Matching design for augmenting the control arm of a randomized controlled trial using real-world data.

Randomized clinical trials (RCTs) have often been considered as the gold standard in drug development, but they may not be fully powered due to limited patient population and can even lead to ethical concerns in rare disease studies. In situations like this, real-world data (RWD)/historical data can be utilized to augment or possibly serve as the control arm for the current trial. If a subset of subjects from the RWD/historical trial could be matched to the concurrent control arm subjects and they are deemed comparable following certain criteria, then pooling the matched subjects from the historical control arm and the concurrent control arm can boost the power. In this paper, we propose two matching methods of borrowing historical control data that not only balance key observed baseline covariates but also ensure the comparability of responses between the historical and concurrent controls. Close similarity in response variables among controls reduces Type I error inflation and provides further protection against unmeasured confounding bias, which is a major challenge in using RWD. Simulation studies are conducted to evaluate the empirical performance of the two matching methods in terms of Type I error rate and power, and an illustrative description of a planned study is presented.

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.

BACKGROUND: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODS: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTS: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).

Improvements in health-related quality of life with belimumab, a B-lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomised controlled BLISS trials.

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. CLINICALTRIALSGOV NUMBER: NCT00424476, NCT00410384.

Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the phase III belimumab trials.

OBJECTIVE: To identify predictors of moderate-to-severe systemic lupus erythematosus (SLE) flare in 562 patients treated with standard therapy alone in phase III belimumab trials, and to evaluate the impact of standard therapies on preventing flares. METHODS: Post hoc analysis assessed baseline demographics, disease activity, and biomarkers in patients with and those without flare at treatment weeks 24 and 52. Severe flare was defined by the modified SLE Flare Index (SFI) and the development of any new British Isles Lupus Assessment Group (BILAG) A domain score. Severe and moderate flare was defined by development of 1 new BILAG A domain score or 2 new BILAG B domain scores. Baseline characteristics associated with a ≥10% absolute difference or a ≥50% increase in flare rates were considered predictive. RESULTS: Frequencies of flares over 52 weeks according to the SFI, any new BILAG A domain score, and 1 new BILAG A domain score or 2 new BILAG B domain scores were 23.7%, 23.1%, and 32.0%, respectively. Flare predictors by univariate analysis on all 3 indices at weeks 24 and 52 were a score ≥12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI); anti-double-stranded DNA (anti-dsDNA) positivity; proteinuria (≥0.5 gm/24 hours); BILAG renal, vasculitic, and hematologic scores; elevated C-reactive protein levels; and B lymphocyte stimulator (BLyS) levels ≥2 ng/ml. Independent predictors by multivariate analysis at week 52 were SELENA-SLEDAI and/or BILAG renal involvement and anti-dsDNA ≥200 IU/ml (on all 3 indices); SELENA-SLEDAI and/or BILAG neurologic and vasculitic involvement (on 2 indices: any new BILAG A domain score and 1 new BILAG A domain score or 2 new BILAG B domain scores); BLyS levels ≥2 ng/ml (on 2 indices: the SFI and 1 new BILAG A domain score or 2 new BILAG B domain scores); and low C3 level (on the SFI). Baseline medications did not significantly decrease or increase moderate-to-severe SLE flare risk. CONCLUSION: Patients who were receiving standard SLE therapy and had renal, neurologic, or vasculitic involvement, elevated anti-dsDNA or BLyS levels, or low C3 had increased risk of clinically meaningful flare over 1 year. Hydroxychloroquine use was not predictive.

Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the safety profile of long-term belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease. METHODS: Patients who were randomized to receive intravenous placebo or belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52-week double-blind treatment period were then allowed to enter a 24-week open-label extension phase. During the extension period, patients in the belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24-week extension period were allowed to participate in the long-term continuation study of monthly belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient-years in 1-year intervals. RESULTS: Of the 364 patients who completed the 52-week double-blind treatment period, 345 entered the 24-week extension, and 296 continued treatment with belimumab in the long-term continuation study. Safety data through 4 years of belimumab exposure (1,165 cumulative patient-years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4-year belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year followup period. Rates of serious infection decreased from 5.9/100 patient-years to 3.4/100 patient-years, and no specific type of infection predominated. CONCLUSION: Belimumab added to standard therapy was generally well-tolerated over the 4-year treatment period in patients with SLE, which suggests that belimumab can be administered long term with an acceptable safety profile.

Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus.

OBJECTIVE: To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients. METHODS: Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels. RESULTS: Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks. CONCLUSION: Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.

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.

Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response.

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.

Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials.

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.

A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.

OBJECTIVE: To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE). METHODS: In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline). RESULTS: Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. CONCLUSION: Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

Clinical, laboratory and health-related quality of life correlates of Systemic Lupus Erythematosus Responder Index response: a post hoc analysis of the phase 3 belimumab trials.

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.

Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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].

Bioavailability, Pharmacokinetics, and Safety of Belimumab Administered Subcutaneously in Healthy Subjects.

