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Objectives To identify factors that predict response to belimumab treatment in the phase 3 BLISS trials of autoantibody-positive systemic lupus erythematosus (SLE) and further analyse clinical efficacy in various patient subsets. Methods The BLISS trials compared belimumab 1 and 10 mg/kg versus placebo, all plus standard SLE therapy, over 52 or 76 weeks. Pooled subgroup analyses of week 52 SLE responder index rates (the primary endpoint in both trials) were performed based on demographic characteristics and baseline disease activity indicators. Pooled multivariate analysis was performed to determine predictors of response and treatment effect. Results Pooled univariate and multivariate analyses (N=1684) identified baseline factors associated with an increased benefit of belimumab versus placebo. These factors included the Safety Of Estrogens In Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) ≥10, low complement, anti-dsDNA positivity and corticosteroid use. Efficacy outcomes were assessed in the low complement/anti-dsDNA-positive and SELENA–SLEDAI ≥10 subgroups. Week 52 SLE Responder Index rates in the low complement/anti-dsDNA-positive subgroup were 31.7%, 41.5% (p=0.002) and 51.5% (p<0.001) with placebo and belimumab 1 mg/kg and 10 mg/kg, respectively; corresponding rates in the SELENA–SLEDAI ≥10 subgroup were 44.3%, 58.0% (p<0.001) and 63.2% (p<0.001). Further analysis of secondary endpoints in the low complement/anti-dsDNA-positive subgroup showed that compared with placebo, belimumab produced greater benefits regarding severe flares, corticosteroid use and health-related quality of life. Conclusions These findings suggest that belimumab has greater therapeutic benefit than standard therapy alone in patients with higher disease activity, anti-dsDNA positivity, low complement or corticosteroid treatment at baseline. ClinicalTrials.gov identifiers NCT00424476 and NCT00410384

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Safety data were pooled and analyzed from one phase 2 and two phase 3 double-blind, placebo-controlled, repeat-dose systemic lupus erythematosus (SLE) trials of belimumab 1, 4 (phase 2 only), and 10 mg/kg. Types and rates of adverse events (AEs) were similar across treatment groups. Rates of patients experiencing any serious AE were 16.6%, 19.5%, 13.5%, and 18.0% with placebo, and belimumab 1, 4, and 10 mg/kg, respectively; rates of serious infusion reactions (including hypersensitivity reactions) occurring on the same days as infusions were 0.4%, 0.9%, 0%, and 0.9%, and rates of serious infections were 5.5%, 7.1%, 6.3%, and 5.3%. Malignancy rates/100 patient-years (excluding non-melanoma skin cancer) were 0.29 with placebo vs. 0.20 with all belimumab doses combined; mortality rates/100 patient-years were 0.43 vs. 0.73. These data support the conclusion that belimumab in combination with standard SLE therapy was generally well tolerated in a predominantly autoantibody-positive population with active SLE. ClinicalTrials.gov identifiers: LBSL02: NCT00071487; BLISS-52: NCT00424476; BLISS-76: NCT00410384.

Objective To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. Methods Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) organ domain scores. Results At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA–SLEDAI, and immunological by SELENA–SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA–SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (≤16%) at baseline, including the SELENA–SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA–SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. Conclusions Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.

