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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

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.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder with a variable and unpredictable clinical course, which is characterized by autoantibody formation and fluctuating inflammation (1, 2). Current standard therapy for the management of SLE involves the use of corticosteroids, antimalarial agents, and immunosuppressive agents, either alone or in combination (3–6). Current treatments are widely acknowledged to have potentially dangerous side effects, especially when used in the long term.

Despite improvements in the treatment and prognosis of SLE during the past several decades, these patients are at high risk of serious morbidity, including infections (especially of the respiratory and urinary systems), coronary artery disease, and hematologic and solid tumors (7–14). Patients with SLE also have a 2–5-fold greater risk of death from all causes than the general population (15, 16). Thus, there are significant unmet needs in this population.

Biologic agents targeting specific immunologic pathways offer a new approach to the treatment of SLE. B lymphocyte stimulator is a critical cytokine for the maturation and survival of B cells (17). This cytokine is overexpressed in patients with SLE and other autoimmune diseases, and the levels correlate with increased SLE disease activity and elevated titers of anti–double-stranded DNA antibody (18–22). Belimumab (Benlysta; Human Genome Sciences, Inc. and GlaxoSmithKline) is a human IgG1λ monoclonal antibody that binds to soluble human B lymphocyte stimulator and inhibits its biologic activity (18, 19).

The results of a phase II, placebo-controlled, dose-ranging trial of belimumab in 449 patients with active SLE who were receiving standard therapies for the disease have previously been reported (23). Belimumab was generally well tolerated, and the incidence rates of adverse events (AEs) and abnormal laboratory findings were similar across the active treatment and placebo groups. The coprimary efficacy end points in that study, however, were not met. A post hoc analysis identified a subset of patients (72% of the original cohort) with autoantibody-positive SLE (antinuclear antibody titer ≥1:80 or anti–double-stranded DNA ≥30 IU/ml) in whom belimumab reduced the disease activity and risk of SLE flare as compared with placebo. In 2 pivotal phase III studies, autoantibody-positive patients with SLE who were receiving standard therapy were randomized to placebo or belimumab 1 or 10 mg/kg and treated for 48 or 72 weeks (24, 25). Both trials met the primary end point, demonstrating a significantly higher response rate (as assessed by the SLE Responder Index) at week 52 in patients treated with belimumab. In addition, belimumab was generally well tolerated in these studies, with an overall safety profile similar to placebo.

The present study is an ongoing open-label continuation study of the original phase II trial, which was designed to assess the safety profile of belimumab over 4 years of exposure in combination with standard therapy in patients with active SLE (23).

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Study design.

The initial study enrolled patients with active SLE in a 52-week phase II randomized, double-blind, placebo-controlled trial of intravenous belimumab (1, 4, or 10 mg/kg; administered on days 0, 14, and 28 and then every 28 days thereafter) plus standard therapy, which could include corticosteroids, antimalarial agents, and immunosuppressants, either alone or in combination (23). Patients completing the 52-week double-blind period entered a 24-week open-label extension phase. During this phase, belimumab patients either received the same dose or were switched to 10 mg/kg at the investigator's discretion, and placebo patients were switched to belimumab 10 mg/kg. Upon completion of the 24-week extension period, patients who had achieved a satisfactory response to therapy (defined as an improvement in the physician's global assessment score versus baseline [day 0] or versus week 52 and no severe SLE flare in the last 30 days of the extension period) could enter a long-term open-label continuation protocol and receive intravenous belimumab 10 mg/kg every 28 days. Standard therapy (i.e., background medications) could be altered anytime during the course of a patient's participation in any of these studies according to the opinion of the treating physician. The addition of intravenous cyclophosphamide or new biologic agents, however, was not permitted. The primary objective of the extension and continuation studies was to evaluate the long-term safety and tolerability of belimumab in these patients.

The studies were reviewed and approved by an institutional review board or ethics committee at each study site, and all patients gave informed consent before continuing in the long-term protocol. The initial and long-term trials are registered as ClinicalTrials.gov nos. NCT00071487 and NCT00583362, respectively.

