An Upstream Strategy for Treating Severe Asthma

Severe asthma is asthma that can’t be controlled with inhaled corticosteroids, long-acting beta2 agonist (LABA), or both. Between 5% to 10% of people with an asthma diagnosis are in the severe asthma category. For them, the treatment is a growing number of biologics that home in on the cytokines that fuel the inflammatory cascades that underlie the disease.

But there is a problem in a zeroing in on a particular cytokine or two, argues a review paper published earlier this month in the Journal of Asthma and Allergy.

“Patients with severe asthma can have disease driven by multiple cytokines or exhibit variability in their cytokine profile, which may limit disease control by a single specific downstream anti-cytokine biologic,” wrote lead author Jane R. Parnes, executive medical director, medical sciences, at Amgen, and her colleagues.

The solution they discuss in their review involves traveling “upstream” to inhibition cytokine called thymic stromal lymphopoietin (TSLP) that researchers have identified as having a role in initiating cytokine cascades that make up the uncontrolled asthma that characterizes asthma. TSLP is produced by ciliated epithelial cells , mast cells, macrophages and endothelial cells, in Parnes and her colleagues description, and they do so in response to a variety of “insults”— allergens, viruses, bacteria, pollutants. Animals studies have shown, they say, have shown that TSLP is necessary and sufficient for development for type 2 inflammation that causes allergic and eosinophilic asthma.

Tezspire (tezepelumab), approved by the FDA in December 2021, is a biologic designed to inhibit TSLP and therefore block its downstream effects.

Parnes is an employee of Amgen, who developed and is marketing Tezspire along with AstraZeneca. Several of her co-authors are also Amgen or AstraZeneca employees and stockholders.

The review discusses the evidence from eight clinical trials of Tezspire that suggests that the TSLP inhibitors manages to stifle multiple inflammatory pathways. Parnes and her colleagues focus on the phase 2b PATHWAY trial and the pivotal Phase 3 NAVIGATOR trial, the results of which were published in the May 13, 2021, issue of the New England Journal of Medicine. The NAVIGATOR trial was a yearlong, double-blind, placebo-controlled trial that enrolled just over 1,000 adults and adolescents with severe, uncontrolled asthma. The primary endpoint was annualized rate of asthma exacerbations. Asthma exacerbations were defined as the use or an increased dose of systemtic glucocosteroids, an emergency department visit because of asthma or an asthma-related inpatient hospitalization. The results showed that Tezspire cut these asthma exacerbation events by half (56%) relative to the placebo.

Parnes and her fellow review article authors — which include Andrew Menzies-Gow, of the Royal Brompton and Harefield Hospitals in London and the principal investigator of the NAVIGATOR trial — note that one of the important features of the NAVIGATOR trial is that had equal number of patients with high (300 or more cells per microliter) and low (less than 300 cells per microliter) blood eosinophil counts.

In the study, Tezspire reduced AAER compared with placebo by 70% among those with high eosinophil level, by 41% among those with levels lower than 300 cells per microliter, and by 39% among those with eosinophil levels of less than 150 cells per microliter. They also parsed other subgroup analyses including those with and without allergies to perennial aeroallergens and those eligible for omalizumab treatment and so on.

“Together,” they wrote, “these results demonstrate that tezepelumab (they refer to the drug by its generic name) improves asthma outcomes in a broad range of patients with severe asthma, regardless if eosinophil count, FeNO (fractional exhaled nitric oxide), allergic status or omalizumab eligibility.”