Systemic lupus erythematosus is a heterogeneous autoimmune disease that is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of B-lymphocyte stimulator (BLyS). The efficacy and safety of the fully human monoclonal antibody belimumab (BLyS-specific inhibitor) was assessed in patients with active systemic lupus erythematosus. Patients (aged ≥18 years) who were seropositive with scores of at least 6 on the Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) were enrolled in a multicentre phase 3 study, which was done in Latin America, Asia-Pacific, and eastern Europe. Patients were randomly assigned by use of a central interactive voice response system in a 1:1:1 ratio to belimumab 1 mg/kg or 10 mg/kg, or placebo by intravenous infusion in 1 h on days 0, 14, and 28, and then every 28 days until 48 weeks, with standard of care. Patients, investigators, study coordinators, and sponsors were masked to treatment assignment. Primary efficacy endpoint was improvement in the Systemic Lupus Erythematosus Responder Index (SRI) at week 52 (reduction ≥4 points in SELENA-SLEDAI score; no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new B organ domain score; and no worsening [<0·3 increase] in Physician's Global Assessment [PGA] score) versus baseline. Method of analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00424476. 867 patients were randomly assigned to belimumab 1 mg/kg (n=289) or 10 mg/kg (n=290), or placebo (n=288). 865 were treated and analysed in the belimumab (1 mg/kg, n=288; 10 mg/kg, n=290) and placebo groups (n=287). Significantly higher SRI rates were noted with belimumab 1 mg/kg (148 [51%], odds ratio 1·55 [95% CI 1·10–2·19]; p=0·0129) and 10 mg/kg (167 [58%], 1·83 [1·30–2·59]; p=0·0006) than with placebo (125 [44%]) at week 52. More patients had their SELENA-SLEDAI score reduced by at least 4 points during 52 weeks with belimumab 1 mg/kg (153 [53%], 1·51 [1·07–2·14]; p=0·0189) and 10 mg/kg (169 [58%], 1·71 [1·21–2·41]; p=0·0024) than with placebo (132 [46%]). More patients given belimumab 1 mg/kg (226 [78%], 1·38 [0·93–2·04]; p=0·1064) and 10 mg/kg (236 [81%], 1·62 [1·09–2·42]; p=0·0181) had no new BILAG A or no more than 1 new B flare than did those in the placebo group (210 [73%]). No worsening in PGA score was noted in more patients with belimumab 1 mg/kg (227 [79%], 1·68 [1·15–2·47]; p=0·0078) and 10 mg/kg (231 [80%], 1·74 [1·18–2·55]; p=0·0048) than with placebo (199 [69%]). Rates of adverse events were similar in the groups given belimumab 1 mg/kg and 10 mg/kg, and placebo: serious infection was reported in 22 (8%), 13 (4%), and 17 (6%) patients, respectively, and severe or serious hypersensitivity reactions on an infusion day were reported in two (<1%), two (<1%), and no patients, respectively. No malignant diseases were reported. Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease. Human Genome Sciences and GlaxoSmithKline.

Objective Assess the effects of belimumab treatment plus standard systemic lupus erythematosus (SLE) therapy on health-related quality of life (HRQOL) in patients with active, autoantibody-positive SLE. Methods Patients received standard therapy plus placebo or belimumab 1 or 10 mg/kg in two multicentre, randomised controlled trials of 52 (BLISS-52; N=865) and 76 (BLISS-76; N=819) weeks’ duration. Responders were evaluated by SLE Responder Index at week 52. Patient-reported outcome assessments included SF-36, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, and EQ-5D. Results Mean SF-36 Physical Component Summary (PCS) scores at week 24 was a major secondary endpoint. Baseline SF-36 scores were 1.5 SDs below age-/sex-matched US norms with similar improvement at week 24 across treatment groups. Mean changes from baseline in PCS scores were significantly (p<0.05) greater with belimumab 1 mg/kg (4.20) and 10 mg/kg (4.18) versus placebo (2.96) in BLISS-52, week 52. In BLISS-76, significantly (p<0.05) greater improvements were seen with belimumab 1 mg/kg in PCS (belimumab 1 mg/kg=4.37, 10 mg/kg=3.41 vs placebo=2.85) and Mental Component Summary (MCS) scores (belimumab 1 mg/kg=3.14, 10 mg/kg=2.70 vs placebo=1.40) at week 52, and in MCS score at week 76 (belimumab 1 mg/kg=3.05, 10 mg/kg=2.28 vs placebo=1.36). In pooled analysis, significantly greater improvements in PCS, SF-36 vitality domain, and FACIT-Fatigue scores at week 52 were evident with both belimumab doses. Conclusions The clinically meaningful improvements in HRQOL in autoantibody-positive patients with active SLE treated with belimumab and standard therapy are consistent with the reductions in disease activity observed in these trials. ClinicalTrials.gov number NCT00424476, NCT00410384.