Safety data monitoring during the phase II and 24-week extension studies was performed by an independent external data monitoring committee that met approximately every 3 months. During the long-term continuation period, a sponsor committee reviewed the safety data approximately every 6 months.

Safety measures.

Adverse events were recorded approximately every 4 weeks during both studies. Laboratory data for safety assessments (hematology, chemistry, coagulation, Ig isotypes [IgG, IgA, IgM, and IgE], and urinalysis) were collected every 2 months throughout the studies. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 13.1 and were graded for severity using the Adverse Event Severity Grading Tables, modified from the Adult Toxicity Tables of the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (26).

Statistical methods.

The pooled results at all belimumab doses were compared with placebo during the 52-week double-blind period (23). For the long-term continuation analysis, data were pooled and presented by 1-year intervals starting from the time patients received their first dose of belimumab plus 28 days. Data were pooled because no dose response was observed in the safety measures and since after 1.5 years in the study, all patients continued with belimumab 10 mg/kg. The data set used for analysis included 4 years of belimumab exposure for patients originally randomized to receive belimumab and for patients who switched to belimumab after 1 year of placebo treatment. Data from patients who received placebo during the double-blind period who switched to belimumab were combined with data from all patients who were originally receiving belimumab, i.e., the first year of belimumab treatment was the second year in the study for patients originally assigned to placebo.

Incidence rates of AEs and abnormal laboratory findings are expressed per 100 patient-years for each 1-year interval. For patients who discontinued during a given interval, 8 weeks of followup safety data were included in the last interval, if available.

Adverse events of special interest, i.e., infusion-related reactions (including hypersensitivity reactions), infections, and malignant neoplasms, were evaluated by creating composite definitions of these events using MedDRA preferred terms.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Patient disposition and baseline demographics.

Baseline demographic and SLE disease characteristics of the patients who entered the long-term continuation study were similar to those of the original double-blind study population (23) (Table 1).

Table 1. Baseline demographic and clinical characteristics of the 296 SLE patients participating in the long-term continuation period*
  • *

    Baseline information was collected at the time the systemic lupus erythematosus (SLE) patients entered the double-blind period of the study. Patients were receiving 10 mg/kg of belimumab. SELENA–SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index; BILAG = British Isles Lupus Assessment Group; ANA = antinuclear antibody; anti-dsDNA = anti–double-stranded DNA; LLN = lower limit of normal.

Women, no. (%)276 (93.2)
Race/ethnicity, no. (%) 
 Caucasian213 (72.0)
 Black/African American65 (22.0)
 Asian5 (1.7)
 Other13 (4.4)
Age, mean ± SD years42.6 ± 11.5
Disease duration, mean ± SD years8.8 ± 7.8
Disease activity 
 SELENA–SLEDAI score, mean ± SD9.2 ± 4.55
 No. (%) with ≥1 BILAG A or ≥2 BILAG B domain scores190 (64.2)
 Physician's global assessment score, mean ± SD1.4 ± 0.51
 No. (%) with ≥1 severe SLE flare40 (13.5)
Laboratory assessments, no. (%) 
 ANA titer ≥1:80 (n = 294)217 (73.8)
 Anti-dsDNA titer ≥30 IU/ml149 (50.3)
 C4 <90 mg/dl (LLN) (n = 293)122 (41.6)
 C3 <16 mg/dl (LLN) (n = 294)83 (28.2)
 Grades 3/4 hypogammaglobulinemia1 (0.3)
Medication use, no. (%) 
 Corticosteroid use199 (67.2)
  >7.5 mg/day97 (32.8)
  Baseline dosage, mean ± SD mg/day9.9 ± 8.7
 Antimalarial agents209 (70.6)
 Immunosuppressive agents148 (50.0)
  Azathioprine56 (18.9)
  Mycophenolate mofetil42 (14.2)
  Methotrexate49 (16.6)
  Leflunomide12 (4.1)

Among the 364 patients completing the 52-week double-blind treatment period, 345 entered the 24-week extension phase. Of the 321 patients completing the 24-week extension period, 296 continued treatment with belimumab 10 mg/kg monthly in the long-term continuation study (Figure 1). The cumulative patient exposure to belimumab after the first 4 years of treatment was 1,165 patient-years from October 2003 through August 2009.

