Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials.

INTRODUCTION: Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials. METHODS: Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels. RESULTS: Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52, and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-λ protein levels, and impacted apoptosis-associated and neutrophil extracellular traps-(NET)osis-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and γδT cells and a decrease of monocytes following anifrolumab treatment. DISCUSSION: Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis.

Trial of Anifrolumab in Active Systemic Lupus Erythematosus.

BACKGROUND: Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. METHODS: We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. RESULTS: A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. CONCLUSIONS: Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.).

Lupus low disease activity state attainment in the phase 3 TULIP trials of anifrolumab in active systemic lupus erythematosus.

OBJECTIVES: In patients with systemic lupus erythematosus (SLE), lupus low disease activity state (LLDAS) attainment is associated with improved outcomes. We investigated LLDAS attainment in anifrolumab-treated patients. METHODS: We performed post hoc analysis of pooled Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP-1) (NCT02446912) and TULIP-2 (NCT02446899) anifrolumab phase 3 trial data in patients with moderate to severe SLE receiving standard therapy. LLDAS was defined as: SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician's Global Assessment ≤1, prednisone ≤7.5 mg/day and no non-standard immunosuppressant dosing. Time to first LLDAS attainment was compared between groups using Cox regression modelling; responses were compared using logistic regression. RESULTS: Agnostic to treatment, 205/819 (25.0%) patients attained LLDAS at week 52; 186/205 (90.7%) were also British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA)-responders. Among BICLA-responders at week 52, 186/318 (58.5%) attained LLDAS; 203/380 (53.4%) SLE Responder Index-4 (SRI(4)) responders attained LLDAS. Improvements from baseline in patient global assessment scores at week 52 were threefold greater in LLDAS-attainers. At week 52, 30.0% of anifrolumab-treated patients and 19.6% of placebo were in LLDAS (OR 1.8, 95% CI 1.3 to 2.5, p=0.0011). Compared with placebo, anifrolumab treatment was associated with earlier LLDAS attainment (time to first LLDAS, HR 1.76, 95% CI 1.35 to 2.30, p<0.0001), increased cumulative time in LLDAS (p<0.0001) and higher likelihood of sustained LLDAS (p<0.001). Anifrolumab treatment was also associated with higher rates of Definition of Remission in SLE remission at week 52 (15.3% vs 7.6%; OR 2.2, 95% CI 1.4 to 3.6, p=0.0013). CONCLUSIONS: LLDAS attainment was highly associated with, but more stringent than, BICLA and SRI(4) responses. Compared with placebo, anifrolumab treatment was associated with earlier, more frequent, and more prolonged and sustained LLDAS. TRIAL REGISTRATION NUMBERS: NCT02446912 and NCT02446899.

Sustained glucocorticoid tapering in the phase 3 trials of anifrolumab: a post hoc analysis of the TULIP-1 and TULIP-2 trials.

OBJECTIVES: Glucocorticoid sparing is a key priority for SLE management. We evaluated the effects of sustained glucocorticoid tapering in patients with SLE. MATERIAL AND METHODS: This was a post hoc analysis of the randomized, placebo-controlled, 52-week phase 3 Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of anifrolumab (300 mg i.v. once every 4 weeks for 48 weeks) plus standard therapy in patients with moderate to severe SLE. In a cohort of patients receiving glucocorticoids (prednisone or equivalent) 10 mg or more per day at baseline, we assessed changes in glucocorticoid dosage, patient-reported outcomes (PROs) and safety. Outcome measures were compared between sustained glucocorticoid taper responders (7.5 mg or less per day by week 40 sustained through week 52) and non-responders, regardless of treatment group, and between patients receiving anifrolumab or placebo. RESULTS: Among the 726 patients in the TULIP trials, 375 patients received glucocorticoids 10 mg or more per day at baseline, and of these, 155 (41%) patients were sustained glucocorticoid taper responders. Compared with non-responders (n = 220), sustained glucocorticoid taper responders reduced their mean cumulative glucocorticoid dose by 32%, improved PRO scores, reduced blood pressure and experienced fewer serious adverse events. Sustained glucocorticoid tapering was achieved by 51% (96/190) of patients receiving anifrolumab vs 32% (59/185) receiving placebo. Compared with placebo, more anifrolumab-treated patients achieved both sustained glucocorticoid taper and reduced overall disease activity [38% (72/190) vs 23% (43/185)]. CONCLUSIONS: Sustained glucocorticoid tapering is associated with clinical benefits. Anifrolumab treatment has potential to reduce disease activity and glucocorticoid exposure, a key goal of SLE management. STUDY REGISTRATION: ClinicalTrials.gov identifier: NCT02446912 and NCT02446899.

