Belimumab: anti-BLyS monoclonal antibody; Benlysta; BmAb; LymphoStat-B.

Belimumab is a fully human monoclonal antibody for the treatment of autoimmune disorders that is being developed by Human Genome Sciences and GlaxoSmithKline. Two pivotal phase III trials in systemic lupus erythematosus have been concluded with the primary endpoints being met in both studies. A phase II trial in rheumatoid arthritis has also been completed, with positive results. Marketing authorization submissions are being prepared in the major markets worldwide. This review discusses the development history and scientific profile of belimumab.

1. Introduction

Human Genome Sciences (HGS) is developing belimumab, a fully human monoclonal antibody, for the treatment of autoimmune disorders, particularly systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). The product is designed for intravenous injection, and specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator (BLyS™). Phase III development for the treatment of SLE has been completed, and HGS is preparing marketing authorization submissions worldwide, including in the US, Canada, Europe, Asia, and Latin America. A subcutaneous formulation is in phase II development in the US and Mexico for the treatment of SLE.

B-lymphocyte stimulator is a naturally occurring protein discovered by HGS, which 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. Belimumab (Benlysta™, formerly LymphoStat-B®) was identified as a candidate for clinical development by HGS in collaboration with Cambridge Antibody Technology (now MedImmune); more than 1000 distinct human antibodies specific to BLyS™ were characterized under the collaboration, and the discovery program was completed in May 2001.

1.1 Company Agreements

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.[1]

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.[2,3]

In March 2000, HGS and Cambridge Antibody Technology expanded their agreement into a 10-year collaboration and product development alliance, providing HGS with the right to use the antibody technology of Cambridge Antibody Technology to develop fully 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 HGS’s manufacturing facility, located in Rockville (MD, USA). HGS holds commercial rights to the drug.[4]

HGS and Cambridge Antibody Technology signed a collaborative agreement in August 1999 to study the B-lymphocyte stimulator as a human protein target.

1.2 Key Development Milestones

1.2.1 Systemic Lupus Erythematosus

HGS and GSK have conducted two pivotal phase III trials, BLISS-76 (NCT00410384) and BLISS-52 (NCT00424476), to evaluate belimumab intravenous injection for SLE. BLISS-76 and BLISS-52 were randomized, double-blind, placebo-controlled studies, which investigated the efficacy and safety of belimumab (1 or 10 mg/kg) plus standard of care (SOC) in patients with active SLE. Belimumab 10 mg/kg met the primary endpoint at week 52 in both studies. Furthermore, at week 76 in BLISS-76, higher (although non-significant) response rates were observed in patients who received belimumab plus SOC compared with those who received placebo plus SOC, as measured by the SLE Responder Index (SRI). Further topline secondary endpoint data from BLISS-76 have been reported.[5,6]

In both phase III trials, dosing took place on days 0, 14, and 28, then every 28 days for the rest of the trials. The trials were conducted under the US FDA’s Special Protocol Assessment (SPA) process. Bliss-76, a 76-week trial, was initiated in February 2007 and completed in February 2010. The trial enrolled 810 patients in the US, Canada, Mexico, Costa Rica, Puerto Rico, the EU, and Israel. BLISS-52, a 52-week trial, was initiated in May 2007 and completed in July 2009. The trial enrolled 867 patients in Argentina, Brazil, Chile, Peru, Colombia, Australia, the EU, Russia, China, Hong Kong, South Korea, the Philippines, Taiwan, and India. HGS and GSK expect to submit marketing applications in the US, Europe, and other regions in the second quarter of 2010.[7-15]

The primary efficacy endpoint of both BLISS trials was the novel, evidence-based SRI at week 52. It is defined by: (i) a reduction from baseline of at least 4 points on the SELENA SLEDAI disease activity scale; (ii) no worsening of disease as measured by the Physician’s Global Assessment (PGA) [worsening defined as an increase of 0.30 points or more from baseline]; and (iii) no new BILAG (British Isles Lupus Activity Group) A organ domain score, and no more than one new BILAG B organ domain score.[16]

Results from a phase II trial in 449 patients with SLE demonstrated that belimumab improved or stabilized SLE over 2.5 years. The double-blind, placebo-controlled trial 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.[17-19] The 208-week data from this study were reported in June 2009.[20]

Belimumab has received fast-track status for the treatment of SLE from the FDA and has also been selected for inclusion in the agency’s continuous Marketing Application Pilot 2 program.[21,22]

1.2.2 Normalization of Antibody Levels

A 1-year phase II study (NCT01025193) will assess the efficacy and safety of belimumab in decreasing the alloantibody levels in sensitized patients awaiting kidney transplantation. The trial began in February 2010 and is enrolling patients by invitation in the US.