Objective Correlates of systemic lupus erythematosus (SLE) Responder Index (SRI) response with clinical trial end points were examined using pooled data from the Study of Belimumab in Subjects with SLE (BLISS) trials (N=1684). Methods Changes in clinical, laboratory and health-related quality of life measures from baseline at 52 weeks were compared between SRI responders (n=761) and non-responders (n=923). Results More SRI responders than non-responders had ≥4-point (100% vs 3.8%) and ≥7-point (40.3% vs 1.3%) Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index reductions, no new British Isles Lupus Assessment Group (BILAG) A and ≤1 new B scores (91.9% vs 35.9%), and a 25% reduction in corticosteroid dose decrease of 25% from >7.5 mg/d to ≤7.5 mg/d (25.5% vs 13.9%), and fewer had a corticosteroid increase from ≤7.5 mg/d to >7.5 mg/d (4.1% vs 21.3%; all p<0.001). More responders than non-responders had improved organ domains: Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (mean 1.45 vs 0.40), BILAG (2.00 vs 0.39), and greater improvement in Physician's Global Assessment (all p<0.001). Risks for developing any SLE flare or severe flare were reduced in responders by 42% and 87%, respectively (p<0.001). Responders reported greater improvements in Medical Outcomes Survey Short Form version 2 Physical and Mental Components and all domain scores, and Functional Assessment of Chronic Illness Therapy-Fatigue score compared with non-responders (all p<0.001). Conclusion Overall, SRI response in patients with active, autoantibody-positive SLE was associated with improvements in clinical, laboratory and patient-reported outcome measures, indicating that SRI response was associated with a global benefit. Trial registration number NCT00424476; NCT00410384.

Hepatitis B virus (HBV) is a global health concern that can cause acute and chronic liver diseases. Thus, there is an urgent need to research novel anti-HBV agents. Our previous reports show that -phenylbenzamide derivatives exert broad-spectrum antiviral effects against HIV-1, HCV, and EV71 by increasing intracellular levels of APOBEC3G (A3G). As A3G is capable of inhibiting the replication of HBV, we screened the -phenylbenzamide derivatives against HBV. In this study, a new derivative, -(4-chlorophenyl)-4-methoxy-3-(methylamino) benzamide (IMB-0523), was synthesized and its anti-HBV activity was evaluated in vitro and in vivo. The acute toxicity and pharmacokinetic profiles of IMB-0523 were also investigated. Our results show that IMB-0523 has higher anti-HBV activity in both wild-type HBV (IC : 1.99 µM) and drug-resistant HBV (IC : 3.30 µM) than lamivudine (3TC, IC : 7.37 µM in wild-type HBV, IC : >440 µM in drug-resistant HBV). The antiviral effect of IMB-0523 against HBV may be due to an increased level of intracellular A3G. IMB-0523 also showed low acute toxicity (LD : 448 mg/kg) in mice and promising PK properties (AUC : 7535.10±2226.73 µg·h/L) in rats. Further, IMB-0523 showed potent anti-HBV activity in DHBV-infected ducks. Thus, IMB-0523 may be a potential anti-HBV agent with different mechanisms than current anti-HBV treatment options.

Toltrazuril (Tol) is used to prevent and combat coccidiosis. However, its low aqueous solubility and poor oral bioavailability limit clinical application. To overcome the shortcomings, toltrazuril-hydroxypropyl-β-cyclodextrin inclusion complex (Tol-HP-β-CD) was prepared and characterized. The comparative plasma disposition kinetics of Tol was analyzed after a single orally administered dose of 10 mg/kg Tol or Tol-HP-β-CD in rabbits. Solution-stirring method was selected to prepare the inclusion complex. Complex formation was characterized by thin-layer chromatography, Fourier transform infrared spectrophotometry, and H nuclear magnetic resonance spectroscopy. In plasma profile, plasma samples were collected between 1 and 10 days following administration. Plasma Tol concentrations were determined by high-performance liquid chromatography. In rabbit plasma, the time to peak concentration ( ) of Tol-HP-β-CD was shorter than that of Tol (12 h vs 24 h). (19.92±1.02 μg/mL) and area under the concentration-time curve (AUC0-∞, 1,176.86±70.26 mg/L h) of the Tol-HP-β-CD group significantly increased ( ,0.01) than those of the Tol group ( , 8.02±1.04 μg/mL; AUC0-∞, 514.03±66.65 mg/L h). It can be concluded that the Tol-HP-β-CD increased the aqueous solubility and enhanced the oral bioavailability in rabbits. Complexation with HP-β-CD is a feasible way to prepare a rapidly absorbed and more bioavailable Tol oral product.

