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

Abstract

ObjectiveTo 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).MethodsPatients (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.ResultsThe 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).ConclusionAnifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.

Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial

“…A secondary analysis of the SRI-6 response was undertaken to examine whether the SRI-6 primary end point may have been confounded by imbalances in corticosteroid taper. In this end point, adapted from a recently published trial result,14 response was defined as meeting the week 52 SRI-6 criteria while also having an oral corticosteroid dose from week 40 through week 52 that was lower than the dose on day 1. With this analysis, 23.3% of blisibimod-treated subjects met the end point vs 14.3% of the control arm (P=0.056, figure 2F).…”

“…Specifically, when steroid reduction is included in the end point, analogous to the phase II SLE trial with anifrolumab,14 lower responder rates were observed and greater treatment effect with blisibimod. The secondary analyses of the effects of blisibimod on corticosteroid taper suggest that background corticosteroid use may have confounded the primary efficacy end point, since many of the control subjects received corticosteroid doses that were higher than baseline throughout the trial, averaging 3–5 mg/day higher than the blisibimod group, in which the mean dose was below baseline from week 12 onwards.…”

Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome

“…Measuring the IFN signature in patients with SLE might in the future be used in clinical decision-making 8. The necessity to quantify gene expression and the lack of a uniformly accepted gene set or scoring system hamper its implementation in clinical practice.…”

“…Anifrolumab, a monoclonal antibody against IFNAR, the receptor for type I IFN, showed clinical efficacy in a phase IIb clinical trial in SLE, particularly in those patients with an IFN signature 8. The detection of the IFN signature may therefore soon be used to guide treatment decisions in SLE and possibly other autoimmune diseases.…”

The Future of B-cell Activating Factor Antagonists in the Treatment of Systemic Lupus Erythematosus

“…In this latter trial, the absolute percentage difference in clinical response between patients treated with the highest dose of sifalimumab and those treated with placebo was 14% [80], similar to the absolute percentage differences observed in the successful trial with belimumab or tabalumab. Of note, however, were results from the phase-IIb trial of the anti-IFNα receptor mAb, anifrolumab, in which the absolute percentage difference in clinical response between patients treated with the optimal dose of anifrolumab and those treated with placebo being 26% [81]. Although comparisons of response rates across different trials are notoriously unreliable and must be taken with a large grain of salt, the strikingly greater response rate in the trial that targeted the IFNα receptor rather than IFNα itself raises the plausibility of im-proved results in BAFF-centric trials that target BAFF receptors rather than BAFF itself.…”