (Th2) immune regulator that, among other actions, attenuates lymphocyte maturation by attenuating activation of antigen presenting cells. This week in NEJM, Corren et al. present the results of PATHWAY — a phase-2 randomized, double-blind, placebo-controlled trial of tezepelumab in patients with poorly controlled moderate-to-severe asthma despite medium-to-high doses of inhaled steroids.

In this international trial, 584 patients were randomized to receive low-, medium-, or high-dose tezepelumab or placebo every 4 or 2 weeks for one year. At 52 weeks, all tezepelumab groups exhibited a significant reduction (61%, 71%, and 66%, respectively) in the primary endpoint of the annualized asthma exacerbation rate (AER), compared to the placebo group (P<0.001 for all comparisons). This difference was independent of baseline eosinophil count or other indicators of Th2 status. Additionally, prebronchodilator forced expiratory volume in 1 second was significantly increased at week 52 in all tezepelumab groups, and time to first exacerbation was significantly delayed.

However, two serious drug-related adverse events were reported; febrile infection complicated by Guillian-Barré syndrome and severe pneumonia complicated by stroke, suggesting that inhibition of TSLP might impair host defenses. Importantly, substantial and persistent decreases in blood eosinophil counts and fraction of exhaled nitric oxide (FENO) levels (a marker for allergic asthma) were observed in all tezepelumab groups.

In a related editorial, Dr. Elisabeth Bel, Professor, Department of Respiratory Medicine at University of Amsterdam notes, “Tezepelumab is the first biologic that has a substantial positive effect on two important markers of inflammation of asthma — namely, blood-eosinophil levels and the the fraction of exhaled nitric oxide (FENO). Other biologics tested to date in patients with asthma show differential effects on these inflammatory markers.” Dr. Jeffrey Drazen, Editor-in-Chief of NEJM and an asthma researcher adds, “As new specific tools are developed and used to treat asthma, we are slowly dissecting the underlying mechanisms of this complex clinical syndrome.”

This study provides further insights into the pathobiology of asthma and raises important questions about what mediates exacerbations not prevented by tezepelumab. Could infectious pathogens and neutrophil recruitment play an additional role?

Dr. Bel concludes, “…tezepelumab appears to be the broadest and most promising biologic for the treatment of persistent uncontrolled asthma to date. It reduces asthma exacerbation rate by more than half and improves lung function irrespective of asthma phenotype.” However, further studies are needed to explore the efficacy and safety of this biologic before its role in treatment of patients like Ms. Karini can be determined.

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Bhavna Seth is a Resident at Boston Medical Center.