Elsevier

The Lancet Rheumatology

Volume 4, Issue 4, April 2022, Pages e282-e292
The Lancet Rheumatology

Articles
Efficacy of anifrolumab across organ domains in patients with moderate-to-severe systemic lupus erythematosus: a post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials

https://doi.org/10.1016/S2665-9913(21)00317-9Get rights and content

Summary

Background

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by multisystem involvement. We aimed to evaluate the efficacy of anifrolumab on organ domain-specific SLE disease activity.

Methods

In this post-hoc analysis, data were pooled from the randomised, placebo-controlled, phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab (300 mg intravenously once every 4 weeks for 48 weeks) in patients aged 18–70 years with moderate-to-severe SLE. We evaluated changes from baseline to week 52 in British Isles Lupus Assessment Group 2004 (BILAG-2004) and SLE Disease Activity Index 2000 (SLEDAI-2K) organ domain scores, Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score (CLASI-A), swollen and tender joint counts, haematology, and serology.

Findings

Among the 726 patients included, the mean age was 41·8 years (SD 11·9); 674 (93%) were female, 52 (7%) were male, and 479 (66%) were White. 360 patients received anifrolumab 300 mg (180 patients in each trial), and 366 received placebo (184 patients in TULIP-1 and 182 patients in TULIP-2). The most frequently affected organ domains at baseline were musculoskeletal (645 [89%] patients based on BILAG-2004; 684 [94%] with SLEDAI-2K) and mucocutaneous (627 [86%] with BILAG-2004; 699 [96%] based on SLEDAI-2K). At week 52, anifrolumab treatment resulted in greater improvements versus placebo in the musculoskeletal system (176 [56%] of 317 patients vs 143 [44%] of 328 with BILAG-2004; 164 [49%] of 335 vs 141 [40%] of 349 with SLEDAI-2K), the mucocutaneous system (168 [54%] of 315 vs 119 [38%] of 312 with BILAG-2004; 190 [55%] of 348 vs 138 [39%] of 351 SLEDAI-2K), and immunological system (44 [19%] of 237 vs 26 [11%] of 230 with SLEDAI-2K). Less frequently affected domains had varied responses. Among patients with a CLASI-A of 10 or more at baseline, greater proportions of patients receiving anifrolumab than placebo achieved a reduction of 50% or more in CLASI-A at week 52 (49 [46%] of 107 vs 24 [25%] of 94). Among patients with at least six swollen joints, more patients in the anifrolumab group than in the placebo group had a 50% or more reduction from baseline to week 52 in swollen joint count (99 [57%] of 174 vs 92 [46%] of 200), but the difference between groups was not significant for 50% or more reduction in tender joint count.

Interpretation

Across the two pivotal phase 3 trials, anifrolumab treatment improved SLE disease activity across multiple organ domains.

Funding

AstraZeneca.

Introduction

Systemic lupus erythematosus (SLE), an autoimmune disease with heterogeneous clinical manifestations, is associated with significant morbidity and mortality.1, 2, 3 Any organ can be affected in SLE, but the skin, joints, and kidneys are most commonly involved.4, 5, 6 Incomplete disease control leads to progressive organ damage, poor quality of life, and increased mortality, with approximately half of all patients with SLE developing organ damage within 10 years of diagnosis.7, 8, 9 Therefore, the capacity of a medical intervention to improve activity across multiple systems, and thereby potentially prevent organ damage, is a desirable attribute.

Type I interferons are cytokines that have been implicated in SLE pathogenesis based on the finding of increased interferon-stimulated gene expression in most patients with SLE.10 Anifrolumab is a fully human, immunoglobulin G1κ monoclonal antibody that binds to the type I interferon receptor subunit 1 and inhibits signalling by all type I interferons.11, 12 In the phase 3 TULIP-2 (NCT02446899) trial of anifrolumab in patients with moderate-to-severe SLE, treatment response (assessed using British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA]) was achieved by significantly more patients receiving anifrolumab than those receiving placebo at week 52.13 Similar results with this composite endpoint were observed in the phase 2 MUSE (NCT01438489) and phase 3 TULIP-1 (NCT02446912) trials, although TULIP-1 did not meet its primary endpoint of the proportion of patients achieving an SLE Responder Index score of 4 (SRI-4) at week 52.14, 15 Importantly, composite endpoints used in SLE trials, such as BICLA and the SRI-4, dichotomise changes in disease activity across different organ domains into a binary responder versus non-responder result. Although helpful for definitive demonstration of efficacy, this approach limits the ability to interpret treatment efficacy across the many organ domains that potentially affect patients with SLE.