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Figure 1. Distribution of the study patients during the open-label long-term exposure study of belimumab treatment in patients with systemic lupus erythematosus. DC = discontinuation; DB = double-blind; pat req = patient request; AE = adverse event; dis prog = disease progression; compl = compliance; LTE = long-term extension; LTFU = lost to followup; inv dec = investigator decision.

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The overall rate of discontinuation during the first year of belimumab exposure was 16% and the rate decreased during years 2–4 of the long-term continuation study (range 9–14%). In year 1, the 2 most common reasons for discontinuation were patient request (6%) and AE (5%), and the rates declined over time.

Summary of adverse events.

The incidence rates of AEs, treatment-related AEs, and serious and/or severe AEs were similar, as previously reported, for the placebo and belimumab groups during the double-blind portion of the study, and these rates either remained stable or declined over the 4 years of belimumab exposure (23) (Figure 2). The most common MedDRA system organ class AEs reported throughout the 4-year period was infections and infestations, with upper respiratory tract infections predominating (Table 2). The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. The serious AEs of highest incidence (5 patients in any year) were cellulitis and transient ischemic attack, both with incidence rates of 1.3/100 patient-years in year 1 and with declining rates over time.

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Figure 2. Incidence rates of adverse events (AEs), infections, malignant neoplasms, and mortality over 4 years of exposure of systemic lupus erythematosus patients to treatment with belimumab. Rate = (100 × the number of patients developing the given AE in the given interval)/(total patient-years in the given interval). Patients orginally randomized to receive placebo were included from the time of their first belimumab exposure.

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Table 2. Summary of adverse events occurring during the double-blind period versus the long-term continuation period*
 52-week double-blind placebo-controlled period (year 1)Long-term continuation period (years 1–4), all belimumab-treated patients
Placebo (n = 113)Belimumab (n = 336)Year 1 (n = 424)Year 2 (n = 339)Year 3 (n = 274)Year 4 (n = 248)
  • *

    Except where indicated otherwise, values are the number of adverse events (AEs) (rate/100 patient-years). MMF = mycophenolate mofetil.

  • By descending frequency of system organ class during the double-blind study period in the belimumab treatment group.

  • By descending frequency of Medical Dictionary for Regulatory Activities (MedDRA) preferred term during the double-blind study period in the belimumab treatment group.

  • §

    Infusion reactions included >160 MedDRA preferred terms (e.g., erythema, flushing, rash, urticaria) occurring on the day of an infusion and having a duration of ≤7 days. Hypersensitivity reactions were those that started on the day of an infusion (regardless of duration) and were defined according to the following MedDRA preferred terms: anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock, angioedema, drug hypersensitivity, hypersensitivity, and tachyphylaxis.

