Higher doses of corticosteroids, commonly used in patients with systemic lupus erythematosus, are associated with organ damage
A new analysis of the Phase III TULIP clinical trial programme showed that treatment with anifrolumab, a potential first-in-class type I interferon inhibitor, resulted in a greater reduction in disease flares while having a sustained reduction in doses of oral corticosteroids (OCS) compared to placebo, with both groups of patients receiving standard therapy.1 The data will be presented at ACR Convergence 2020, the annual meeting of the American College of Rheumatology (ACR), taking place virtually 5-9 November 2020.
OCS are often used in standard systemic lupus erythematosus (SLE) treatment.2 Long-term OCS use can increase the risk of organ damage and other significant side effects including higher risk of infections, cardiovascular disease, osteoporosis and cataracts.3,4 Higher doses of corticosteroids are associated with increased organ damage in patients with SLE.3
The new pooled analysis from the Phase III TULIP-1 and -2 studies showed 40% of patients treated with anifrolumab plus standard therapy had a sustained reduction in OCS use without experiencing a disease flare through 52 weeks (versus 17.3% in placebo plus standard therapy).1 Treatment with anifrolumab was associated with lower flare rates overall compared to placebo, and also on the skin and in the mouth (mucocutaneous) as well as in joints (musculoskeletal), the two organ domains most frequently affected at the start of the study.1
Professor Richard Furie, Chief of the Division of Rheumatology at Northwell Health, New York, US, said: “A leading treatment goal for systemic lupus erythematosus patients is to prevent flares while also averting the short- and long-term health consequences that can result from treatment with oral corticosteroids. In current clinical practice, tapering oral corticosteroids can sometimes result in flares, so achieving both goals simultaneously is difficult and remains an area of unmet need. This new analysis of the anifrolumab Phase III trials provides important insights into anifrolumab’s potential to impact patients in a clinically meaningful manner.”
Richard Marshall, Senior Vice President and Global Head of Respiratory and Immunology Late Stage Development, BioPharmaceuticals R&D, said: “This new analysis adds to the body of evidence of anifrolumab in systemic lupus erythematosus by illustrating its effect on preventing flares while allowing a sustained reduction in oral corticosteroids. Patients face significant unmet medical needs in this difficult-to-treat disease and we are working to make this potential new treatment available as soon as possible.”
The safety profile and tolerability of anifrolumab in the pooled analysis were consistent with the known profile from the TULIP clinical trial programme.1
Additional pooled data being presented at ACR showed that treatment with anifrolumab plus standard therapy resulted in greater improvements in multiple organ systems for patients with moderate to severe SLE compared to placebo plus standard therapy, and had early and sustained improvements in skin disease activity.5,6
Systemic lupus erythematosus
SLE is an autoimmune disease in which the immune system attacks healthy tissue in the body.7 It is a chronic and complex disease with a variety of clinical manifestations that can impact many organs and can cause a range of symptoms including pain, rashes, fatigue, swelling in joints and fevers.8 More than 50% of patients with SLE develop permanent organ damage, caused by the disease or existing treatments, which exacerbates symptoms and increases the risk of mortality.9,10 At least five million people worldwide have a form of lupus.11 There has been only one medicine approved for SLE in the last 60 years.12
TULIP-1, TULIP-2, MUSE
All three trials for anifrolumab (TULIP-1, TULIP-2 and MUSE) were randomised, double-blinded, placebo-controlled trials in patients with moderate to severe autoantibody-positive SLE who were receiving standard therapy.13,14,15
The pivotal TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) Phase III programme includes two trials, TULIP-1 and TULIP-2, that evaluated the efficacy and safety of anifrolumab versus placebo.13,14 TULIP-2 demonstrated superiority across multiple efficacy endpoints versus placebo with both arms receiving standard therapy.13 In the trial, 362 eligible patients were randomised (1:1) and received a fixed-dose intravenous infusion of 300mg anifrolumab or placebo every four weeks. TULIP-2 assessed the effect of anifrolumab in reducing disease activity as measured by the BILAG-Based Composite Lupus Assessment (BICLA) scale. In TULIP-1, 457 eligible patients were randomised (1:2:2) and received a fixed-dose intravenous infusion of 150mg anifrolumab, 300mg anifrolumab or placebo every four weeks, in addition to standard therapy.14 The trial did not meet its primary endpoint based on the SLE Responder Index 4 (SRI4) composite measure.