1.2.3 Rheumatoid Arthritis

HGS reported results from a phase II trial (NCT00071812) of belimumab intravenous injection in RA, in the US. The monoclonal antibody was well tolerated, biologically active and significantly reduced the signs and symptoms of RA. The company is continuing to collect data from the continuation trial (NCT00583557), which is enrolling patients who completed the original trial and benefited from treatment.[19,23] In June 2009, HGS initiated a phase IV expanded access trial (NCT00931086) for patients who participated in the phase II continuation trial. However, in July 2009, HGS reported that expanded access was no longer available for belimumab in RA.

1.2.4 Subcutaneous Formulation

GSK and HGS initiated a phase II trial (NCT00732940) of the subcutaneous formulation of belimumab in patients with SLE in October 2008. The randomized, open-label trial will enroll 56 patients in the US and Mexico, and will evaluate the safety, tolerability, and efficacy of belimumab under two dosing schedules; 100 mg on days 0, 7, and 14, and then every other week until day 168, and 200 mg on days 0, 2, and 4 followed by 100 mg three times per week until day 168. Patients on both dosing schedules have the option to continue on the same dose through a 144 week continuation period.

2. Scientific Summary

2.1 Pharmacokinetics

In a multicenter, double-blind, placebo-controlled, dose-escalating, phase I trial, 70 patients with SLE were randomized to determine the safety and pharmacology of belimumab in adult patients who were receiving standard therapies. Belimumab or placebo was administered intravenously at 1, 4, 10, or 20 mg/kg. With single doses, the half-life of belimumab was shown to be between 13 and 17 days, with a slow clearance of 4 ± 1.56 mL/day/kg, and a small Vss of 68 ± 20.8 mL/kg, which is consistent with that of other fully human monoclonal antibodies. A dose-proportional pharmacokinetic profile was observed.[4,24]

2.2 Adverse Events

2.2.1 Rheumatoid Arthritis

In a double-blind, placebo-controlled, multicenter, phase II trial in 283 patients with RA, patients received, by the intravenous route, either placebo or belimumab (1, 4, or 10 mg/kg) on days 0, 14, and 28, and then every 28 days for a total of 24 weeks. Belimumab was not significantly different to placebo for adverse events, serious adverse events or laboratory abnormalities; significant infusion reactions (injection site reactions) were rare.[23]

Features and properties

2.2.2 Systemic Lupus Erythematosus

Belimumab 10 and 1 mg/kg plus SOC was generally well tolerated in the pivotal phase III BLISS-76 trial in patients with SLE. The rate of overall adverse events (AEs), serious and/or severe AEs, all infections, serious and/or severe infections, and discontinuations due to AEs, was comparable between groups receiving belimumab plus SOC and those receiving placebo plus SOC. Serious and/or severe AEs were reported in 29.0% of patients receiving belimumab and 26.2% of patients receiving placebo. Infections were reported in 74.3% and 69.1% of patients receiving belimumab and placebo, respectively. Serious and/or severe infections were reported in 1.2% and 3.6% of belimumab and placebo recipients, respectively. Serious and/or severe infusion reactions were reported in 1.1% and 0.7% of patients in belimumab and placebo groups, respectively. Discontinuations due to AEs occurred in 7.5% and 8.4% of patients in belimumab and placebo groups, respectively. One new malignancy was reported between weeks 52 and 76, with a total of 2, 4, and 1 subjects affected in the belimumab 10 mg/kg, 1 mg/kg, and placebo groups, respectively. A total of three deaths occurred during the study, with 1, 2, and 0 deaths in the belimumab 10 mg/kg, 1 mg/kg, and placebo groups, respectively.[6] Interim results were previously reported.[8]

In the BLISS-52 trial, belimumab was generally well tolerated. Belimumab and placebo were associated with similar incidences of adverse events, serious adverse events, infections, and fatalities. Serious infections were reported in 5.9% of placebo recipients, and 6.1% of belimumab recipients. The most frequently reported adverse events were headache, arthralgia, upper respiratory tract infections, urinary tract infections, and influenza. There were no reports of malignancy.[10,25,26]

