Subcutaneous Belimumab Research Articles

Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study

ObjectivesDisease activity control in patients with systemic lupus erythematosus (SLE) with corticosteroid and immunosuppressant withdrawal is a treatment goal. We evaluated whether this could be attained with sequential subcutaneous belimumab...

Disruption of memory B-celltrafficking by belimumab in patients with systemic lupus erythematosus.

Autoreactive memory B cells (MBCs) contribute to chronic and progressive courses in autoimmune diseases like SLE. The efficacy of belimumab (BEL), the first approved biologic treatment for SLE and LN, is generally attributed to depletion of activated naïve B cells and inhibition of B-cellactivation. BEL's effect on MBCs is currently unexplained. We performed an in-depth cellular and transcriptomic analysis of BEL's impact on the blood MBC compartment in patients with SLE. A retrospective meta-analysis was conducted, pooling flow cytometry data from four randomized trials involving 1245 patients with SLE treated with intravenous BEL or placebo. Then, extensive MBC phenotyping was performed using high-sensitivity flow cytometry in patients with mild/moderate SLE and severe SLE/LN treated with subcutaneous BEL. Finally, transcriptomic characterization of surging MBCs was performed by single-cell RNA sequencing. In BEL-treated patients, a significant increase in circulating MBCs, in a broad range of MBC subsets, was established at week 2, gradually returning to baseline by week 52. The increase was most prominent in patients with higher SLE disease activity, serologically active patients and patients aged ≤18 years. MBCs had a non-proliferating phenotype with a prominent decrease in activation status and downregulation of numerous migration genes. Upon BEL initiation, an increase of MBCs was firmly established. In the small cohort investigated, circulating MBCs were de-activated, non-proliferative and demonstrated characteristics of disrupted lymphocyte trafficking, expanding on our understanding of the therapeutic mechanism of B-cell-activating factor inhibition by BEL. ClinicalTrials.gov, http://clinicaltrials.gov, NCT00071487, NCT00410384, NCT01632241, NCT01649765, NCT03312907, NCT03747159.

Impact of subcutaneous belimumab on disease activity, patient satisfaction, and metabolic profile in long-lasting systemic lupus erythematosus.

Atherosclerosis is a major complication of systemic lupus erythematosus (SLE) and is exacerbated by the disease itself, drug toxicity, and metabolic syndrome. Although belimumab (BEL) can ameliorate disease activity and reduce prednisolone (PSL) dose in SLE, its effect on metabolic profiles is obscure. We aimed to assess the effects of subcutaneous BEL on disease activity and metabolic profiles. A total of 106 patients with SLE who received subcutaneous BEL were included, and 76 patients who started BEL treatment at least 1year prior were evaluated. Clinical information, including retention rate, disease activity, renal outcome, patient satisfaction, and metabolic profiles, were retrospectively analysed. The retention rate of BEL was > 80% after 2years, and ineffectiveness and pain were the major reasons for discontinuation of BEL treatment. Satisfaction with side effects was higher in the BEL group than that in the PSL group. Belimumab significantly improved disease activity, lupus nephritis, and PSL dosage, with a median reduction of 4mg/day. These effects were observed in active disease and positive C1q-binding immune complex, and PSL reduction ≥ 5mg was achievable in such cases. Patients with PSL reduction of ≥ 5mg showed significantly lower blood low-density lipoprotein and triglyceride by 13 and 17mg/dL, respectively, while those with PSL reduction of < 5mg remained unaltered. Subcutaneous BEL was effective in improving disease activity and proteinuria in patients with chronic disease while reducing PSL. Reduction in PSL by BEL also improved lipid status, which could synergistically reduce cardiovascular risk in SLE. Key Points • Significant reduction of disease activity, proteinuria, and prednisolone was observed in patients using subcutaneous belimumab. • Patient satisfaction was higher in terms of side effects in subcutaneous belimumab compared with prednisolone. • Reduction in prednisolone by belimumab contributed to the improvement of lipid status and would reduce the cardiovascular risk.

Application of SLE-DAS to assess subcutaneous belimumab efficacy in a cohort of systemic lupus erythematosus patients.

