Studies Give Additional Info on Tezepelumab, Dupilumab Biologics for Asthma

This story has been corrected to say that only one of the trials missed its primary end point.

Data on 2 biologics, tezepelumab and dupilumab, were presented at an ATS 2021 International Conference session.

Michael E. Wechsler, MD, MMSc, a pulmonologist at National Jewish Health, provided additional detail from 3 trials on tezepelumab, which will be aimed at treating patients with severe asthma, if approved. Results from one of the studies, the phase 3 NAVIGATOR trial looking at efficacy and safety in adults and adolescents, were published last week in The New England Journal of Medicine.

Tezepelumab targets and blocks thymic stromal lymphopoietin (TSLP), an epithelial cell–derived cytokine that plays a role in a wide range of asthma inflammatory pathways.

Weschsler said the biologic targets T2 inflammation, both allergic and eosinophilic, and also appears to have a role in non-T2 inflammation.

In allergic asthma, TSLP is involved in the production of interleukin (IL)-4 and IL-13, which activate mast cells and immunoglobulin E in eosinophilic asthma; it spurs IL-5; in non-T2 inflammation, it is implicated in TH17 inflammation; and in both types of inflammation, it creates structural effects through the production of fibroblasts and collagen.

By blocking TSLP from its receptor, tezepelumab reduces the effect of those inflammatory processes, as shown by reduced IL-5, as well as some biomarkers, Weschler said.

Last week, AstraZeneca, which is partnering on the drug with Amgen and funded the studies, submitted a Biologics License Application to the FDA. Sixty percent of patients with severe asthma on a biologic still do not have optimal control of their disease, and there is a need for therapies that address a wider spectrum of inflammation, the companies have said.

Besides highlighting the NAVIGATOR trial, Wechsler also presented SOURCE, a phase 3 study examining the effect on adults dependent on oral corticosteroid (OCS) therapy; and CASCADE, a phase 2 study looking at mechanistic bronchoscopy in patients with moderate-to-severe asthma.

In the 48-week SOURCE study, 150 patients were randomized to receive tezepelumab 210 mg every 4 weeks or placebo as add-on therapy, with patients maintained on their currently prescribed high-dose inhaled corticosteroid plus plus a long-acting β agonist (LABA) with or without other asthma controller therapy.

After a run-in period, the dose of OCS was gradually tapered downward and ended by week 36; between weeks 36 and 44, the patients only received tezepelumab.

The therapy missed its primary end point in this study, which was a statistically significant reduction in daily OCS without worsening asthma control.

But Wechsler highlighted that, from baseline, “a greater proportion of patients treated with tezepelumab were able to reduce their oral corticosteroid dose by 90% to 100% compared to placebo [54.1% vs 46.1%].” This wasn’t seen in other categories of reductions, however. He cited the possibility that a large placebo effect, stemming from the duration of the OCS reduction phase and multiple attempts to reduce OCS dose, may be to blame for the result.

He said additional studies are needed to confirm the efficacy of the therapy in reducing the dose of OCS used by patients who depend on it.

The secondary end point, which measured the reduction in the annualized rate of asthma exacerbations over 48 weeks, was met, with a 31% reduction in attacks compared with placebo. There were also improvements in lung function, asthma control scores, and asthma quality of life score.

The CASCADE study, meanwhile, examined the change in baseline in airway submucosal inflammatory cells in bronchoscopic biopsies. There was a statistically significant difference in the level of eosinophils but not in other markers of inflammation, including neutrophils, T cells positive for CD3 or CD4, or mast cells positive for tryptase or chymase.

Meanwhile, the NAVIGATOR study included patients who had 2 or more exacerbations in the past 12 months and poor asthma control, as well as an equal proportion of patients with eosinophil levels above and below 300 cells/mcL.

They were taking medium or high-dose inhaled glucocorticoids (daily dose of ≥500 mcg of fluticasone propionate or equivalent) for at least 12 months and at least 1 additional controller medication, with or without oral glucocorticoids, for at least 3 months before joining the study.

Patients were randomized to receive either tezepelumab by subcutenous injection every 4 weeks or placebo every 4 weeks; the dose of tezepelumab was 210 mg.

Besides the overall results, which showed that tezepelumab reduced exacerbations by 56% overall and 41% in those with eosinophils less than 300 cells/mcL, Wechsler said the trial also showed that the therapy cut exacerbations in patients with a wide range of eosinophil levels (from low to high as well as in various biomarkers).

It also cut the rate of exacerbations linked with emergency department visits by 79% and significantly improved lung function in a range of eosinophil levels.

Another presentation, given by Leonard B. Bacharier, MD, an allergist/immunologist and professor of pediatrics at the Monroe Carell Jr. Children’s Hospital at Vanderbilt University Medical Center, focused on a pediatric study for dupilumab, which targets IL-4 and IL-13.

Dupilumab, sold as Dupixent, is already approved for atopic dermatitis in patients 6 years and older with moderate-to-severe atopic dermatitis that is not well controlled with topical medication; for use with other asthma drugs for the maintenance treatment of moderate-to-severe eosinophilic or oral steroid dependent asthma in patients 12 years and older; and for adults with chronic rhinosinusitis with nasal polyposis.

The VOYAGE trial looked at the efficacy and safety of the biologic in children aged 6 to 12 years and found that it reduced exacerbations by nearly 60%, as well as improved lung function and improved overall symptom control. It also reduced fractional exhaled nitric oxide, a type of biomarker.

An FDA decision about expanding the use of dupilumab for children as young as 6 with asthma is expected by October 21, 2021.