WILMINGTON, Del.--(BUSINESS WIRE)--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 annualized 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 microliter.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 microliter and 70% in patients with greater than or equal to 300 cells per microliter.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 randomized 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 microliter 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 hospitalizations.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 program
Building on the Phase IIb PATHWAY trial, the Phase III PATHFINDER program included two trials, NAVIGATOR and SOURCE.22,23 The program includes additional planned mechanistic and long-term safety trials.
NAVIGATOR is a Phase III, randomized, 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
NAVIGATOR primary endpoints2
Tezepelumab added to SoC vs placebo added to SoC
AAER – overall patient population
Over 52 weeks
56% reduction (95% CI: 47, 63; p<0.001)
AAER – baseline eosinophil counts < 300 cells/µL
Over 52 weeks
41% reduction (95% CI: 25, 54; p<0.001)
CI: confidence interval
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). 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).
SOURCE is a Phase III multicenter, randomized, 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 (LABA), and chronic treatment with maintenance OCS therapy. The primary endpoint is the categorized percentage reduction from baseline in the daily OCS dose, while not losing asthma control.23
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.24
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.3,10 TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.3,10 Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity.3,25 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.3,25 Tezepelumab acts at the top of the inflammation cascade and has the potential to treat a broad population of severe asthma patients regardless of their type of inflammation.3,25
AstraZeneca and Amgen collaboration
In 2020, Amgen and AstraZeneca updated the 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 commercialize 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 recognized as collaboration revenue. In all countries outside the US and Canada, AstraZeneca will solely commercialize 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
Respiratory & Immunology is one of AstraZeneca’s three therapy areas and is a key growth driver for the Company.
AstraZeneca is an established leader in respiratory care, and its inhaled and biologic medicines reached more than 53 million patients in 2019. Building on a 50-year heritage, the Company aims to transform the treatment of asthma and COPD by focusing on earlier biology-led treatment, eliminating preventable asthma attacks, and removing COPD as a top-three leading cause of death. The Company’s early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction.
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.
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory & Immunology. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.
- Bonini M, Di Paolo M, Bagnasco D, et al. Minimal clinically important difference for asthma endpoints: an expert consensus report. Eur Respir Rev. 2020; 29: 190137.
- Menzies-Gow A, Corre J, Bourdin A, et al. Efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma: results from the phase 3 NAVIGATOR study. L 46. AAAAI poster. February 2021.
- Corren J, Parnes JR, Wang L, et al. Tezepelumab in Adults with Uncontrolled Asthma [published correction appears in N Engl J Med. 2019 May 23; 380 (21): 2082]. N Engl J Med. 2017; 377 (10): 936-946.
- Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388 (10039): 31-44.
- Castro M, Corren J, Pavord I.D, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018; 378:2486-2496.
- Bleecker ER, FitzGerald JM, Chanez P, et al, on behalf of the SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting beta2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016: 388 (10056): 2115-2127.
- FitzGerald JM, Bleecker ER, Nair P, et al, on behalf of the CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor alpha monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016: 388(10056): 2128-2141.
- FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2017; 6 (1): 51-64.
- Ortega HG, Liu MC, Pavord ID, et al; on behalf of the MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371(13):1198-207.
- Varricchi G, Pecoraro A, Marone G, et al. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Front Immunol. 2018; 9: 1595.
- The Global Asthma Network. The Global Asthma Report 2018. [Online]. Available at: http://www.globalasthmareport.org/Global%20Asthma%20Report%202018.pdf.[Last accessed: February 2021].
- Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43: 343–73.
- Wenzel S. Severe Asthma in Adults. Am J Respir Crit Care Med. 2005; 172; 149–60.
- Peters SP, Ferguson G, Deniz Y, et al. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006; 100 (7): 1139-51.
- Hyland ME, Masoli M, Lanario JW, et al. A Possible Explanation for Non-responders, Responders and Super-responders to Biologics in Severe Asthma. Explor Res Hypothesis Med. 2019; 4:35–38.
- Tran TN, Zeiger RS, Peters SP, et al. Overlap of atopic, eosinophilic, and TH2-high asthma phenotypes in a general population with current asthma. Ann Allergy Asthma Immunol. 2016; 116:37–42.
- Fernandes AG, Souza-Machado C, Coelho RC, et al. Risk factors for death in patients with severe asthma. J Bras Pneumol. 2014; 40 (4): 364-372.
- Chastek B, Korrer S, Nagar SP, et al. Economic Burden of Illness Among Patients with Severe Asthma in a Managed Care Setting. J Manag Care Spec Pharm. 2016; 22: 848–861.
- Hartert TV, Speroff T, Togias A, et al. Risk factors for recurrent asthma hospital visits and death among a population of indigent older adults with asthma. Ann Allergy Asthma Immunol. 2002; 89: 467–73.
- Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med. 2014; 12; 24: 14009.
- World Allergy Organization (WAO). The management of severe asthma: economic analysis of the cost of treatments for severe asthma. Available at: https://www.worldallergy.org/educational_programs/world_allergy_forum/anaheim2005/blaiss.php [Last accessed: February 2021].
- Menzies-Gow A, Colice G, Griffiths JM et al. NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020; 21(1): 266.
- Weschler ME, Colice G, Griffiths JM, et al. SOURCE: A Phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of Tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma. Respir Res. 2020; 21(1), 264.
- Clinicaltrials.gov. Extension Study to Evaluate the Safety and Tolerability of Tezepelumab in Adults and Adolescents With Severe, Uncontrolled Asthma (DESTINATION) [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT03706079. [Last accessed: February 2021].
- Li Y, Wang W, LV Z et al. Elevated Expression of IL-33 and TSLP in the Airways of Human Asthmatics In Vivo: A Potential Biomarker of Severe Refractory Disease. The Journal of Immunology. 2018; 200: 2253–2262.
US-49744 Last Updated 2/21