Tezepelumab NAVIGATOR Phase 3 Trial Met Primary Endpoint Of A Statistically Significant And Clinically Meaningful Reduction In Exacerbations In A Broad Population Of Patients With Severe Asthma
THOUSAND OAKS, Calif., Nov. 9, 2020 /PRNewswire/ -- Amgen (NASDAQ:AMGN) and AstraZeneca today announced positive topline results from the Phase 3 NAVIGATOR trial in which the investigational medicine tezepelumab demonstrated a statistically significant reduction in exacerbations compared to placebo in patients with severe asthma.
The NAVIGATOR trial met the primary endpoint 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. SoC was medium- or high-dose inhaled corticosteroids (ICS) plus at least one additional controller medication with or without oral corticosteroids (OCS).
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. Similar reductions in AAER were observed in the subgroup of patients with baseline eosinophil counts less than 150 cells per microliter.
The significant exacerbation rate reductions demonstrated with tezepelumab in patients with baseline eosinophil counts less than 300 cells per microliter support the U.S. Food and Drug Administration Breakthrough Therapy Designation granted to tezepelumab in Sept. 2018 for patients with severe asthma, without an eosinophilic phenotype.
Tezepelumab was very well tolerated in patients with severe asthma. Preliminary analyses show no clinically meaningful differences in safety results between the tezepelumab and placebo groups. Results from the NAVIGATOR trial will be presented at an upcoming medical meeting.
Tezepelumab is a potential first-in-class medicine that blocks the action of thymic stromal lymphopoietin (TSLP), an epithelial cytokine that plays a key role across the spectrum of asthma inflammation.1,2 NAVIGATOR is the first Phase 3 trial to show benefit in severe asthma by targeting TSLP.
"We are absolutely thrilled with the topline results of the NAVIGATOR study in this broad population of patients with severe asthma, regardless of eosinophil count," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "Tezepelumab represents a potential new class of biologics that could enable us to treat severe asthma at the top of the inflammatory cascade, addressing a high unmet need among the millions of patients living with severe asthma throughout the world. Tezepelumab has the potential to revolutionize care with efficacy demonstrated even in patients with a low eosinophil count."
Professor Andrew Menzies-Gow, director of the Lung Division, Royal Brompton Hospital, London, UK, and principal investigator of the NAVIGATOR trial said: "Due to the complex nature of severe asthma, many patients continue to face debilitating asthma despite receiving standard of care inhaled medicines and currently approved biologics. Today's ground-breaking results show that tezepelumab has the potential to transform care for a broad population of severe asthma patients who are underserved today, including those without an eosinophilic phenotype."
Amgen and AstraZeneca Collaboration
Earlier 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 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 U.S. and AstraZeneca will record sales in Canada. Outside the U.S., Amgen will record sales as collaboration revenue.
Tezepelumab is an investigational, potential first-in-class human monoclonal antibody that works on the primary source of inflammation: the airway epithelium, which is the first point of contact for viruses, allergens, pollutants, and other environmental insults. Specifically, tezepelumab targets and blocks TSLP, a key epithelial cytokine that sits at the top of multiple inflammatory cascades and initiates an overreactive immune response to allergic, eosinophilic and other types of airway inflammation associated with severe asthma.1,2,3
TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles.1,2 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 By working at the top of the cascade, tezepelumab helps stop inflammation at the source and has the potential to treat a broad population of severe asthma patients.2,3
NAVIGATOR and the PATHFINDER clinical trial program
Building on the Phase 2b PATHWAY trial, the Phase 3 PATHFINDER program included two trials, NAVIGATOR and SOURCE.4,5 The program includes additional planned mechanistic and long-term safety trials.