The efficacy and safety of anifrolumab in Japanese patients with systemic lupus erythematosus: TULIP-2 subanalysis.

OBJECTIVES: Evaluate the efficacy and safety of anifrolumab in the subpopulation of Japanese patients with systemic lupus erythematosus (SLE) in phase 3 TULIP-2 trial. METHODS: TULIP-2 was a 52-week randomized placebo-controlled trial (N = 362) that evaluated efficacy and safety of anifrolumab 300 mg IV every 4 weeks vs. placebo in patients with moderate to severe SLE who were receiving standard therapy. We performed a post hoc analysis of the primary and key secondary endpoints, and safety, of TULIP-2 in the Japanese subpopulation. RESULTS: In the Japanese subpopulation (anifrolumab, n = 24; placebo, n = 19), the proportion of patients who achieved a British Isles Lupus Assessment Group-based Composite Lupus Assessment response at Week 52 (primary endpoint) was greater in the anifrolumab group vs. placebo [50.0% (12/24) vs. 15.8% (3/19); treatment difference: 34.2%, 95% confidence interval 6.9, 61.5; nominal p = .014]. Improvement in skin activity and flare rates (key secondary endpoints) were favourable for anifrolumab vs. placebo. Consistent with the overall population, anifrolumab had an acceptable safety and tolerability profile. CONCLUSIONS: The efficacy and safety of anifrolumab 300 mg in Japanese patients with SLE was consistent with the demonstrated clinical profile of anifrolumab for the overall TULIP-2 population.

Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials.

OBJECTIVES: In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results. METHODS: TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient. RESULTS: Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients. CONCLUSIONS: Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials. TRIAL REGISTRATION NUMBERS: NCT02446912 and NCT02446899.

Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials.

OBJECTIVES: To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups. METHODS: We 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. RESULTS: In 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. CONCLUSIONS: Overall, 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 NUMBER: NCT02446912, NCT02446899.

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.

Relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with systemic lupus erythematosus.

OBJECTIVES: To characterize the relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with moderate to severe SLE despite standard therapy, using pooled data from two phase 3 trials. METHODS: TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks). For the exposure-response analysis, BILAG-based Composite Lupus Assessment (BICLA) or SLE Responder Index [SRI(4)] response rates at week 52 in each quartile/tertile of average anifrolumab serum concentration (Cave) were compared for anifrolumab and placebo in all-comers, patients who completed treatment, and IFN gene signature (IFNGS)-high patients who completed treatment, using average marginal effect logistic regression. Relationships between exposure and key safety events were assessed graphically. RESULTS: Of patients in TULIP-1/TULIP-2 who received anifrolumab (150 mg, n = 91; 300 mg, n = 356) or placebo (n = 366), 574 completed treatment, of whom 470 were IFNGS high. In the exposure-efficacy analyses, BICLA and SRI(4) treatment differences favouring anifrolumab 300 mg vs placebo were observed across Cave subgroups and all analysis populations. Logistic regression identified Cave as a significant covariate for predicted BICLA response, as higher anifrolumab Cave predicted greater efficacy. There was no evidence of exposure-driven incidence of key safety events through week 52 in patients receiving anifrolumab 150 or 300 mg. CONCLUSION: While higher Cave predicted greater efficacy, consistent positive benefit favouring anifrolumab 300 mg vs placebo was observed in BICLA and SRI(4) responses across Cave subgroups in the TULIP trials. There was no evidence of exposure-driven safety events. CLINICALTRIAL.GOV NUMBERS: NCT02446912, NCT02446899.

Exposure-response analysis for selection of optimal dosage regimen of anifrolumab in patients with systemic lupus erythematosus.

OBJECTIVES: The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I IFN receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure-response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. METHODS: The exposure-response relationship, pharmacokinetics (PK) and SLE Responder Index (SRI(4)) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. RESULTS: The population PK model found that type I IFNGS-high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I IFN alpha receptor-mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. CONCLUSIONS: Based on PK, efficacy and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.

Anifrolumab reduces flare rates in patients with moderate to severe systemic lupus erythematosus.

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 identifiersTULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912);TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).

