New Tezepelumab Data Continue To Strengthen Profile For A Broad Population Of Severe Asthma Patients

NAVIGATOR Data Published in New England Journal of Medicine, and Latest Data from Tezepelumab Clinical Program Presented at ATS 2021 International Conference

Tezepelumab Reduced Exacerbations by 77% in Subgroup of Patients with Elevated Inflammatory Biomarkers in NAVIGATOR

Tezepelumab Reduced Exacerbations Requiring Hospitalization by 85%

News provided by

Amgen

May 13, 2021, 02:00 ET

THOUSAND OAKS, Calif., May 13, 2021 /PRNewswire/ -- Amgen (NASDAQ:AMGN) and AstraZeneca today announced detailed results for tezepelumab, a potential first-in-class treatment, from the pivotal NAVIGATOR Phase 3 trial demonstrating superiority across every primary and key secondary endpoint in a broad population of severe asthma patients, compared to placebo when added to standard of care (SoC). These results were published in the New England Journal of Medicine and will be presented this week at the American Thoracic Society (ATS) 2021 International Conference.^1,2

In one of the pre-specified exploratory analyses of NAVIGATOR, reductions in annualized asthma exacerbation rates (AAERs) were observed over 52 weeks in tezepelumab-treated patients compared to placebo when added to SoC across four patient subgroups, based on blood eosinophil count and fractional exhaled nitric oxide (FeNO) levels. Blood eosinophil counts and FeNO levels are two key inflammatory biomarkers used by clinicians to inform treatment options and were defined as blood eosinophil count (≥300 or <300 cells per microlitre) and FeNO (≥25 or <25 parts per billion).

In patients with elevated baseline blood eosinophil counts (≥300 cells per microlitre) and FeNO levels (≥25 parts per billion), tezepelumab achieved a clinically meaningful 77% reduction in the AAER, compared to placebo.^1,2

In a separate exploratory analysis of exacerbations requiring hospitalizations, tezepelumab showed an 85% reduction over 52 weeks compared to placebo when added to SoC.

Tezepelumab also demonstrated statistically significant improvements in key secondary endpoints compared to placebo in lung function, asthma control and health-related quality of life. Improvements were observed in tezepelumab-treated patients as early as week two of treatment or the first time point assessment and were sustained throughout the treatment period.¹

These results build on the NAVIGATOR data presented in February 2021 which showed a statistically significant and clinically meaningful³ reduction in the primary endpoint of AAER over 52 weeks in the overall patient population. Clinically meaningful reductions in AAER compared to placebo were observed in the tezepelumab-treated patients irrespective of blood eosinophil counts, allergy status or FeNO level.¹

"Managing severe asthma is challenging with multiple inflammatory pathways often contributing to the complexity of a patient's disease. These latest results underscore the potential of tezepelumab to transform treatment for a broad population of severe asthma patients regardless of their type of inflammation," said Professor Andrew Menzies-Gow, Director of the Lung Division, Royal Brompton Hospital, London, UK, and principal investigator of the NAVIGATOR Phase 3 trial.

"Severe, uncontrolled asthma is debilitating, with patients experiencing frequent exacerbations that lead to hospitalization. For this reason, we were incredibly pleased to see that patients who received tezepelumab during the trial had a reduction in both ER visits and hospitalizations," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "Advancing the science to address unmet patient needs such as these has been the driving force behind Amgen's inflammation research for more than two decades. Along with our partner AstraZeneca, we are incredibly proud of these results and tezepelumab's potential for a broad population of patients with asthma."

Additional Data to be Presented

Further results from the tezepelumab PATHFINDER clinical trial program will be presented at the ATS conference this week, including the primary analyses from the SOURCE Phase 3 and CASCADE Phase 2 trials.

As previously disclosed, the SOURCE Phase 3 trial did not meet the primary endpoint of a statistically significant reduction in the daily oral corticosteroid (OCS) dose, without loss of asthma control, with tezepelumab compared to placebo. Data to be presented show the number of patients that achieved a ≥90% reduction in OCS dose was numerically higher for tezepelumab-treated patients at 54.1% compared to 46.1% in the placebo group.⁴

In SOURCE, tezepelumab-treated patients showed improvements in exacerbations, forced expiratory volume in one second and patient-reported outcomes compared to placebo,⁴ consistent with improvements shown in pooled post-hoc analyses in OCS dependent patients from the PATHWAY Phase 2 and NAVIGATOR Phase 3 trials. New trials are being planned to evaluate the ability of tezepelumab to reduce OCS use while maintaining asthma control in patients with chronic maintenance OCS therapy. Any new trial would aim to address unique aspects of the SOURCE trial design that may have contributed to the result of the primary endpoint.

