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.
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.
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.
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.
The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method is constantly used to calculate the binding free energy of protein-ligand complexes, and has been shown to effectively balance ...computational cost against accuracy. The relative binding affinities obtained by the MM/PBSA approach are acceptable, while it usually overestimates the absolute binding free energy. This paper proposes four free energy estimators based on the MM/PBSA for enthalpy change combined with interaction entropy (IE) for entropy change using different weights for individual energy terms. The Δ
G
PBSA_IE
method is determined to be an optimal estimator based on its performance in terms of the correlation between experimental and theoretical values and error estimations. This approach is optimized using high-quality experimental values from a training set containing 84 protein-ligand systems, and the coefficients for the sum of electrostatic energy and polar solvation free energy, van der Waals (vdW) energy, non-polar solvation energy and entropy change are obtained by multivariate linear fitting to the corresponding experimental values. A comparison between the traditional MM/PBSA method and this method shows that the correlation coefficient is improved from 0.46 to 0.72 and the slope of the regression line increases from 0.10 to 1.00. More importantly, the mean absolute error (MAE) is significantly reduced from 22.52 to 1.59 kcal mol
−1
. Furthermore, the numerical stability of this method is validated on a test set with a similar correlation coefficient, slope and MAE to those of the training set. Based on the above advantages, the Δ
G
PBSA_IE
method can be a powerful tool for a reliable and accurate estimation of binding free energy and plays a significant role in a detailed energetic investigation of protein-ligand interaction.
Modifying the energy term and considering the entropic contribution by IE method significantly improve the accuracy of predicted binding free energy in MM/PBSA method.
Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding Human Genome Sciences and GlaxoSmithKline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity.
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.
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.
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.
Molecular dynamics (MD) simulations were performed employing the polarized protein-specific charge (PPC) to explore the origin of the cooperativity in streptavidin-biotin systems (wild type, two ...single mutations and one double-mutation). The results of the experiment found that the existence of cooperativity is mainly the result of the entropic effect. In this study, the entropic contribution to the binding free energy was calculated using the recently developed interaction entropy (IE) method, and computational results are in excellent agreement with the experimental observations and are further verified by the calculation of the thermodynamic integration. Comparison of different force fields in terms of predicted binding strength ordering, cooperativity of energy and the stability of hydrogen bonding suggests that the PPC force field combined IE method is a suitable choice. In addition, the IE method enables us to obtain the residue-specific entropic contributions to the streptavidin-biotin binding affinity and identify ten hot-spot residues providing the dominant contribution to the cooperative binding. Importantly, the overall cooperativity obtained from the ten residues also comes mainly from the entropic effect in our study. The calculation of the potential of mean force shows that the unbinding of streptavidin-biotin is a multi-step process, and each step corresponds to the formation and rupture of the hydrogen bond network. And S45A mutation may increase the rigidity of the linker region, making the flap region relatively difficult to open. The present study provides significant molecular insight into the binding cooperativity of the streptavidin-biotin complex.
Molecular dynamics (MD) simulations were performed employing the polarized protein-specific charge (PPC) to explore the origin of the cooperativity in streptavidin-biotin systems (wild type, two single mutations and one double-mutation).
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.
...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.
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.
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.
NCT00424476, NCT00410384.
The borrowing of historical control data can be an efficient way to improve the treatment effect estimate of the current control group in a randomized clinical trial. When the historical and current ...control data are consistent, the borrowing of historical data can increase power and reduce Type I error rate. However, when these 2 sources of data are inconsistent, it may result in a combination of biased estimates, reduced power, and inflation of Type I error rate. In some situations, inconsistency between historical and current control data may be caused by a systematic variation in the measured baseline prognostic factors, which can be appropriately addressed through statistical modeling. In this paper, we propose a Bayesian hierarchical model that can incorporate patient‐level baseline covariates to enhance the appropriateness of the exchangeability assumption between current and historical control data. The performance of the proposed method is shown through simulation studies, and its application to a clinical trial design for amyotrophic lateral sclerosis is described. The proposed method is developed for scenarios involving multiple imbalanced prognostic factors and thus has meaningful implications for clinical trials evaluating new treatments for heterogeneous diseases such as amyotrophic lateral sclerosis.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing).
Patients (n ...= 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study.
Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%-9% during years 2-7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%-60% from baseline over 2-7 years with belimumab. Corticosteroid use decreased over time with ≥ 50-55% reduction in median dose during years 5-7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment.
Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. ClinicalTrials.gov numbers: NCT00071487 and NCT00583362.
At present, the calculated binding free energy obtained using the molecular mechanics/Poisson-Boltzmann (Generalized-Born) surface area (MM/PB(GB)SA) method is overestimated due to the lack of ...knowledge of suitable interior dielectric constants in the simulation on the interaction of Human Immunodeficiency Virus (HIV-1) protease systems with inhibitors. Therefore, the impact of different values of the interior dielectric constant and the entropic contribution when using the MM/PB(GB)SA method to calculate the binding free energy was systemically evaluated. Our results show that the use of higher interior dielectric constants (1.4–2.0) can clearly improve the predictive accuracy of the MM/PBSA and MM/GBSA methods, and computational errors are significantly reduced by including the effects of electronic polarization and using a new highly efficient interaction entropy (IE) method to calculate the entropic contribution. The suitable range for the interior dielectric constant is 1.4–1.6 for the MM/PBSA method; within this range, the correlation coefficient fluctuates around 0.84, and the mean absolute error fluctuates around 2 kcal/mol. Similarly, an interior dielectric constant of 1.8–2.0 produces a correlation coefficient of approximately 0.76 when using the MM/GBSA method. In addition, the entropic contribution of each individual residue was further calculated using the IE method to predict hot-spot residues, and the detailed binding mechanisms underlying the interactions of the HIV-1 protease, its inhibitors, and bridging water molecules were investigated. In this study, the use of a higher interior dielectric constant and the IE method can improve the calculation accuracy of the HIV-1 system.
Abstract
Electrocatalytic CO
2
reduction into value-added multicarbon products offers a means to close the anthropogenic carbon cycle using renewable electricity. However, the unsatisfactory ...catalytic selectivity for multicarbon products severely hinders the practical application of this technology. In this paper, we report a cascade AgCu single-atom and nanoparticle electrocatalyst, in which Ag nanoparticles produce CO and AgCu single-atom alloys promote C-C coupling kinetics. As a result, a Faradaic efficiency (FE) of 94 ± 4% toward multicarbon products is achieved with the as-prepared AgCu single-atom and nanoparticle catalyst under ~720 mA cm
−2
working current density at −0.65 V in a flow cell with alkaline electrolyte. Density functional theory calculations further demonstrate that the high multicarbon product selectivity results from cooperation between AgCu single-atom alloys and Ag nanoparticles, wherein the Ag single-atom doping of Cu nanoparticles increases the adsorption energy of *CO on Cu sites due to the asymmetric bonding of the Cu atom to the adjacent Ag atom with a compressive strain.
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