tis, dec 22, 2020 08:02 CET

AstraZeneca and Amgen today announced high-level results from the SOURCE Phase III trial which assessed the efficacy and safety of the potential new medicine tezepelumab compared to placebo in 150 severe asthma patients who required maintenance use of oral corticosteroids (OCS) on top of standard of care (SoC).

The 48-week trial did not meet the primary endpoint of a statistically significant reduction in the daily OCS dose, without loss of asthma control, with tezepelumab compared to placebo. Tezepelumab’s effect on other efficacy parameters was similar to those observed in previous trials, including the registrational Phase III NAVIGATOR trial.

Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “Based on the totality of evidence, including the compelling exacerbation reduction results seen in the registrational NAVIGATOR Phase III trial and the PATHWAY Phase IIb trial, we remain confident that tezepelumab has the potential to improve care for a broad population of severe asthma patients. Our initial analysis of SOURCE in oral corticosteroid-dependent asthma indicates that the trial design may have contributed to the result of the primary endpoint. We are in the process of further analysing the data from SOURCE and look forward to sharing these results with the medical community.”

The safety profile of tezepelumab in the trial was consistent with previous trials. Detailed results from the SOURCE trial will be presented at a forthcoming medical meeting.

On 10 November 2020, AstraZeneca and Amgen announced positive results from the NAVIGATOR Phase III trial which met the primary endpoint and demonstrated a statistically significant and clinically meaningful reduction in the annualised asthma exacerbation rate (AAER) in a broad population of patients with severe asthma, including those with low levels of eosinophils.

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 Tezepelumab is being developed by AstraZeneca in collaboration with Amgen.

Severe asthma

Asthma is a heterogeneous disease affecting an estimated 339 million people worldwide.^3,4 Approximately 10% of asthma patients have severe asthma,^4,5 which may be uncontrolled despite high doses of SoC asthma controller medicines and currently available biologic medicines. Some of these patients may require the use of long-term OCS^4-6 which can lead to serious short- and long-term adverse effects.^7-9 Severe, uncontrolled asthma is debilitating and potentially fatal, with patients experiencing frequent exacerbations and significant limitations on lung function and health-related quality of life.^4,6,10 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.^5,11,12

PATHFINDER clinical trial programme

Building on the positive PATHWAY Phase IIb trial, the PATHFINDER Phase III programme includes the registrational NAVIGATOR trial and the supportive SOURCE trial.^2,13-16 The programme includes additional planned mechanistic and long-term safety trials.

SOURCE is a Phase III multicentre, randomised, double-blinded, parallel-group, placebo-controlled trial for 48 weeks in 150 adult patients with severe asthma who require continuous treatment with inhaled corticosteroids (ICS) plus long-acting beta2-agonists (LABA), and chronic treatment with maintenance OCS therapy.^14,16  In the trial, patients were randomised to receive tezepelumab 210mg 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.^14,16

The primary efficacy endpoint was the percentage reduction from baseline in the prescribed daily OCS maintenance dose at 48 weeks while not losing asthma control. Secondary endpoints included the effect of tezepelumab on AAER, lung function, asthma control, quality of life, work productivity and activity impairment.^14,16

NAVIGATOR is a Phase III, randomised, 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 ICS plus at least one additional controller medicine with or without oral corticosteroids. 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 microlitre, 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 per microlitre.^13,15,17

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.¹⁸

Tezepelumab

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.^1,2 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.^2,19 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control.^2,19 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.^2,19

AstraZeneca and Amgen 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 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

Respiratory & Immunology is one of AstraZeneca’s three therapy areas and is a key future 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

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

Contacts

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References

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. The Global Asthma Report 2019. [Online]. Available at: https://www.globalasthmanetwork.org/publications/Global_Asthma_Report_2019.pdf. [Last accessed: December 2020].
4. 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 (2): 343-373.
5. Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med. 2005; 172: 149-160.
6. 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.
7. Sweeney J, Patterson CC, Menzies-Gow A, et al. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry. Thorax. 2016; 71 (4): 339-346.
8. Sullivan PW, Ghushchyan VH, Globe G,et al. Oral corticosteroid exposure and adverse effects in asthmatic patients. J Allergy Clin Immunol. 2018; 141 (1): 110-116.e7.
9. Hyland ME, Whalley B, Jones RC, et al. A qualitative study of the impact of severe asthma and its treatment showing that treatment burden is neglected in existing asthma assessment scales. Quality of Life Research. 2015; 24 (3): 631-619.
10. 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.
11. 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.
12. 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.
13. Clinicaltrials.gov. Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma (NAVIGATOR) [Online]. Available at: https://clinicaltrials.gov/ct2/show/NCT03347279. [Last accessed: December 2020].
14. 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: December 2020].
15. 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.
16. Wechsler 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.
17. AstraZeneca plc. Tezepelumab NAVIGATOR Phase III trial met primary endpoint of a statistically significant and clinically meaningful reduction in exacerbations in a broad population of patients with severe asthma. Available at: https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/tezepelumab-navigator-phase-iii-trial-met-primary-endpoint.html. [Last accessed: December 2020].
18. 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: December 2020].
19. 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.