The long-term safety profile of belimumab in a phase II trial in 449 patients with SLE showed that at 3 years, the overall AE, serious AE, and severe AE incidence rates were comparable between the placebo and belimumab groups in intervals 1 (0–0.5 years) and 2 (0.5–1 years) and the rates did not increase over 3 years of exposure to belimumab. The cumulative incidence rate for malignancies (0.91% vs 0.85%) and serious infections (3.6% vs 3.4%) was similar between belimumab and placebo, respectively. At week 52 of the trial, 345 patients entered a 24-week extension phase in which all patients received belimumab (1, 4, or 10 mg/kg). At week 76, 296 patients entered a further non-blind long-term continuation phase in which all patients received belimumab 10 mg/kg.[27,28]

Four-year data from the same trial showed that belimumab could be safely administered in patients with SLE. By week 208, overall exposure to belimumab was 1192 patient-years. The incidence rates for 100 patients in all AE categories were similar to those observed during the 52-week double-blind period, and remained the same or decreased during continuous treatment for over 4 years. The frequency of flares by SS SLE Flare Index (SFI) decreased from 72% at 6 months, 62% at 1 year (vs 76% and 73%, respectively, with placebo), and declined to 16% at 4 years. Also, the frequency of new BILAG A or 2 B flares decreased from 30% at 6 months to 23% at 1 year (vs 33% and 25%, respectively, with placebo) and declined to 5% at 4 years.[20,29]

In a multicenter, double-blind, placebo-controlled, dose-escalating, phase I trial, 70 patients with SLE were randomized to determine the safety and pharmacology of belimumab in adult patients who were receiving standard therapies. Belimumab or placebo was administered intravenously at 1, 4, 10, or 20 mg/kg. Patients received a placebo, a single dose of belimumab, or two doses of belimumab 21 days apart. Results showed that belimumab was well tolerated with no clinically significant differences from placebo in adverse events or laboratory abnormalities. Six patients experienced serious AEs, with a similar frequency seen in placebo and treatment groups. One patient experienced an infusion reaction at the highest single dose, while one patient developed neutralizing antibodies to belimumab. No drug-related serious AEs were reported.[22,24]

History

2.3 Pharmacodynamics

2.3.1 Immunological Disorders

In a multicenter, double-blind, placebo-controlled, dose-escalating, phase I trial, 70 patients with SLE were randomized to determine the safety and pharmacology of belimumab in adult patients who were receiving standard therapies. Belimumab or placebo were administered intravenously at 1, 4, 10, or 20 mg/kg. Patients received placebo, a single dose of belimumab, or two doses of belimumab 21 days apart. The half-life of belimumab was shown to be consistent with that of other human monoclonal antibodies, and a dose-proportional pharmacokinetic profile was observed. Additionally, belimumab significantly reduced the levels of circulating B (CD20) cells. In patients treated with belimumab, reductions in CD20+ cells ranging from 12% to 47% compared to placebo were observed at the last visit, and at other timepoints after day 42 for single-dose cohorts and after day 49 for double-dose cohorts. In addition, significant reductions in anti-double-stranded DNA (dsDNA) autoantibody levels were observed in some belimumab treatment cohorts. No change in SLE disease activity was observed over this short treatment period.[4,22,24]

In a preclinical study, belimumab at doses of 5, 15, or 50 mg/kg was administered to cynomolgus monkeys by intravenous injection every 2 weeks for 13 or 26 weeks. Safety and pharmacology endpoints were measured at 3 and 6 months, and after an 8-month treatment-free period. Results showed that belimumab is well tolerated and biologically active at the doses administered. Despite decreases in B lymphocytes, monkeys treated with belimumab had no increase in infections. Data showed that belimumab significantly reduces circulating B cells (CD20+) and mature B cells (CD20+/CD21+) after 13 weeks of exposure, as well as B cells in the lymphoid tissue. In contrast, neither CD3+ T lymphocytes or CD3-/CD14+ monocytes were affected by belimumab. There was also a general correlation between peripheral blood B lymphocytes, tissue B lymphocytes representation, spleen weights and histologic findings. The treatment-related effects of belimumab were reversible within the 8-month treatment-free period.[4,30]

2.3.2 Rheumatic Disease

In a double-blind, placebo-controlled, multicenter, phase II trial in 283 patients with rheumatoid arthritis, patients received, by the intravenous route, either placebo or belimumab (1, 4, or 10 mg/kg) on days 0, 14 and 28, and then every 28 days for a total of 24 weeks. Relative to placebo, belimumab significantly reduced levels of circulating B cells (CD20+ and other subsets) and rheumatoid factor.[23,31]