To assess the efficacy of subcutaneous (sc) belimumab (BLM) by the application of SLE-DAS in a monocentric SLE cohort. We evaluated SLE patients treated with sc BLM from March 2019. Disease activity has been assessed by SLEDAI-2k, SLE-DAS and PGA (Physician Global Assessment) in all the established time-points [baseline (T0), after 1 (T1), 3 (T3), 6 (T6) and 12 (T12) months]. Furthermore, we applied and compared the achievement of remission according to SLE-DAS values (SLEDAS ≤2.08 + PDN ≤5mg/daily) and DORIS definition (clinical SLEDAI- 2k=0 + PGA<0.5 + antimalarial treatment, PDN≤5mg/daily, stable immunosuppressive treatment). We enrolled 86 patients [M/F 5/81, median age 48 years (IQR 17.5), median disease duration 166 months (IQR 216)]. At baseline, median values of SLEDA-2k and SLE-DAS were 6 (IQR 4) and 5.77 (IQR 4.33), respectively, and they significantly correlated (r=0.719, CI 95% 0.586-0.815, p<0.0001). Median duration of treatment was 14 months (IQR 20). We found a significant reduction of SLEDAI-2k and SLE-DAS already at T1, maintained in the subsequent time-points (p<0.0001). At T12, a remission state was achieved by 60.4% of patients according to SLE-DAS definition and by 62.3% according to the DORIS definition. Both definitions of remission have demonstrated an agreement of 84%, with a Cohen's kappa equal to 0.6. In this study we applied SLE-DAS to assess the efficacy of sc BLM, by analysing its over-time changes and by comparing its performance with SLEDAI-2k. Indeed, our results suggest the usefulness of this new activity index in a real-life setting.

Effect of Belimumab on Preventing de novo Renal Lupus Flares

Belimumab was recently approved for treating lupus nephritis (LN), yet de novo LN cases during belimumab treatment given for nonrenal causes have been reported. Identification of reliable signals of impending flare is imperative. We evaluated belimumab efficacy in preventing de novo renal flares and factors associated with renal flare occurrence in nephritis-naïve patients with systemic lupus erythematosus (SLE) who are receiving add-on belimumab or placebo in 5 phase 3 clinical trials using Cox regression analysis. Of 1844 eligible patients, 136 (7.4%) developed a de novo renal flare during a 52-week long follow-up. Asian origin (Adjusted Hazard Ratio [HRadj]: 1.97; 95% confidence interval [CI]: 1.32-2.94; P= 0.001), positive baseline anti-double stranded DNA (anti-dsDNA) levels (HRadj: 1.32; 95% CI: 1.07-1.63; P= 0.008), and increasing mean prednisone dose during follow-up (HRadj: 1.03; 95% CI: 1.02-1.04; P< 0.001) were associated with de novo renal flares. Low-dose intravenous (IV) belimumab (1 mg/kg monthly) yielded a nearly 3-fold lower hazard of de novo renal flare (HRadj: 0.38; 95% CI: 0.20-0.73; P= 0.004). Subcutaneous (SC) belimumab (200 mg weekly) also yielded a lower hazard (HRadj.: 0.69; 95% CI: 0.54-0.88; P= 0.003). The labeled IV dose (10 mg/kg monthly) conferred no clear protection (HRadj.: 0.74; 95% CI: 0.50-1.09; P= 0.127). We corroborated the substantial vulnerability of the Asian SLE population to renal affliction. Add-on low-dose IV belimumab (1 mg/kg) and SC belimumab appeared protective against renal flares in nephritis-naïve patients with SLE. The approved IV dose (10 mg/kg) yielded no clear protection.

Pharmacokinetics and Safety of Intravenous and Subcutaneous Auto-injector Single-dose Belimumab in Healthy Chinese Volunteers: A phase 1, Randomized, Open-label Study.

