AstraZeneca Announces Positive Phase 3 TULIP-2 Trial Results for Anifrolumab in Moderate-to-Severe Systemic Lupus Erythematosus

Today, AstraZeneca announced that its investigational monoclonal antibody anifrolumab, for the treatment of moderate-to-severe systemic lupus erythematosus (SLE), achieved positive results in the pivotal Phase 3 TULIP-2 trial, including a significant reduction in disease activity. The latest data from TULIP-2 were presented at the 19th Annual Meeting of the American College of Rheumatology (ACR) held in Atlanta, USA.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with an incidence rate of approximately 30 cases per 100,000 people in China. Approximately 90% of SLE patients are female. The main symptoms of SLE include fatigue, arthritis, myalgia, rash, hair loss, and fever; in severe cases, it can cause damage to vital organs such as the heart, lungs, and kidneys, posing a life-threatening risk. The pathogenesis of SLE is still under investigation and involves factors such as immune system dysregulation, the presence of autoantibodies against nuclear antigens (ANA), genetic susceptibility, environmental triggers, and activation of both innate and adaptive immune systems. Current guidelines recommend the use of antimalarial drugs, glucocorticoids, and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., for arthritis and serositis), along with immunosuppressants to control lupus activity and prevent organ damage. Over the past 60 years, only one new biologic agent, belimumab, has been approved for the treatment of lupus erythematosus.

Anifrolumab binds to subunit 1 of the type I interferon receptor, thereby antagonizing all activities associated with type I interferons (IFN-α, IFN-β, and IFN-ω). Type I interferons are a class of cytokines involved in inflammatory responses. IFN-α promotes the activation and differentiation of various immune cells, including driving the differentiation of autoreactive B lymphocytes into immunoglobulin-secreting plasma cells, promoting dendritic cell maturation, and inducing their expression of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Elevated type I interferon signatures are present in 60% to 80% of patients with systemic lupus erythematosus (SLE), and type I interferon levels are positively correlated with the SLE Disease Activity Index (SLEDAI) score.

▲Mechanism of Action of Anifrolumab (Image source: Reference [2])

In the TULIP-2 trial, 365 patients with moderate-to-severe systemic lupus erythematosus (SLE) were randomized into two groups to receive either 300 mg of anifrolumab or placebo via intravenous injection every four weeks, in addition to standard therapy. The trial results demonstrated that at week 52, anifrolumab achieved the primary endpoint by producing a statistically significant improvement in the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate (47.8% vs. 31.5%). BICLA response requires improvement in disease activity across all organ systems involved at baseline, without any new flares. Furthermore, anifrolumab led to statistically significant improvements in several secondary endpoints, including a higher proportion of patients achieving a reduction in oral corticosteroid (OCS) dosage to ≤10 mg/day (51.5% vs. 30.2%) and a greater reduction in the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) score at week 12 (49% vs. 25%).

Mr. Mene Pangalos, Executive Vice President of Biopharmaceuticals R&D at AstraZeneca, stated, “SLE is a debilitating autoimmune disease. Over the past 60 years, only one new therapy has been approved. Therefore, the results from the TULIP-2 trial are particularly exciting. We have comprehensive and robust data demonstrating its efficacy, and we are committed to bringing this potential new therapy to patients as soon as possible.”

References:

[1]. Anifrolumab achieved a statistically significant reduction in disease activity, a statistically significant reduction in oral corticosteroid use and improvement in skin manifestations. Retrieved Nov. 11, 2019, from https://www.astrazeneca.com/media-centre/press-releases/2019/anifrolumab-phase-iii-trial-meets-primary-endpoint-in-systemic-lupus-erythematosus-29082019.html

[2]. Timothy B. Niewold. et al. （2016）Targeting type I interferon in systemic lupus erythematosus. Nature reviews rheumatology. https://www.nature.com/articles/nrrheum.2016.83

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