A new post-hoc analysis of pooled data from the TULIP Phase III clinical trials being presented at the annual European Congress of Rheumatology (EULAR 2021) showed anifrolumab was consistently associated with improvements in both skin rash and arthritis across three different disease measures each, compared to placebo, in patients with moderate to severe systemic lupus erythematosus (SLE).1
The analysis examined disease manifestations in the two most commonly impacted organ domains in SLE.2-3 Anifrolumab is a potential first-in-class type I interferon inhibitor.
For skin rash, the difference in response rates for anifrolumab versus placebo at week 52 were 13.5% SLE Disease Activity Index (SLEDAI), 15.5% British Isles Lupus Assessment Group index (BILAG) and 15.6% modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI). For arthritis, differences in response rates were 8.2% SLEDAI, 11.8% BILAG and 12.6% joint response.3
Joan Merrill, Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, US, said: “Arthritis and rash are the most common and persistent problems in lupus and often have a significant impact on a person's life. The strength of the data from this analysis is that anifrolumab was found to be consistently effective using three different ways of looking at rash and three different approaches to arthritis. Capturing multiple aspects of improvement increases confidence that anifrolumab may be an important option for patients.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The data being presented at EULAR add to the growing body of evidence for anifrolumab that demonstrate a compelling clinical profile with the potential to address significant unmet medical needs in this debilitating disease. With no new systemic lupus erythematosus treatments in over a decade, we’re working to make this new medicine available as soon as possible.”
The most frequently reported adverse events for anifrolumab in the TULIP-1 and TULIP-2 trials were upper respiratory tract infection, bronchitis, infusion-related reactions and herpes zoster.4-5
AstraZeneca’s application for anifrolumab in SLE is under review by regulatory authorities in the US, EU and Japan, with decisions anticipated in the second half of 2021. Anifrolumab is not currently approved in any country.
Systemic lupus erythematosus
Systemic lupus erythematosus is an autoimmune disease in which the immune system attacks healthy tissue in the body.6 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.7 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.8-9 At least five million people worldwide have a form of lupus.10 No new treatments have been approved for SLE in over 10 years.11
TULIP-1, TULIP-2 in SLE
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. Both were randomised, double-blinded, placebo-controlled trials in patients with moderate to severe autoantibody-positive SLE who were receiving standard therapy.4-5 Standard therapy consisted of oral corticosteroids (OCS), antimalarials and immunosuppressants (methotrexate, azathioprine or mycophenolate mofetil, known as MMF). TULIP-2 demonstrated superiority across multiple efficacy endpoints versus placebo with both arms receiving standard therapy. 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.4 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. The trial did not meet its primary endpoint based on the SLE Responder Index 4 (SRI4) composite measure.5
In SLE, along with the pivotal TULIP Phase III programme, anifrolumab continues to be evaluated in a long-term extension Phase III trial.12 A Phase II trial of anifrolumab in SLE using subcutaneous delivery has been completed.13 In addition, AstraZeneca is exploring the potential of anifrolumab in a variety of diseases where type I interferon plays a key role, including lupus nephritis, cutaneous lupus erythematosus and myositis.14
The analysis presented at EULAR included three different disease measures per organ domain.3
Post-hoc analysis of pooled data from the TULIP Phase III clinical trial programme; rash and arthritis3
Endpoint and disease measure
Results at 52 weeks
Difference in anifrolumab compared to placebo (each plus standard therapy); all p values are nominal
Complete resolution in the respective organ manifestation as measured by SLE
Disease Activity Index 2000 (SLEDAI-2K)
13.5% skin rash (p <0.001);
8.2% arthritis (p=0.029)
At least one severity grade lowering in respective organ domain as measured by British Isles Lupus Assessment Group index (BILAG)
15.5% skin rash (p<0.001);
11.8% arthritis (p=0.002)
At least 50% improvement in rash as measured by modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI)
At least 50% decrease in swollen/tender joint counts, when ≥ six at baseline
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 lupus.16-17 The majority of adults with lupus have increased type I interferon signalling, which is known to be associated with disease activity and severity.16,18
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, part of BioPharmaceuticals, is one of AstraZeneca’s three therapy areas and is a key growth driver for the Company.
AstraZeneca is an established leader in respiratory care with 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 (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines in Oncology and BioPharmaceuticals, including 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.
1. Merrill JT, et al. Anifrolumab Effects on Rash and Arthritis in Patients With SLE and Impact of Interferon Signal in Pooled Data From Phase 3 Trials. Oral presentation at: the 2021 European Alliance of Associations for Rheumatology (EULAR) European Congress of Rheumatology; 3 June 2021; virtual. Abstract ID: 1471.
2. 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 presentation at: American College of Rheumatology (ACR) Convergence 2020; 5-9 November 2020; virtual. Abstract ID: 0985.
3. Merrill JT, et al. Anifrolumab effects on rash and arthritis: impact of the type I interferon gene signature in the phase IIb MUSE study in patients with systemic lupus erythematosus. Lupus Sci Med. 2018;5(1):e000284. Accessed June 2021.
4. Morand E, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020;382(3):211-221. Accessed June 2021.
5. Furie R, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019;1(4):e208-e219. Accessed June 2021.
6. The Lupus Foundation of America. What is Lupus? Available online. Accessed June 2021.
7. American College of Rheumatology. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis & Rheumatology. 1999; 42:1785-1796. Accessed June 2021.
8. Bruce IN, 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. Accessed June 2021.
9. Segura BT, et al. Damage accrual and mortality over long-term follow-up in 300 patients with systemic lupus erythematosus in a multi-ethnic British cohort. Rheumatol. 2020;59(3):524-533. Accessed June 2021.
10. The Lupus Foundation of America. Lupus facts and statistics. Available online. Accessed June 2021.
11. Mahieu MA, et al. A critical review of clinical trials in systemic lupus erythematosus. Lupus. 2016;25(10):1122-1140. Accessed June 2021.
12. ClinicalTrials.gov. Long Term Safety of Anifrolumab in Adult Subjects With Active Systemic Lupus Erythematosus (TULIP SLE LTE). NCT Identifier: NCT02794285. Accessed June 2021.
13. Chatham WW, et al. Long-Term Safety and Efficacy of Anifrolumab in Adults With Systemic Lupus Erythematosus: Results of a Phase II Open-Label Extension Study. Arthritis Rheumatol. 2021;73(5):816-825. Accessed June 2021.
14. Crow MK, et al. Report of the inaugural Interferon Research Summit: interferon in inflammatory diseases. Lupus Sci Med. 2018;5(1):e000276. Accessed June 2021.
15. Furie R, et al. Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017;69(2):376-386. Accessed June 2021.
16. Lauwerys BR, et al. Type I interferon blockade in systemic lupus erythematosus: where do we stand?. Rheumatol. 2013;53(8):1369-1376. Accessed June 2021.
17. Sarkar MK, 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. Accessed June 2021.
18. Crow MK. Type I Interferon in the Pathogenesis of Lupus. J Immunol. 2014;192(12):5459-5468. Accessed June 2021.