The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases.

Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway.

Anifrolumab, a monoclonal antibody to the type I interferon receptor subunit 1, for the treatment of systemic lupus erythematosus: an overview from clinical trials.

Chronic activation of the type I interferon (IFN) pathway plays a critical role in systemic lupus erythematosus (SLE) pathogenesis. Anifrolumab is a human monoclonal antibody to the type I IFN receptor subunit 1, which blocks the action of type I IFNs. Two phase 3 studies (TULIP-1 and TULIP-2) and a phase 2b study (MUSE) provide substantial evidence for the efficacy and safety of anifrolumab for moderately to severely active SLE. In all three studies, monthly intravenous anifrolumab 300 mg was associated with treatment differences >16% compared with placebo at Week 52 in British Isles Lupus Assessment Group-based Composite Lupus Assessment response rates. The combined data across a range of other clinically significant endpoints (e.g. oral corticosteroid reduction, improved skin disease, flare reduction) further support the efficacy of anifrolumab for SLE treatment. The safety profile of anifrolumab was generally similar across all studies; serious adverse events occurred in 8-16% and 16-19% of patients receiving anifrolumab and placebo, respectively. Herpes zoster incidence was greater with anifrolumab (≤7%) vs placebo (≤2%). Evidence from these clinical trials suggests that in patients with active SLE, anifrolumab is superior to placebo in achieving composite endpoints of disease activity response and oral corticosteroid reduction.

Safety and tolerability of anifrolumab, a monoclonal antibody targeting type I interferon receptor, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

Objectives: This study evaluated the safety and tolerability of anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, in Japanese patients with moderate-to-severe systemic lupus erythematosus (SLE).Methods: In this open-label, phase 2, dose-escalation study, patients received intravenous (IV) anifrolumab 100, 300, or 1000 mg every 4 weeks from days 29 to 337 (Stage 1). Patients who completed Stage 1 continued anifrolumab 300 mg every 4 weeks for 156 weeks (Stage 2). The primary objective was to evaluate the safety of anifrolumab for 48 weeks (Stage 1) and 156 weeks (Stage 2). The pharmacokinetics and pharmacodynamics of anifrolumab were also assessed.Results: Of 20 patients enrolled in Stage 1, 17 received IV anifrolumab 100 mg (n = 6), 300 mg (n = 5), or 1000 mg (n = 6). Adverse events (AE) and serious AE (SAE) incidences were similar between dose cohorts. SAEs occurred in 41% (Stage 1) and 33% (Stage 2) of patients; AEs leading to discontinuation occurred in 24% (Stage 1) and 22% (Stage 2) of patients. Anifrolumab had non-linear pharmacokinetics after the first and last dose and dose-dependently suppressed the IFN gene signature.Conclusion: Anifrolumab was well tolerated among Japanese patients with moderate-to-severe SLE.

Safety and tolerability of sifalimumab, an anti-interferon-α monoclonal antibody, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

Objectives: To evaluate the safety of sifalimumab in Japanese patients with systemic lupus erythematosus (SLE).Methods: This phase 2, open-label study consisted of a 52-week initial stage (Stage I) and a long-term extension (Stage II). In Stage I, sequential cohorts of patients received ascending doses of sifalimumab (intravenous [IV] 1.0, 3.0, and 10.0 mg/kg or subcutaneous 100 mg every 2 weeks; IV 600 and 1200 mg every 6 weeks). In Stage II, patients enrolled before June 2012 received the same dose of sifalimumab as during Stage I for up to 157 weeks or sifalimumab 600 mg IV every 4 weeks if they enrolled later. The safety of sifalimumab was assessed by adverse events (AEs).Results: Thirty patients enrolled in Stage I and 21 patients entered Stage II. The majority of patients experienced AEs (96.7% in Stage I and 100% in Stage II); most were mild or moderate in severity. Serious AEs occurred in 30.0% and 57.1% of patients in Stage I and II, respectively; most were instances of SLE flares. The proportion of patients in Stage I and II who had AEs leading to discontinuation was 10.0% and 28.6%, respectively.Conclusion: Sifalimumab was well tolerated in Japanese patients with SLE.

Lupus Low Disease Activity State (LLDAS) attainment discriminates responders in a systemic lupus erythematosus trial: post-hoc analysis of the Phase IIb MUSE trial of anifrolumab.

