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

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.

Keywords: biological therapy; lupus erythematosus; systemic; therapeutics.

Conflict of interest statement

Competing interests: EMV has received grant support from AstraZeneca, Roche/Genentech and Sandoz; received consulting fees from AstraZeneca, GlaxoSmithKline, Roche/Genentech, Aurinia and Sandoz; and was a speaker at a speaker bureau for Becton Dickinson and GlaxoSmithKline. JTM has received grant/research support from Bristol Myers Squibb and GlaxoSmithKline, and consultancy fees from AbbVie, Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen, Provention, Remegen and UCB. 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 AbbVie, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono and UCB; received grant support from Bristol Myers Squibb and received consulting fees from Amgen, Biogen, CSL, Neovacs and Wolf Biotherapeutics. RAF has received grant/research support and consulting fees from AstraZeneca. INB is a National Institute for Health Research (NIHR) Senior Investigator Emeritus and is funded by the NIHR Manchester Biomedical Research Centre; has received grant/research support from Genzyme/Sanofi, GlaxoSmithKline, Roche and UCB; received consulting fees from Eli Lilly, GlaxoSmithKline, ILTOO, Merck Serono and UCB and was a speaker for AstraZeneca, GlaxoSmithKline and UCB. YT has received speaking fees and/or honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly, Gilead, Mitsubishi-Tanabe and YL Biologics, and has received research grants from AbbVie, Asahi-Kasei, Chugai, Boehringer-Ingelheim, Corrona, Daiichi-Sankyo, Eisai, Kowa, Mitsubishi-Tanabe and Takeda. SM has received grant/research support and consulting fees from AstraZeneca. KCK has received consulting fees from AstraZeneca. RNK, KS, GA and RJ 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

BICLA response at week 52 by subgroup. aSerological markers refer to anti-dsDNA antibodies (positive or negative), C3 (low or normal) and C4 (low or normal). The percentage of responders, the difference in estimates, associated 95% CIs and nominal p values were calculated using a stratified Cochran-Mantel-Haenszel approach, with stratification factors of SLEDAI-2K score at screening, baseline GC dosage, type I IFNGS test result at screening and study. Anti-dsDNA, antidouble-stranded DNA; BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; BMI, body mass index; C, complement; CI, confidence interval; GC, oral glucocorticoid; IFNGS, interferon gene signature; n, number of responders; N, number of patients in group; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.

Figure 2

Adjusted difference in cumulative percentages of patients with ≥1 AE during treatment with anifrolumab 300 mg versus placebo by subgroup in pooled TULIP-1 and TULIP-2 data. aSerological markers refer to anti-dsDNA antibodies (positive or negative), C3 (low or normal) and C4 (low or normal). Percentages indicate cumulative proportions that were adjusted using the Cochran-Mantel-Haenszel approach. Anti-dsDNA, antidouble-stranded DNA; AE, adverse event; BMI, body mass index; C, complement; CI, confidence interval; GC, oral glucocorticoid; IFNGS, interferon gene signature; n, number of responders; N, number of patients in group; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.

Figure 3

Adjusted difference in cumulative percentages of patients with ≥1 SAE during treatment with anifrolumab 300 mg versus placebo by subgroup in pooled TULIP-1 and TULIP-2 data. aSerological markers refer to anti-dsDNA antibodies (positive or negative), C3 (low or normal) and C4 (low or normal). Percentages indicate cumulative proportions that were adjusted using the Cochran-Mantel-Haenszel approach. Anti-dsDNA, anti-double-stranded DNA; BMI, body mass index; C, complement; CI, confidence interval; GC, oral glucocorticoid; IFNGS, interferon gene signature; n, number of responders; N, number of patients in group; SAE, serious adverse event; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index 2000.

Figure 4

BICLA response estimates and SEs from weeks 4–52 in (A) type I IFNGS-high and (B) IFNGS-low patients in pooled TULIP data. The percentage of responders was calculated using a stratified Cochran-Mantel-Haenszel approach, with stratification factors SLEDAI-2K score at screening, baseline GC dosage and study. Points represent response estimates plotted with SE. *Nominal p

Figure 5

Sustained oral GC taper by subgroup for patients with SLE in pooled data from the TULIP-1 and TULIP-2 trials. A sustained oral GC taper was defined as a dosage reduction to ≤7.5 mg/day from week 40 to week 52 in patients receiving ≥10 mg/day at baseline (prednisone or equivalent). The percentage of responders, the difference in estimates, associated 95% CIs and nominal p values were calculated using a stratified Cochran-Mantel-Haenszel approach, with stratification factors of SLEDAI-2K score at screening, type I IFNGS test result at screening and study. Anti-dsDNA, antidouble-stranded DNA; BMI, body mass index; C, complement; CI, confidence interval; GC, glucocorticoid; IFNGS, interferon gene signature; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000.

Figure 6

Annualised flare rate through week 52 by subgroup for patients with SLE in pooled data from the TULIP-1 and TULIP-2 trials. A flare is defined as either ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B items compared with the previous visit. The annualised flare rate was calculated using a negative binomial regression model, which included covariates of treatment group, stratification factors and study, and was adjusted for variations in exposure time. Anti-dsDNA, antidouble-stranded DNA; BILAG-2004, British Isles Lupus Assessment Group-2004; BMI, body mass index; C, complement; CI, confidence interval; GC, glucocorticoid; IFNGS, interferon gene signature; SLE, systemic lupus erythematosus; SLEDAI-2K, SLE Disease Activity Index 2000.