The investigational monoclonal antibody tezepelumab proved to be an effective therapy for uncontrolled severe asthma in patients with and without perennial and seasonal allergies, a post-hoc analysis of data from the phase II PATHWAY study found.
The subgroup analysis focused on patients who did and did not have baseline sensitivity to perennial allergens such as pet dander and cockroach, as well as seasonal allergies such as to ragweed and Bermuda grass. Most of the patients had experienced one or two asthma exacerbations within the year prior to study enrollment.
Compared with placebo, treatment with tezepelumab was associated with a reduction in exacerbations among patients with severe allergic asthma and in patients with severe asthma without allergen sensitivity, reported Jonathan Corren, MD, of the David Geffen School of Medicine at the University of California Los Angeles.
“For severe allergic asthma I think most people would agree that there is a considerable unmet need,” Corren said in a video presentation at the virtual American College of Allergy, Asthma & Immunology meeting. “If we look at the data worldwide, nearly 340 million people have asthma. It has been estimated that up to 10% of these patients have severe asthma and around half that number have very poorly controlled disease.”
Corren noted that allergic asthma is by far the most common asthma phenotype, affecting about 90% of children with asthma and 60% of adults with asthma.
“Many people, despite what they take on a daily basis — all the inhalers and other agents — have persistent symptoms,” he said. “They may have serious exacerbations requiring steroids and even emergency care in hospitals.”
Biologic therapies approved for asthma include the immunoglobulin (Ig) E-antibody targeting drug omalizumab (Xolair); mepolizumab (Nucala), reslizumab (Cinqair), and benralizumab (Fasenra), which target eosinophilic pathways; and dupilumab (Dupixent), which targets specific receptors associated with allergic inflammation.
Tezepelumab is a novel, investigational human monoclonal antibody that targets and blocks the epithelial cytokine thymic stromal lymphopoietin (TSLP) — expression is increased in the airways of asthma patients, and has been shown to be released in response to asthma exacerbation triggers, such as allergens, viruses, and other airborne irritants.
The therapy is being developed jointly by Amgen and AstraZeneca, which announced initial phase III trial results of the drug in patients with severe asthma on Nov. 9.
The phase III NAVIGATOR trial included adolescent (defined as those over age 12) and adult patients with severe, uncontrolled asthma despite treatment with a medium- or high-dose inhaled corticosteroid plus at least one additional medication with and without high eosinophil counts (≥300 cells/μL).
In the Nov. 9 announcement, the companies noted that the primary endpoint of the phase III trial was met, with tezepelumab added to standard of care (SoC) “demonstrating a statistically significant and clinically meaningful reduction compared to placebo plus SoC in the annualized asthma exacerbation rate (AAER) over 52 weeks in the overall patient population.”
“In the subgroup of patients with baseline eosinophil counts less than 300 cells per microliter, the trial met the primary endpoint with tezepelumab demonstrating a statistically significant and clinically meaningful reduction in AAER,” the statement continued. “Similar reductions in AAER were observed in the subgroup of patients with baseline eosinophil counts less than 150 cells per microliter.”
The phase III findings support the FDA’s move in September 2018 to grant Breakthrough Therapy Designation status to the novel monoclonal antibody for the treatment of severe asthma in patients without eosinophilic phenotype.
In the PATHWAY phase IIb study, roughly one third of patients (167) were positive for both perennial and seasonal allergies at baseline, while 69 (13.9%) were positive for perennial allergens alone and 41 (8.3%) were positive for seasonal allergens alone.
Compared with placebo-treated patients with and without allergen positivity, perennial and seasonal allergen-positive and negative patients treated with tezepelumab had significant reductions in asthma exacerbations.
“Interestingly, if we look at the patients with any allergen, those treated with placebo had a slightly higher exacerbation rate than those patients who were were FEIA [fluorescence enzyme immunoassay] negative,” Corren said.
“Irrespective of the allergen we chose to look at there were significant reductions of exacerbations on the order of approximately 50% upwards to the high of 70%, suggesting strongly that tezepelumab, by blocking TSLP, is having an effect on the severity of asthma, whether it be type 2 inflammatory pathway or the non-type 2, and similarly whether it is allergic or non-allergic,” he said.
Compared with placebo, tezepelumab was shown to improve pre-bronchodilator forced expiratory volume in one second in patients with and without allergic asthma during the 52-week study. The improvement was measurable in the 4th week and reached a plateau that remained stable over the ensuing 48 weeks of the study.
Tezepelumab also elicited significantly greater reductions in blood eosinophil count in patients with and without perennial or seasonal allergies, Corren reported.
He explained that the suppressive effect on blood eosinophils irrespective of allergy status suggests there is a large group of non-allergic asthma patients with eosinophilia who respond to treatment that blocks TSLP.
Tezepelumab also had greater activity than placebo on exhaled nitric oxide and total serum IgE irrespective of allergen positivity status, Corren added.
The PATHWAY study and post-hoc analysis was funded by AstraZeneca and Amgen.
Corren reported receiving grants from AstraZeneca during the conduct of the study, as well as grants and other financial relationships with Genentech, Novartis, Regeneron, and Sanofi outside of the study; three of the four co-authors are employees of AstraZeneca, and the other is an employee of Amgen.