Total no. of patient-years109.9320.1374.0299.1258.1234.2
AEs/100 patient-years      
 AEs110 (100.1)326 (101.8)413 (110.4)322 (107.7)260 (100.8)237 (101.2)
 Serious AEs22 (20.0)55 (17.2)70 (18.7)52 (17.4)49 (19.0)31 (13.2)
 Severe AEs21 (19.1)63 (19.7)81 (21.7)43 (14.4)38 (14.7)23 (9.8)
 Serious and/or severe AEs31 (28.2)86 (26.9)112 (29.9)70 (23.4)55 (21.3)40 (17.1)
 Discontinuations due to AEs8 (7.3)21 (6.6)24 (6.4)8 (2.7)5 (1.9)8 (3.4)
Incidence rates of AEs by system organ class (≥50/100 patient-years in double-blind study)      
 Infections/infestations82 (74.6)254 (79.4)313 (83.7)237 (79.3)192 (74.4)181 (77.3)
 Musculoskeletal/connective tissue disorders79 (71.9)222 (69.4)273 (73.0)209 (69.9)150 (58.1)133 (56.8)
 Skin/subcutaneous tissue disorders57 (51.9)193 (60.3)219 (58.5)133 (44.5)83 (32.2)69 (29.5)
 Gastrointestinal disorders63 (57.3)187 (58.4)223 (59.6)149 (49.8)102 (39.5)74 (31.6)
 Nervous system disorders53 (48.2)168 (52.5)187 (50.0)124 (41.5)84 (32.6)72 (30.7)
 General disorders/administration site conditions63 (57.3)165 (51.6)191 (51.1)128 (42.8)74 (28.7)58 (24.8)
Top 6 most frequently observed AEs not of special interest, by MedDRA preferred term      
 Arthralgia40 (36.4)111 (34.7)128 (34.2)97 (32.4)63 (24.4)53 (22.6)
 Headache26 (23.7)94 (29.4)103 (27.5)52 (17.4)32 (12.4)28 (12.0)
 Fatigue34 (30.9)87 (27.2)94 (25.1)56 (18.7)22 (8.5)17 (7.3)
 Nausea27 (24.6)86 (26.9)95 (25.4)46 (15.4)29 (11.2)22 (9.4)
 Diarrhea19 (17.3)61 (19.1)67 (17.9)32 (10.7)29 (11.2)11 (4.7)
 Arthritis19 (17.3)57 (17.8)65 (17.4)34 (11.4)11 (4.3)14 (6.0)
Infusion reactions, including hypersensitivity§      
 Overall23 (20.9)79 (24.7)87 (23.3)32 (10.7)14 (5.4)14 (6.0)
 Serious and/or severe1 (0.9)1 (0.3)01 (0.3)1 (0.4)0
 Resulted in discontinuation1 (0.9)1 (0.3)1 (0.3)01 (0.4)0
Infections      
 Serious and/or severe5 (4.5)23 (7.2)31 (8.3)18 (6.0)10 (3.9)11 (4.7)
 Resulted in discontinuation1 (0.9)3 (0.9)3 (0.8)001 (0.4)
Most frequent infection AEs, by MedDRA preferred term (≥10/100 patient-years in double-blind study)      
 Upper respiratory tract infection33 (30.0)101 (31.6)118 (31.6)78 (26.1)65 (25.2)67 (28.6)
 Urinary tract infection18 (16.4)55 (17.2)62 (16.6)44 (14.7)37 (14.3)26 (11.1)
 Sinusitis21 (19.1)43 (13.4)52 (13.9)48 (16.1)56 (21.7)28 (12.0)
 Bronchitis8 (7.3)32 (10.0)37 (9.9)29 (9.7)35 (13.6)25 (10.7)
Infection AEs by baseline immunosuppressant use      
 No immunosuppressants, no.58167211164135119
 Patient-years, no.56.1154.8183.1146.3125.8112.0
 Overall infections40 (71.3)130 (84.0)159 (86.8)113 (77.2)95 (75.5)80 (71.4)
 Serious and/or severe2 (3.6)11 (7.1)13 (7.1)8 (5.5)3 (2.4)3 (2.7)
Immunosuppressants including MMF, no.55169213175139129
 Patient-years, no.53.9165.3190.9152.8132.3122.2
 Overall infections42 (78.0)124 (75.0)154 (80.7)124 (81.2)97 (73.3)101 (82.7)
 Serious and/or severe3 (5.6)12 (7.3)18 (9.4)10 (6.5)7 (5.3)8 (6.5)
Non-MMF immunosuppressants, no.3711714712910092
 Patient-years, no.37.7118.4137.5110.294.586.6
 Overall infections26 (68.9)85 (71.8)104 (75.6)91 (82.6)69 (73.0)69 (79.7)
 Serious and/or severe1 (2.7)5 (4.2)11 (8.0)7 (6.4)2 (2.1)7 (8.1)
MMF, no.185266463937
 Patient-years, no.16.247.053.442.637.835.6
 Overall infections16 (99.1)39 (83.0)50 (93.7)33 (77.5)28 (74.2)32 (90.0)
 Serious and/or severe2 (12.4)7 (14.9)7 (13.1)3 (7.0)5 (13.2)1 (2.8)
Infection AEs by baseline corticosteroid use      
 No corticosteroids, no.311121411179992
  Patient-years, no.29.1107.5126.9105.894.089.0
  Overall infections21 (72.2)87 (80.9)106 (83.5)82 (77.5)70 (74.4)70 (78.7)
  Serious and/or severe3 (2.8)4 (3.2)3 (2.8)2 (2.1)4 (4.5)
 Corticosteroids, no.82224283222175156
  Patient-years, no.80.8212.5247.1193.3164.0145.3
  Overall infections61 (75.5)167 (78.6)207 (83.8)155 (80.2)122 (74.4)111 (76.4)
  Serious and/or severe5 (6.2)20 (9.4)27 (10.9)15 (7.8)8 (4.9)(4.8)

Deaths.

