Drug Evaluation
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Update on belimumab for the management of systemic lupus erythematosus 1.
Introduction
2.
Body of the review
3.
Conclusion
4.
Expert opinion
Pamela MK Lutalo & David P D’Cruz† †
St Thomas’ Hospital, Guy’ s and St Thomas’ Hospitals NHS Foundation Trust, Louise Coote Lupus Unit, London, UK
Introduction: Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug to be licensed and approved by the US FDA and the European Medicines Evaluation Agency for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE). The clinical effectiveness and impact of this drug on lupus morbidity and mortality is evaluated in this review. Areas covered: An overview of the efficacy and safety of belimumab based on 7-year longitudinal continuation study data from SLE patients enrolled in the Phase II double-blind, randomised, placebo-controlled, 52-week study of belimumab 1, 4 and 10 mg/kg doses and an overview of the open-label 24-week extension of belimumab plus standard immunosuppressant therapy. A review of the current belimumab clinical trials, the experience of belimumab in real-world settings and a description of the impact that belimumab has had on the healthcare quality of life of SLE patients. Expert opinion: The emerging clinical data have shed light on the areas in which belimumab is of greatest benefit and areas for further evaluation in clinical trials. It is anticipated that regular updates from ongoing trials of belimumab in SLE, practising physicians, data from the continuation arms of clinical trials and data from international biologics registries will have an influence on the role of belimumab in the management of SLE. Keywords: B cell depletion, B lymphocyte stimulator, belimumab, systemic lupus erythematosus Expert Opin. Biol. Ther. (2014) 14(11):1701-1708
1.
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease whose immunopathogenesis involves B cells, autoantibodies, immune complex deposition and complement dysregulation [1-3]. Environmental triggers such as ultraviolet light, infection and cigarette smoke, and hormonal factors such as oestrogen and genetic susceptibility contribute to the onset of disease [4,5]. SLE predominantly occurs in women, particularly from puberty to menopause, with a female to male ratio of 9:1 [6]. There is a relatively higher global prevalence of SLE in African-Americans, Afro-Caribbeans and Hispanics compared with Asians and Caucasians [7]. SLE may manifest as mild, moderate or severe disease, which may be associated with significant morbidity and mortality. Physicians manage systemic manifestations of active lupus and lupus symptoms with a wide array of therapeutic interventions including analgesia, NSAIDs, anti-malarial drugs: hydroxychloroquine and mepacrine, immunosuppressant drugs -- azathioprine, cyclophosphamide, ciclosporin A, methotrexate, mycophenolate mofetil, tacrolimus -- and biological drugs -- rituximab and belimumab (Box 1).
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Box 1. Drug summary. Drug name Phase Indication Pharmacology Route of administration
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Pivotal trials
Belimumab US FDA approved 2011 European Medicines Evaluation Agency approved 2011 Seropositive adult SLE patients excluding patients with lupus nephritis and CNS manifestations of SLE B-Lys-specific inhibition B lymphocyte stimulator antagonist mAb Intravenous infusion belimumab 10 mg/kg at 2-week intervals for three doses followed by weight-based infusions 10 mg/kg every 4 weeks Phase I clinical trial Phase II clinical trial Phase III clinical trials BLISS-52 and BLISS-76 Belimumab in SLE study randomised placebo-controlled trials Primary end point SLE responder index response at week 52
B-Lys: B lymphocyte stimulator; SLE: Systemic lupus erythematosus.
Biological drugs targeting B cells are the new frontier in lupus management and may revolutionise the management of this complex disease [8]. Since 2011, the biological drug belimumab, which is a fully humanised mAb against B lymphocyte stimulator (B-LyS), has been licensed and approved by the US FDA and the European Medicines Evaluation Agency (EMEA). The license is for autoantibody-positive SLE, which remains moderately to severely active despite optimised standard immunosuppression. It excludes severe lupus nephritis and cerebral lupus, which were not evaluated in the Phase III randomised placebo-controlled clinical trials Belimumab International SLE Study BLISS-52 and BLISS-76 [9,10]. Overall clinical effectiveness in inducing and maintaining disease remission is important as is the prevention of chronic damage, organ failure and the reduction of the disease or concomitant drug-related morbidity. The Phase II, randomised, double-blind, placebo-controlled, belimumab doserange trial evaluated the biological activity, tolerability, safety and efficacy of belimumab in combination with standard immunosuppressant therapy in active SLE. The BLISS-52 and BLISS-76 Phase III randomised, double-blind, placebocontrolled clinical trials demonstrated the clinical effectiveness of intravenous (i.v.) belimumab 10 mg/kg infusions in combination with standard, optimised immunosuppressant drugs, except other biologics and cyclophosphamide [9,10]. This review will provide an overview of the efficacy and safety of belimumab based on longitudinal continuation study data from SLE patients enrolled in the Phase II double-blind, randomised, placebo-controlled, 52-week dose-ranging belimumab trial and the open-label 24-week extension study of belimumab in combination with standard immunosuppressant drugs. The current clinical experience of belimumab in real-world settings and the impact that belimumab has had on the healthcare quality of life of SLE patients will be discussed in this review. Ongoing clinical trials aimed at addressing important questions concerning the role of belimumab in lupus nephritis, patients of African ancestry and the possibility of 1702
an alternative route of administration, such as the subcutaneous route, will be discussed in this review. 2.
Body of the review
Clinical effectiveness of belimumab Evidence from the 7-year longitudinal continuation study data
2.1
2.1.1
In order to define clinical effectiveness in SLE clinical trials, a new measure of efficacy was devised called the SLE Responder Index (SRI), which combines data from the British Isles Lupus Assessment Group (BILAG) scores, SELENA-SLEDAI scores and Physicians’ Global Assessment (PGA) [11]. The SRI is defined as ‡ 4 point reduction in SELENA-SLEDAI, no new BILAG A score and £ 1 new BILAG B score and no worsening of the PGA score, which is an increase of ‡ 0.3 from baseline [11]. The clinical effectiveness of belimumab was demonstrated in the randomised, double-blind, placebo-controlled clinical trials BLISS-52 and BLISS-76. In BLISS-52, 58% of the autoantibody-positive SLE patients in the 10 mg/kg belimumab group met the SRI response criteria at week 52 compared with 44% of the SLE patients in the placebo group at week 52 [9,10]. In the BLISS-76 trial, 43.2% of SLE patients in the 10 mg/kg belimumab group were SRI responders compared with 33.5% in the placebo group at 52 weeks, although at 76 weeks there was no significant difference between the treatment arms [10,11]. A longitudinal continuation study of SLE patients enrolled in the Phase II belimumab trial is ongoing. The main aim of this study is to evaluate the efficacy and safety of belimumab plus standard immunosuppressant therapy beyond the 76-week clinical trial time period [13]. The following measures of clinical efficacy are being assessed during this continuation study: . Concomitant medication including medication for SLE
disease control such as corticosteroids and immunosuppressants recorded every 4 weeks.