IntroductionBelimumab is a recombinant human immunoglobulin G1λ monoclonal antibody indicated as an intravenous (IV) 10 mg/kg and subcutaneous (SC) 200-mg dose for the treatment of systemic lupus erythematosus (SLE). Belimumab 10 mg/kg IV has been approved for the treatment of patients with SLE in China. This phase 1 study investigated the pharmacokinetics (PK), safety, and tolerability of belimumab 200 mg SC and the approved IV formulation in a healthy Chinese population.MethodsThis was a 13-week open-label, randomized, parallel-group study in healthy Chinese volunteers. Eligible volunteers were randomized (1:2) to receive a single dose of IV or SC (via auto-injector) belimumab 200 mg. PK and safety endpoints were evaluated using descriptive statistics.ResultsThirty-six healthy Chinese volunteers were enrolled and all completed the study. Concentration–time profiles were as expected for both formulations. Overall, 130 adverse events (AEs) were reported, with 28 AEs reported in 11 (91.7%) volunteers in the IV group and 102 AEs in 24 (100%) volunteers in the SC group. Of the 130 AEs, 104 (80.0%) were considered to be treatment-related (27 [20.8% of total AEs] treatment-related AEs in the IV group; 77 [59.2% of total AEs] in the SC group). Although the occurrence of AEs was higher in the SC group, most volunteers (91.7%) experienced AEs of mild intensity. The most frequently reported AEs included injection site pain (n = 19 [79.2%]) and oropharyngeal pain (n = 5 [20.8%]) in the SC group, and positive bacterial test, upper respiratory tract infection, blood uric acid increase, white blood cell count increase, asthenia, and diarrhea (n = 2 [16.7%], each) in the IV group.ConclusionsPK profiles of 200 mg SC and IV belimumab administrations were similar to previous studies, and safety profiles were acceptable, supporting the use of the SC dose in Chinese patients with SLE.Trial registrationNCT04136145.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00366-0.

Within-trial economic analysis of flare data from the BLISS-SC trial of subcutaneous belimumab in systemic lupus erythematosus

ObjectiveThe management of systemic lupus erythematosus (SLE) flares can incur substantial healthcare costs. In the phase III BLISS-SC trial, subcutaneous (SC) belimumab 200 mg plus standard therapy was associated with...

Lupus low disease activity (SLE) in patients treated with belimumab: a single-center real-life experience (2016-2019).

We have been conducting an evaluation of innovative therapies in patients with SLE during the past 15years. We combine the results observed on extension studies from four different trials in patients receiving either intravenous or subcutaneous belimumab, and evaluated, in Caucasian and Black Brazilian patients. Seventy-four patients were part of the study. The Lupus Low Disease Activity State (LLDAS) shown to be an available tool to detect a response in trials was used in this study and statistical comparisons between the different result groups were determined. The period of evaluation was from 12 to 48months. Seventy-four patients completed the initial study. Four refused to continue the extension evaluation. Seven belonged to the black group (10%); sixty-three were Caucasian (90%). One patient was discontinued due to pregnancy. Nine received a subcutaneous presentation (12.8%). In the subgroup analysis, one patient in the black group had flare (14.2%); five in the intravenous administration had severe flares (8.1%) and were discontinued. Ten had flares adjusted with steroids (eight articular or skin reactivation) and two with renal disease. Of the five severe flares, two required hospitalization. The mean time duration to achieve LLDAS was 6months. Twenty-seven achieved a steroid-free status and the remaining two patients on 2.5mg and seventeen were stable on daily 5.0 mg of prednisone. Using the LLDAS, it was possible to show that the majority of patients receiving belimumab for prolonged periods go into remission steroid-free or in low disease activity in association with the corresponding immunosuppressive treatment. Key Points • Prolonged real-life evaluation confirms the efficacy and steroid-sparing of Belimumab in SLE patients with active disease.

Budget Impact Analysis Of Subcutaneous Belimumab In Patients With Systemic Lupus Erythematosus In Spain.