Five deaths occurred during the 4 years of belimumab exposure, with an incidence rate of 0.4/100 patient-years (95% confidence interval [95% CI] 0.14–1.0). Two deaths occurred during the double-blind period: 1 suicide in a patient with history of depression who was receiving belimumab 1 mg/kg, and 1 death from aspiration pneumonia that led to sepsis and respiratory failure in a patient who was receiving belimumab 10 mg/kg. Three deaths occurred during the long-term continuation period: 1 death from advanced atherosclerotic coronary artery disease in a patient with a history of hypertension (during year 2), 1 suicide due to oxycodone and alcohol intoxication (during year 3), and 1 death from cytomegaloviral (CMV) pneumonia (during year 4). Only the case of CMV pneumonia was considered by the investigator to be possibly related to the study agent. That patient died of respiratory failure that was considered to be secondary to pneumonia and immunosuppression. The patient had history of pneumonia and, in addition to the belimumab, was taking several concomitant immunosuppressants, including corticosteroids, methotrexate, and leflunomide.

Adverse events of special interest.

Infusion reactions.

Rates of infusion reactions, including hypersensitivity reactions, were similar with placebo and belimumab during the double-blind period (20.9 and 24.7/100 patient-years, respectively). During the long-term continuation period, the rate decreased to 6.0/100 patient-years by year 4, with nausea and headache reported most frequently (Table 2). Two severe and/or serious infusion reactions were reported: a patient in year 2 with vertigo, and a patient in year 3 with symptoms of dyspnea, nausea, vomiting, mouth swelling, chest tightness, abdominal pain, and difficulty breathing, which resolved on the day of occurrence, but resulted in discontinuation of belimumab. Hypersensitivity reactions were only observed during the first year of belimumab exposure, were infrequent, and included 3 patients with angioedema (2 discontinued [1 receiving placebo and 1 receiving belimumab] during the double-blind period) and 1 with hypersensitivity from environmental allergies.

Infections.

Infection rates remained stable during the long-term continuation period (Table 2). Upper respiratory tract and urinary tract infections, sinusitis, and bronchitis were the most frequent infections in year 1. Rates were comparable to those that had been seen with placebo during the double-blind period. The rate of serious and/or severe infections was highest in year 1 (8.3/100 patient-years) and declined in years 2–4. Individual serious infections occurred at a rate ≤2/100 patient-years in any yearly interval, and no specific infection predominated. Cellulitis and pneumonia were the most common serious infections in year 1 (1.3 and 0.8/100 patient-years, respectively), and the rates declined in years 2–4. In all, 4 infections resulted in discontinuation of belimumab in the 4-year analysis.

Opportunistic infections.

Two opportunistic infections were reported; both occurred during the long-term continuation period. One opportunistic infection reported during year 4 was assessed as not serious (coccidioidomycosis in an endemic area of Arizona) and was considered to be probably not related to study drug, and the patient continued to receive belimumab treatment. The other opportunistic infection (fatal CMV pneumonia) also occurred during year 4 (described above).

Immunosuppressant use and infection rates.

The proportions of patients taking ≥1 immunosuppressant over the 4 yearly intervals during the study were fairly constant (49–54%) (Figure 3). Incidence rates for overall and serious and/or severe infections during the double-blind period were similar or numerically higher for patients receiving belimumab as compared with placebo, regardless of the use of immunosuppressants at baseline (Table 2). Compared with year 1 of exposure, the rates of overall and serious and/or severe infections were stable or decreased during the following 3 years of belimumab treatment regardless of the use of immunosuppressants at baseline.

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Figure 3. Percentages of systemic lupus erythematosus patients receiving an immunosuppressant or corticosteroid over the 4 years of study.

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During the double-blind period, patients who were taking mycophenolate mofetil (MMF) at baseline had a higher incidence of overall and serious and/or severe infections than other patients, regardless of whether they received placebo or belimumab (Table 2). During the 4-year exposure period, serious and/or severe infection rates ranged from 2.1 to 8.1/100 patient-years in patients who did not receive MMF and from 2.8 to 13.2/100 patient-years in those who did receive MMF. The cumulative rate of serious and/or severe infections in patients who received MMF with belimumab over 4 years was 1.5-fold greater than that in patients who received immunosuppressants other than MMF with belimumab (9.4 versus 6.3/100 patient-years). Patients who took MMF and those who did not had similar levels of IgG, IgA, and IgM over time (data not shown).

Corticosteroid use and infection rates.

Sixty-seven percent of patients receiving belimumab were taking corticosteroids at baseline, with an average dosage of 9.9 mg/day (Table 1). The proportion of patients taking corticosteroids over the 4 yearly intervals during the study decreased 9% from years 1 to 4, and the average corticosteroid dose was reduced after the first year of therapy (Figure 3). In these patients, the average median percentage change from baseline for the last 30 days of a 1-year interval were 0%, −25%, −33%, and −50% for years 0–1, 1–2, 2–3, and 3–4, respectively. During the double-blind period, rates of overall infections by corticosteroid use at baseline were similar regardless of whether patients received placebo or belimumab (Table 2). Compared with year 1 of exposure, rates of overall and serious and/or severe infections were decreased during the following 3 years of belimumab treatment regardless of the use of corticosteroids. Serious and/or severe infection rates were, however, 2.5-fold higher in patients receiving corticosteroids than in those receiving no corticosteroids at baseline.

Baseline demographic data, including SLE disease activity, autoantibodies, low complement levels, and B cell subsets, were evaluated in patients treated with prednisone and/or MMF as compared with those not treated with prednisone and/or MMF. There were no significant differences in distribution across treatment groups. In patients treated with MMF and those not treated with MMF at baseline, SLE disease activity, autoantibodies, low complement levels, and B cell subsets were similar, except that patients treated with MMF were more likely to have renal disease with proteinuria >1.0 gm/24 hours. In patients treated with prednisone and those not treated with prednisone at baseline, there were no significant differences in the Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index, the physician's global assessment scores, and SLE plasma cells. There were, however, greater proportions of patients treated with prednisone than those not treated with prednisone who had British Isles Lupus Assessment Group A scores (renal and vasculitis), autoantibodies, and low complement levels at baseline, but patients treated with prednisone had a lower number of B cells.

Malignancies.

Malignancies (excluding nonmelanoma skin cancers) occurred at a rate of 0.34/100 patient-years (95% CI 0.09–0.88) during the 4-year exposure period: 2 solid organ cancers (lung cancer with metastases to bone and bone marrow in year 2, and breast cancer in year 3) and 2 hematologic malignancies (B cell lymphoma in year 2, and multiple myeloma in year 4) were reported in 4 patients. Seven nonmelanoma skin cancers were reported during the 4-year exposure period: 3 squamous cell carcinomas (1 in year 1, and 2 in year 4) and 4 basal cell carcinomas (2 in year 2, 1 in year 3, and 1 in year 4); the average age of these patients was 61.7 years (range 53–72 years).

Abnormal laboratory findings (grade 3 or 4).

Rates of grade 3 or 4 abnormal laboratory findings were similar with placebo and belimumab during the double-blind portion of the study (23). In year 1 of exposure, grade 3 or 4 lymphopenia and increased prothrombin time (PT) occurred in ≥14% of patients (Table 3). In the long-term continuation study, laboratory testing of PT time was not required and was only performed if the investigators deemed it to be clinically indicated. Most patients (75–100%) with elevated PT (grades 3/4) were receiving warfarin. The remaining grade 3 or 4 abnormal laboratory findings occurred in ≤6.9% of patients and either remained stable or declined through the following 3 years of treatment. Other grade 3 or 4 abnormal laboratory findings (liver function, clinical chemistry, and electrolytes) occurred in <2% of patients and did not increase over time (data not shown).

Table 3. Grade 3 or 4 abnormal laboratory findings occurring during belimumab exposure (2%/100 patient-years in any year interval) and immunoglobulin changes
 Year 1 (n = 424)Year 2 (n = 339)Year 3 (n = 274)Year 4 (n = 248)
  • *

    Values in parentheses represent grade 3 abnormal laboratory values and are provided as a reference.

  • During the long-term continuation period, the protocol did not require regularly scheduled prothrombin time assessments. Assessments were performed only when the investigators deemed it to be clinically indicated. At years 1–4, a total of 421, 274, 37, and 39 patients, respectively, were assessed. Of the patients with grades 3/4 prothrombin time, 75%, 85%, 100%, and 100% were receiving warfarin at years 1–4, respectively.

  • At years 1–4, a total of 418, 337, 272, and 247 patients, respectively, were assessed.

% with grade 3 or 4 abnormal laboratory findings*    
 White blood cells (<2,000/mm3)3.34.22.62.0
 Neutrophils (<1,000/mm3)6.45.64.44.9
 Lymphocytes (<500/mm3)22.019.314.313.4
 Hemoglobin (≤8.0 gm/dl)2.61.50.41.2
 Prothrombin time (>1.5× upper limit of normal)14.312.024.317.9
 Proteinuria (24-hour collection; ≥2 gm/24 hours)6.93.61.51.2
 Hypogammaglobulinemia (≤399 mg/dl)1.91.21.11.2
Median % change in Ig levels from baseline    
 IgG−9.1−10.9−10.2−12.9
 IgA−11.9−14.2−15.4−17.9
 IgM−25.9−35.6−41.2−46.6
 IgE−28.7−35.7−40.0−45.5

Immunoglobulins.

During 4 years of belimumab exposure, the median levels of IgG and IgA declined slightly after year 1 compared with baseline and remained stable over the following 3 years (Table 3). The median IgM and IgE levels declined further after year 1 of therapy. The frequency of grade 3 hypogammaglobulinemia (250–399 mg/dl) was 1.9% in year 1, did not change from years 2 to 4 (Table 3) and was not associated with increases in infection rates (including severe and/or serious infections [data not shown]). No patients experienced grade 4 hypogammaglobulinemia (<250 mg/dl) or discontinued belimumab due to hypogammaglobulinemia.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

This report describes safety data in patients with moderate-to-severe SLE disease activity at baseline despite receiving standard therapy for the disease who were exposed to belimumab for 4 years, which is the longest reporting period from an ongoing trial of a biologic agent in patients with SLE. The long-term continuation study allowed for standard therapy to continue as needed along with belimumab, with no therapeutic modifications mandated to the physicians or their patients. The demographic and other baseline characteristics of the population of patients who elected to participate in the long-term continuation study were similar to those of the study population enrolled in the double-blind trial, which addresses the risk of selection bias at the start of the study (23). It can, however, be expected that the population of patients who entered the long-term study and continued throughout the 4 years may have been enriched in individuals who responded best to belimumab or tolerated this treatment better.

During the 4 years of belimumab treatment, no new safety concerns emerged. Interpretation is, however, limited because there was no control group in the long-term continuation study. In 2 large phase III placebo-controlled studies of belimumab that lasted for 52 or 76 weeks, the incidence rates of AEs (including serious AEs and infections) were similar in the belimumab and placebo groups (25, 26). The data in the present long-term analysis are consistent with the findings in the phase II and phase III placebo-controlled trials; that is, no specific patterns of infections and no increase in the incidence or severity of AEs were observed (23, 25, 26).

