Positive full results from the pivotal NAVIGATOR Phase III trial showed AstraZeneca and Amgen’s tezepelumab demonstrated a statistically significant and clinically meaningful1 reduction in the annualised asthma exacerbation rate (AAER) in severe, uncontrolled asthma patients.2 The results were presented at the American Academy of Asthma Allergy & Immunology Virtual Annual Meeting.2
Tezepelumab, a potential first-in-class medicine, when added to standard of care (SoC) achieved a 56% reduction (p<0.001) in AAER over 52 weeks in the overall patient population, compared to placebo when added to SoC.2 SoC was medium- or high-dose inhaled corticosteroids (ICS) plus at least one additional controller medication with or without oral corticosteroids (OCS).2
Tezepelumab is the only biologic medicine to consistently and significantly reduce AAER in a broad population of severe asthma patients irrespective of baseline eosinophil count across Phase II and Phase III clinical trials.2-9
In a pre-planned subgroup analysis, tezepelumab achieved a statistically significant and clinically meaningful 41% reduction (p<0.001) in AAER in patients with baseline eosinophil counts less than 300 cells per microlitre.2 Importantly, clinically meaningful reductions in AAER were also observed in two additional subgroups: 39% in patients with baseline eosinophil counts less than 150 cells per microlitre and 70% in patients with greater than or equal to 300 cells per microlitre.2
Additionally, clinically meaningful reductions in AAER compared to placebo were observed in the tezepelumab-treated patients irrespective of allergy status and fractional exhaled nitric oxide (FeNO) level, biomarkers used by clinicians to inform treatment options.2
Professor Andrew Menzies-Gow, Director of the Lung Division, Royal Brompton Hospital, London, UK, and principal investigator of the NAVIGATOR Phase III trial, said: “These are ground-breaking results for the many patients with severe asthma who continue to face debilitating symptoms despite receiving standard of care inhaled medicines and currently approved biologics. Tezepelumab has the potential to transform treatment for a broad population of patients with severe asthma regardless of their type of inflammation, including those with and without an eosinophilic phenotype.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The unprecedented results from the NAVIGATOR Phase III trial show tezepelumab is the first and only asthma biologic to demonstrate in randomised trials clinically meaningful exacerbation reductions, irrespective of blood eosinophil counts, allergy status and fractional exhaled nitric oxide. There is now a strong body of evidence showing the benefit of targeting the top of the inflammatory cascade with tezepelumab, and we look forward to bringing this potential first-in-class medicine to a broad population of severe asthma patients as soon as possible.”
Tezepelumab demonstrated statistically significant improvements in every key secondary endpoint compared to placebo, including lung function measurements, asthma control and health-related quality of life.2
There were no clinically meaningful differences in safety results between the tezepelumab and placebo groups. The most frequently reported adverse events were nasopharyngitis, upper respiratory tract infection and headache.2
NAVIGATOR is a pivotal Phase III trial that will form the basis of regulatory submission.
Tezepelumab blocks the action of thymic stromal lymphopoietin (TSLP), an epithelial cytokine that plays a key role across the spectrum of asthma inflammation.3,10 NAVIGATOR is the first Phase III trial to show benefit in severe asthma by targeting TSLP.2
The statistically significant and clinically meaningful exacerbation rate reductions demonstrated with tezepelumab in patients with baseline eosinophil counts less than 300 cells per microlitre support the US Food and Drug Administration Breakthrough Therapy Designation granted to tezepelumab in September 2018 for patients with severe asthma, without an eosinophilic phenotype.2,3 Tezepelumab is being developed by AstraZeneca in collaboration with Amgen.
Asthma is a heterogeneous disease affecting an estimated 339 million people worldwide.11,12 Approximately 10% of asthma patients have severe asthma.12,13 Despite the use of inhaled asthma controller medicine, currently available biologic therapies and OCS, many severe asthma patients remain uncontrolled.12-14 Due to the complexity of severe asthma, many patients have unclear or multiple drivers of inflammation and may not qualify for or respond well to a current biologic medicine.13-16
Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.12,13,17 Patients with severe asthma are at an increased risk of mortality and have twice the risk of asthma-related hospitalisations.18-20 There is also a significant socio-economic burden, with these patients accounting for 50% of asthma-related costs.21
NAVIGATOR and the PATHFINDER clinical trial programme
Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER programme included two trials, NAVIGATOR and SOURCE.22,23 The programme includes additional planned mechanistic and long-term safety trials.
NAVIGATOR is a Phase III, randomised, double-blinded, placebo-controlled trial in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma, who were receiving treatment with medium- or high-dose ICS plus at least one additional controller medication with or without OCS. The trial population included approximately equal proportions of patients with high (≥ 300 cells/µL) and low (< 300 cells/µL) blood eosinophil counts. The trial comprised a five to six week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients received their prescribed controller medications without change throughout the trial.22
The primary efficacy endpoint was the AAER during the 52-week treatment period. Key secondary endpoints included the effect of tezepelumab on lung function, asthma control and health-related quality of life.22