ObjectiveTo evaluate the budget impact and the direct costs of the introduction of subcutaneous belimumab (SC) into the Spanish National Health Service (NHS) for patients with systemic lupus erythematosus (SLE) in Spain.MethodsThis study was conducted from the Spanish NHS perspective with a time horizon of 3 years. The budget impact analysis compared the cost difference between two scenarios: current market (standard therapy (ST) and intravenous belimumab (IV)) and other market in which patients switched from belimumab IV to belimumab SC until reaching 17% of the total market share. The eligible population was calculated to receive treatment with belimumab, applying the EPISER (study of the prevalence of rheumatic diseases in adult population in Spain) prevalence (91 per 100,000 inhabitants), Autoimmune Systemic Diseases Study Group (GEAS) incidence (2 per 100,000 inhabitants), and the risk of annual mortality to the Spanish adult population. Patients with severe active lupus nephritis and with severe active CNS lupus were excluded. Patients’ characteristics, flare rates and severity, and healthcare resource consumption were evaluated based on data from the literature and interviews with an expert panel. A sensitivity analysis was performed.ResultsCurrently, there is an estimated 34,697 adult patients with SLE in Spain and 3849 patients who are eligible to be treated with belimumab. The introduction of belimumab SC into the Spanish NHS could generate savings in direct healthcare costs of 6 million euros over the 3 years.ConclusionThe introduction of belimumab SC shows direct savings for the Spanish NHS. These savings could contribute to sustainability and decision-making.

Phase III, multicentre, randomised, double-blind, placebo-controlled, 104-week study of subcutaneous belimumab administered in combination with rituximab in adults with systemic lupus erythematosus (SLE): BLISS-BELIEVE study protocol

IntroductionBelimumab, an anti-B-lymphocyte-stimulator antibody, is approved for the treatment of active, autoantibody-positive systemic lupus erythematosus (SLE). Rituximab, a B cell-depleting anti-CD20 antibody, remains in the SLE treatment armamentarium despite failed...

Subcutaneous formulation of belimumab in treatment of systemic lupus erythematosus: a critical review with focus on safety and satisfaction.

Belimumab is a novel add-on therapy that has been approved for patients with active and antibody-mediated systemic lupus erythematosus. It is a monoclonal antibody that decreases the activation of B-cells and consequently decreases antibodies’ production. Recently, the US Food and Drug Administration approved subcutaneous belimumab for patients who have received training on using it. Subcutaneous belimumab can be administered using either a prefilled syringe or an auto-injector device. Weekly subcutaneous belimumab seems to be as effective as monthly intravenous belimumab with a similar safety margin. In this article, we reviewed the literature on subcutaneous belimumab focusing on safety and patients’ experiences and satisfaction. Overall, subcutaneous belimumab appears to be preferred over intravenous belimumab for a number of reasons. However, more studies are still required to prove these findings.

Clinical response beyond the Systemic Lupus Erythematosus Responder Index: post-hoc analysis of the BLISS-SC study

ObjectiveThe Systemic Lupus Erythematosus (SLE) Responder Index (SRI), developed as a primary outcome measure for use in clinical trials, captures improvement in SLE disease activity without concomitant worsening in disease...

Subcutaneous belimumab in the treatment of systemic lupus erythematosus.

Systemic lupus erythematosus is a chronic autoimmune disease with various clinical manifestations, organ involvement and laboratory findings. The disease can involve any organ including skin, joints, kidneys, central and peripheral nervous system, cardiovascular system and more. Currently, the cornerstone of treatment includes antimalarial and immunosuppressive medications and glucocorticosteroids. Recently, great effort has been invested in finding more targeted drugs for achieving better control of the disease with less adverse events. Intravenous belimumab was the first and only biologic drug to be approved by the US FDA and Health Canada for lupus over the last 50 years, and recently was studied in subcutaneous form. This paper will review the major belimumab trials with a focus on the subcutaneous form.

Evaluating The Addition To Formulary of Belimumab For The Treatment of Systemic Lupus Erythematosus: A Cost-Effectiveness Model

