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Remission is the established therapeutic goal for patients with systemic lupus erythematosus (SLE) and is currently defined by the widely adopted Definition Of Remission In SLE (DORIS) criteria. Attainment of remission is rare in the clinical setting, thus an alternative, pragmatic treatment target of low disease activity, as defined by the Lupus Low Disease Activity State (LLDAS), provides a less stringent and more attainable treatment goal for a wider proportion of patients compared with DORIS remission. Randomized controlled trials and real-world analyses have confirmed the positive clinical benefits of achieving either DORIS remission or LLDAS. The treat-to-target (T2T) approach utilizes practical clinical targets to proactively tailor individual treatment regimens. Studies in other chronic inflammatory diseases using the T2T approach demonstrated significantly improved clinical outcomes and quality-of-life measures compared with established standard of care. However, such trials have not yet been performed in patients with SLE. Here we review the evolution of DORIS remission and LLDAS definitions and the evidence supporting the positive clinical outcomes following DORIS remission or LLDAS attainment, before discussing considerations for implementation of these outcome measures as potential T2T objectives. Adoption of DORIS remission and LLDAS treatment goals may result in favorable patient outcomes compared with established standard of care for patients with SLE. Plain Language Summary: Systemic lupus erythematosus (SLE) is a complex disease that can affect many organs. It can lead to life-threatening complications and poor quality of life. As SLE is very different in each person, it can be challenging to measure disease activity. Doctors are encouraged to set clinical targets to tailor treatment for each patient. Clinical targets include scoring systems that measure disease improvement. Remission is an established clinical target. When a patient is in remission, disease activity is controlled, and the patient does not experience any symptoms. As remission is difficult to achieve, experts developed a more realistic yet still favorable state. This is the lupus low disease activity state, when lupus symptoms are minimal on stable therapy. Doctors use remission and low disease activity in clinical trials to compare existing SLE drugs with new treatments, including biologic drugs. Biologics target key parts of the immune system to help suppress SLE. In this review, we looked at recent clinical trials and found that biologic drugs can help patients achieve remission or low disease activity. Patients who achieved these clinical targets had slower disease progression and improved quality of life. Clinical trials in SLE should continue to use remission and low disease activity targets to help compare treatments. Doctors are encouraged to use them in their routine clinics as treatment targets to measure SLE disease control. Low disease activity state may be particularly helpful as an initial target for patients who are not yet in remission. [ABSTRACT FROM AUTHOR]

The type I interferon (IFN) signaling pathway is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Anifrolumab is a monoclonal antibody that targets the type I IFN receptor subunit 1. Anifrolumab is approved in several countries for patients with moderate to severe SLE receiving standard therapy. The approved dosing regimen of anifrolumab is a 300-mg dose administered intravenously every 4 weeks; this was initially based on the results of the Phase 2b MUSE and further confirmed in the Phase 3 TULIP-1 and TULIP-2 trials, in which anifrolumab 300-mg treatment was associated with clinically meaningful improvements in disease activity with an acceptable safety profile. There have been several published analyses of the pharmacokinetic and pharmacodynamic profile of anifrolumab, including a population–pharmacokinetic analysis of 5 clinical studies of healthy volunteers and patients with SLE, in which body weight and type I IFN gene expression were significant covariates identified for anifrolumab exposure and clearance. Additionally, the pooled Phase 3 SLE population has been used to evaluate how serum exposure may be related to clinical responses, safety risks, and pharmacodynamic effects of the 21-gene type I IFN gene signature (21-IFNGS). The relevance of 21-IFNGS with regard to clinical efficacy outcomes has also been analyzed. Herein, the clinical pharmacokinetics, pharmacodynamics, and immunogenicity of anifrolumab as well as results of population–pharmacokinetics and exposure–response analyses are reviewed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the pharmacokinetic/pharmacodynamic and pharmacodynamic/efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate to severe systemic lupus erythematosus. Data were pooled from the randomized, 52‐week, placebo‐controlled TULIP‐1 and TULIP‐2 trials of intravenous anifrolumab (150 mg/300 mg, every 4 weeks for 48 weeks). Pharmacodynamic neutralization was measured with a 21‐gene type I interferon gene signature (21‐IFNGS) in patients with high IFNGS. The pharmacokinetic/pharmacodynamic relationship was analyzed graphically and modeled with a nonlinear mixed‐effects model. British Isles Lupus Assessment Group–based Composite Lupus Assessment (BICLA) response rates were compared across 21‐IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 were IFNGS high. Over 52 weeks, higher average anifrolumab serum concentrations were associated with increased median 21‐IFNGS neutralization, which was rapid and sustained with anifrolumab 300 mg (>80%, weeks 12‐52), lower and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. The proportion of patients with week 24 anifrolumab trough concentration exceeding the IC80 (3.88 μg/mL) was greater with anifrolumab 300 mg vs anifrolumab 150 mg (≈83% vs ≈27%), owing to the higher estimated median trough concentration (15.6 vs 0.2 μg/mL). BICLA response rates increased with 21‐IFNGS neutralization; more patients had a BICLA response in the highest vs lowest neutralization quartiles at week 52 (58.1% vs 37.6%). In conclusion, anifrolumab 300 mg every 4 weeks rapidly, substantially, and sustainably neutralized the 21‐IFNGS and was associated with clinical efficacy, supporting this dosing regimen in patients with systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