2.4 Therapeutic Trials

2.4.1 Immunological Disorders

Systemic Lupus Erythematosus

Treatment with belimumab 10 mg/kg plus SOC was associated with higher response rates than placebo plus SOC, in 76-week, topline secondary endpoint data from the phase III BLISS-76 trial. In this trial, patients were randomized to receive intravenously injected belimumab 1 mg/kg (n = 271), 10 mg/kg (n = 273), or placebo (n = 275) on days 0, 14, and 28, and the every 28 days thereafter for the duration of the study; all patients also received SOC. At week 76, belimumab plus SOC was associated with higher, although non-significant, response rates, compared with placebo plus SOC. Based on intent-to-treat analysis at week 76, response rates for belimumab plus SOC compared with placebo plus SOC, as measured by the SRI, were 39.1%, 38.5%, and 32.4% for belimumab 1 mg/kg, 10 mg/kg and placebo, respectively (p = 0.11, p = 0.13 for belimumab 1 mg/kg and 10 mg/kg, respectively, vs placebo). The SRI defines patient response as an improvement in SELENA SLEDAI score of ≥4 points, with no clinically significant BILAG worsening and no clinically significant worsening in PGA. The proportion of patients with a reduction in SELENA SLEDAI score of ≥4 points was 41.4% for belimumab 10 mg/kg, 42.1% for belimumab 1 mg/kg, and 33.8% for placebo (p = 0.066 and p = 0.049 for belimumab 10 mg/kg and 1 mg/kg, respectively, vs placebo). Mean improvement from baseline in PGA was 0.51, 0.53, and 0.49 for belimumab 10 mg/kg, belimumab 1 mg/kg, and placebo, respectively (p = 0.21 for both belimumab 10 and 1 mg/kg vs placebo). Approximately 46% of patients enrolled in BLISS-76 were receiving steroids at study entry, the percentage of these patients who had their average steroid dose reduced by at least 25% from baseline to ≤7.5 mg/day during the last 12 weeks of the study, was 24.2%, 26.9%, and 17.5% for patients receiving belimumab 10 mg/kg, belimumab 1 mg/kg, and placebo, respectively. At week 76, the mean reduction in SELENA SLEDAI score was 37.0% for belimumab 10 mg/kg, 36.1% for belimumab 1 mg/kg, and 27.8% for placebo (p = 0.01 and p = 0.03 for belimumab 10 mg/kg and 1 mg/kg vs placebo, respectively). The primary endpoint was met at week 52, with belimumab 10 mg/kg plus SOC demonstrating a significant improvement in patient response, as assessed using the SRI, compared with placebo plus SOC.[5,6,8]

Forecasts

An intent-to-treat analysis of data from the BLISS-52 trial showed that belimumab (10 or 1 mg/kg) was associated with a clinically and statistically significant increase in the response rate at week 52, compared with placebo, in patients with serologically active SLE treated with standard therapy (57.6%, 51.4% vs 43.6% of patients; p = 0.0006 and p = 0.013 for 10 mg/kg and 1 mg/kg belimumab, respectively). Compared with placebo, belimumab (10 mg/kg or 1 mg/kg) was associated with a significantly greater proportion of patients experiencing a reduction in SELENA SLEDAI scores of at least 4 points by week 52 (58%, 53% vs 46% of patients; p = 0.0024 and p = 0.019 for 10 mg/kg and 1 mg/kg, respectively, vs placebo), with improvement observed for 10 mg/kg belimumab within 4–8 weeks and reaching statistical significance at week 16 and weeks 24–52 (p < 0.05 vs placebo). The average prednisone dose was reduced by at least 25% from baseline to ≤7.5 mg/day, during the last 12 weeks of the study (weeks 40–52), in a significantly greater proportion of belimumab (20.6% and 18.6% for 1 and 10 mg/kg, respectively) recipients compared with placebo recipients (12%). At week 24, there were no significant differences between placebo and either belimumab group in terms of improvements in health related quality of life (HR-QOL) as assessed by the SF-36 Physical Component Summary (PCS) score. HR-QOL improvement as measured by the SF-36 PCS score at week 52 was significantly greater in both belimumab groups versus placebo (p = 0.025 for 10 mg/kg and p = 0.027 for 1 mg/kg belimumab, respectively). When assessed with the FACIT-Fatigue Scale, improved fatigue scores were observed in the 10 mg/kg belimumab group versus placebo within 4–8 weeks, and both belimumab groups achieved statistically significant improvement of fatigue by week 52 (p < 0.05 for both belimumab groups vs placebo). Compared with placebo, belimumab (1 and 10 mg/kg) was associated with a significant improvement in the PGA at week 24; improvement was noted within 4–8 weeks of treatment initiation. Belimumab significantly delayed time to first disease flare versus placebo (SLE Flare Index/SFI): median = 119 days for 10 mg/kg belimumab, 126 days for 1 mg/kg belimumab, and 84 days for placebo (p = 0.0036 and p = 0.0026 for 10 mg/kg and 1 mg/kg, respectively vs placebo). The risk of having severe disease flares (SFI) was reduced over 52 weeks by 43% in the 10 mg/kg group and by 24% in the 1 mg/kg group versus placebo (p = 0.0055 and p = 0.1342 for 10 mg/kg and 1 mg/kg, respectively). The risk of having one BILAG A (severe flare) or more than one BILAG B (moderate flare) organ domain score was reduced by 42% in the 10 mg/kg group and by 13% in the 1 mg/kg versus placebo (p = 0.0016 and p = 0.3722 for 10 mg/kg and 1 mg/kg, respectively).[10,25,26,32]

