ObjectivesTo characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups.MethodsWe 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.ResultsIn 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.ConclusionsOverall, 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 numberNCT02446912, NCT02446899.

ObjectiveIn phase II and III trials, anifrolumab, a human monoclonal antibody that binds type I interferon receptor subunit 1, has shown efficacy in adults with moderate to severe SLE. We evaluated the safety and tolerability of anifrolumab using data pooled from these trials to more precisely estimate the rate and severity of adverse events (AEs).MethodsData were pooled from patients receiving monthly intravenous anifrolumab 300 mg or placebo in MUSE, TULIP-1 and TULIP-2. Key safety endpoints included percentages and exposure-adjusted incidence rates (EAIRs) of patients who experienced AEs, serious AEs (SAEs), AEs leading to discontinuation and AEs of special interest.ResultsDuring treatment, 86.9% of patients receiving anifrolumab 300 mg (n=459) experienced AEs (≥1) versus 79.4% receiving placebo (n=466), and 4.1% versus 5.2% experienced an AE leading to discontinuation of investigational product. SAEs (≥1) were experienced by 11.8% and 16.7% of patients receiving anifrolumab and placebo, respectively (EAIR risk difference (95% CI) −7.2 (−12.5 to –1.9)), including lupus exacerbations classified as SAEs (1.5% and 3%, respectively). Infections occurred in 69.7% and 55.4% of patients receiving anifrolumab and placebo, respectively; difference in reported rates was driven by herpes zoster (HZ) and mild and moderate respiratory (excluding pneumonia) infections. The risk of HZ was increased with anifrolumab versus placebo (6.1% vs 1.3%, respectively; EAIR risk difference (95% CI) 5.4 (2.8 to 8.4)); most HZ events were mild or moderate, cutaneous and resolved without treatment discontinuation. Serious infections occurred in 4.8% and 5.6% of patients receiving anifrolumab and placebo, respectively.ConclusionsIn this pooled analysis of 925 patients with moderate to severe SLE, monthly intravenous anifrolumab 300 mg was generally well tolerated over 52 weeks with an acceptable safety profile. Anifrolumab was associated with an increased incidence of HZ and respiratory tract infections and lower reported rate of SLE worsening as SAEs.

Objective. To investigate long-term safety and tolerability of anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate-to-severe systemic lupus erythematosus (SLE).Methods. This 3-year, multinational, open-label extension study included adult patients who completed treatment (48 weeks of anifrolumab or placebo; 12-week follow-up) in the MUSE phase IIb randomized controlled trial (RCT). Patients initially received 1,000 mg of anifrolumab intravenously every 4 weeks, which was reduced to 300 mg every 4 weeks based on the benefit/risk profile established in the MUSE trial. Adverse events (AEs) were assessed monthly. Exploratory end points included the SLE Disease Activity Index 2000 (SLEDAI-2K),

Background Systemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab’s effect on flares, including those arising with glucocorticoid taper. Methods TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). For patients receiving baseline glucocorticoid ≥10 mg/day, attempted taper to ≤7.5 mg/day prednisone or equivalent from Weeks 8–40 was required and defined as sustained reduction when maintained through Week 52. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores versus the previous visit. Flare assessments were compared for patients receiving anifrolumab versus placebo. Results Compared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates (rate ratio 0.75, 95% confidence interval [CI] 0.60–0.95), prolonged time to first flare (hazard ratio 0.70, 95% CI 0.55–0.89), and fewer patients with ≥1 flare (difference −9.3%, 95% CI −16.3 to −2.3), as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had ≥1 flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from ≥10 mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185). Conclusions Analyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE. ClinicalTrials.gov identifiers TULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912); TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).

Objective To explore long‐term safety and tolerability of anifrolumab 300 mg compared with placebo in patients with systemic lupus erythematosus (SLE) who completed a Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trial and enrolled in the placebo‐controlled 3‐year long‐term extension (LTE) study (http://clinicaltrials.gov identifier: NCT02794285). Methods In the blinded LTE study, patients continued anifrolumab 300 mg, switched from anifrolumab 150 mg to 300 mg, or were re‐randomized from placebo to receive either anifrolumab 300 mg or to continue placebo, administered every 4 weeks. Primary comparisons in the LTE study were between patients who received anifrolumab 300 mg or placebo throughout the TULIP and LTE studies. For rare safety events, comparisons included patients who received any anifrolumab dose during TULIP or LTE. When exposure differed, exposure‐adjusted incidence rates (EAIRs) per 100 patient‐years were calculated. Results In the LTE study, EAIRs of serious adverse events (SAEs) were 8.5 with anifrolumab compared with 11.2 with placebo; likewise, EAIRs of AEs leading to treatment discontinuation were 2.5 versus 3.2, respectively. EAIRs of non‐opportunistic serious infections were comparable between groups (3.7 with anifrolumab versus 3.6 with placebo). Exposure‐adjusted event rates of COVID‐related AEs, including asymptomatic infections, were 15.5 with anifrolumab compared with 9.8 with placebo. No COVID‐related AEs occurred in fully vaccinated individuals. EAIRs of malignancy and major acute cardiovascular events were low and comparable between groups. Anifrolumab was associated with lower cumulative glucocorticoid use and greater mean improvement in the SLE Disease Activity Index 2000, compared with placebo. Conclusion This LTE study represents the longest placebo‐controlled clinical trial performed in SLE to date. No new safety findings were identified in the LTE study, supporting the favorable benefit–risk profile of anifrolumab for patients with moderate‐to‐severe SLE receiving standard therapy.