Tezepelumab granted Priority Review by U.S. FDA

AmgenAmgen (NASDAQ:AMGN) announced that the U.S. Food and Drug Administration (FDA) has accepted a Biologics License Application (BLA) and granted Priority Review for tezepelumab in the treatment of asthma. Tezepelumab is being developed by Amgen in collaboration with AstraZeneca.

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 goal date for a decision by the FDA 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)

"Severe asthma is a challenging, complex disease for physicians and millions of patients and has a high unmet medical need," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We are proud to advance an innovative, first-in-class monoclonal antibody that targets the top of the inflammatory cascade and represents a potentially transformative treatment option for a broad population of patients with severe asthma. We look forward to bringing tezepelumab to patients as quickly as possible."

The BLA was based on results from the PATHFINDER clinical trial program, including results from the pivotal NAVIGATOR Phase 3 trial in which 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 medication 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 3 trial were published in the New England Journal of Medicine in May 2021.

Tezepelumab was granted an FDA Breakthrough Therapy Designation for patients with severe asthma without an eosinophilic phenotype in September 2018.

About Severe Asthma

Globally, there are approximately 2.5 million patients with severe asthma who are uncontrolled or biologic eligible, with approximately 1 million in the U.S. Many patients with severe asthma have an inadequate response to currently available biologics and oral corticosteroids and thus fail to achieve asthma control.(2,6,9) Uncontrolled asthma occurs when symptoms persist despite treatment. Severe, uncontrolled asthma is debilitating with patients experiencing frequent exacerbations, significant limitations on lung function and a reduced quality of life.(2,6,9) Patients with severe uncontrolled asthma have twice the risk of asthma-related hospitalizations.(10,11) There is also a significant socio-economic burden, with these severe, uncontrolled asthma patients accounting for 50% of asthma-related costs.(12)

Multiple inflammatory pathways are involved in the pathogenesis of asthma.(13-15) Eosinophilic asthma, and more broadly, T2 inflammation-driven asthma, accounts for about two-thirds of patients with severe asthma.(15) These patients are typically characterized as having elevated levels of inflammatory biomarkers, including blood eosinophils, serum IgE and fractional exhaled nitric oxide (FeNO).(16,17) 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.(17)

About the NAVIGATOR and the PATHFINDER Clinical Trial Program

Building on the Phase 2b PATHWAY trial, the Phase 3 PATHFINDER program included two trials, NAVIGATOR8,18 and SOURCE.19,20 The program includes additional planned mechanistic and long-term safety trials.(21)

NAVIGATOR is a Phase 3, randomized, double-blinded, placebo-controlled trial in 1,061 adults (18-80 years old) and adolescents (12-17 years old) with severe, uncontrolled asthma, who were receiving treatment with medium- or high-dose inhaled corticosteroids (ICS) plus at least one additional controller medication with or without OCS. NAVIGATOR met the primary endpoint with tezepelumab added to standard of care (SoC) demonstrating a statistically significant and clinically meaningful reduction in the annualized asthma exacerbation rate (AAER) over 52 weeks in the overall patient population, compared to placebo added to SoC. The trial also met the primary endpoint in the subgroup of patients with baseline eosinophil counts less than 300 cells per microliter, with tezepelumab demonstrating a statistically significant and clinically meaningful reduction in AAER in that patient population. Similar reductions in AAER were observed in the subgroup of patients with baseline eosinophil counts less than 150 cells pstoper microliter.(21,22)

NAVIGATOR is the first Phase 3 trial to show benefit in severe asthma irrespective of eosinophils by targeting the thymic stromal lymphopoietin (TSLP). The U.S. Food and Drug Administration Breakthrough Therapy Designation was granted to tezepelumab in September 2018 for patients with severe asthma, without an eosinophilic phenotype.

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. In the trial, patients were randomized to receive tezepelumab 210 mg every four weeks or placebo as add-on therapy, with patients maintained on their currently prescribed ICS plus LABA, with or without other asthma controller therapy.

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.(23)

About Tezepelumab

Tezepelumab is being developed by AstraZeneca in collaboration with Amgen (see AstraZeneca and Amgen collaboration below) as 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 thymic stromal lymphopoietin (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.(24,25)

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.(24,26) Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.(24,26) 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.(24,26)

About the Amgen and AstraZeneca 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 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.

Amgen Inflammation

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.

About Amgen

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.

1. US Food and Drug Administration. Priority Review. Available at: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review. [Last accessed: June 2021].
2. Wenzel S. Severe Asthma in Adults. Am J Respir Crit Care Med. 2005;172;149-60.
3. Peters SP, et al. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006;100:1139-51. 4. Hyland ME, 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.
5. Tran TN, 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.
6. Chung KF, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014; 43: 343-73.
7. Fernandes AG, et al. Risk factors for death in patients with severe asthma. J Bras Pneumol. 2014; 40 (4): 364-372.
8. Menzies-Gow A, et al. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. 2021;384:1800-1809. DOI: 10.1056/NEJMoa2034975.
9. 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.
10. 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. 11. 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: April 2021].
12. Busse WW. Biological Treatments for Severe Asthma: A Major Advance in Asthma Care. Allergol Int 2019; 68: 158-66.
13. 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.
14. 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.
15. 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.
16. 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: April 2021].
17. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015; 15: 57-65.
18. Menzies-Gow A, 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;21:266.
19. Wechsler ME, et al. Oral corticosteroid-sparing effect of tezepelumab in adults with severe asthma. Am J Respir Crit Care Med. 2021;203:A1197.
20. Weschler ME, 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;21:264.
21. Diver S, et al. Effect of Tezepelumab on Airway Inflammation in Patients with Moderate-to-Severe Uncontrolled Asthma: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study (CASCADE). Am J Respir Crit Care Med. 2021;203:A1456.
22. Corren J, Bourdin A, Chupp G, et al. Efficacy of tezepelumab in patients with severe, uncontrolled asthma grouped by baseline blood eosinophil count and fractional exhaled nitric oxide level: results from the NAVIGATOR phase 3 study. Am J Respir Crit Care Med. 2021;203:A1198.
23. 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: May 2021].
24. Corren J, et al. Tezepelumab in adults with uncontrolled asthma [supplementary appendix; updated April 18, 2019]. N Engl J Med. 2017;377:936-946.
25. Varricchi G, et al. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Front Immunol. 2018;9:1595.
26. Li Y, et al. Elevated Expression of IL-33 and TSLP in the Airways of Human Asthmatics In Vivo: A Potential Biomarker of Severe Refractory Disease. J Immunol. 2018;200:2253-2262.

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