Background Increased activity of the type I interferon (IFN) pathway is central to the pathogenesis of SLE. Blocking the type I receptor may reduce SLE activity more effectively than inhibiting IFN-α alone.
Objectives Efficacy and safety of anifrolumab were assessed in a Phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate to severe SLE (the MUSE study).
Methods 305 patients were treated for 48 weeks with intravenous anifrolumab (300 mg or 1000 mg) or placebo, in addition to standard-of-care medications. Randomization was stratified by SLE Disease Activity Index 2000 (SLEDAI-2K) score (<10 or ≥10), oral corticosteroid (OCS) dose (<10 or ≥10 mg/day), and IFN gene signature status (high vs. low) based on a 4-gene expression assay. The primary endpoint was the percentage of patients achieving an SLE Responder Index [SRI(4)] response at Day 169 with sustained reduction of OCS (<10 mg/day and ≤Day 1 dose from Day 85 to 169).
Results The primary endpoint was met by more anifrolumab-treated patients [placebo vs. 300 mg vs. 1000 mg: 17.6%, 34.3% (p=0.014), 28.8% (p=0.063)] with greater effect sizes observed in the 75% of patients who had a high baseline IFN signature [13.2%, 36.0% (p=0.004), 28.2% (p=0.029)]. At Day 365 more anifrolumab-treated patients achieved SRI(4) responses [40.2%, 62.6%, (p<0.001), 53.8%, (p=0.043)], BILAG-based Composite Lupus Assessment (BICLA) [25.7%, 53.5% (p<0.001), 41.2% (p=0.018)], modified SRI(6) [28.4%, 49.5% (p=0.002), 44.7% (p=0.015)], and SLEDAI-2K ≤2 [17.6%, 35.4% (p=0.004), 32.7% (p=0.012)]. Major clinical response (BILAG “C” or better in all domains at Day 169 maintained to Day 365) was achieved by 6.9%, 19.2% (p=0.012), and 17.3% (p=0.025) of patients. BILAG “A” flares were reported in more placebo- vs. anifrolumab-treated patients (16.7%, 9.1%, 10.6%). In patients with baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score ≥10, more anifrolumab-treated patients attained a ≥50% reduction by Day 365 [30.8%, 63.0% (p=0.013), 58.3% (p=0.077)]. In patients with ≥8 swollen and ≥8 tender joints at baseline more anifrolumab-treated patients achieved ≥50% decrease in joint count [48.6%, 69.6% (p=0.038), 64.6% (p=0.156)]. Although steroid tapering was not mandated, OCS reduction to ≤7.5 mg/d at Day 365 was achieved by 26.6%, 56.4%, and 31.7% of patients. The observed benefits were driven by results in the IFN-high subpopulation (figure). Median suppression of 21 IFN-regulated genes was ∼90% for both doses of anifrolumab. Patients in the placebo group had the lowest incidence of Herpes zoster (2.0%, 5.1%, 9.5%) and cases reported as influenza (2.0%, 6.1%, 7.6%); there were no differences in the incidence of serious adverse events (18.8%, 16.2%, 17.1%). The incidence of infusion-related reactions was similar (5.9%, 2.0%, 3.8%).
Conclusions Anifrolumab significantly reduced disease activity across all clinical endpoints. Enhanced effects in IFN-high patients support the pathobiology of this treatment strategy.
Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK
Disclosure of Interest R. Furie Consultant for: MedImmune, J. Merrill Grant/research support from: MedImmune; Genentech/Roche, Consultant for: Medimmune, Genentech/Roche, Neovacs, V. Werth Consultant for: MedImmune, M. Khamashta: None declared, K. Kalunian Grant/research support from: MedImmune, Consultant for: AstraZeneca, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune, J. Drappa Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Employee of: MedImmune, S. Yoo Shareholder of: AstraZeneca; Regenx Bio, Consultant for: Regenx Bio