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. . . . .
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PGA measured every 8 weeks. BILAGs measured every 16 weeks. SELENA-SLEDAI measured every 16 weeks. SLE Flare Index (SFI) measured every 16 weeks. Complement levels (C3 and C4) measured every 16 weeks. . Autoantibody titres measured every 16 weeks. It should be noted that disease activity indices and laboratory markers of active lupus are only measured once every 16 weeks, which may result in under-reporting or detection of lupus flares between clinic assessments. To date, the 7-year longitudinal study data from the Phase II belimumab clinical trials have been published as follows: . Year 1: pooled data of SLE patients total n = 424, which
constitutes SLE patients treated with belimumab i.v. 1, 4 or 10 mg/kg during the double-blind study (n = 336) and SLE patients switched from placebo to belimumab 10 mg/kg in the continuation phase (n = 88). . Year 2: all patients in the longitudinal continuation study were treated with belimumab n = 339. In total, 19 patients continued belimumab i.v. 1 mg/kg and 23 patients continued belimumab i.v. 4 mg/kg during the 24-week extension phase of the clinical trial. . Years 3 -- 7: all patients were treated with belimumab i.v. 10 mg/kg. A total of 296 patients were enrolled in the long-term continuation study at the end of 76 weeks of the belimumab; however, only 177 patients remain in this study to date [13]. SRI response by year 2 was achieved in 57% of belimumabtreated patients [13]. SRI response by year 7 was achieved in 65% of belimumab-treated patients [13]. The majority of patients in the continuation study cohort are autoantibody positive (n = 135). The percentage of autoantibody-positive patients who achieved SRI response at year 1 was 46, year 2 was 57 and years 3 -- 7 was 55 -- 65. The percentage of autoantibody-negative patients who achieved SRI response at year 1 was 44, year 2 was 48 and years 3 -- 7 was 58 -- 69 [13]. Evidence from the 7-year longitudinal continuation study data for SLE flare rates
2.1.2
The SFI was used to ascertain the proportion of patients who experienced lupus flares, in particular severe flares, in a given year. The data from years 1 -- 7 of the long-term continuation study show that belimumab-treated patients experiencing all types of lupus flares decreased from 70 to 40% and severe lupus flares decreased from 7 to 2% [13] in autoantibodypositive patients. Further analysis of the autoantibody-positive group compared with the autoantibody-negative group reveals that although there is no significant difference between the groups in the rate of all lupus flares during the 7-year
continuation phase, the rates of severe flares are higher in the autoantibody-negative group during years 3 -- 7 (decreasing from 13.2 to 6.5%) compared with the autoantibodypositive group (decreasing from 7 to 2%) [14]. In the long-term continuation study, years 2 -- 7 the BILAG 1A/2B flare rate decreased from 21 to 8% in the autoantibodypositive cohort. The autoantibody-negative cohort had a variable decline in BILAG 1A/2B flare rates from year 2 (18.2%) to year 7 (12.8%) and had generally higher BILAG 1A/2B flare rates in year 1 (31.6%) compared with the autoantibody-positive cohort [14]. Evidence from the 7-year longitudinal continuation study data: PGA
2.1.3
In the long-term continuation study year 7, the PGA mean percentage change improved to -48% in belimumab-treated autoantibody-positive patients. Interestingly, although the PGA response in the autoantibody-negative patients was relatively lower in years 1 and 2 (-24.7 and -35%, respectively), the improvement was greater in years 3 to 7 (-49.2 to -61.3%, respectively) compared with the autoantibody-positive patients [14]. Evidence from the 7-year longitudinal continuation study data: laboratory data
2.1.4
Complement normalisation from low baseline C3 and C4 was evident during the double-bind period of the belimumab Phase II clinical trial, with 21% of patients normalising C3 in both the placebo and belimumab groups and 24 and 38% of patients normalising C4 in the placebo and belimumab groups, respectively [9,10]. Over 7 years of belimumab treatment, 66% of patients achieved normalised C3 and 71% patients achieved normalised C4 [13]. The titres of serum IgG autoantibodies, such as antibodies to ribonucleoprotein, anti-Smith, antibodies to double stranded DNA (antidsDNA) and anti-cardiolipin, generally decreased between years 1 and 7 in the belimumab-treated patients [14]. Evidence from the 7-year longitudinal continuation study data: corticosteroid and concomitant immunosuppressant drug usage
2.1.5
There was a 25% reduction in the corticosteroid dose and median absolute reduction of 2 mg/day of corticosteroid by year 2 of belimumab treatment. By year 7, there was a 55% reduction in the corticosteroid dose and median absolute reduction of 4 mg/day of corticosteroid. Between years 2 and 7, 13.2 and 20% of patients increased the dose of prednisone. The percentage of patients who were treated with corticosteroids decreased from 73.9% at year 2 to 65.2% at year 7 [14]. During years 1 -- 4, there was a steady state in the percentage of patients prescribed concomitant immunosuppressants; however, this declined from years 5 -- 7 from a baseline immunosuppressant use of 53.5 to 39.5%, with the greatest change
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being in the methotrexate-treated group (baseline 18.2% to year 7 10%) [13]. New immunosuppressant therapy was added in 0.5 -- 2.8% as documented in the 16-week interval data [13].
Clinical practice experience in North America and Europe
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2.1.6
The OBSErve study was a multicentre, retrospective, medical chart review study conducted in the US. The primary objective was to evaluate the characteristics and outcomes of SLE patients who were treated with belimumab in clinical practice over a 6-month period, and the secondary objective was to describe the healthcare resource utilisation among patients who received treatment with belimumab [14]. The data were selected from community-based rheumatology practices in which ‡ 10 SLE patients were treated and were based on physician judgement of clinical improvement and are presented below [14]. The study collected observational data from 501 SLE patients at a baseline time point of 6 months prior to belimumab treatment and data at 6 months post-initiation of belimumab in combination with standard immunosuppressant drugs. The overall physician impression of clinical response after eight infusions of belimumab over 6 months was reported as a categorical scale of < 20%, ‡ 20%, ‡ 50% and ‡ 80% improvement. After 6 months of belimumab in combination with standard immunosuppressant drugs, the overall physician impression of clinical response was 88% of the patients showing 20% improvement, 49% of the patients showing ‡ 50% improvement and 11% of the patients showing ‡ 80% improvement from baseline and only 1% of the patients reported to have no change in clinical disease activity postbelimumab treatment. A total of 297 of the 368 patients received corticosteroids at baseline. Corticosteroids were successfully discontinued in 9% of these patients, 13% were on the baseline dose of corticosteroid dose at 6 months post-belimumab, 86% patients were able to successfully decrease the dose of corticosteroids, and 2% patients were on a higher dose of corticosteroids at 6 months compared with baseline. The average reduction in corticosteroid dose was 11.5 ± 12.2 mg prednisone equivalent over the 6-month period. Patients experienced fewer inpatient hospital admissions after belimumab compared with before belimumab, with 2% patients having ‡ 1 hospital admission 6 months postbelimumab compared with 5% patients pre-belimumab. 15% of the patients had ‡ 1 emergency room visit at baseline compared with 6% patients 6 months after belimumab. The frequency of unscheduled medical visits at baseline was also reduced in belimumab-treated patients with 30% of patients post-belimumab having ‡ 1 unscheduled physician visits compared with 52% patients pre-belimumab. Limitations of this observational study are the lack of a control group of 1704
belimumab-naive SLE patients for comparison and the lack of adverse event reporting or safety data. Impact of belimumab on health-related quality of life in SLE
2.1.7
Although the BLISS trials were not individually powered to detect statistically significant differences in health-related quality of life (HRQOL) measures such as short-form 36 (SF-36) FACIT-Fatigue and EQ-5D scores with belimumab plus standard treatment versus standard treatment alone, a post hoc analysis of pooled data is able to demonstrate the benefit of belimumab on HRQOL in SLE patients. The mean SF-36 mental component scores (MCS) physical component summary (PCS) scores improved significantly from baseline in the belimumab treatment groups at week 52 and MCS at week 76 compared with placebo group. The pooled analysis of both belimumab groups in the BLISS trials showed evidence of improvement at week 52 in FACITFatigue scores, SF-36 vitality domain and SF-36 PCS scores [15]. Clinical safety and tolerability of belimumab Evidence from the 7-year longitudinal continuation study data: adverse events
2.2
2.2.1
The longitudinal continuation study data from the SLE patients enrolled in the Phase II randomised, double-blind, placebo-controlled 52-week trial and 24-week open-label extension trial of belimumab and standard immunosuppressants have been collected to ascertain the safety of belimumab using clinical and laboratory reported data on adverse events [16]. Adverse Event Severity Grading Tables modified from the US National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Disease Adult Toxicity Tables have been used to organise the reported adverse events into different grades of severity [13]. Adverse event rates were calculated as the number of adverse events per 100 patient-years for each 1-year interval. During the long-term continuation study, the incidence of adverse events remained stable or declined overall during 7 years of belimumab treatment. Evidence from the 7-year longitudinal continuation study data: infections
2.2.2
Infections were the most common reported adverse event years 1 -- 7 [13]. . Overall infections: 83.7/100 patient-years in year 1,
79.2/100 patient-years in year 2, 74.4/100 patient-years in year 3, 77.3/100 patient-years in year 4, 67.2/100 patient-years in year 5, 63.8/100 patients-years in year 6 and 76.6/100 patient-years in year 7. . Serious infections: 5.9/100 patient-years in year 1, 4.7/100 patient-years in year 2, 3.1/100 patient-years in year 3, 3.4/100 patient-years in year 4, 2.8/100
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patient-years in year 5, 4/100 patients-years in year 6 and 3/100 patient-years in year 7. Upper respiratory tract infections were the commonest recorded infection in this study. Evidence from the 7-year longitudinal continuation study: hypogammaglobulinemia
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2.2.3
Grade 3 -- 4 hypogammaglobulinemia (< 400 mg/dl) was reported in 1.1 -- 2.6% of patients treated with belimumab, many of whom had a baseline grade 1 -- 3 hypogammaglobulinemia. Interestingly, this was not associated with an increase in the serious infection rate [13]. Belimumab was discontinued in four patients due to hypogammaglobulinemia. Evidence from the 7-year longitudinal continuation study data: infusion reactions and hypersensitivity
2.2.4
Infusion reactions were documented according to a list generated from > 160 Medical Dictionary for Regulatory Activities (MedDRA) preferred terms such as rashes, erythema, flushing and urticaria. Infusion reactions were defined as occurring on the day of belimumab infusion and up to 7 days post-infusion. Hypersensitivity reactions were defined as MedDRA-preferred terms that started on the day of belimumab infusion regardless of adverse event duration: anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock, angioedema, drug hypersensitivity, hypersensitivity and tachyphylaxis [13]. Hypersensitivity reactions were only observed in the first year of treatment. Infusion reaction rates were documented in the long-term continuation study data [14]. . Infusion reaction rates 23.3/100 patient-years in year 1,
10.7/100 patient-years in year 2, 5.4/100 patient-years in year 3, 6/100 patient-years in year 4, 3.7/100 patient-years in year 5, 3/100 patients-years in year 6 and 1.2/100 patient-years in year 7. . The one and only serious infusion reaction occurred in year 3 0.4/100 patients-years.
Evidence from the 7-year longitudinal continuation study data: malignancies
2.2.5
Malignancies excluding non-melanoma skin cancers occurred at a rate of 0.7/100 patient-years (95% CI 0.4 -- 1.27) during the 7 years of the long-term continuation study [13]. Comparison may be made with the overall SLE patient background malignancy rate of 0.53/100 patient-years [17]. . Malignancy rates 0.3/100 patient-years in year 1, 1.7/
100 patient-years in year 2, 1.2/100 patient-years in year 3 n = 3, 1.7/100 patient-years in year 4, 1.9/100 patient-years in year 5, 2.5/100 patients-years in year 6 and 1.2/100 patient-years in year 7.
. Years 1 -- 4: two solid organ malignancies, two haemato-
logical malignancies and seven non-melanoma skin cancers were reported. . Years 5 -- 7: breast cancer (years 5, 6 and 7), colon cancer (year 5), malignant melanoma (year 5), renal cell carcinoma (year 5) and lung cancer (year 6). Four nonmelanoma skin cancers were reported in years 5 -- 7, which included squamous cell carcinoma (n = 2 in year 6 and n = 1 in year 7) and one basal cell carcinoma in year 6.
Evidence from the Phase II and Phase III belimumab clinical trials: mortality
2.2.6
The pooled data from the Phase III randomised, doubleblind, placebo-controlled trials BLISS-52 and BLISS-76, Phase II randomised, double-blind, placebo-controlled trial of belimumab and standard immunosuppressant drugs in SLE and the 7-year longitudinal continuation study data from the SLE patients enrolled in the Phase II belimumab trial report 11 deaths in the SLE patients treated with belimumab and standard immunosuppressant drugs. The reported cause of death is due to infection (n = 4), suicide (n = 2), SLE (n = 1), cardiac disease (n = 1), cerebrovascular disease (n = 1), malignancy (n = 1) and unknown aetiology (n = 1). The deaths reported in the 7-year longitudinal continuation study of SLE patients enrolled in the Phase II belimumab trial included five deaths in years 1 -- 4, no deaths in years 5 -6 and two deaths in year 7 [13]. The recent deaths have not been directly attributed to belimumab by the study investigators; however, it is important to note that during the BLISS clinical trials two patient suicides in the belimumab group were reported and there have been reports of a higher incidence of psychiatric symptoms, such as depression, in patients treated with belimumab. The mortality rate is 0.4/100 patient-years (95% CI 0.16 -- 0.83) that is below the published mortality rate for SLE patients, which is 1.63/100 patient-years [18]. Clinical practice experience of adverse events in North America and Europe
2.2.7
To date, there have been two spontaneous cases of progressive multifocal leukoencephalopathy (PML) in SLE patients treated with belimumab. One was a reported fatality related to PML that developed in a 40-year-old female lupus patient treated with belimumab and standard immunosuppressant drugs. She had initially been diagnosed with CNS lupus based on her neurological decline and MRI brain images. The belimumab was discontinued, she was treated with high-dose corticosteroids and two cycles of intravenous cyclophosphamide but her condition deteriorated and she was transferred to another institution where a repeat MRI brain scan showed multifocal, confluent areas of T2 hyperintensity in the cerebral white matter bilaterally and cerebrospinal fluid PCR was positive for JC virus, thus confirming that she had PML. She had received a total of 10 monthly belimumab
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infusions in addition of mycophenolate mofetil and low-dose prednisolone and had relatively mild lupus at the time of neurological deterioration, therefore the conclusion made by her physicians was that the PML was associated with immunosuppressant drug therapy [19].
the UK, the National Institute of Clinical Excellence (NICE) has not approved belimumab for SLE patients, therefore individual funding requests are required to treat SLE patients in the UK with belimumab. 3.
Current clinical trials in belimumab 2.3.1 Lupus nephritis
Conclusion
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2.3
BLISS-LN study is a Phase III, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of belimumab plus standard of care versus placebo plus standard of care in adult subjects with active lupus nephritis, which will provide clinically relevant information about the use of belimumab in lupus nephritis NCT01639339 (www. clinicaltrials.gov). A post hoc analysis of 267 SLE patients with renal disease at baseline in the BLISS trials indicated the possibility that belimumab in combination with mycophenolate mofetil could result in renal organ disease improvement [20]. The BLISS-LN study is powered to evaluate the efficacy of belimumab in active lupus nephritis. African ancestry A Phase III/IV multicentre, randomised, double-blind, placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult subjects of black race with SLE is planned as a new clinical trial NCT01632241 (www. clinicaltrials.gov). An exploratory analysis of the data from 148 black patients in the BLISS trials reported lower clinical effectiveness in this group of patients compared with other ethnic groups. This new clinical trial will be powered to evaluate this further and provide data that will be of use in clinical practice. 2.3.2
Subcutaneous belimumab BLISS-SC study is a Phase III, randomised, double-blind, placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab administered subcutaneously NCT014 84496 (www.clinicaltrials.gov). If positive, this study will reduce infusion costs and will be more acceptable to patients and clinicians. 2.3.3
Regulatory affairs The FDA and EMEA licensed and approved belimumab for the management of autoantibody-positive SLE patients who lack a clinical response to standard treatment. Regulatory bodies and health insurance companies may require fulfilment of these criteria prior to initiation of belimumab. At present, standard treatment is defined by the physician’s clinical judgement and usually consists of corticosteroids, an anti-malarial drug and one additional immunosuppressant: azathioprine, methotrexate or mycophenolate mofetil. Regulatory bodies often require objective documentation of the response to belimumab therapy to justify continuation of the treatment. This is usually recorded at 6 months post-initiation of belimumab. The cost of belimumab is a limiting factor in some regions. In 2.4
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The longitudinal long-term continuation study of SLE patients enrolled in the Phase II belimumab plus standard immunosuppressant therapy trial is evaluating the efficacy and safety of this therapeutic intervention beyond the 52-week randomised, double-blind, placebo-controlled clinical trial period, and the 24-week open-label extension period is ongoing. Observational clinical data from medical practice show that belimumab in combination with standard immunosuppressant drugs is efficacious and generally well tolerated for the long-term maintenance of clinical remission in SLE patients. 4.
Expert opinion
B cells play a crucial role in the immunopathogenesis of SLE as they develop into plasma cells that secrete pathogenic autoantibodies that lead to immune complex deposition. In addition, patients with autoimmune diseases such as SLE have significantly elevated serum B-LyS levels, therefore the inhibition of the B cell survival factor B-LyS, by belimumab, is a logical therapeutic intervention. There is a role for belimumab in the management of SLE patients. The serological improvement and normalisation of complement in the majority of SLE patients treated with belimumab parallels the overall improvement in disease activity scores and reduction in the SFI in belimumab-treated patients. The longitudinal continuation study data and clinical observational data report the clinical efficacy of belimumab in combination with standard immunosuppressant drugs in autoantibody-positive SLE patients who have active disease despite optimised standard therapy. In our opinion, this will remain the main indication for belimumab therapy. It is yet to be determined whether or not belimumab has a role as a first-line remission induction immunosuppressant therapy. In our opinion, belimumab may be beneficial early in the management of SLE after induction of disease remission as the significant reduction of the corticosteroid cumulative dose and lupus flare rates attributed to belimumab may limit damage accrual related to recurrent flares and corticosteroid use. The exact cohort of SLE patients who would benefit most from belimumab is being established. In our opinion, autoantibody-positive SLE patients with high dsDNA titres, low complement levels, active disease in predominantly mucocutaneous or musculoskeletal domains will benefit significantly from belimumab therapy, as evidenced by the clinical trial data. However, the question remains whether
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Belimumab
belimumab will be beneficial in autoantibody-negative SLE patients long term. This is mainly because unexpectedly the long-term continuation study data show evidence of clinical responsiveness to belimumab in years 3 -- 7 in the autoantibody-negative patients, which is numerically slightly superior to the autoantibody-positive patients as assessed by SRI and PGA. It is important to take into account when interpreting the long-term continuation study data that the patients were assessed for evidence of disease activity or flare once every 16 weeks after the end of the 76-week clinical trial period. This limits the opportunity to record flares or evidence of disease activity to these specific clinic visits, thereby increasing the chances of underreporting of SLE disease activity or flares. The role of belimumab in the management of severe systemic manifestations of SLE is being investigated. The current belimumab trial in severe lupus nephritis may provide information that will determine whether or not belimumab is beneficial in lupus nephritis. At present, belimumab is not recommended in cerebral lupus as it has not been evaluated in clinical trials and there are insufficient data to provide evidence of its efficacy in this situation. The ongoing clinical trials in SLE patients of African ancestry may provide useful information pertaining to the efficacy and safety of this drug in this ethnic group. Overall the belimumab safety profile is acceptable, with the long-term continuation study data complementing the clinical trial data in terms of low incidence of serious infections, malignancies and death. The occurrence of two cases of progressive multifocal leukoencephalopathy over the 7 years of belimumab treatment should be highlighted and physicians should remain vigilant in reporting this adverse event. It is likely that this indicates the susceptibility of heavily immunosuppressed patients to the reactivation of JC virus than a specific adverse event unique to belimumab as PML has been reported with rituximab and mycophenolate mofetil use. To date, there have not been any specific opportunistic infections or pattern to infections that have emerged from the 7-year study data to raise alarm. The level of hypogammaglobulinemia and lymphopenia has not been directly linked to the incidence of infections, although there has been a trend to discontinue belimumab in cases of severe hypogammaglobulinemia.