We characterized the population pharmacokinetics of anifrolumab, a type I interferon receptor–blocking antibody. Pharmacokinetic data were analyzed from the anifrolumab (intravenous [IV], every 4 weeks) arms from 5 clinical trials in patients with systemic lupus erythematosus (SLE) (n = 664) and healthy volunteers (n = 6). Population pharmacokinetic modeling was performed using a 2‐compartment model with parallel linear and nonlinear elimination pathways. The impact of covariates (demographics, interferon gene signature [IFNGS, high/low], disease characteristics, renal/hepatic function, SLE medications, and antidrug antibodies) on pharmacokinetics was evaluated. Time‐varying clearance (CL) was characterized using an empirical sigmoidal time‐dependent function. Anifrolumab exposure increased more than dose‐proportionally from 100 to 1000 mg IV every 4 weeks. Based on population pharmacokinetics modeling, the baseline median linear CL was 0.193 L/day in IFNGS‐high patients and 0.153 L/day in IFNGS‐low/healthy volunteers. After a year, median anifrolumab linear CL decreased by 8.4% from baseline. Body weight and IFNGS were significant pharmacokinetic covariates, whereas age, sex, race, disease activity, SLE medications, and presence of antidrug antibodies had no significant effect on anifrolumab pharmacokinetics. Anifrolumab at a concentration of 300 mg IV every 4 weeks was predicted to be below the lower limit of quantitation in 95% of patients ≈10 weeks after a single dose and ≈16 weeks after stopping dosing at steady state. To conclude, anifrolumab exhibited nonlinear pharmacokinetics and time‐varying linear CL; doses ≥300 mg IV every 4 weeks provided sustained anifrolumab concentrations. This study provides further evidence to support the use of anifrolumab 300 mg IV every 4 weeks in patients with moderate to severe SLE. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: 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. To understand the relevance of BICLA in clinical practice, we investigated relationships between BICLA response and routine SLE assessments, patient‐reported outcomes (PROs), and medical resource utilization. Methods: This was a post hoc analysis of pooled data from the phase III, randomized, placebo‐controlled, 52‐week TULIP‐1 (ClinicalTrials.gov identifier: NCT02446912; n = 457) and TULIP‐2 (ClinicalTrials.gov identifier: NCT02446899; n = 362) trials of intravenous anifrolumab (150/300 mg once every 4 weeks) in patients with moderate‐to‐severe SLE. Changes from baseline to week 52 in clinical assessments, PROs, and medical resource use were compared in BICLA responders versus nonresponders, regardless of treatment assignment. Results: BICLA responders (n = 318) achieved significantly improved outcomes compared with nonresponders (n = 501), including lower flare rates, higher rates of attainment of sustained oral glucocorticoid taper to ≤7.5 mg/day, greater improvements in PROs (Functional Assessment of Chronic Illness Therapy–Fatigue, Short Form 36 Health Survey), and fewer SLE‐related hospitalizations/emergency department visits (all nominal P < 0.001). Compared with nonresponders, BICLA responders had greater improvements in global and organ‐specific disease activity (Physician's Global Assessment, SLE Disease Activity Index 2000, Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity, and joint counts; all nominal P < 0.001). BICLA responders had fewer lupus‐related serious adverse events than nonresponders. Conclusion: BICLA response is associated with clinical benefit in SLE assessments, PROs, and medical resource utilization, confirming its value as a clinical trial end point that is associated with measures important to patient care. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

geting 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) anifrolu- mab 100, 300, or 1000mg every 4 weeks from days 29 to 337 (Stage 1). Patients who completed Stage 1 continued anifrolumab 300mg 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 100mg (n = 6), 300mg (n = 5), or 1000mg (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 discontinu- ation occurred in 24% (Stage 1) and 22% (Stage 2) of patients. Anifrolumab had non-linear pharmaco- kinetics 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. [ABSTRACT FROM AUTHOR]

Background: Naloxegol is a novel selective, peripherally acting μ-opioid receptor antagonist for treating opioid-induced constipation (OIC) in patients with chronic pain syndromes. We analyzed the cardiovascular (CV) safety of naloxegol based on data from its development program prior to approval by the US Food and Drug Administration in 2015.Methods: Comprehensive CV safety analyses were performed in 4 clinical studies of naloxegol (12.5 and/or 25 mg) in patients with noncancer pain and OIC: two 12-week, double-blind, randomized studies; a 12-week, double-blind, extension study; and a 52-week, randomized, open-label study versus usual care. Evaluations of baseline CV risk were obtained from medical histories and clinical findings at the time of study initiation.Results: Across the 4 studies (N = 2135), 68% of patients had ≥1 CV risk factor and 41% had a history of CV disease, diabetes, or ≥2 other CV risk factors. There were no increases in blood pressure, heart rate, or the rate-pressure product with naloxegol versus placebo. The rates of major adverse cardiovascular events (MACE) per 100 patient-years of exposure were 1.13 (95% confidence interval [CI], 0.31-2.89) for placebo/usual care and 0.75 (95% CI, 0.24-1.75) for naloxegol. The relative risk of MACE for all doses of naloxegol versus placebo was 0.67 (95% CI, 0.14-3.36).Conclusion: These data demonstrate that naloxegol has a CV safety profile comparable to placebo/usual care in patients with OIC. Although the observed number of events was low, the data show no CV signal in patients with OIC treated with naloxegol. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment. Methods. Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout. Results. Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth. Conclusions. TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.). [ABSTRACT FROM AUTHOR]