Tezepelumab reduces exacerbations in broad population of patients with severe asthma

A presenter at the American Thoracic Society International Conference provided an update on the latest clinical evidence from phase 3 studies of tezepelumab in a broad population of patients with severe asthma.

“Despite advances in treatment, the burden of severe asthma remains. Inflammation asthma remains a complex, heterogeneous and dynamic process, and even with biologic treatment, 60% of U.S. patients with severe asthma have suboptimally controlled disease, and there’s a need for alternative treatments for severe asthma to treat a wider spectrum of inflammation,” Michael E. Wechsler, MD, MMSc, professor of medicine at National Jewish Health in Denver, said during the breaking news session.

Tezepelumab (AstraZeneca, Amgen) is a monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP), which is an epithelial-cell-derived cytokine that plays an important role across asthma inflammation.

Wechsler provided an update on the PATHFINDER clinical trial program of tezepelumab, including results of the NAVIGATOR, SOURCE and CASCADE trials.

NAVIGATOR

The phase 3 NAGIVATOR trial evaluated the efficacy and safety of tezepelumab in adults and adolescents with severe, controlled asthma.

The randomized, double-blind, placebo-controlled trial enrolled 1,061 patients with severe, uncontrolled asthma who were on baseline background medications that included medium- to high-dose inhaled corticosteroids (ICS) plus additional controller medications, including long-acting beta agonists, long-acting muscarinic agents or leukotriene modifiers with or without oral corticosteroids (OCS).

Patients were randomly assigned to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Equal proportions of patients had blood eosinophil counts of at least 300 cells/L and less than 300 cells/L. After a 52-week treatment period, there was a 12-week follow-up period.

At 52 weeks, tezepelumab reduced the annualized asthma exacerbation rate by 56% (95% CI, 47-63) overall, and by 41% (95% CI, 25-54) in patients with blood eosinophils less than 300 cells/L and by 70% (95% CI, 60-78) in patients with blood eosinophils of at least 300 cells/L.

Wechsler said tezepelumab reduced exacerbations in patients with a broad range of inflammatory profiles.

At 52 weeks, tezepelumab also reduced the rate of exacerbations associated with hospitalization or ED visits; improved lung function; improved asthma control, symptoms and quality of life; and reduced blood eosinophil counts, FeNO and IgE.

SOURCE

The phase 3 SOURCE trial evaluated the OCS-sparing effect of tezepelumab in adults with severe, OCS-dependent asthma.

The randomized, double-blind, placebo-controlled trial involved 150 patients who required continuous treatment with ICS plus LABA and chronic treatment with maintenance OCS therapy. Patients were randomly assigned to receive tezepelumab 210 mg every 4 weeks or placebo as add-on therapy, with patients maintained on their currently prescribed ICS plus LABA, with or without other asthma controller therapy.

The primary efficacy endpoint was the percentage reduction from baseline in prescribed daily OCS maintenance dose at 48 weeks while not losing asthma control. The trial did not meet the primary endpoint (cumulative OR = 1.28; 95% CI, 0.69-2.35).

According to Wechsler, the lack of difference in the primary endpoint may be due in part to the large placebo effect from a long duration of the OCS phase and multiple attempts to reduce the OCS dose.

“While the study did not meet its primary endpoint, a greater proportion of patients treated with tezepelumab were able to reduce their corticosteroid doses by 90% to 100% compared to placebo,” he said.

A greater reduction in OCS dose was observed with tezepelumab vs. placebo in patients with baseline eosinophils 150 cells/L or greater and 300 cells/L or greater.

There was improvement in secondary endpoints with tezepelumab, including annualized exacerbation rate, FEV₁, and asthma control, symptoms and quality of life.

“While the efficacy data in oral steroid patients remains uncertain, it warrants further study to confirm some of the efficacy that was observed in terms of reducing oral corticosteroid dose in oral steroid-dependent patients,” he said.

CASCADE

CASCADE is a phase 2 mechanistic bronchoscopy study in patients with moderate-to-severe asthma.

The randomized, double-blind, placebo-controlled study involved 116 patients who were receiving medium- to high-dose ICS plus at least one additional controller with or without OCS for at least 3 months and pre-bronchodilator FEV₁ of at least 50% predicted and more than 1 L. Patients were randomly assigned to receive tezepelumab 210 mg every 4 weeks or placebo. Due to the COVID-19 pandemic, the treatment period was extended with home dosing at 28, 32, 36, 44 and 48 weeks, as needed, until patients could visit for end of treatment assessments and bronchoscopy.

The primary endpoint was change from baseline in airway submucosal inflammatory cells in bronchoscopic biopsies. Tezepelumab resulted in a significant reduction in airway submucosal eosinophils in bronchoscopic biopsies compared with placebo. There was no significant difference in terms of neutrophils, T cells as measured by CD3 positive or CD4 positive cells, or mast cells that were either tryptase positive or kinase positive, he said.

The researchers also looked at change from baseline or screening in airway mucosal eosinophils by subgroups, which was a prespecified exploratory endpoint, and observed a reduction with tezepelumab irrespective of baseline blood eosinophil count and baseline FeNO. Another prespecified exploratory endpoint was change from baseline in airway hyperresponsiveness to mannitol. Tezepelumab significantly improved airway hyperresponsiveness.

Taken together, the studies also demonstrate that tezepelumab is well tolerated, with no meaningful difference in adverse events compared with placebo, Wechsler said.