Bearing in mind the level of immunosuppression SLE patients generally experience, it may be worth investigating the possibility of using belimumab with anti-malarial drugs alone to ascertain the clinical effectiveness of this combination compared with the standard belimumab with conventional immunosuppressant combination. The question concerning duration of belimumab treatment is yet to be answered. However, the 7-year long-term continuation data indicate an increase in efficacy of belimumab with time, which is associated with an improvement in lupus biomarkers and a reduction in the corticosteroid dose or usage. Belimumab also reduces the incidence and severity of flares overall; therefore, at present, the general consensus is to continue belimumab therapy unless there are any adverse events or contraindications that would preclude continuation. In our opinion, the maintenance of clinical remission with belimumab and the subsequent reduction in damage associated with recurrent lupus flares and high-dose steroids are desirable outcomes that may influence the physician’s decision to continue belimumab therapy long term. In our opinion, the observational real-world data are useful in providing further information about the role of belimumab in clinical practice. Although it is limited by lack of controls for comparison and may have selection or reporting bias, it is still important to consider all information pertaining to this new drug. Belimumab is currently being used in clinical practice, and over the next 5 years data will accumulate from clinical trials, observational studies, case series and case reports that could determine the place for belimumab in SLE management.
Declaration of interest DP D’Cruz reports participation in Advisory Boards and Consultancies for Human Genome Sciences and has received consulting fees and/or has participated in clinical trials for GlaxoSmithKline, Bristol Myers Squibb, and Eli-Lilly. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008;358(9):929-39
4.
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Sestak AL, Furnrohr BG, Harley JB, et al. The genetics of systemic lupus erythematosus and implications for targeted therapy. Ann Rheum Dis 2011;70(Suppl 1):i37-43 Blank M, Shoenfeld Y, Perl A. Cross-talk of the environment with the host genome and the immune system through endogenous retroviruses in systemic lupus erythematosus. Lupus 2009;18(13):1136-43 Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum 2007;56(4):1251-62
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Symmons DP. Frequency of lupus in people of African origin. Lupus 1995;4(3):176-8
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Looney RJ. B cell-targeted therapies for systemic lupus erythematosus: an update on clinical trial data. Drugs 2010;70(5):529-40
9.
Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-
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belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum 2012;64(10):3364-73
controlled, phase 3 trial. Lancet 2011;377(9767):721-31 10.
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Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebocontrolled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63(12):3918-30 Luijten KM, Tekstra J, Bijlsma JW, Bijl M. The Systemic Lupus Erythematosus Responder Index (SRI); a new SLE disease activity assessment. Autoimmun Rev 2012;11(5):326-9
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Data on file. Study 117295. 2012.Available from: http://www.gskclinicalstudyregister.com
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Ginzler EM, Wallace DJ, Merrill JT, et al. Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol 2014;41(2):300-9
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Collins CE, Dall’Era MO, McGuire A, et al. 12-month outcomes associated with belimumab in patients with systemic lupus erythematosus in clinical practice settings: the observe study [abstract]. Arthritis Rheum 2013;65(Suppl):1740
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Strand V, Levy RA, Cervera R, et al. Improvements in health-related quality of life with belimumab, a B-lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomised controlled BLISS trials. Ann Rheum Dis 2014;73(5):838-44
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Merrill JT, Ginzler EM, Wallace DJ, et al. Long-term safety profile of
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Bernatsky S, Boivin JF, Joseph L, et al. An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum 2005;52(5):1481-90
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Bernatsky S, Boivin JF, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006;54(8):2550-7
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Fredericks C, Kvam K, Bear J, et al. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus 2014. [Epub ahead of print]
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Dooley MA, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus 2013;22(1):63-72
Affiliation
Pamela MK Lutalo1 & David P D’Cruz†2 † Author for correspondence 1 St Thomas’ Hospital, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, Louise Coote Lupus Unit, Westminster Bridge Road, London SE1 7EH, UK 2 Professor, St Thomas’ Hospital, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, Louise Coote Lupus Unit, Westminster Bridge Road, London SE1 7EH, UK E-mail: david.d’[email protected]
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Update on belimumab for the management of systemic lupus erythematosus 1.
Introduction
2.
Body of the review
3.
Conclusion
4.
Expert opinion
Pamela MK Lutalo & David P D’Cruz† †
St Thomas’ Hospital, Guy’ s and St Thomas’ Hospitals NHS Foundation Trust, Louise Coote Lupus Unit, London, UK
Introduction: Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug to be licensed and approved by the US FDA and the European Medicines Evaluation Agency for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE). The clinical effectiveness and impact of this drug on lupus morbidity and mortality is evaluated in this review. Areas covered: An overview of the efficacy and safety of belimumab based on 7-year longitudinal continuation study data from SLE patients enrolled in the Phase II double-blind, randomised, placebo-controlled, 52-week study of belimumab 1, 4 and 10 mg/kg doses and an overview of the open-label 24-week extension of belimumab plus standard immunosuppressant therapy. A review of the current belimumab clinical trials, the experience of belimumab in real-world settings and a description of the impact that belimumab has had on the healthcare quality of life of SLE patients. Expert opinion: The emerging clinical data have shed light on the areas in which belimumab is of greatest benefit and areas for further evaluation in clinical trials. It is anticipated that regular updates from ongoing trials of belimumab in SLE, practising physicians, data from the continuation arms of clinical trials and data from international biologics registries will have an influence on the role of belimumab in the management of SLE. Keywords: B cell depletion, B lymphocyte stimulator, belimumab, systemic lupus erythematosus Expert Opin. Biol. Ther. (2014) 14(11):1701-1708
1.