Also being presented at the ATS Conference, results from the CASCADE Phase 2 mechanistic trial showed that in a broad population of patients with moderate to severe asthma, tezepelumab reduced eosinophils in airway tissue compared to placebo across subgroups of baseline blood eosinophil count, FeNO level and allergic status.⁵ Importantly, tezepelumab was also associated with a reduction in airway hyper-responsiveness compared to placebo,⁵ which is a major hallmark of asthma irrespective of eosinophilic airway inflammation.

There were no clinically meaningful differences in safety results between the tezepelumab and placebo groups in NAVIGATOR,¹ SOURCE⁴ and CASCADE.⁵ The most frequently reported adverse events for tezepelumab in the NAVIGATOR trial were nasopharyngitis, upper respiratory tract infection, headache and asthma,¹ in the SOURCE trial were nasopharyngitis, upper respiratory tract infection, asthma, and bronchitis bacterial, and in the CASCADE trial were nasopharyngitis, post-procedural (bronchoscopy) complications and headache.

About Severe Asthma
Globally, there are approximately 2.5 million severe asthma patients who are uncontrolled or biologic eligible, with approximately 1 million in the U.S. Many severe asthma patients have an inadequate response to currently available biologics and oral corticosteroids and thus fail to achieve asthma control.^6-8Uncontrolled 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.^6-8 Patients with severe uncontrolled asthma have twice the risk of asthma-related hospitalizations.^9,10There is also a significant socio-economic burden, with these severe uncontrolled asthma patients accounting for 50% of asthma-related costs.¹¹

Multiple inflammatory pathways are involved in the pathogenesis of asthma.^12-14 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).^15,16 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.¹⁶

NAVIGATOR and the PATHFINDER Clinical Trial Program
Building on the Phase 2b PATHWAY trial, the Phase 3 PATHFINDER program included two trials, NAVIGATOR^1,17 and SOURCE.^4,18The program includes an additional planned long-term safety trial, DESTINATION and a mechanistic trial, CASCADE.⁵

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 SoC demonstrating a statistically significant and clinically meaningful reduction in the 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.²⁵

NAVIGATOR endpoint: AAER in patients grouped by baseline blood eosinophil count and FeNO¹
Biomarker subgroup	Results over 52 weeks Tezepelumab added to SoC versus placebo added to SoC
Blood eosinophil count ≥300 cells/mcl FeNO ≥25 parts per billion	77% reduction (95% CI: 67, 84)
Blood eosinophil count ≥300 cells/mcl FeNO <25 parts per billion	39% reduction (95% CI: -7, 65)
Blood eosinophil count <300 cells/mcl FeNO ≥25 parts per billion	53% reduction (95% CI: 33, 67)
Blood eosinophil count <300 cells/mcl FeNO <25 parts per billion	29% reduction (95% CI: 0, 50)

CI: Confidence interval

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.

CASCADE is a Phase 2 mechanistic, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in adults aged 18–75 years with moderate to severe, uncontrolled asthma. The primary endpoint was the change from baseline (pre-dose) to end of treatment in airway submucosal inflammatory cells (eosinophils, neutrophils, T cells and mast cells) from bronchoscopic biopsies.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.¹⁹

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.^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.^20,22By 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.^20,22

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.

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

Amgen Forward-Looking Statements
This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including any statements on the outcome, benefits and synergies of collaborations, or potential collaborations, with any other company, including BeiGene, Ltd. or any collaboration to manufacture therapeutic antibodies against COVID-19, or the Otezla® (apremilast) acquisition (including anticipated Otezla sales growth and the timing of non-GAAP EPS accretion), as well as estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes, effects of pandemics or other widespread health problems such as the ongoing COVID-19 pandemic on Amgen's business, outcomes, progress, or effects relating to studies of Otezla as a potential treatment for COVID-19, and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission reports filed by Amgen, including its most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Unless otherwise noted, Amgen is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.