Background Identification and validation of potential serologic biomarkers of clinically meaningful SLE flare are major unmet medical needs in clinical practice and trials. Objectives To examine biomarker predictors of SLE flares at baseline in the combined placebo groups from the belimumab BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) phase 3 trials. Methods The BLISS trials enrolled patients with active SLE (SELENA SLEDAI ≥6) who were autoantibody positive (antinuclear antibody [ANA] or anti-double-stranded DNA [anti-dsDNA]), on stable standard therapy for 30 d, and without severe active lupus nephritis or CNS SLE. Patients were randomized to placebo, or belimumab 1 or 10 mg/kg, plus standard therapy. Changes in prednisone were allowed early in the trials, but had to be within 25% or 5 mg of baseline dose. Flare (moderate-severe) was defined as 1 new BILAG A or 2 new B scores, or by modified SLE Flare Index (SFI). Laboratory biomarkers evaluated included ANA, anti-dsDNA, anti-Smith, complement (C) 3, C4, C-reactive protein (CRP), proteinuria >0.5 g/24 h, immunoglobulin, B- and T-cell subsets, and B-lymphocyte stimulator (BLyS) quartile levels. The proportion of placebo patients with abnormal tests who developed a new flare was compared with the proportion without a flare. Meaningful difference was defined as: ≥10% absolute difference (% flare - % no flare) or nominal p values for pairwise comparison (likelihood ratio test); and ≥50% increase ([% flare - % no flare]/% no flare). Results By wk 24 in the placebo group (n=562), 25.3% of patients (n=142) had a flare by BILAG and 12.8% (n=72) by SFI. Predictors of wk-24 flare (% with vs without flare) are shown in the table. Table 1. Univariate Analysis of Predictors of 24-Wk Flare % BILAG A/2B Flare% SFI Severe Flare WithWithoutWithWithout (n=142)(n=420)(n=72)(n=490) Low C359.2#39.066.7#40.8 Low C464.8+50.263.952.4 CRP47.1+34.451.4*35.6 Proteinuria >0.5g/24 h33.1#17.143.1#17.9 Positive anti-dsDNA (>200 IU/mL)47.9#28.359.7#29.4 Positive anti-Smith39.0*28.446.5+28.9 BLyS ≥2 ng/mL36.4#21.354.2#20.7 #p<0.001; +p<0.01; *p<0.05. Conclusions SLE patients on standard therapy with low C3/4, positive CRP, proteinuria >0.5 g/24 h, positive anti-dsDNA or anti-Smith, or BLyS ≥2 ng/mL were at increased risk for SLE flare over 24 wk. Flare definitions (BILAG and SFI) had high concordance regarding predictors; univariate risk factors were the same for both definitions at 24 wk. Study limitations: laboratory tests were defined as categorical variables (present/absent) and time-varying nature of the characteristics over the 24 wk was not examined. The data suggest serologic tests predict clinically meaningful flare over 24 wk, and may be useful in the identification of patients at greater risk for flares in clinical practice and trials. Disclosure of Interest M. Petri Consultant for: GlaxoSmithKline/Human Genome Sciences, R. van Vollenhoven Grant/Research support from: GlaxoSmithKline/Human Genome Sciences, R. Levy Speakers Bureau: GlaxoSmithKline/Human Genome Sciences, S. Navarra Speakers Bureau: GlaxoSmithKline/Human Genome Sciences, R. Cervera Grant/Research support from: GlaxoSmithKline/Human Genome Sciences, Consultant for: GlaxoSmithKline/Human Genome Sciences, Z. Zhong Shareholder of: Human Genome Sciences, Employee of: Human Genome Sciences, W. Freimuth Shareholder of: Human Genome Sciences, Employee of: Human Genome Sciences, J. Buyon Grant/Research support from: Human Genome Sciences, Consultant for: GlaxoSmithKline/Human Genome Sciences