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease whose immunopathogenesis involves B cells, autoantibodies, immune complex deposition and complement dysregulation [1-3]. Environmental triggers such as ultraviolet light, infection and cigarette smoke, and hormonal factors such as oestrogen and genetic susceptibility contribute to the onset of disease [4,5]. SLE predominantly occurs in women, particularly from puberty to menopause, with a female to male ratio of 9:1 [6]. There is a relatively higher global prevalence of SLE in African-Americans, Afro-Caribbeans and Hispanics compared with Asians and Caucasians [7]. SLE may manifest as mild, moderate or severe disease, which may be associated with significant morbidity and mortality. Physicians manage systemic manifestations of active lupus and lupus symptoms with a wide array of therapeutic interventions including analgesia, NSAIDs, anti-malarial drugs: hydroxychloroquine and mepacrine, immunosuppressant drugs -- azathioprine, cyclophosphamide, ciclosporin A, methotrexate, mycophenolate mofetil, tacrolimus -- and biological drugs -- rituximab and belimumab (Box 1).
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Box 1. Drug summary. Drug name Phase Indication Pharmacology Route of administration
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Pivotal trials
Belimumab US FDA approved 2011 European Medicines Evaluation Agency approved 2011 Seropositive adult SLE patients excluding patients with lupus nephritis and CNS manifestations of SLE B-Lys-specific inhibition B lymphocyte stimulator antagonist mAb Intravenous infusion belimumab 10 mg/kg at 2-week intervals for three doses followed by weight-based infusions 10 mg/kg every 4 weeks Phase I clinical trial Phase II clinical trial Phase III clinical trials BLISS-52 and BLISS-76 Belimumab in SLE study randomised placebo-controlled trials Primary end point SLE responder index response at week 52
B-Lys: B lymphocyte stimulator; SLE: Systemic lupus erythematosus.
Biological drugs targeting B cells are the new frontier in lupus management and may revolutionise the management of this complex disease [8]. Since 2011, the biological drug belimumab, which is a fully humanised mAb against B lymphocyte stimulator (B-LyS), has been licensed and approved by the US FDA and the European Medicines Evaluation Agency (EMEA). The license is for autoantibody-positive SLE, which remains moderately to severely active despite optimised standard immunosuppression. It excludes severe lupus nephritis and cerebral lupus, which were not evaluated in the Phase III randomised placebo-controlled clinical trials Belimumab International SLE Study BLISS-52 and BLISS-76 [9,10]. Overall clinical effectiveness in inducing and maintaining disease remission is important as is the prevention of chronic damage, organ failure and the reduction of the disease or concomitant drug-related morbidity. The Phase II, randomised, double-blind, placebo-controlled, belimumab doserange trial evaluated the biological activity, tolerability, safety and efficacy of belimumab in combination with standard immunosuppressant therapy in active SLE. The BLISS-52 and BLISS-76 Phase III randomised, double-blind, placebocontrolled clinical trials demonstrated the clinical effectiveness of intravenous (i.v.) belimumab 10 mg/kg infusions in combination with standard, optimised immunosuppressant drugs, except other biologics and cyclophosphamide [9,10]. This review will provide an overview of the efficacy and safety of belimumab based on longitudinal continuation study data from SLE patients enrolled in the Phase II double-blind, randomised, placebo-controlled, 52-week dose-ranging belimumab trial and the open-label 24-week extension study of belimumab in combination with standard immunosuppressant drugs. The current clinical experience of belimumab in real-world settings and the impact that belimumab has had on the healthcare quality of life of SLE patients will be discussed in this review. Ongoing clinical trials aimed at addressing important questions concerning the role of belimumab in lupus nephritis, patients of African ancestry and the possibility of 1702
an alternative route of administration, such as the subcutaneous route, will be discussed in this review. 2.
Body of the review
Clinical effectiveness of belimumab Evidence from the 7-year longitudinal continuation study data
2.1
2.1.1
In order to define clinical effectiveness in SLE clinical trials, a new measure of efficacy was devised called the SLE Responder Index (SRI), which combines data from the British Isles Lupus Assessment Group (BILAG) scores, SELENA-SLEDAI scores and Physicians’ Global Assessment (PGA) [11]. The SRI is defined as ‡ 4 point reduction in SELENA-SLEDAI, no new BILAG A score and £ 1 new BILAG B score and no worsening of the PGA score, which is an increase of ‡ 0.3 from baseline [11]. The clinical effectiveness of belimumab was demonstrated in the randomised, double-blind, placebo-controlled clinical trials BLISS-52 and BLISS-76. In BLISS-52, 58% of the autoantibody-positive SLE patients in the 10 mg/kg belimumab group met the SRI response criteria at week 52 compared with 44% of the SLE patients in the placebo group at week 52 [9,10]. In the BLISS-76 trial, 43.2% of SLE patients in the 10 mg/kg belimumab group were SRI responders compared with 33.5% in the placebo group at 52 weeks, although at 76 weeks there was no significant difference between the treatment arms [10,11]. A longitudinal continuation study of SLE patients enrolled in the Phase II belimumab trial is ongoing. The main aim of this study is to evaluate the efficacy and safety of belimumab plus standard immunosuppressant therapy beyond the 76-week clinical trial time period [13]. The following measures of clinical efficacy are being assessed during this continuation study: . Concomitant medication including medication for SLE
disease control such as corticosteroids and immunosuppressants recorded every 4 weeks.
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. . . . .
