AstraZeneca plc (LON:AZN) Biologics License Application (BLA) for tezepelumab has been accepted and granted Priority Review for the treatment of asthma from the US Food and Drug Administration (FDA). Tezepelumab is being developed by AstraZeneca in collaboration with Amgen.
The FDA grants Priority Review to applications for medicines that offer significant advantages over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.1 The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is during the first quarter of 2022.
Despite recent advances in severe asthma, many patients may not qualify for or respond well to current biologic medicines.2-5 Patients with severe, uncontrolled asthma experience frequent exacerbations, significant limitations on lung function and a reduced quality of life.2,6,7
The BLA was based on results from the PATHFINDER clinical trials programme, including results from the pivotal NAVIGATOR Phase III trial. In NAVIGATOR, tezepelumab demonstrated superiority across every primary and key secondary endpoint, compared to placebo, in a broad population of patients with uncontrolled asthma while receiving treatment with medium- or high-dose inhaled corticosteroids (ICS) plus at least one additional controller medicine with or without oral corticosteroids (OCS).8
There were no clinically meaningful differences in safety results between the tezepelumab and placebo groups in the NAVIGATOR trial.8 The most frequently reported adverse events with tezepelumab were nasopharyngitis, upper respiratory tract infection and headache.8
Results from the NAVIGATOR Phase III trial were published in The New England Journal of Medicine in May 2021.
Tezepelumab received Breakthrough Therapy Designation for patients with severe asthma, without an eosinophilic phenotype in September 2018.
Asthma is a heterogeneous disease affecting an estimated 339 million people worldwide.6,9 Approximately 10% of asthma patients have severe asthma.2,6 Despite the use of inhaled asthma controller medicine, currently available biologic therapies and oral corticosteroids (OCS), many severe asthma patients remain uncontrolled.2,3,6 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.2-5
Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.2,6,7 Patients with severe asthma are at an increased risk of mortality and compared to patients with persistent asthma have twice the risk of asthma-related hospitalisations.10-12 There is also a significant socio-economic burden, with these patients accounting for 50% of asthma-related costs.13
Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER programme included two trials, NAVIGATOR8,14 and SOURCE.15,16 The programme includes additional planned mechanistic and long-term safety trials.17-19
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 standard of care (SoC). SoC was treatment with medium- or high-dose ICS plus at least one additional controller medicine 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 medicines without change throughout the trial.8
The primary efficacy endpoint was the annualised asthma exacerbation rate (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.8
As part of prespecified analyses, the AAER over 52 weeks was also assessed in patients grouped by baseline blood eosinophil count, fractional exhaled nitric oxide (FeNO) level, serum specific immunoglobin E (IgE) status (perennial allergen sensitivity positive or negative).8 These are inflammatory biomarkers used by clinicians to inform treatment options and involve tests analysing a patient’s blood (eosinophils/IgE) and exhaled air (FeNO).
There were no clinically meaningful differences in safety results between the tezepelumab and placebo groups in the NAVIGATOR trial.8 The most frequently reported adverse events for tezepelumab were nasopharyngitis, upper respiratory tract infection and headache.8
NAVIGATOR is the first Phase III trial to show benefit in severe asthma irrespective of eosinophils by targeting thymic stromal lymphopoietin (TSLP).8 These results 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.
SOURCE is a Phase III multicentre, randomised, double-blinded, parallel-group, placebo-controlled trial for 48 weeks in adult patients with severe asthma who require continuous treatment with ICS plus long-acting beta2-agonists, and chronic treatment with maintenance OCS therapy. The primary endpoint is the categorised percentage reduction from baseline in the daily OCS dose, while not losing asthma control.16
Patients who participated in the NAVIGATOR and SOURCE trials were eligible to continue in DESTINATION, a Phase III extension trial assessing long-term safety and efficacy.17
Tezepelumab is a potential first-in-class human monoclonal antibody that inhibits the action of TSLP, a key epithelial cytokine that sits at the top of multiple inflammatory cascades and is critical in the initiation and persistence of allergic, eosinophilic and other types of airway inflammation associated with severe asthma.20,21 TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.20,21 Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.20,22 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.20,22 Tezepelumab acts at the top of the inflammation cascade and has the potential to help address a broad population of severe asthma patients regardless of their type of inflammation.20,22
Mene Pangalos, Executive Vice President, AstraZeneca BioPharmaceuticals R&D, said: “This decision brings us a step closer to delivering a much-needed, first-in-class medicine for asthma patients, many of whom remain uncontrolled and at risk of asthma attacks despite the availability of inhaled and biologic medicines. Tezepelumab has demonstrated reductions in exacerbations irrespective of blood eosinophil counts, allergy status and fractional exhaled nitric oxide, and has the potential to transform treatment for a broad population of severe asthma patients.”