Update On SOURCE Phase 3 Trial For Tezepelumab In Patients With Severe, Oral Corticosteroid-Dependent Asthma

Amgen (NASDAQ:AMGN) and AstraZeneca today announced the SOURCE 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.

The 48-week trial 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). Tezepelumab's effect on other efficacy parameters was similar to those observed in previous studies, including the registrational Phase 3 NAVIGATOR study. Further analyses of the data are ongoing.

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

"The recent results from our NAVIGATOR trial were impressive, both in terms of the overall clinical data and the reduction in exacerbation rate with tezepelumab treatment, and we continue to work with AstraZeneca on planned regulatory filings in 2021. While the SOURCE results were surprising, they provide important insights into the use of oral corticosteroids and the patients who are receiving them, which we look forward to exploring further," said David M. Reese , M.D., executive vice president of Research and Development at Amgen. "On initial review, the study design may have contributed to the results observed on the primary endpoint."

On November 10 ^th , 2020, AstraZeneca and Amgen announced positive results from the NAVIGATOR Phase 3 trial which met the primary endpoint and demonstrated a statistically significant and clinically meaningful reduction in the annualized 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 derived cytokine that plays a key role across the spectrum of asthma inflammation. ^2,3

Severe asthma is a complex, heterogenous disease and many patients continue to face debilitating symptoms despite receiving standard of care inhaled medicines and currently approved biologics. ^5-8

In September 2018 , the US Food and Drug Administration granted Breakthrough Therapy Designation for tezepelumab in patients with severe asthma, without an eosinophilic phenotype. ⁴ Tezepelumab is being developed by AstraZeneca in collaboration with Amgen (see AstraZeneca and Amgen collaboration below).

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.

About Tezepelumab
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. ^2,3,12

TSLP is released in response to multiple triggers associated with asthma exacerbations, including allergens, viruses and other airborne particles. ^2,3 Expression of TSLP is increased in the airways of patients with asthma and has been correlated with disease severity. ^3,12 Blocking TSLP may prevent the release of pro-inflammatory cytokines by immune cells, resulting in the prevention of asthma exacerbations and improved asthma control. ^3,12 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. ^3,12

PATHFINDER Clinical Trial Program
Building on the positive Phase 2b PATHWAY trial, the Phase 3 PATHFINDER program included two trials, the registrational NAVIGATOR study and SOURCE. ^12-15 The program includes additional planned mechanistic and long-term safety trials.

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. ¹³ In the trial, patients were randomized 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. ¹³

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 annualized asthma exacerbation rate, lung function, asthma control, quality of life, work productivity and activity impairment. The SOURCE trial population included approximately 35% of subjects with high (≥ 300 cells/µL) and 65% with low ( 13

Patient's OCS dose was optimized during an 8-week optimization period. For the first eight  weeks of the 48-week treatment period, patients remained on their optimized OCS dose. OCS dose reduction was started at week four, with the possibility of a dose reduction every 4 weeks if asthma control was maintained up until week 40. From week 40 onwards, patients remained on the OCS dose reached at week 40 (or earlier if the OCS dose reduction failed because of clinical deterioration) or remained on complete OCS elimination if possible. ¹³

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 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 per microliter. ¹⁵

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. ¹⁶

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 .

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References

1. 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.
2. Varricchi G, Pecoraro A, Marone G, et al . Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Front Immunol . 2018; 9: 1595.
3. 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.
4. AstraZeneca plc. Tezepelumab granted Breakthrough Therapy Designation by US FDA. Available at: https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2018/tezepelumab-granted-breakthrough-therapy-designation-by-us-fda-07092018.html . [Last accessed: November 2020 ].
5. Winders TA, Wilson AM, Fletcher MJ, McGuinness A, Price DB. A Patient-Centered Description of Severe Asthma: Patient Understanding Leading to Assessment for a Severe Asthma Referral (PULSAR). Patient . 2019;12(5):539-549.
6. Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med . 2005; 172: 149-160.
7. 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.
8. 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.
9. Voorham J, Xu X, Price DB, et al . Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma. Allergy . 2019;74 (2): 273-283.
10. 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.
11. Sullivan PW, Ghushchyan VH, Globe G, Schatz M. Oral corticosteroid exposure and adverse effects in asthmatic patients. J Allergy Clin Immunol . 2018; 141 (1): 110-116.
12. 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.
13. Wechsler, M.E., Colice, G., Griffiths, J.M. 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.
14. 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: November 2020 ].
15. 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: November 2020 ].
16. 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: November 2020 ].

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