In a phase II trial, belimumab exhibited durable biological activity, appeared safe and well tolerated, and reduced disease activity in 449 patients with serologically active SLE. The percentage of patients who achieved the combined response rate increased from 46% at week 52 to 56% at week 76. There was an increase from 29% at week 52 to 38% at week 76 in SLE disease activity as measured by SELENA SLEDAI and 33% to 41% as measured by the PGA. There was a mean improvement in HR-QOL, measured by the SF-36 PCS score, from 3.0 points at week 52 to 3.4 points at week 76. In addition, there was no increase in infections or infectious events observed over time.[21,33,34]

Additionally, significant improvements after treatment with belimumab in seropositive patients included reduction in the number of patients experiencing neurological and musculoskeletal organ domain flares, as measured by BILAG scores at week 52. In patients who entered the 24-week extension phase of the trial, the combined patient response rate increased to 54% and 63% had a clinical benefit. Improvement in SLE disease activity, as measured by the SELENA SLEDAI scale, occurred in 58% of patients and 94% had no new BILAG A organ flare and no more than one new BILAG B organ flare. Furthermore, 94% of patients showed no worsening in SLE disease activity as measured by the PGA. Belimumab decreased the overall frequency of SLE disease flares and the frequency of severe SLE disease flares as measured by the SELENA SLEDAI scale. The compound also produced stable reductions in immunoglobulins, a reversion of autoantibody levels from positive to negative, and a normalization of IgG in 57% of patients with hypergammaglobulinemia at baseline.[35-37]

Three-year data from the same trial showed that the combined response rate in serologically active patients with SLE who received belimumab increased from 46% (at week 52) to 52% (at week 160). At week 52, 345 patients entered a 24-week extension phase in which all patients received belimumab (1, 4, or 10 mg/kg). At week 76, 296 patients entered a further nonblind long-term continuation phase in which all patients received belimumab 10 mg/kg. The overall frequency of SLE disease flares and the frequency of severe disease flares decreased in patients who received belimumab for 3 years, and the proportion of patients who reduced prednisone dose relative to baseline increased. Autoantibody levels (anti-dsDNA, anti-RNP, anti-Smith) reverted from positive to negative with belimumab treatment, immunoglobulin levels were reduced (with no increase in infectious events) and, in patients with low baseline complement, C3 and C4 complement were increased.[17,27,38,39]

Four-year data from the same trial showed that treatment with belimumab was associated with sustained improvement or stabilization of SLE disease, including decreased frequency of flares in serologically active patients. There was an increase from 46% to 57% in the response rate (defined by an improvement in the SELENA SLEDAI score of ≥4 points, no BILAG worsening and no worsening in PGA). There was a decrease from 62% to 16% in the overall frequency of SLE disease flares and from 8% to 1% in the frequency of severe disease flares (by the SELENA SLEDAI Flare Index) observed from week 52 to week 208. Additionally, 5% of patents compared with 23% of patients, at weeks 208 and 52, respectively, experienced one or more that one new BILAG A organ domain score.[20]

2.4.2 Rheumatic Disease

Rheumatoid Arthritis

Belimumab showed significant therapeutic effect in a double-blind, placebo-controlled, multicenter, phase II trial in 283 patients with RA who had failed previous treatment. Patients received, by the intravenous route, either placebo or belimumab (1, 4, or 10 mg/kg) on days 0, 14 and 28, and then every 28 days for a total of 24 weeks. Concomitant therapy included disease-modifying antirheumatic drugs and prednisone ≤10 mg/day. The primary efficacy endpoint, rate of American College of Rheumatology (ACR) 20% response at week 24, was 36%, 31%, and 17% for belimumab 1 mg/kg, all belimumab groups combined, and placebo, respectively. The difference between belimumab and placebo was significant for both the 1 mg/kg dose and the combined belimumab groups (p = 0.011 and p = 0.02, respectively).[23,31]