Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis.

OBJECTIVE: To assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis. METHODS: This phase II double-blinded study randomised 147 patients (1:1:1) to receive monthly intravenous anifrolumab basic regimen (BR, 300 mg), intensified regimen (IR, 900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). The primary endpoint was change in baseline 24-hour urine protein-creatinine ratio (UPCR) at week (W) 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response (CRR) at W52. Exploratory endpoints included more stringent CRR definitions and sustained glucocorticoid reductions (≤7.5 mg/day, W24-52). Safety was analysed descriptively. RESULTS: Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At W52, 24-hour UPCR improved by 69% and 70% for combined anifrolumab and placebo groups, respectively (geometric mean ratio=1.03; 95% CI 0.62 to 1.71; p=0.905). Serum concentrations were higher with anifrolumab IR versus anifrolumab BR, which provided suboptimal exposure. Numerically more patients treated with anifrolumab IR vs placebo attained CRR (45.5% vs 31.1%), CRR with UPCR ≤0.5 mg/mg (40.9% vs 26.7%), CRR with inactive urinary sediment (40.9% vs 13.3%) and sustained glucocorticoid reductions (55.6% vs 33.3%). Incidence of herpes zoster was higher with combined anifrolumab vs placebo (16.7% vs 8.2%). Incidence of serious adverse events was similar across groups. CONCLUSION: Although the primary endpoint was not met, anifrolumab IR was associated with numerical improvements over placebo across endpoints, including CRR, in patients with active lupus nephritis. TRIAL REGISTRATION NUMBER: NCT02547922.

Causal cascade of direct and indirect effects of anifrolumab on patient-reported outcomes: structural equation modelling of two Phase 3 trials.

OBJECTIVES: SLE significantly impairs health-related quality of life (HRQoL). In this post hoc analysis, structural equation modelling was used to examine the 'causal cascade' of interaction between anifrolumab, disease activity and patient-reported outcomes (PROs) in pooled data from the phase 3 TULIP-1 and TULIP-2 trials. METHODS: Data were pooled from the TULIP-1 (n = 364) and TULIP-2 (n = 362) randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). We evaluated changes from baseline to week 24 and week 52 in four clinical (BICLA, BILAG-2004, SLEDAI-2K and changes in glucocorticoid dosage) and six PRO measures (SF-36, FACIT-F, EQ-5D, LupusQoL, PHQ-8 and pain NRS) in our hypothesized model of interactions. RESULTS: Our hypothesized model had an acceptable fit to the pooled TULIP trial data. At week 24, significant paths revealed that when compared with placebo, anifrolumab treatment improved disease activity as measured by BICLA, BILAG-2004, SLEDAI-2K and changes to glucocorticoid dosage. In turn, these clinical measures reduced pain, which improved fatigue, physical functioning, mood/emotions and HRQoL. When the model incorporated number of glucocorticoid tapers as the measure of change in glucocorticoid dosage, treatment effects of anifrolumab on glucocorticoid tapers were not retained at week 52. However, at week 52 treatment indirectly improved HRQoL through its direct effects on BICLA. CONCLUSIONS: Anifrolumab is associated with significant patient-reported improvements in aspects of HRQoL including pain, fatigue, mood and physical function. These benefits are from the direct effect of anifrolumab treatment on disease activity and reduction in glucocorticoid dosage.

Anifrolumab in lupus nephritis: results from second-year extension of a randomised phase II trial.