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PGA measured every 8 weeks. BILAGs measured every 16 weeks. SELENA-SLEDAI measured every 16 weeks. SLE Flare Index (SFI) measured every 16 weeks. Complement levels (C3 and C4) measured every 16 weeks. . Autoantibody titres measured every 16 weeks. It should be noted that disease activity indices and laboratory markers of active lupus are only measured once every 16 weeks, which may result in under-reporting or detection of lupus flares between clinic assessments. To date, the 7-year longitudinal study data from the Phase II belimumab clinical trials have been published as follows: . Year 1: pooled data of SLE patients total n = 424, which
constitutes SLE patients treated with belimumab i.v. 1, 4 or 10 mg/kg during the double-blind study (n = 336) and SLE patients switched from placebo to belimumab 10 mg/kg in the continuation phase (n = 88). . Year 2: all patients in the longitudinal continuation study were treated with belimumab n = 339. In total, 19 patients continued belimumab i.v. 1 mg/kg and 23 patients continued belimumab i.v. 4 mg/kg during the 24-week extension phase of the clinical trial. . Years 3 -- 7: all patients were treated with belimumab i.v. 10 mg/kg. A total of 296 patients were enrolled in the long-term continuation study at the end of 76 weeks of the belimumab; however, only 177 patients remain in this study to date [13]. SRI response by year 2 was achieved in 57% of belimumabtreated patients [13]. SRI response by year 7 was achieved in 65% of belimumab-treated patients [13]. The majority of patients in the continuation study cohort are autoantibody positive (n = 135). The percentage of autoantibody-positive patients who achieved SRI response at year 1 was 46, year 2 was 57 and years 3 -- 7 was 55 -- 65. The percentage of autoantibody-negative patients who achieved SRI response at year 1 was 44, year 2 was 48 and years 3 -- 7 was 58 -- 69 [13]. Evidence from the 7-year longitudinal continuation study data for SLE flare rates
2.1.2
The SFI was used to ascertain the proportion of patients who experienced lupus flares, in particular severe flares, in a given year. The data from years 1 -- 7 of the long-term continuation study show that belimumab-treated patients experiencing all types of lupus flares decreased from 70 to 40% and severe lupus flares decreased from 7 to 2% [13] in autoantibodypositive patients. Further analysis of the autoantibody-positive group compared with the autoantibody-negative group reveals that although there is no significant difference between the groups in the rate of all lupus flares during the 7-year
continuation phase, the rates of severe flares are higher in the autoantibody-negative group during years 3 -- 7 (decreasing from 13.2 to 6.5%) compared with the autoantibodypositive group (decreasing from 7 to 2%) [14]. In the long-term continuation study, years 2 -- 7 the BILAG 1A/2B flare rate decreased from 21 to 8% in the autoantibodypositive cohort. The autoantibody-negative cohort had a variable decline in BILAG 1A/2B flare rates from year 2 (18.2%) to year 7 (12.8%) and had generally higher BILAG 1A/2B flare rates in year 1 (31.6%) compared with the autoantibody-positive cohort [14]. Evidence from the 7-year longitudinal continuation study data: PGA
2.1.3
In the long-term continuation study year 7, the PGA mean percentage change improved to -48% in belimumab-treated autoantibody-positive patients. Interestingly, although the PGA response in the autoantibody-negative patients was relatively lower in years 1 and 2 (-24.7 and -35%, respectively), the improvement was greater in years 3 to 7 (-49.2 to -61.3%, respectively) compared with the autoantibody-positive patients [14]. Evidence from the 7-year longitudinal continuation study data: laboratory data
2.1.4
Complement normalisation from low baseline C3 and C4 was evident during the double-bind period of the belimumab Phase II clinical trial, with 21% of patients normalising C3 in both the placebo and belimumab groups and 24 and 38% of patients normalising C4 in the placebo and belimumab groups, respectively [9,10]. Over 7 years of belimumab treatment, 66% of patients achieved normalised C3 and 71% patients achieved normalised C4 [13]. The titres of serum IgG autoantibodies, such as antibodies to ribonucleoprotein, anti-Smith, antibodies to double stranded DNA (antidsDNA) and anti-cardiolipin, generally decreased between years 1 and 7 in the belimumab-treated patients [14]. Evidence from the 7-year longitudinal continuation study data: corticosteroid and concomitant immunosuppressant drug usage
2.1.5
There was a 25% reduction in the corticosteroid dose and median absolute reduction of 2 mg/day of corticosteroid by year 2 of belimumab treatment. By year 7, there was a 55% reduction in the corticosteroid dose and median absolute reduction of 4 mg/day of corticosteroid. Between years 2 and 7, 13.2 and 20% of patients increased the dose of prednisone. The percentage of patients who were treated with corticosteroids decreased from 73.9% at year 2 to 65.2% at year 7 [14]. During years 1 -- 4, there was a steady state in the percentage of patients prescribed concomitant immunosuppressants; however, this declined from years 5 -- 7 from a baseline immunosuppressant use of 53.5 to 39.5%, with the greatest change
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being in the methotrexate-treated group (baseline 18.2% to year 7 10%) [13]. New immunosuppressant therapy was added in 0.5 -- 2.8% as documented in the 16-week interval data [13].
Clinical practice experience in North America and Europe
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2.1.6
The OBSErve study was a multicentre, retrospective, medical chart review study conducted in the US. The primary objective was to evaluate the characteristics and outcomes of SLE patients who were treated with belimumab in clinical practice over a 6-month period, and the secondary objective was to describe the healthcare resource utilisation among patients who received treatment with belimumab [14]. The data were selected from community-based rheumatology practices in which ‡ 10 SLE patients were treated and were based on physician judgement of clinical improvement and are presented below [14]. The study collected observational data from 501 SLE patients at a baseline time point of 6 months prior to belimumab treatment and data at 6 months post-initiation of belimumab in combination with standard immunosuppressant drugs. The overall physician impression of clinical response after eight infusions of belimumab over 6 months was reported as a categorical scale of < 20%, ‡ 20%, ‡ 50% and ‡ 80% improvement. After 6 months of belimumab in combination with standard immunosuppressant drugs, the overall physician impression of clinical response was 88% of the patients showing 20% improvement, 49% of the patients showing ‡ 50% improvement and 11% of the patients showing ‡ 80% improvement from baseline and only 1% of the patients reported to have no change in clinical disease activity postbelimumab treatment. A total of 297 of the 368 patients received corticosteroids at baseline. Corticosteroids were successfully discontinued in 9% of these patients, 13% were on the baseline dose of corticosteroid dose at 6 months post-belimumab, 86% patients were able to successfully decrease the dose of corticosteroids, and 2% patients were on a higher dose of corticosteroids at 6 months compared with baseline. The average reduction in corticosteroid dose was 11.5 ± 12.2 mg prednisone equivalent over the 6-month period. Patients experienced fewer inpatient hospital admissions after belimumab compared with before belimumab, with 2% patients having ‡ 1 hospital admission 6 months postbelimumab compared with 5% patients pre-belimumab. 15% of the patients had ‡ 1 emergency room visit at baseline compared with 6% patients 6 months after belimumab. The frequency of unscheduled medical visits at baseline was also reduced in belimumab-treated patients with 30% of patients post-belimumab having ‡ 1 unscheduled physician visits compared with 52% patients pre-belimumab. Limitations of this observational study are the lack of a control group of 1704
