Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials

Ian N Bruce, Richard A Furie, Eric F Morand, Susan Manzi, Yoshiya Tanaka, Kenneth C Kalunian, Joan T Merrill, Patricia Puzio, Emmanuelle Maho, Christi Kleoudis, Marius Albulescu, Micki Hultquist, Raj Tummala, Ian N Bruce, Richard A Furie, Eric F Morand, Susan Manzi, Yoshiya Tanaka, Kenneth C Kalunian, Joan T Merrill, Patricia Puzio, Emmanuelle Maho, Christi Kleoudis, Marius Albulescu, Micki Hultquist, Raj Tummala

Abstract

Objectives: In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.

Methods: TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient.

Results: Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients.

Conclusions: Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials.

Trial registration numbers: NCT02446912 and NCT02446899.

Keywords: Autoimmune Diseases; Biological Therapy; Lupus Erythematosus, Systemic.

Conflict of interest statement

Competing interests: INB has received grant/research support from Genzyme/Sanofi, GSK, Roche and UCB; received consulting fees from AstraZeneca, Eli Lilly, GSK, ILTOO, Merck Serono and UCB; and speaker/honoraria from AstraZeneca, GSK and UCB. INB is a National Institute for Health Research (NIHR) Senior Investigator Emeritus and is funded by the NIHR Manchester Biomedical Research Centre. RAF has received grant/research support and consulting fees from AstraZeneca. EFM received grant support from AstraZeneca, Bristol Myers Squibb, Janssen, Merck Serono and UCB; was a consultant for AstraZeneca, Eli Lilly, Janssen and Merck Serono; and was a speaker at a speaker bureau for AstraZeneca. SM has received grants and other support and has been a member of an advisory board for AstraZeneca. YT has received speaking fees and/or honoraria from AbbVie, Asahi Kasei, Astellas, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi and YL Biologics, and has received research grants from AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Takeda and UCB. KCK has received consulting fees from AbbVie, Amgen, AstraZeneca, Biogen, Chemocentryx, Eli Lilly, Equillium, Genentech/Roche, GSK, Janssen and Nektar; and has received grant/research support from BMS, Irdosia, Kirin, Pfizer, Resolve, Takeda and UCB. JTM has received grant/research support from BMS and GSK and has received consulting fees from AstraZeneca, AbbVie, Amgen, Aurinia, BMS, EMD Serono, GSK, Remegen, Janssen, Provention and UCB. PP, EM, CK, MA, MH and RT are employees of AstraZeneca.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Concordance between patient responder status for BICLA and SRI(4) outcomes at week 52 in TULIP-1, TULIP-2 and MUSE (%). BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; SRI(4), Systemic Lupus Erythematosus Responder Index of ≥4.
Figure 2
Figure 2
Proportion of patients with and without sustained taper of glucocorticoids to ≤7.5 mg/day from week 40 to week 52 among patients receiving ≥10 mg/day at baseline, stratified by BICLA/SRI(4) response in TULIP-1. All patients included in this analysis were receiving glucocorticoids (prednisone or equivalent) ≥10 mg/day at baseline. BICLA– and SRI(4)– refer to non-responders; BICLA+ and SRI(4)+ refer to responders. BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; GC, glucocorticoid; SRI(4), Systemic Lupus Erythematosus Responder Index of ≥4.
Figure 3
Figure 3
Reasons for (A) SRI(4) response and (B) BICLA non-response at week 52 in TULIP-1 among BICLA non-responders/SRI(4) responders. BICLA– and SRI(4)– refer to non-responders; BICLA+ and SRI(4)+ refer to responders. BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000; SRI(4), Systemic Lupus Erythematosus Responder Index of ≥4.

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