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that causes potentially irreversible organ damage. A previous cost-effectiveness model (CEM) evaluating intravenous belimumab in SLE was a patient microsimulation model with a series of risk equations describing disease activity and survival models to depict time to organ damage. This model was substantially revised to use a semi-Markov model that still captures the complexity of SLE and analyses subcutaneous belimumab. Post hoc regression analyses of the intravenous belimumab US long-term extension study (BEL112233) and the Toronto Lupus Cohort were conducted to identify drivers of utilities, disease progression and SLE-related mortality (HO-15-15879/206347). Costs were based on LUCIC (Systemic LUpus Erythematosus Cost of Care in Canada; 114745). Results demonstrated that the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and the presence of cardiovascular damage were sufficient to capture organ damage effects. Thus, health states were defined by treatment, SDI score and presence/absence of cardiovascular damage. The model uses a 1-year cycle length to analyse over a modifiable lifetime time horizon. Patient distribution at time=0 and Year 1 outcomes are based on source clinical trials. Thereafter, disease activity measured by adjusted mean SLEDAI (AMS), flares, and probability of organ damage progression are modelled separately for each health state and dynamically updated each cycle. Health state costs and utilities are based on multivariate regression analyses that increment payoffs for each cycle. A new CEM framework was developed within a Markov model, which further allowed incorporation of AMS, flares and organ damage progression in SLE. Total costs and outcomes were similar to the previous CEM. This modelling study has simplified clinical assumptions of SLE to produce a Markov model that may be used by additional stakeholders due to its increased transparency and shorter run time. Study funded by GSK.

Subcutaneous and intravenous belimumab in the treatment of systemic lupus erythematosus: a review of data on subcutaneous and intravenous administration

ABSTRACTIntroduction: Loss of B cell tolerance is a hallmark feature of the pathogenesis of Systemic Lupus Erythematosus (SLE). Recent advances in B cell therapy have focused on targeted therapy aimed at inhibiting B cell activation and reducing B cell survival. Belimumab, a human monoclonal antibody against B cell activating factor (BAFF) was licensed in 2011 for the treatment of SLE.Areas covered: We review the data on the intravenous and subcutaneous formulations of belimumab in the management of patients with SLE. BLISS-52 and BLISS-76 demonstrated the efficacy of intravenous belimumab (10mg/kg) as an add-on therapy in SLE patients with active disease. A recent phase III trial of intravenous belimumab reported similar results in North East Asian patients. Subcutaneous belimumab (200mg/weekly) has demonstrated similar efficacy, safety and tolerability and was approved by the FDA in 2017 for the treatment of active autoantibody positive SLE patients receiving standard therapy.Expert commentary: Belimumab is generally safe and well tolerated. The most common clinical manifestations of SLE in the clinical trials were arthritis, mucocutaneous disease and serositis. Patients with severe lupus nephritis and central nervous system disease were excluded from these clinical trials.

Belimumab in the management of systemic lupus erythematosus – an update

ABSTRACTIntroduction: Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug licensed and approved by the US FDA and the European Medicines Agency (EMA) for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE).Areas covered: This manuscript evalues the recent data concerning belimumab’s safety and clinical effectiveness and its current place in the treatment of SLE. This includes an overview of the recent data coming from the post-hoc analyses of the BLISS trials, real-life experience with belimumab and the accumulating data on its safety. Attention is also paid to the progress made in the identification of predictors of response to belimumab, recent phase I/II/III studies with subcutaneous belimumab, and experience with B cell modulation coming from recent trials with other B cell modulating drugs.Expert opinion: Belimumab currently has its established role in the treatment of patients with SLE with serologic activity and clinical activity namely in mucocutaneous and musculoskeletal domains despite standard of care treatment. Better identification of patients who can benefit from treatment with belimumab is warranted. Data from ongoing studies in lupus nephritis and other data from observational studies are eagerly awaited.

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty‐Two–Week Randomized, Double‐Blind, Placebo‐Controlled Study

ObjectiveTo assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE).MethodsPatients with moderate‐to‐severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results.ResultsOf 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA–SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25–2.25]; P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35–0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40–52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95–2.84]; P = 0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by ≥2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo.ConclusionIn patients with moderate‐to‐severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

Evaluation of a novel autoinjector for subcutaneous self-administration of belimumab in systemic lupus erythematosus