Research in context

Evidence before this study

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with manifestations in multiple organs. Evidence supports dysregulation of the type I interferon pathway in SLE pathogenesis. Anifrolumab is a human monoclonal antibody that binds to the type I interferon-α receptor subunit 1 and inhibits the effects of all type I interferon subtypes on gene expression and downstream inflammatory and immunological sequelae. We searched ClinicalTrials.gov and PubMed for all studies registered or published in English, respectively, up to March 29, 2021, with the search terms (“anifrolumab” [All Fields]) AND (“systemic lupus erythematosus” [All Fields]). The search identified one phase 1 trial, two phase 2 trials, one phase 2b trial, one phase 2b long-term extension, one phase 2b exposure–response analysis, and two phase 3 trials of anifrolumab in patients with moderate-to-severe SLE. The search also identified one pooled analysis of safety in the phase 3 TULIP-1 and TULIP-2 trials. Although TULIP-1 did not achieve its primary endpoint, the two phase 3 TULIP trials of anifrolumab 300 mg given intravenously to patients with moderate-to-severe SLE showed that anifrolumab treatment was associated with improved overall disease activity, reduced glucocorticoid use and flares, and improved skin disease.

Added value of this study

This post-hoc analysis of pooled data from the pivotal TULIP-1 and TULIP-2 trials, which were undertaken in patients with moderate-to-severe active SLE, the majority of whom were female and mostly aged 30–50 years, examined the effect of anifrolumab on organ-specific disease manifestations. Anifrolumab, when added to standard SLE therapy, was effective in reducing disease activity across organ systems most commonly affected at trial entry, including the musculoskeletal, mucocutaneous, and immunological domains.

Implications of all the available evidence

Anifrolumab has recently been approved in the USA for the treatment of patients aged 18 years or older with moderate-to-severe SLE, who are receiving standard therapy. Given the clinical heterogeneity of SLE, a particularly important attribute of a new therapy is its ability to reduce disease activity regardless of the pattern of organ system involvement. This post-hoc analysis shows the capacity of anifrolumab to treat diverse SLE manifestations.

Organ-specific measures of skin and joint responses were assessed as secondary endpoints in TULIP-1 and TULIP-2.13, 15 Results in both trials suggested benefit of anifrolumab in cutaneous disease activity in patients with active skin disease at baseline; treatment benefit in the improvement of swollen and tender joint counts was suggested in TULIP-1, but treatment differences in joint counts were not significant in TULIP-2.13, 15 The similarity in design of the TULIP-1 and TULIP-2 trials facilitated pooling of data for assessment of individual organ systems with greater statistical power than is possible with the individual trials alone. Therefore, using pooled data from the TULIP-1 and TULIP-2 trials, we aimed to assess the effects of anifrolumab on individual SLE organ domain disease activity.

Section snippets

Study design and participants

In this post-hoc analysis, we pooled data from the TULIP-1 and TULIP-2 trials, in which patients who had moderate-to-severe SLE despite standard therapy with oral glucocorticoids, antimalarials, immunosuppressants, or a combination of these were randomly assigned to receive anifrolumab 300 mg or placebo intravenously every 4 weeks for 48 weeks.

The study design and methods have been described in detail previously.13, 15 In brief, all patients were aged 18–70 years and fulfilled the American

Results

Data were pooled for 726 patients; 360 received anifrolumab 300 mg (180 patients in each trial), and 366 received placebo (184 patients in TULIP-1 and 182 patients in TULIP-2). Baseline demographics and background treatment for SLE were similar between groups (appendix pp 2–3). Of the 726 patients enrolled, the mean age was 41·8 years (SD 11·9); 674 (93%) were female, 52 (7%) were male, and 479 (66%) were White (appendix pp 2–3). At baseline, 595 (82%) of 726 patients were receiving oral

Discussion

In this post-hoc analysis of pooled data from the TULIP-1 and TULIP-2 trials, anifrolumab treatment was associated with greater improvement in the most frequently affected organ domains (mucocutaneous, musculoskeletal, and immunological) of patients with moderate-to-severe SLE compared with placebo. Anifrolumab treatment also resulted in greater improvements in skin disease and swollen joint counts, as well as in several less frequently affected domains, and resulted in greater frequency of

Data sharing

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy.

Declaration of interests

EFM has received grant support from, was a consultant for, and was a speaker at a speaker bureau for AstraZeneca; received grant support and consulting fees from Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline (GSK), Janssen, and EMD Serono; and received consulting fees from Amgen, Biogen, and Wolf Biotherapeutics. RAF has received grant and research support and consulting fees from AstraZeneca. INB has received grant or research support from Genzyme/Sanofi, GSK, Roche, and UCB; received

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