Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials

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Abstract

Objectives

To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups.

Methods

We performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers.

Results

In pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal p<0.001). BICLA response treatment differences with anifrolumab versus placebo were comparable to the total population across most predefined subgroups, including subgroups for baseline glucocorticoid dosage (<10/≥10 mg/day prednisone/equivalent) and for clinical disease activity (SLE Disease Activity Index 2000 score <10/≥10). Subgroups with larger treatment differences included IFNGS-high patients (18.2%), patients with abnormal baseline serological markers (23.1%) and Asian patients (29.2%). The safety profile of anifrolumab was similar across subgroups.

Conclusions

Overall, this study supports the consistent efficacy and safety of anifrolumab across a range of patients with moderate-to-severe SLE. In a few subgroups, small sample sizes limited conclusions from being drawn regarding the treatment benefit with anifrolumab.

Trial registration number

NCT02446912, NCT02446899.

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Most cited references 45

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Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

E. Baechler, F Batliwalla, G Karypis … (2003)

Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.

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Trial of Anifrolumab in Active Systemic Lupus Erythematosus

Eric F Morand, Richard Furie, Yoshiya Tanaka … (2019)

Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point.

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Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus

Richard Furie, Munther A. Khamashta, Joan Merrill … (2017)

Objective To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE). Methods Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4‐gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]–based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent‐to‐treat (ITT) population and type I IFN–high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2‐sided), within each of the 2 study populations for the primary end point analysis. Results The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo‐treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ‐specific end points. Herpes zoster was more frequent in the anifrolumab‐treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). Conclusion Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Rheum Dis

Journal ID (iso-abbrev): Ann Rheum Dis

Journal ID (hwp): annrheumdis

Journal ID (publisher-id): ard

Title: Annals of the Rheumatic Diseases

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0003-4967

ISSN (Electronic): 1468-2060

Publication date (Print): July 2022

Publication date (Electronic): 25 March 2022

Volume: 81

Issue: 7

Pages: 951-961

Affiliations

[1 ] departmentLeeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine , University of Leeds , Leeds, UK

[2 ] departmentNIHR Leeds Biomedical Research Centre , Leeds Teaching Hospitals NHS Trust , Leeds, UK

[3 ] Oklahoma Medical Research Foundation , Oklahoma City, Oklahoma, USA

[4 ] departmentCentre for Inflammatory Disease Monash Health , Monash University , Melbourne, Victoria, Australia

[5 ] departmentDivision of Rheumatology , Donald and Barbara Zucker School of Medicine at Hofstra/Northwell , Great Neck, New York, USA

[6 ] departmentCentre for Epidemiology Versus Arthritis, The University of Manchester , NIHR Manchester Biomedical Research Centre , Manchester, UK

[7 ] departmentManchester Academic Health Science Centre , Manchester University NHS Foundation Trust , Manchester, UK

[8 ] departmentThe First Department of Internal Medicine, School of Medicine , University of Occupational and Environmental Health Japan , Kitakyushu, Japan

[9 ] departmentLupus Center of Excellence, Autoimmunity Institute , Allegheny Health Network , Pittsburgh, Pennsylvania, USA

[10 ] departmentDivision of Rheumatology, Allergy and Immunology , University of California San Diego , La Jolla, California, USA

[11 ] departmentBioPharmaceuticals R&D , AstraZeneca US , Gaithersburg, Maryland, USA

[12 ] departmentBioPharmaceuticals R&D , AstraZeneca R&D , Gothenburg, Sweden

Author notes

[Correspondence to ] Dr Raj Tummala, BioPharmaceuticals R&D, AstraZeneca US, Gaithersburg, Maryland, USA; Raj.Tummala@ 123456astrazeneca.com

Author information

Edward M Vital http://orcid.org/0000-0003-1637-4755

Eric F Morand http://orcid.org/0000-0002-9507-3338

Yoshiya Tanaka http://orcid.org/0000-0002-0807-7139

Article

Publisher ID: annrheumdis-2021-221425

DOI: 10.1136/annrheumdis-2021-221425

PMC ID: 9213795

PubMed ID: 35338035

SO-VID: 8aa47d00-de7e-42c3-9aef-2eb019019790

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 27 August 2021

Date accepted : 26 January 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004325, AstraZeneca;

Award ID: N/A

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ScienceOpen disciplines: Immunology

Keywords: biological therapy,lupus erythematosus,systemic,therapeutics

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ScienceOpen disciplines: Immunology

Keywords: biological therapy, lupus erythematosus, systemic, therapeutics

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Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials

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Abstract

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Cures Within Reach: Autoimmune Lymphoproliferative Syndrome (ALPS)

Most cited references 45

Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

Trial of Anifrolumab in Active Systemic Lupus Erythematosus

Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus

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Cited by 29

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