Objective: To study self-administration and pharmacokinetics (PK) of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE). Methods: Patients previously treated with belimumab self-administered belimumab 200 mg SC weekly for 8 weeks using an autoinjector. The primary endpoint was the proportion of patients able to self-administer their first and second dose (weeks 1 and 2) in the clinic. The proportion able to self-administer at weeks 4 and 8 (clinic) and weeks 3, 5, 6, and 7 (home) were secondary endpoints. Belimumab PK, safety, and injection-site pain were assessed. Results: 91/95 patients completed the study (withdrawals: adverse events (AEs): 3; lost to follow-up: 1). 93% were female, and mean (SD) age was 44.8 (12.50) years. The majority (99%, 89/90; no attempt, n = 5) successfully self-administered belimumab SC at weeks 1 and 2 (5 had clinic staff assistance), and 98% (85/87) successfully self-administered at weeks 4 and 8. Home-administration success rates were high (93%, (81/87) at weeks 3, 5, 6, and 7). Week 8 median trough concentration was 113 µg/mL. For patients with a ≤ 1.5-week interval between IV SC administration, week-1 concentrations were higher vs. week 8 (+ 51% median) but within a range observed with IV dosing; those with a ≥ 2.5-week interval had median differences close to 0. AEs and serious AEs were low, with no deaths; pain levels were low and decreased with subsequent injections. Conclusion: Patients with SLE successfully self-administered belimumab SC using a novel autoinjector; the PK profile was stable following a switch from IV with acceptable AE and pain levels. The recommended dosing interval between IV to SC dosing is 1 – 4 weeks.

Systemic lupus erythematosus 2014.

Systemic lupus erythematosus 2014.

Belimumab

Belimumab is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. Belimumab is in phase III trials for the treatment of systemic lupus erythematosus (SLE) and has completed a phase II trial in rheumatoid arthritis (RA); the product may also have potential in the treatment of other autoimmune disorders. In May 2001, Cambridge Antibody Technology (now MedImmune) completed its discovery programme and Human Genome Sciences identified belimumab as a candidate for clinical development. More than 1000 distinct human antibodies specific to BLyS were characterized by the collaboration.B-lymphocyte stimulator is a naturally occurring protein discovered by Human Genome Sciences that stimulates B-lymphocytes to develop into mature B cells. Laboratory studies have indicated that higher than normal levels of B-lymphocyte stimulator may contribute to the pathogenesis of autoimmune diseases, such as SLE and RA. Human Genome Sciences (HGS) and Cambridge Antibody Technology signed a collaborative agreement in August 1999 to study the B-lymphocyte stimulator as a human protein target. HGS is also developing other BLyS products. In March 2000, HGS and Cambridge Antibody Technology expanded their agreement into a 10-year collaboration and product development alliance, providing Human Genome Sciences with the right to use the antibody technology of Cambridge Antibody Technology to fully develop human antibodies for therapeutic and diagnostic purposes. Cambridge Antibody Technology will receive royalty payments on product sales from HGS, as well as the development and milestone payments it has already received. Belimumab will be manufactured in Human Genome Sciences' manufacturing facility, located in Rockville, MD, USA. HGS holds commercial rights to the drug. In July 2005, GlaxoSmithKline (GSK) exercised its co-development and co-promotion option to belimumab. In an agreement made in June 1996, HGS had granted a 50/50 co-development and co-promotion option to GSK for certain therapies that complete phase IIa trials successfully. The companies subsequently entered into a definite worldwide, co-development and commercialization agreement in August 2006, under which HGS will be responsible for conducting phase III trials of the product, with assistance from GSK. The companies will share equally phase III/IV development costs, sales and marketing expenses, and profits. In October 2007, Cambridge Antibody Technology was integrated into MedImmune. Both companies were previously independent subsidiaries of AstraZeneca. MedImmune is now the operationally independent biologics business unit of AstraZeneca. Human Genome Sciences intends to initiate a phase II trial of subcutaneous belimumab by mid-2008. Results from a phase II trial in 449 patients with SLE demonstrated that belimumab improved or stabilized SLE over 2.5 years. The phase II trial was a double-blind, placebo-controlled, multicentre study that evaluated the safety, optimal dosing, and preliminary efficacy of belimumab in patients with active SLE over 52 weeks initially, followed by a continuation phase for a total of 2.5 years. Belimumab has received fast-track designation for the treatment of SLE from the US FDA and has also been selected for inclusion in the agency's continuous Marketing Application Pilot 2 programme.