This Phase 1 study evaluated the absolute bioavailability, pharmacokinetics (PK), tolerability, and safety of belimumab 200 mg/mL administered subcutaneously (SC) to healthy subjects as a single dose and as multiple doses up to 240 mg. In all, 118 subjects (age range 18-55 years; body weight 51-115 kg) were enrolled. Seventy-eight subjects received a single dose of belimumab 240 mg intravenously, or 2 × 120, 1 × 240, or 1 × 200 mg SC. Forty subjects received 4 weekly injections of belimumab 2 × 120 or 1 × 200 mg SC. Randomization was stratified by weight (<75 kg vs. ≥75 kg) and injection site (abdomen vs. thigh). Following single belimumab SC doses, bioavailability was 74-82%, indicating that belimumab SC was well absorbed, and bioavailability was similar among the three SC groups. Following 4 weekly belimumab SC doses, bioavailability was similar to that following single SC administration. Four subjects had persistent positive immune responses; neutralizing antibodies in these subjects were not detected and there was no apparent impact on PK. Belimumab was generally well tolerated after single and multiple SC dosing, and 200 mg SC weekly dosing is expected to provide an exposure similar to 10 mg/kg intravenously every 28 days.

Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging Study.

OBJECTIVE: To evaluate the efficacy/safety of belimumab in patients with rheumatoid arthritis (RA). METHODS: Patients fulfilling American College of Rheumatology (ACR) criteria for RA for ≥ 1 year who had at least moderate disease activity while receiving stable disease-modifying antirheumatic drug (DMARD) therapy and failed ≥ 1 DMARD were randomly assigned to placebo or belimumab 1, 4, or 10 mg/kg, administered intravenously on Days 1, 14, and 28, and then every 4 weeks for 24 weeks (n = 283). This was followed by an optional 24-week extension (n = 237) in which all patients received belimumab. Primary efficacy endpoint was the Week 24 ACR20 response. RESULTS: Week 24 ACR20 responses with placebo and belimumab 1, 4, and 10 mg/kg were 15.9%, 34.7% (p = 0.010), 25.4% (p = 0.168), and 28.2% (p = 0.080), respectively. Patients taking any belimumab dose who continued with belimumab in the open-label extension had an ACR20 response of 41% at 48 weeks. A similar ACR20 response (42%) at 48 weeks was seen in patients taking placebo who switched in the extension to belimumab 10 mg/kg. Greater response rates were observed in patients who at baseline were rheumatoid factor-positive, anticitrullinated protein antibody-positive, or tumor necrosis factor inhibitor-naive, or had elevated C-reactive protein levels, Disease Activity Score 28 > 5.1, or low B lymphocyte stimulator levels (< 0.858 ng/ml). Adverse event rates were similar across treatment groups. CONCLUSION: In this phase II trial, belimumab demonstrated efficacy and was generally well tolerated in patients with RA who had failed previous therapies. [ClinicalTrials.gov identifier NCT00071812].

Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial.

OBJECTIVE: In patients with systemic lupus erythematosus (SLE), evidence suggests that most vaccines (except live-virus vaccines) are safe, although antibody response may be reduced. This substudy from the phase III, randomized, double-blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE. METHODS: In BLISS-76, patients with autoantibody-positive, active SLE were treated with placebo or belimumab 1 or 10 mg/kg every 2 weeks for 28 days and every 28 days thereafter, plus standard SLE therapy, for 76 weeks. This analysis included a subset of patients who had received pneumococcal or tetanus vaccine within 5 years or influenza vaccine within 1 year of study participation. Antibodies to vaccine antigens were tested at baseline and Week 52, and percentage changes in antibody levels from baseline and proportions of patients maintaining levels at Week 52 were assessed. Antibody titers were also assessed in a small number of patients vaccinated during the study. RESULTS: Consistent with preservation of the memory B cell compartment with belimumab treatment, the proportions of patients maintaining antibody responses to pneumococcal, tetanus, and influenza antigens were not reduced. In a small group receiving influenza vaccine on study, antibody responses were frequently lower with belimumab, although titer levels were > 1:10 in all patients treated with 10 mg/kg and in the majority treated with 1 mg/kg. CONCLUSION: Treatment with belimumab did not affect the ability of patients with SLE to maintain antibody titers to previous pneumococcal, tetanus, and influenza immunizations. [ClinicalTrials.gov registration number NCT 00410384].

Novel evidence-based systemic lupus erythematosus responder index.

OBJECTIVE: To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials. METHODS: Data from a randomized, double-blind, placebo-controlled study in 449 patients of 3 doses of belimumab (1, 4, 10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56-week period were analyzed. The Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36 health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321 serologically active SLE patients (antinuclear antibodies >/=1:80 and/or anti-double-stranded DNA antibodies >/=30 IU/ml) at baseline was retrospectively evaluated using the SRI. RESULTS: SRI response is defined as 1) a >/=4-point reduction in SELENA-SLEDAI score, 2) no new BILAG A or no more than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician's global assessment by >/=0.3 points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week 52 compared with 29% of the placebo patients (P = 0.006). SRI responses were independent of baseline autoantibody subtype. CONCLUSION: This evidence-based evaluation of a large randomized, placebo-controlled trial in SLE resulted in the ability to define a robust responder index based on improvement in disease activity without worsening the overall condition or the development of significant disease activity in new organ systems.

A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus.

OBJECTIVE: To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE). METHODS: Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score >/=4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study. Coprimary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare. RESULTS: Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA-SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24-52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer >/=1:80 and/or anti-double-stranded DNA [anti-dsDNA] >/=30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (-28.8% versus -14.2%; P = 0.0435), physician's global assessment (-32.7% versus -10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti-dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups. CONCLUSION: Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.