No forward-looking statement can be guaranteed and actual results may differ materially from those Amgen projects. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for Amgen to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and Amgen expects similar variability in the future. Even when clinical trials are successful, regulatory authorities may question the sufficiency for approval of the trial endpoints Amgen has selected. Amgen develops product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as Amgen may have believed at the time of entering into such relationship. Also, Amgen or others could identify safety, side effects or manufacturing problems with its products, including its devices, after they are on the market.

Amgen's results may be affected by its ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing its products and global economic conditions. In addition, sales of Amgen's products are affected by pricing pressure, political and public scrutiny and reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment. Furthermore, Amgen's research, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. Amgen's business may be impacted by government investigations, litigation and product liability claims. In addition, Amgen's business may be impacted by the adoption of new tax legislation or exposure to additional tax liabilities. If Amgen fails to meet the compliance obligations in the corporate integrity agreement between Amgen and the U.S. government, Amgen could become subject to significant sanctions. Further, while Amgen routinely obtains patents for its products and technology, the protection offered by its patents and patent applications may be challenged, invalidated or circumvented by its competitors, or Amgen may fail to prevail in present and future intellectual property litigation. Amgen performs a substantial amount of its commercial manufacturing activities at a few key facilities, including in Puerto Rico, and also depends on third parties for a portion of its manufacturing activities, and limits on supply may constrain sales of certain of its current products and product candidate development. An outbreak of disease or similar public health threat, such as COVID-19, and the public and governmental effort to mitigate against the spread of such disease, could have a significant adverse effect on the supply of materials for Amgen's manufacturing activities, the distribution of Amgen's products, the commercialization of Amgen's product candidates, and Amgen's clinical trial operations, and any such events may have a material adverse effect on Amgen's product development, product sales, business and results of operations. Amgen relies on collaborations with third parties for the development of some of its product candidates and for the commercialization and sales of some of its commercial products. In addition, Amgen competes with other companies with respect to many of its marketed products as well as for the discovery and development of new products. Further, some raw materials, medical devices and component parts for Amgen's products are supplied by sole third-party suppliers. Certain of Amgen's distributors, customers and payers have substantial purchasing leverage in their dealings with Amgen. The discovery of significant problems with a product similar to one of Amgen's products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on its business and results of operations. Amgen's efforts to collaborate with or acquire other companies, products or technology, and to integrate the operations of companies or to support the products or technology Amgen has acquired, may not be successful. A breakdown, cyberattack or information security breach could compromise the confidentiality, integrity and availability of Amgen's systems and Amgen's data. Amgen's stock price may be volatile and may be affected by a number of events. Global economic conditions may magnify certain risks that affect our business. Amgen's business performance could affect or limit the ability of the Amgen Board of Directors to declare a dividend or its ability to pay a dividend or repurchase its common stock. Amgen may not be able to access the capital and credit markets on terms that are favorable to it, or at all.

The scientific information discussed in this news release related to Amgen's product candidates is preliminary and investigative. Such product candidates are not approved by the U.S. Food and Drug Administration, and no conclusions can or should be drawn regarding the safety or effectiveness of the product candidates.

Further, any scientific information discussed in this news release relating to new indications for Amgen's products is preliminary and investigative and is not part of the labeling approved by the U.S. Food and Drug Administration for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses.

CONTACT: Amgen, Thousand Oaks
Michael Strapazon, 805-313-5553 (media)
Megan Fox, 805-447-1423 (media)
Arvind Sood, 805-447-1060 (investors)

References

1.	Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. N Engl J Med. 2021 Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2034975
2.	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.
3.	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.
4.	Wechsler ME, Mezies-Gow A, Brightling CE, et al. Oral corticosteroid-sparing effect of tezepelumab in adults with severe asthma. Am J Respir Crit Care Med. 2021;203:A1197.
5.	Diver S, Khalfaoui L, Emson C, 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.
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 at: https://www.worldallergy.org/educational_programs/world_allergy_forum/anaheim2005/blaiss.php [Last accessed: April 2021].
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.	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].
16.	Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 2015; 15: 57-65.
17.	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;21:266.
18.	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;21:264.
19.	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: April 2021].
20.	Corren J, Parnes JR, Wang L, et al. Tezepelumab in Adults with Uncontrolled Asthma [published correction appears in N Engl J Med. 2019;380:2082]. N Engl J Med. 2017;377:936-946.
21.	Varricchi G, Pecoraro A, Marone G, et al. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Front Immunol. 2018;9:1595.
22.	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