Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial:  post-hoc  analysis of the Phase IIb MUSE trial of anifrolumab

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Abstract

Objectives

In a post-hoc analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between anifrolumab and placebo.

Methods

Patients received intravenous placebo (n=102) or anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician’s Global Assessment ≤1, prednisolone ≤7.5 mg/d and standard immunosuppressant dosage tolerance) was assessed. Associations with endpoints and LLDAS attainment differences between treatments were explored.

Results

LLDAS attainment at Week 52 was associated with SLE Responder Index 4 (SRI[4]) and British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) (74/85[87%] and 62/84[74%] were also SRI[4] and BICLA responders, respectively; both nominal p<0.001). Only 74/159 (47%) of SRI(4) and 62/121 (51%) of BICLA responders reached LLDAS.

Anifrolumab-treated patients achieved earlier LLDAS, and more spent at least half their observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34 to 6.92, nominal p=0.008; 1,000 mg: 2.17, 95% CI 0.93 to 5.03, nominal p=0.072) vs placebo-treated patients. At Week 52, 17/102 (17%), 39/99 (39%) and 29/104 (28%) of patients on placebo, anifrolumab 300 and 1,000 mg, respectively, attained LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73 to 6.76, p<0.001; 1,000 mg: 2.03, 95% CI 1.01 to 4.07, nominal p=0.046).

Conclusions

LLDAS attainment represents a clinically meaningful SLE outcome measure, and anifrolumab is associated with more patients who met LLDAS criteria versus placebo. These data support LLDAS as an SLE RCT endpoint.

Trial registration number

NCT1438489; Post-results.

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Most cited references 10

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Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

M Hochberg (1997)

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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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Both prolonged remission and Lupus Low Disease Activity State are associated with reduced damage accrual in systemic lupus erythematosus.

Alexandre E Voskuyl, Michel Tsang-A-Sjoe, Irene E. M. Bultink … (2017)

To identify predictors of organ damage and specifically the relationship between prolonged disease remission or low disease activity and damage accrual in a longitudinal cohort of SLE patients.

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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): May 2018

Publication date (Electronic): 2 February 2018

Volume: 77

Issue: 5

Pages: 706-713

Affiliations

[1 ] departmentCentre for Inflammatory Diseases , Monash University , Melbourne, Victoria, Australia

[2 ] AstraZeneca , Gothenburg, Sweden

[3 ] MedImmune LLC , Gaithersburg, MD, USA

[4 ] AstraZeneca , Gaithersburg, MD, USA

Author notes

[Correspondence to ] Dr Eric F Morand, Centre for Inflammatory Diseases, Monash University, Melbourne, Victoria, Australia; eric.morand@ 123456monash.edu

Article

Publisher ID: annrheumdis-2017-212504

DOI: 10.1136/annrheumdis-2017-212504

PMC ID: 5909750

PubMed ID: 29420200

SO-VID: ddbe86d7-d7b2-4731-82cd-2cc8e295fab3

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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 06 October 2017

Date revision received : 07 December 2017

Date accepted : 03 January 2018

Funding

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

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ScienceOpen disciplines: Immunology

Keywords: anifrolumab,systemic lupus erythematosus,low disease activity state,treat-to-target

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ScienceOpen disciplines: Immunology

Keywords: anifrolumab, systemic lupus erythematosus, low disease activity state, treat-to-target

Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hoc analysis of the Phase IIb MUSE trial of anifrolumab

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Abstract

Objectives

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Cures Within Reach: Autoimmune Lymphoproliferative Syndrome (ALPS)

Most cited references 10

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.

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

Both prolonged remission and Lupus Low Disease Activity State are associated with reduced damage accrual in systemic lupus erythematosus.

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