OBJECTIVES: In a post-hoc analysis, we aimed to validate the Lupus Low Disease Activity State (LLDAS) definition as an endpoint in an systemic lupus erythematosus (SLE) Phase IIb randomised controlled trial (RCT) (MUSE [NCT01438489]) and then utilize LLDAS to discriminate between anifrolumab and placebo. METHODS: Patients received intravenous placebo (n=102) or anifrolumab (300 mg, n=99; 1,000 mg, n=104) Q4W plus standard of care for 48 weeks. LLDAS attainment (SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician's Global Assessment ≤1, prednisolone ≤7.5 mg/d and standard immunosuppressant dosage tolerance) was assessed. Associations with endpoints and LLDAS attainment differences between treatments were explored. RESULTS: LLDAS attainment at Week 52 was associated with SLE Responder Index 4 (SRI[4]) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) (74/85[87%] and 62/84[74%] were also SRI[4] and BICLA responders, respectively; both nominal p<0.001). Only 74/159 (47%) of SRI(4) and 62/121 (51%) of BICLA responders reached LLDAS.Anifrolumab-treated patients achieved earlier LLDAS, and more spent at least half their observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34 to 6.92, nominal p=0.008; 1,000 mg: 2.17, 95% CI 0.93 to 5.03, nominal p=0.072) vs placebo-treated patients. At Week 52, 17/102 (17%), 39/99 (39%) and 29/104 (28%) of patients on placebo, anifrolumab 300 and 1,000 mg, respectively, attained LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73 to 6.76, p<0.001; 1,000 mg: 2.03, 95% CI 1.01 to 4.07, nominal p=0.046). CONCLUSIONS: LLDAS attainment represents a clinically meaningful SLE outcome measure, and anifrolumab is associated with more patients who met LLDAS criteria versus placebo. These data support LLDAS as an SLE RCT endpoint. TRIAL REGISTRATION NUMBER: NCT1438489; Post-results.

Treatment with Naloxegol Versus Placebo: Pain Assessment in Patients with Noncancer Pain and Opioid-Induced Constipation.

OBJECTIVE: To summarize results from pain and opioid use assessments with naloxegol in adults with opioid-induced constipation (OIC) and chronic noncancer pain. METHODS: Two phase 3 randomized, double-blind, 12-week studies evaluated the efficacy and safety of oral naloxegol (12.5 or 25 mg daily) in adults (18 to < 85 years) with confirmed OIC and chronic noncancer pain: KODIAC-04 (NCT01309841) and KODIAC-05 (NCT01323790). Pain level was assessed daily (11-point numeric rating scale [NRS]; 0 = no pain, 10 = worst imaginable pain). Changes from baseline in mean weekly pain scores and opioid dose (weeks 1 through 12) were analyzed using mixed-model repeated measures. RESULTS: At baseline, mean daily NRS average pain scores ranged from 4.5 to 4.8 for all groups in KODIAC-04 (N = 652) and were 4.6 for each group in KODIAC-05 (N = 700). Respective mean ± SD changes from baseline average pain for placebo, naloxegol 12.5 mg, and naloxegol 25 mg were -0.2 ± 1.07, -0.3 ± 1.05 (P = 0.773 vs. placebo), and 0.2 ± 0.95 (P = 0.837 vs. placebo; KODIAC-04) and -0.1 ± 0.94, -0.1 ± 0.87 (P = 0.744), and 0.0 ± 1.18 (P = 0.572; KODIAC-05). At baseline, mean daily opioid doses ranged from 135.6 to 143.2 morphine equivalent units (MEUs)/day in KODIAC-04, and from 119.9 to 151.7 MEUs/day in KODIAC-05. Respective mean ± SD changes from baseline dose were -1.8 ± 30.19, -2.3 ± 20.52 (P = 0.724 vs. placebo), and 0.4 ± 13.01 (P = 0.188 vs. placebo; KODIAC-04) and -0.3 ± 17.14, -1.3 ± 17.11 (P = 0.669 vs. placebo), and 0.1 ± 8.54 (P = 0.863 vs. placebo; KODIAC-05). Changes in maintenance opioid dose were few; reasons for such changes were similar across treatment groups. CONCLUSION: Centrally mediated opioid analgesia was maintained during treatment with naloxegol in patients with noncancer pain and OIC.

Safety and tolerability of dexmecamylamine (TC-5214) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to antidepressant therapy: results of a long-term study.

Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo-treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine.