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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01438489.

© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1

Efficacy results at week 52 in patients with systemic lupus erythematosus (SLE) receiving anifrolumab 300 mg, anifrolumab 1,000 mg, or placebo. Anifrolumab treatment led to a greater rate of response across multiple end points. The benefit observed in the overall modified intent‐to‐treat population was driven by the patients with a high interferon (IFN) gene signature (IFN test high subpopulation), which represents ∼75% of the entire cohort. The odds ratios (ORs), 90% confidence intervals (90% CIs), and P values are from a logistic regression model adjusted for stratification factors. SRI(4) = SLE Responder Index requiring a ≥4‐point reduction in SLE Disease Activity Index 2000 (SLEDAI‐2K) score; OCS = oral corticosteroid; BICLA = British Isles Lupus Assessment Group 2004–based Combined Lupus Assessment.

Figure 2

Efficacy results over time in patients with systemic lupus erythematosus (SLE) receiving anifrolumab 300 mg, anifrolumab 1,000 mg, or placebo. Treatment was given every 4 weeks from week 1 to week 48. A, Proportion of patients achieving an SLE Responder Index response over time in the modified intent‐to‐treat (ITT) population and in the interferon (IFN)–high and IFN‐low subsets. B, Proportion of patients achieving a British Isles Lupus Assessment Group 2004–based Combined Lupus Assessment response over time in the modified ITT population and in the IFN‐high and IFN‐low subsets.

Figure 3

Organ‐specific efficacy results over time in patients with systemic lupus erythematosus (SLE) receiving anifrolumab 300 mg, anifrolumab 1,000 mg, or placebo. Treatment was given every 4 weeks from week 1 to week 48. A, Left, Proportion of patients with a Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score of ≥10 at baseline (n = 77) who had ≥50% improvement in the CLASI score. Right, A representative example of skin response following anifrolumab treatment. B, Left, Proportion of patients with ≥8 swollen and ≥8 tender joints at baseline (n = 37 in the placebo group, n = 46 in the anifrolumab 300‐mg group, and n = 48 in the anifrolumab 1,000‐mg group) who had ≥50% improvement in the swollen and tender joint count. Right, Mean ± SEM change from baseline in the active joint count in the modified intent‐to‐treat population. Joint counts are based on the assessment of 28 joints.