The MUSE Phase II trial evaluated the efficacy and safety of two doses of anifrolumab versus placebo. In MUSE, 305 adults were randomised and received a fixed-dose intravenous infusion of 300mg anifrolumab, 1,000mg anifrolumab or placebo every four weeks, in addition to standard therapy, for 48 weeks.15
The most frequent adverse events in patients who received anifrolumab in the three clinical trials included upper respiratory tract infection, bronchitis, infusion-related reactions and herpes zoster. In TULIP-1 and -2, all cases of herpes zoster were cutaneous in manifestation and most resolved without discontinuation of the intervention.13,14,15
Initial pooled analyses of data from the Phase III TULIP trials were presented at The European League Against Rheumatism, EULAR, European E-Congress of Rheumatology 2020 in June 2020, which included results that showed an early and sustained reduction of SLE disease activity, as measured by the BICLA.16
In addition to the pivotal TULIP Phase III programme, anifrolumab is being evaluated in a long-term extension Phase III trial in SLE and a Phase II trial in lupus nephritis. A Phase II trial of anifrolumab in SLE using subcutaneous delivery has been completed.
AstraZeneca ACR 2020 presentations
Abstracts from the new analyses of the Phase III TULIP and Phase II MUSE clinical trials that will be presented at ACR Convergence 2020 can be found below:
- To view the ‘Comprehensive Efficacy of Anifrolumab Across Organ Domains in Patients with Active SLE: Pooled Data from 2 Phase 3 Trials’ abstract, click here.
- To view the ‘Early and Sustained Reduction in Severity of Skin Disease with Anifrolumab Treatment in Patients with Active SLE Measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI): Pooled Data from 2 Phase 3 Studies’ abstract, click here.
- To view the ‘Flare Reduction and Oral Corticosteroid Taper in Patients with Active SLE Treated with Anifrolumab in 2 Phase 3 Trials’ abstract, click here.
- To view the ‘What Does It Mean to be a BICLA (BILAG-Based Composite Lupus Assessment) Responder? Post Hoc Analysis of the Phase 3 TULIP-1 and TULIP-2 Trials’ abstract, click here.
- To view the ‘Herpes Zoster Events with Anifrolumab in Patients with Active SLE: An Integrated Analysis of Phase 2 and Phase 3 Trials’ abstract, click here.
- To view the ‘Lupus Disease Activity After Cessation of Anifrolumab Treatment During the Phase 2b MUSE Trial Follow-up Period’ abstract, click here.
Anifrolumab is a fully human monoclonal antibody that binds to subunit 1 of the type I interferon receptor, blocking the activity of type I interferons.15 Type I interferons such as IFN-alpha, IFN-beta and IFN-kappa are cytokines involved in regulating the inflammatory pathways implicated in SLE.17,18 The majority of adults with SLE have increased type I interferon signalling, which is known to be associated with disease activity and severity.17,19
AstraZeneca acquired global rights to anifrolumab through an exclusive license and collaboration agreement with Medarex, Inc. in 2004. Medarex was acquired by Bristol-Myers Squibb in 2009.
AstraZeneca in Respiratory & Immunology
Respiratory & Immunology is one of AstraZeneca’s three therapy areas and is a key growth driver for the Company.
Building on a 50-year heritage, AstraZeneca is an established leader in respiratory care across inhaled and biologic medicines. AstraZeneca aims to transform the treatment of asthma and chronic obstructive pulmonary disease (COPD) by eliminating preventable asthma attacks across all severities and removing COPD as a leading cause of death through earlier, biology-led treatment. 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 immune-driven diseases. The Company’s growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential in rheumatology (including SLE), dermatology, gastroenterology and systemic eosinophilic-driven diseases. AstraZeneca’s ambition in immunology is to achieve disease control and ultimately clinical remission in targeted immune-driven diseases.