OBJECTIVE: To characterise the safety and efficacy of anifrolumab in active lupus nephritis (LN) through year 2 of the phase II randomised, double-blind Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-LN trial (NCT02547922) of 2 anifrolumab dosing regimens versus placebo. METHODS: Patients received intravenous anifrolumab 900 mg for the first 3 doses followed by 300 mg anifrolumab (intensified regimen (IR)), 300 mg anifrolumab (basic regimen (BR)) or placebo every 4 weeks throughout. To continue into Year 2, patients must have achieved at least partial renal response and a glucocorticoid tapering target. RESULTS: Of 147 randomised patients, 101 completed Year 1 study treatment; of these, 75 (74%) continued into Year 2 (anifrolumab IR: n=29, BR: n=23 and placebo: n=23). During Year 2, 72% of patients reported ≥1 adverse event (AE); serious AEs were reported in 6.9%, 8.7% and 8.7% of patients (anifrolumab IR, BR and placebo, respectively); 3 patients discontinued treatment due to an AE (anifrolumab IR: n=2 and placebo: n=1) and herpes zoster was reported in 2 patients (anifrolumab IR: n=1 and BR: n=1). The study was ongoing at the start of the pandemic, but no COVID-19 cases were reported. Of the 145 patients receiving treatment, more patients on the IR attained complete renal response at Week 104 compared with those on BR or placebo (27.3% vs 18.6% and 17.8%) and simultaneously achieved sustained glucocorticoid tapering (IR: 25.0%; BR: 18.6% and placebo: 17.8%). The improvements in estimated glomerular filtration rate were numerically larger in both anifrolumab groups versus placebo. CONCLUSIONS: The safety and tolerability profile through Year 2 of TULIP-LN was generally consistent with Year 1, with promising efficacy results for the anifrolumab IR regimen. Collectively, the results support further investigation of an anifrolumab intensified dosing regimen in larger populations of patients with active proliferative LN. TRIAL REGISTRATION NUMBER: NCT02547922.

Clinical meaningfulness of a British Isles Lupus Assessment Group-based Composite Lupus Assessment response in terms of patient-reported outcomes in moderate to severe systemic lupus erythematosus: a post-hoc analysis of the phase 3 TULIP-1 and TULIP-2 trials of anifrolumab.

BACKGROUND: The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials but does not include patient-reported outcomes. To evaluate the clinical meaningfulness of a BICLA response from the patient perspective, we aimed to analyse patient-reported outcomes by BICLA responses with anifrolumab or placebo in patients with moderate to severe SLE. METHODS: We did a post-hoc analysis of pooled data from the phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab, which assessed health-related quality of life using the Short Form 36 Health Survey (SF-36; version 2) and Lupus Quality of Life, fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), pain using the Numerical Rating Scale, and disease activity using Patient Global Assessment. Changes from baseline and proportions of patients reporting improvements in patient-reported outcomes greater than or equal to the minimum clinically important differences and scores greater than or equal to the normative values were compared in BICLA responders and non-responders and by treatment group (intravenous anifrolumab 300 mg or placebo). FINDINGS: 726 patients were included in the TULIP trials, of whom 366 received placebo (184 patients in TULIP-1 and 182 in TULIP-2) and 360 received anifrolumab 300 mg (180 patients in each trial). The mean patient age was 41·8 years (SD 11·9). 674 (93%) patients were female, 52 (7%) were male, and 479 (66%) were White; 283 (39%) were BICLA responders and 443 (61%) were BICLA non-responders. Compared with non-responders, BICLA responders reported greater mean improvements from baseline at week 52 in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores (all nominal p<0·0053). Compared with non-responders, a greater proportion of BICLA responders reported improvements greater than or equal to the minimum clinically important difference across all SF-36 domains; eg, Physical Component Summary (165 [60%] of 277 for responders vs 63 [15%] of 416 for non-responders), Mental Component Summary (140 [51%] of 276 vs 59 [15%] of 416), and role physical (184 [70%] of 264 vs 76 [19%] of 398); Lupus Quality of Life domains; eg, physical health (151 [58%] of 262 vs 60 [15%] of 396), and intimate relationships (77 [41%] of 187 vs 33 [11%] of 286), and FACIT-F (155 [56%] of 276 vs 66 [15%] of 439). Similarly, a greater proportion of BICLA responders had scores equal to or greater than the normative values across all SF-36 domains and FACIT-F compared with BICLA non-responders at week 52. Patients who received anifrolumab reported greater numerical improvements in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores than those who received placebo. INTERPRETATION: BICLA responders reported significant and clinically meaningful improvements in Patient Global Assessment, health-related quality of life, fatigue, and pain compared with BICLA non-responders. More patients with moderate to severe SLE who received anifrolumab were BICLA responders and had improved health-related quality of life, fatigue, and pain than those who received placebo. FUNDING: AstraZeneca.

Long-Term Safety and Efficacy of Anifrolumab in Adults With Systemic Lupus Erythematosus: Results of a Phase II Open-Label Extension Study.

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), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL). RESULTS: Of the 246 patients who completed the RCT, 218 (88.6%) enrolled in the open-label extension study, of which 139 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of open-label extension treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment due to AEs. No new safety signals were identified. Improvement in the SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 health survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-double-stranded DNA showed trends toward sustained improvement. CONCLUSION: Long-term anifrolumab treatment demonstrates an acceptable safety profile with sustained improvement in SLE disease activity, HRQoL, and serologic measures.

