Improvements also demonstrated in lung function and nasal polyp symptoms
Exploratory analysis from NAVIGATOR Phase III trial presented at European Respiratory Society (ERS) International Congress 2021
New data from the pivotal NAVIGATOR Phase III trial showed that AstraZeneca and Amgen’s tezepelumab reduced exacerbations and improved lung function and nasal symptoms in patients with severe, uncontrolled asthma and comorbid nasal polyps.1 Tezepelumab is a potential first-in-class treatment that acts at the top of the inflammatory cascade by targeting thymic stromal lymphopoietin (TSLP), an epithelial cytokine, and has the potential to treat a broad population of severe asthma patients.2,3
The pre-specified exploratory analysis evaluated the effect of tezepelumab in NAVIGATOR patients with or without reported nasal polyps (NP+ or NP−) in the past two years. The analysis showed tezepelumab achieved an 86% reduction in the annualised asthma exacerbation rate (AAER) in NP+ patients (95% CI: 70, 93) and 52% (95% CI: 42, 61) in NP− patients over 52 weeks, compared to placebo when added to standard of care (SoC).1
Tezepelumab improved lung function at week 52 in both groups of patients with an increase in pre-bronchodilator forced expiratory volume in one second (FEV1) of 0.20 L (95% CI: 0.02, 0.37) and 0.13 L (95% CI: 0.08, 0.18) versus placebo in NP+ and NP− patients, respectively.1 Tezepelumab also achieved a clinically relevant improvement in nasal polyp symptoms at week 52, as measured by the Sinonasal Outcome Test (SNOT-22), reducing the SNOT-22 score in NP+ patients by 9.6 points (95% CI: 0.9, 18.2) versus placebo.1,4 The adjusted mean score reductions from baseline for tezepelumab and placebo were 20.10 points (SE: 3.07) and 10.55 points (SE: 2.94). Baseline mean (sd) SNOT-22 score was 49.4 (21.5) and 47.8 (19.0) for tezepelumab and placebo, respectively.1
Professor Andrew Menzies-Gow, Director of the Lung Division, Royal Brompton Hospital, London, UK, the principal investigator of the NAVIGATOR trial, said: “This new analysis from NAVIGATOR is exciting for the up to one in five severe asthma patients who have comorbid nasal polyps. The analysis shows tezepelumab’s ability to reduce exacerbations, improve lung function and reduce the symptoms of nasal polyps in this comorbid population who are typically more prone to asthma attacks, have an increased likelihood of airway obstruction, and may have a worse quality of life.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The remarkable exacerbation reductions seen in asthma patients with comorbid nasal polyps add to the strong body of evidence showing the potential of tezepelumab. Tezepelumab works differently from existing biologic medicines by targeting the top of the inflammatory cascade and we look forward to bringing this potential medicine to a broad population of severe asthma patients, including those with comorbid nasal polyps, as soon as possible.”