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 and 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.
1. Furie R, Morand E, Askanase A, et al. Flare Reduction and Oral Corticosteroid Taper in Patients with Active SLE Treated with Anifrolumab in 2 Phase 3 Trials [Poster]. Presented at: ACR Convergence 2020; 5-9 November 2020. Abstract ID: 1827
2. Tunnicliffe DJ, Singh-Grewal D, Kim S, et al. Diagnosis, Monitoring, and Treatment of Systemic Lupus Erythematosus: A Systematic Review of Clinical Practice Guidelines. Arthritis Care Res. 2015;67(10):1440-1452.
3. Ruiz-Arruza I, Ugarteet A, Cabezas-Rodriguez I, et al. Glucocorticoids and irreversible damage in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2014;53(8):1470-1476.
4. Al Sawah S, Zhang X, Zhu B, et al. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus—the Hopkins Lupus Cohort. Lupus Sci Med. 2015;2(1):e000066.
5. Morand EF, Furie R, Bruce I, et al. Comprehensive Efficacy of Anifrolumab Across Organ Domains in Patients with Active SLE: Pooled Data from 2 Phase 3 Trials [Poster]. Presented at: ACR Convergence 2020; 5-9 November 2020. Abstract ID: 1828
6. Werth V, Furie R, Morand E, et al. Early and Sustained Reduction in Severity of Skin Disease With Anifrolumab Treatment in Patients With Active SLE Measured by the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI): Pooled Data From 2 Phase 3 Studies [Oral]. Presented at: ACR Convergence 2020; 5-9 November 2020. Abstract ID: 0985
7. The Lupus Foundation of America. What is Lupus? Available at: https://www.lupus.org/resources/what-is-lupus. Accessed October 2020.
8. American College of Rheumatology. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis & Rheumatology. 1999;42:1785-1796.
9. Bruce IN, O'Keeffe AG, Farewell V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus: results from the systemic lupus international collaborating Clinics (SLICC) inception cohort. Ann Rheum Dis. 2015;74:1706-1713.
10. Segura BT, Berstein BS, McDonnell T, et al. Damage accrual and mortality over long-term follow-up in 300 patients with systemic lupus erythematosus in a multi-ethnic British cohort. Rheumatology. 2020;59(3):524-533.
11. The Lupus Foundation of America. Lupus facts and statistics. Available at: https://www.lupus.org/resources/lupus-facts-and-statistics. Accessed October 2020.
12. Mahieu MA, Strand V, Simon LS, et al. A critical review of clinical trials in systemic lupus erythematosus. Lupus. 2016;25(10):1122-1140.
13. Morand E, Furie R, Tanaka Y, et al. Efficacy and Safety of Anifrolumab in Patients With Moderate to Severe Systemic Lupus Erythematosus: Results of the Second Phase 3 Randomized Controlled Trial. N Engl J Med. 2020;382(3):211-221.
14. Furie R, Morand E, Bruce I, et al. Anifrolumab: Type I Interferon Inhibition in Active Systemic Lupus Erythematosus in TULIP-1, a Phase 3, Randomized Controlled Trial. Lancet Rheumatol. 2019;1(4):e208-e219.
15. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017;69(2):376-386.
16. Morand E, Furie R, Bruce I, et al. Early and Sustained Responses With Anifrolumab Treatment in Patients With Active Systemic Lupus Erythematosus (SLE) in 2 Phase 3 Trials [Oral]. Presented at: The European League Against Rheumatism, EULAR, European E-Congress of Rheumatology 2020; 3-6 June 2020. Abstract ID: OP0003
17. Lauwerys BR, Ducreux J, Houssiau FA. Type I interferon blockade in systemic lupus erythematosus: where do we stand?. Rheumatology. 2013;53(8):1369-1376.
18. Sarkar MK, Hile GA, Tsoi LC, et al. Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis. 2018;77:1653-1664.
19. Crow MK. Type I Interferon in the Pathogenesis of Lupus. J Immunol. 2014;192(12):5459-5468.