Pharmacokinetics, pharmacodynamics, and safety of subcutaneous anifrolumab in patients with systemic lupus erythematosus, active skin disease, and high type I interferon gene signature: a multicentre, randomised, double-blind, placebo-controlled, phase 2 study.

BACKGROUND: 300 mg of intravenous anifrolumab every 4 weeks added to standard-of-care treatment for patients with systemic lupus erythematosus (SLE) reduced disease activity and glucocorticoid requirement in a previous phase 3 trial. Because patients might find subcutaneous administration more convenient than intravenous delivery, we aimed to evaluate the pharmacokinetics, pharmacodynamics, safety, and efficacy of subcutaneous anifrolumab in patients with SLE, active skin disease, and a high type I interferon gene signature. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 2 study was done at 12 hospitals and outpatient clinics in Hungary, South Korea, Poland, and the USA. Eligible patients were aged 18-70 years, and had SLE with high type I interferon gene signature and an activity score on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) of at least 10. Enrolled participants were randomly assigned (3:1:3:1) by use of a voice-web response system to receive either 150 mg of subcutaneous anifrolumab or corresponding placebo, or 300 mg of subcutaneous anifrolumab or corresponding placebo in addition to stable standard-of-care treatment. The study was double-blinded with respect to intervention but not dose, until 12 weeks. Doses of oral glucocorticoids were tapered after week 12. The primary pharmacokinetic endpoint was the serum concentration of anifrolumab based on the maximum concentration after the first dose and the minimum (trough) concentration before subsequent doses and was measured in all patients who received anifrolumab and had at least one quantifiable serum pharmacokinetics observation following the first dose. The primary pharmacodynamic endpoint was neutralisation of the type I interferon pharmacodynamic signature at week 12 and was assessed in all patients with a high type I interferon pharmacodynamics signature at baseline based on a 21-gene test. Safety was evaluated in the full analysis set, which included all patients who received at least one dose of anifrolumab. This trial is completed and is registered at ClinicalTrials.gov, NCT02962960. FINDINGS: Between March 14, 2017, and Oct 26, 2017, 36 patients were randomly assigned to receive 150 mg of anifrolumab (n=14), 300 mg of anifrolumab (n=13), or placebo (n=9). Two patients in the anifrolumab 150 mg group were excluded from the pharmacodynamic analysis set (n=34). Ten (71%) of 14 patients in the anifrolumab 150 mg group, ten (77%) of 13 patients in the anifrolumab 300 mg group, and nine (100%) of the nine patients in the placebo group completed 52 weeks of treatment. At week 12, pre-dose mean trough serum concentrations of anifrolumab were more than dose proportional between the anifrolumab 150 mg group (19·82 µg/mL [SD 15·01]) and the anifrolumab 300 mg group (60·28 µg/mL [43·66]), and the pharmacokinetics were non-linear. At week 12, the median percentage neutralisation of the type I interferon gene signature was higher with 150 mg (88·0% [median absolute deviation 7·4]) and 300 mg (90·7% [3·3]) of anifrolumab than with placebo (18·5% [8·1]), and more patients in the anifrolumab 150 mg group and the anifrolumab 300 mg group than in the placebo group had neutralisation of 75% or more (eight [67%] of 12 vs ten [77%] of 13 vs one [11%] of nine). At least one adverse event was reported by 23 (85%) of 27 patients in the anifrolumab groups and by seven (78%) of nine patients in the placebo group; most adverse events were of mild-to-moderate severity. Serious adverse events were reported in six (22%) of 27 patients in the anifrolumab groups (four patients in the 150 mg group and two in the 300 mg group). No serious adverse events were reported in the placebo group. Herpes zoster infection was reported by three (11%) of 27 patients in the anifrolumab groups and by one (11%) of nine patients in the placebo group. There were no treatment-related deaths. INTERPRETATION: Anifrolumab, administered subcutaneously every 2 weeks to patients with SLE and moderate-to-severe skin manifestations, had non-linear pharmacokinetics that were more than dose proportional, and neutralised the type I interferon gene signature in a dose-dependent manner. The safety profile was consistent with previous studies of intravenous anifrolumab, supporting the continued development of anifrolumab as a subcutaneously administered therapy for patients with SLE. FUNDING: AstraZeneca.