NAVIGATOR is a Phase 3, 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.4
The primary efficacy endpoint was the annualized asthma exacerbation rate 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.4
SOURCE is a Phase 3 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 % reduction from baseline in the daily OCS dose while not losing asthma control.5
Patients who participated in the NAVIGATOR and SOURCE trials were eligible to continue in DESTINATION, a Phase 3 extension trial assessing long term safety and efficacy.5
About Severe Asthma
Asthma is a complex and heterogeneous disease affecting an estimated 339 million people worldwide.6,7 Approximately 10% of asthma patients have severe asthma.6,7 Yet, many severe asthma patients have an inadequate response to currently available biologics and oral corticosteroids and thus fail to achieve asthma control.6-8 Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.6-8 Patients with severe asthma account for twice as many asthma-related hospitalizations.9,10 There is also a significant socio-economic burden, with these patients accounting for 50% of asthma-related costs.11
Multiple inflammatory pathways are involved in the pathogenesis of asthma.12,13,14 Eosinophilic asthma, and more broadly, T2 inflammation-driven asthma, accounts for about two-thirds of patients with severe asthma.14 These patients are typically characterized as having elevated levels of inflammatory biomarkers, including blood eosinophils, serum IgE and fractional exhaled nitric oxide (FeNO).4,15 However, many patients do not fit the criteria for eosinophilic or allergic asthma, may have unclear or multiple drivers of inflammation, and may not qualify for or respond well to a current biologic medicine.15
Amgen brings therapies to millions of people with inflammatory diseases, with a focus on serving unmet patient needs. For those with debilitating moderate to severe rheumatoid arthritis, psoriatic arthritis, moderate to severe plaque psoriasis, ankylosing spondylitis, asthma, and other chronic conditions, the suffering and needs are severe. Complex diseases of inflammation have defied simple solutions, and the breadth of inflammatory disease and the burden patients bear is not well understood.
For more than two decades, Amgen has been committed to advancing the science and the understanding around inflammation to address the unmet patient needs that exist and expanding our portfolio. We lead with science through discovery research that is disease-agnostic and biology-first, modality-second. In doing so, we have introduced and evolved novel therapies that have changed the lives of patients.
Our commitment to patients is reflected not only in where we have succeeded, but in where we have failed and opened new doors. Throughout, we have remained dedicated to the principle of leading with science, pursuing where pathways and promising discoveries in inflammation take us, and not relenting until innovative solutions for patients are found. It's a commitment that extends beyond introducing novel therapies. We are focused on improving the entire patient journey.
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.
For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.
Amgen Forward-Looking Statements
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- 1 Varricchi G, Pecoraro A, Marone G, et al. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Front Immunol. 2018; 9: 1595.
- 2 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.
- 3 Roseti S, Corren J, Parnes JR, et al. Efficacy and safety of tezepelumab in adults with severe asthma: A randomized phase 2 study. European Respiratory Journal 2017; 50: OA3189.
- 4 Clinicaltrials.gov. Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults With Oral Corticosteroid Dependent Asthma (SOURCE) [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT03406078. [Last accessed: September 2020].
- 5 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: September 2020].
- 6 Kupczyk M, Wenzel S. U.S. and European severe asthma cohorts: what can they teach us about severe asthma? J Intern Med 2012;272:121–32.
- 7 Wenzel S. Severe Asthma in Adults. Am J Respir Crit Care Med. 2005; 172; 149–60.
- 8 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.
- 9 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.
- 10 World Allergy Organization (WAO). The management of severe asthma: economic analysis of the cost of treatments for severe asthma. Available from: https://www.worldallergy.org/educational_programs/world_allergy_forum/anaheim2005/blaiss.php [Last accessed: September 2020]
- 11 Busse WW. Biological Treatments for Severe Asthma: A Major Advance in Asthma Care. Allergol Int 2019; 68: 158–66.
- 12 Godar M, Blanchetot C, de Haard H, et al. Personalized medicine with biologics for severe type 2 asthma: current status and future prospects. MAbs. 2018; 10 (1): 34–45.
- 13 Rabe KF, Busse W, Pavord I, Castro M. Raising the clinical bar beyond current biologics in uncontrolled persistent asthma: translating emerging data in future clinical decisions. EMJ Allergy Immunol. 2018; 3: 60-9.
- 14 Peters MC, Mekonnen ZK, Yuan S, et al. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014; 133: 388–94.
- 15 Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015; 15: 57-65.
Posted: November 2020
- FDA Approves Tezspire (tezepelumab) for Severe Asthma - December 17, 2021
- Tezepelumab Granted Priority Review By U.S. FDA - July 7, 2021
- Amgen Announces Tezepelumab Biologics License Application Submitted To U.S. FDA - May 10, 2021
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