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

Michael E Wechsler, Gene Colice, Janet M Griffiths, Gun Almqvist, Tor Skärby, Teresa Piechowiak, Primal Kaur, Karin Bowen, Åsa Hellqvist, May Mo, Esther Garcia Gil, Michael E Wechsler, Gene Colice, Janet M Griffiths, Gun Almqvist, Tor Skärby, Teresa Piechowiak, Primal Kaur, Karin Bowen, Åsa Hellqvist, May Mo, Esther Garcia Gil

Abstract

Background: Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study.

Methods: SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving < 5 mg) and the effect of tezepelumab on lung function and patient-reported outcomes.

Conclusions: SOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose.

Trial registration: NCT03406078 ( ClinicalTrials.gov ). Registered 23 January 2018. https://ichgcp.net/clinical-trials-registry/NCT03406078.

Keywords: Alarmin; Asthma; Asthma control; Epithelial; Exacerbation; Oral corticosteroids; SOURCE; Steroid-sparing; TSLP; Tezepelumab.

Conflict of interest statement

MW is an employee of National Jewish Health and has received consulting fees from AstraZeneca, Equillium, Genentech, GlaxoSmithKline, Novartis, Regeneron, Restorbio, Sanofi and Teva. GC, KB, ÅH, GA, TP, TS, EGG and JMG are employees and shareholders of AstraZeneca. PK and MM are employees of Amgen Inc.

Figures

Fig. 1
Fig. 1
Mechanism of action by which tezepelumab improves clinical outcomes in patients with asthma. TSLP is released from the airway epithelium in response to insults such as viruses, allergens and pollutants, triggering an inflammatory cascade. Overexpression of TSLP can result in pathologic inflammation that can lead to asthma exacerbations, symptoms, and physiological effects such as bronchoconstriction and airway hyperresponsiveness and remodelling. Tezepelumab specifically blocks TSLP from binding to its heterodimeric receptor, thereby inhibiting the production of various inflammatory cytokines and cell types. Treatment with tezepelumab has thus far been shown to reduce blood eosinophil count, IgE, IL-5, IL-13and FeNO. The effects of tezepelumab on OCS use will be investigated in SOURCE. FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; ILC2, type 2 innate lymphoid cell; OCS, oral corticosteroid; Th, T-helper; TSLP, thymic stromal lymphopoietin
Fig. 2
Fig. 2
Study design. aPatients who enrol in the extension study on the same day as the end-of-treatment visit in SOURCE will not attend follow-up visits at week 54 and week 60. OCS, oral corticosteroids; Q4W, every 4 weeks; s.c., subcutaneous

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