Individuals with SLE have a 2–5-fold increased risk of death as compared with the general population (15, 16). The most common causes of death in patients with SLE are cardiovascular disease, infections (especially pneumonia), renal disease, and complications of lupus disease activity (7, 16). The mortality rate of 0.4/100 patient-years observed in the long-term continuation study of belimumab is less than the rate of 1.63 reported in the literature for SLE patients (16), although the historical rate may be an overestimate, given decreases in SLE mortality rates seen over time, and patients in a clinical trial may be followed up and monitored differently from those in a practice setting (27). Notably, there did not appear to be an increased risk of death associated with belimumab treatment over the 4-year period.

The malignancies (excluding nonmelanoma skin cancer) occurring in patients in the present study are consistent with those expected in an SLE population largely composed of women, and the malignancy rate (0.34/100 patient-years) is similar to the background rate reported in patients with SLE (0.53/100 patient-years) (12). In the long-term continuation study, serious infusion reactions were rare, and the discontinuation rate due to AEs or infections was low and declined over time. Although this may reflect a survivor bias, and patients who may have been more prone to AEs may have been depleted from the study population earlier on, the data suggest that most patients avoided major AEs with belimumab for ≥1 year, and once they reached the 1-year milestone, the likelihood of continuing to do well for up to 4 years was increased.

Several novel targeted biologic therapies have been studied for the treatment of SLE, and it could be hoped that targeted immune modulators may be safer than global immunosuppression, especially with regard to serious infections (28, 29). Mycophenolate mofetil has been used to prevent rejection of transplanted tissue and to treat patients with SLE and lupus nephritis (6, 30, 31). Although it is an effective drug, MMF has been associated with an increased risk of infections and gastrointestinal disorders in clinical trials (30, 32, 33). In comparison with other background treatments (e.g., non-MMF immunosuppressants or no immunosuppressants), the use of MMF at baseline in the present long-term belimumab study was associated with increased rates of serious and/or severe infections over the 4 years of treatment, but this was not reflected in the overall infection rates or Ig levels. High-dose corticosteroids are associated with significant morbidity, including osteoporosis, osteonecrosis, metabolic disorders, infections, weight gain, and hyperlipidemia (3, 4). Similar to the use of MMF, there was an increased risk of serious and/or severe infections, but not overall infections, in patients in the present study who were taking corticosteroids at baseline. The overall use of immunosuppressive agents was fairly constant over 4 years, whereas corticosteroid use decreased.

In this long-term continuation analysis, belimumab was safe and generally well-tolerated over 4 years of treatment in combination with standard therapy for SLE. An important finding of this study was the ability to safely maintain a significant proportion of the original treatment population on combination treatment for this prolonged period of time. Given the heterogeneity of the SLE population and the propensity of many immunosuppressants to cause toxicities in the long term, this provides initial groundwork upon which to build more effective and more tolerable combination treatment strategies for SLE.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Merrill had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Merrill, Ginzler, Wallace, McKay, Condemi, Zhong, Pineda, Klein, Freimuth.

Acquisition of data. Merrill, Ginzler, Wallace, McKay, Lisse, Aranow, Wellborne, Burnette, Condemi, Zhong, Pineda, Freimuth.

Analysis and interpretation of data. Merrill, Ginzler, Wallace, McKay, Lisse, Aranow, Wellborne, Burnette, Condemi, Zhong, Pineda, Klein, Freimuth.

Medical monitor. Klein.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Human Genome Sciences, Inc. was involved in the conception, design, implementation, and supervision of the study, the data analysis and interpretation, the statistical analysis, and the manuscript drafting, revision, and approval. GlaxoSmithKline was involved in the design of the study and the manuscript drafting, revision, and approval. Human Genome Sciences, Inc. and GlaxoSmithKline agreed to submit the manuscript for publication and approved the content of the manuscript. Editorial assistance in the development of the initial draft was provided by Shannon Benedetto (Human Genome Sciences, Inc.). Editorial support throughout the submission process was provided by Geoff Marx (BioScience Communications, New York, NY) and was funded by Human Genome Sciences, Inc. and GlaxoSmithKline. Publication of this article was contingent upon the approval of all of the authors as well as the approval of Human Genome Sciences, Inc. and GlaxoSmithKline.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

The authors wish to thank Shannon Benedetto (Human Genome Sciences, Inc.) and Geoff Marx (BioScience Communications, New York, NY) for editorial support.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES