Efficacy and Safety of Anifrolumab in Patients with Moderate to Severe Systemic Lupus Erythematosus: Results of the Second Phase 3 Randomized Controlled Trial

Abstract

Background/Purpose: Anifrolumab, a human monoclonal antibody to the type I IFN receptor subunit 1, had robust efficacy in a phase 2 study in patients with active SLE. The first phase 3 trial, TULIP-1, did not meet its primary endpoint, SLE responder index (SRI[4]), but multiple other endpoints, including BILAG–based Composite Lupus Assessment (BICLA), suggested clinical benefit. We report results of the second phase 3 trial of anifrolumab.

Methods: TULIP-2 (NCT02446899) is a randomized, double-blind, placebo-controlled trial that evaluated efficacy and safety of IV anifrolumab 300 mg vs placebo every 4 weeks for 48 weeks in patients with moderate to severe SLE despite standard-of-care (SOC) treatment. Patients met ACR SLE criteria and had SLEDAI-2K ≥6 and BILAG >1 A or >2 B. The primary endpoint was BICLA response at week 52. SOC was stable except for mandatory attempts at oral corticosteroid (OCS) tapering to prednisone equivalent ≤7.5 mg/d for patients receiving ≥10 mg/d at baseline. Safety was also assessed.

Results: Of 365 randomized patients, 362 received ≥1 dose of study drug and were included in the analyses (anifrolumab, n=180; placebo, n=182). Baseline demographic and disease characteristics were similar between treatment groups (Table 1). Treatment completion was 85.0% for anifrolumab and 71.4% for placebo.

Anifrolumab was superior to placebo for BICLA response (47.8% vs 31.5%, respectively, P=0.001) and key secondary endpoints: OCS reduction (51.5% vs 30.2%; P=0.014) and Cutaneous Lupus Erythematosus Disease Area and Severity Index response (49.0% vs 25.0%; P=0.039); annualized flare rate was numerically lower in anifrolumab-treated patients (0.43 vs 0.64; rate ratio 0.67 [95% CI: 0.48, 0.94]; P=0.081; Table 2).

Efficacy was further supported by numeric differences favoring anifrolumab in multiple secondary endpoints (unadjusted), including SRI(4) response (55.5% vs 37.3%; nominal P< 0.001) and higher thresholds of SRI(5–8), time to onset of BICLA response sustained to week 52 (hazard ratio [HR], 1.55; 95% CI: 1.11, 2.18; nominal P=0.011; Figure 1A), and time to first flare (HR, 0.65; 95% CI: 0.46, 0.91; nominal P=0.013; Figure 1B). In patients with high baseline IFN gene signature (IFNGS), anifrolumab induced neutralization of IFNGS by week 12 (median suppression 88.0%) that was maintained through week 52. Serum anti-dsDNA trended toward normalization with anifrolumab.

The safety profile of anifrolumab was similar to that of previous trials. Herpes zoster was more common in those receiving anifrolumab (7.2%) than placebo (1.1%). In contrast, serious adverse events were less frequent among anifrolumab- than placebo-treated patients (8.3% and 17.0%, respectively), as were adverse events leading to treatment discontinuation (2.8% and 7.1%). One death occurred in the anifrolumab group (pneumonia). Few patients (0.6%) developed antidrug antibodies.

Conclusion: Anifrolumab was superior to placebo for multiple efficacy endpoints, including overall disease activity, skin disease, and OCS tapering. No new safety signals were identified. TULIP-2 demonstrates efficacy of anifrolumab in moderate to severe SLE.