These findings were presented at the European Respiratory Society (ERS) International Congress 2021, between 5-8 September. There were no clinically meaningful differences in safety results between the tezepelumab and placebo groups in the NAVIGATOR trial. The most frequently reported adverse events with tezepelumab were nasopharyngitis, upper respiratory tract infection and headache.5
Results from the NAVIGATOR Phase III trial were published in The New England Journal of Medicine in May 2021. A Phase III clinical trial, WAYPOINT, has been initiated to explore the efficacy and safety of tezepelumab in adults with severe, chronic rhinosinusitis with nasal polyps.6
Asthma is a heterogeneous disease affecting an estimated 339 million people worldwide.7,8 Approximately 10% of asthma patients have severe asthma.8,9 Despite the use of inhaled asthma controller medicine, currently available biologic therapies and oral corticosteroids (OCS), many severe asthma patients remain uncontrolled.8-10 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.9-12
Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.8,9,13 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.14-16 There is also a significant socio-economic burden, with these patients accounting for 50% of asthma-related costs.17
Nasal polyps are benign growths that arise from the mucosa of the nose and paranasal sinuses.18 Up to 22% of severe asthma patients have comorbid nasal polyps.19 Nasal polyps can block nasal passages and lead to breathing problems, reduction in the sense of smell, nasal discharge, sleep disturbance and other adverse effects on quality of life.20-22
Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER programme included two trials, NAVIGATOR,5,23 SOURCE24 and additional planned mechanistic and long-term safety trials in severe asthma.25,26 In addition, a Phase III clinical trial, WAYPOINT, has been initiated to explore the efficacy and safety of tezepelumab in adults with severe, chronic rhinosinusitis with nasal polyps.6
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 SoC. SoC was treatment with medium- or high-dose inhaled corticosteroids (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 per microlitre) and low (<300 cells per microlitre) 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.5
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.5
Of the 1061 randomised patients, 1059 received either tezepelumab 210 mg (n=528) or placebo (n=531). In total for this pre-specified exploratory analysis, 83 patients had NP in the past 2 years (tezepelumab 210 mg, n=42; placebo, n=41) and 976 did not (tezepelumab 210 mg, n=486; placebo, n=490).1
NAVIGATOR pre-specified exploratory analysis: AAER in severe, uncontrolled asthma patients with or without nasal polyps in the two years before randomisation1
AAER results over 52 weeks
Tezepelumab added to SoC versus placebo added to SoC (relative risk reduction and annualized exacerbation rates)
Severe uncontrolled asthma with reported nasal polyps (NP+)
86% reduction (95% CI: 70, 93)
Severe uncontrolled asthma without reported nasal polyps (NP-)
52% reduction (95% CI: 42, 61)
NAVIGATOR pre-specified exploratory analysis: Pre-bronchodilator FEV1 in severe, uncontrolled asthma patients with or without nasal polyps in the two years before randomisation1
Pre-bronchodilator FEV1 over 52 weeks
Tezepelumab added to SoC versus placebo added to SoC (LS mean difference and LS mean change from baseline)
Severe uncontrolled asthma with reported nasal polyps (NP+)
0.20 L (95% CI: 0.02, 0.37)
Severe uncontrolled asthma without reported nasal polyps (NP-)
0.13 L (95% CI: 0.08, 0.18)
CI: Confidence interval, LS: Least-squares, SE: Standard error
NAVIGATOR is the first Phase III trial to show benefit in severe asthma irrespective of eosinophils by targeting TSLP.5 These results support the US Food and Drug Administration (FDA) Breakthrough Therapy Designation granted to tezepelumab in September 2018 for patients with severe asthma, without an eosinophilic phenotype. In July 2021, tezepelumab was the first and only biologic to be granted Priority Review in the US for the treatment of asthma from the FDA.
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.24 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.25
Tezepelumab is being developed by AstraZeneca in collaboration with Amgen as 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.2,27 TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.24,25 Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.2,3 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.2,3 Tezepelumab acts at the top of the inflammation cascade and has the potential to help address a broad population of severe asthma patients irrespective of biomarker levels.2,3
In 2020, Amgen and AstraZeneca updated a 2012 collaboration agreement for tezepelumab. Both companies will continue to share costs and profits equally after payment by AstraZeneca of a mid single-digit inventor royalty to Amgen. AstraZeneca continues to lead development and Amgen continues to lead manufacturing. All aspects of the collaboration are under the oversight of joint governing bodies. Under the amended agreement in North America, Amgen and AstraZeneca will jointly commercialise tezepelumab; Amgen will record sales in the US and AstraZeneca will record sales in Canada. AstraZeneca’s share of gross profits from tezepelumab in the US will be recognised as collaboration revenue. In all countries outside the US and Canada, AstraZeneca will solely commercialise tezepelumab. AstraZeneca will record all sales outside of the US as product sales and recognise Amgen’s share of gross profit as cost of sales.
AstraZeneca in Respiratory & Immunology
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With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas. The Company’s growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including systemic lupus erythematosus), dermatology, gastroenterology, and systemic eosinophilic-driven diseases. AstraZeneca’s ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide.
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Veeva ID: Z4-37187
Date of Preparation: September 2021