belimumab-naive SLE patients for comparison and the lack of adverse event reporting or safety data. Impact of belimumab on health-related quality of life in SLE
2.1.7
Although the BLISS trials were not individually powered to detect statistically significant differences in health-related quality of life (HRQOL) measures such as short-form 36 (SF-36) FACIT-Fatigue and EQ-5D scores with belimumab plus standard treatment versus standard treatment alone, a post hoc analysis of pooled data is able to demonstrate the benefit of belimumab on HRQOL in SLE patients. The mean SF-36 mental component scores (MCS) physical component summary (PCS) scores improved significantly from baseline in the belimumab treatment groups at week 52 and MCS at week 76 compared with placebo group. The pooled analysis of both belimumab groups in the BLISS trials showed evidence of improvement at week 52 in FACITFatigue scores, SF-36 vitality domain and SF-36 PCS scores [15]. Clinical safety and tolerability of belimumab Evidence from the 7-year longitudinal continuation study data: adverse events
2.2
2.2.1
The longitudinal continuation study data from the SLE patients enrolled in the Phase II randomised, double-blind, placebo-controlled 52-week trial and 24-week open-label extension trial of belimumab and standard immunosuppressants have been collected to ascertain the safety of belimumab using clinical and laboratory reported data on adverse events [16]. Adverse Event Severity Grading Tables modified from the US National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Disease Adult Toxicity Tables have been used to organise the reported adverse events into different grades of severity [13]. Adverse event rates were calculated as the number of adverse events per 100 patient-years for each 1-year interval. During the long-term continuation study, the incidence of adverse events remained stable or declined overall during 7 years of belimumab treatment. Evidence from the 7-year longitudinal continuation study data: infections
2.2.2
Infections were the most common reported adverse event years 1 -- 7 [13]. . Overall infections: 83.7/100 patient-years in year 1,
79.2/100 patient-years in year 2, 74.4/100 patient-years in year 3, 77.3/100 patient-years in year 4, 67.2/100 patient-years in year 5, 63.8/100 patients-years in year 6 and 76.6/100 patient-years in year 7. . Serious infections: 5.9/100 patient-years in year 1, 4.7/100 patient-years in year 2, 3.1/100 patient-years in year 3, 3.4/100 patient-years in year 4, 2.8/100
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Belimumab
patient-years in year 5, 4/100 patients-years in year 6 and 3/100 patient-years in year 7. Upper respiratory tract infections were the commonest recorded infection in this study. Evidence from the 7-year longitudinal continuation study: hypogammaglobulinemia
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2.2.3
Grade 3 -- 4 hypogammaglobulinemia (< 400 mg/dl) was reported in 1.1 -- 2.6% of patients treated with belimumab, many of whom had a baseline grade 1 -- 3 hypogammaglobulinemia. Interestingly, this was not associated with an increase in the serious infection rate [13]. Belimumab was discontinued in four patients due to hypogammaglobulinemia. Evidence from the 7-year longitudinal continuation study data: infusion reactions and hypersensitivity
2.2.4
Infusion reactions were documented according to a list generated from > 160 Medical Dictionary for Regulatory Activities (MedDRA) preferred terms such as rashes, erythema, flushing and urticaria. Infusion reactions were defined as occurring on the day of belimumab infusion and up to 7 days post-infusion. Hypersensitivity reactions were defined as MedDRA-preferred terms that started on the day of belimumab infusion regardless of adverse event duration: anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock, angioedema, drug hypersensitivity, hypersensitivity and tachyphylaxis [13]. Hypersensitivity reactions were only observed in the first year of treatment. Infusion reaction rates were documented in the long-term continuation study data [14]. . Infusion reaction rates 23.3/100 patient-years in year 1,
10.7/100 patient-years in year 2, 5.4/100 patient-years in year 3, 6/100 patient-years in year 4, 3.7/100 patient-years in year 5, 3/100 patients-years in year 6 and 1.2/100 patient-years in year 7. . The one and only serious infusion reaction occurred in year 3 0.4/100 patients-years.
Evidence from the 7-year longitudinal continuation study data: malignancies
2.2.5
Malignancies excluding non-melanoma skin cancers occurred at a rate of 0.7/100 patient-years (95% CI 0.4 -- 1.27) during the 7 years of the long-term continuation study [13]. Comparison may be made with the overall SLE patient background malignancy rate of 0.53/100 patient-years [17]. . Malignancy rates 0.3/100 patient-years in year 1, 1.7/
100 patient-years in year 2, 1.2/100 patient-years in year 3 n = 3, 1.7/100 patient-years in year 4, 1.9/100 patient-years in year 5, 2.5/100 patients-years in year 6 and 1.2/100 patient-years in year 7.
. Years 1 -- 4: two solid organ malignancies, two haemato-
logical malignancies and seven non-melanoma skin cancers were reported. . Years 5 -- 7: breast cancer (years 5, 6 and 7), colon cancer (year 5), malignant melanoma (year 5), renal cell carcinoma (year 5) and lung cancer (year 6). Four nonmelanoma skin cancers were reported in years 5 -- 7, which included squamous cell carcinoma (n = 2 in year 6 and n = 1 in year 7) and one basal cell carcinoma in year 6.
Evidence from the Phase II and Phase III belimumab clinical trials: mortality
2.2.6
The pooled data from the Phase III randomised, doubleblind, placebo-controlled trials BLISS-52 and BLISS-76, Phase II randomised, double-blind, placebo-controlled trial of belimumab and standard immunosuppressant drugs in SLE and the 7-year longitudinal continuation study data from the SLE patients enrolled in the Phase II belimumab trial report 11 deaths in the SLE patients treated with belimumab and standard immunosuppressant drugs. The reported cause of death is due to infection (n = 4), suicide (n = 2), SLE (n = 1), cardiac disease (n = 1), cerebrovascular disease (n = 1), malignancy (n = 1) and unknown aetiology (n = 1). The deaths reported in the 7-year longitudinal continuation study of SLE patients enrolled in the Phase II belimumab trial included five deaths in years 1 -- 4, no deaths in years 5 -6 and two deaths in year 7 [13]. The recent deaths have not been directly attributed to belimumab by the study investigators; however, it is important to note that during the BLISS clinical trials two patient suicides in the belimumab group were reported and there have been reports of a higher incidence of psychiatric symptoms, such as depression, in patients treated with belimumab. The mortality rate is 0.4/100 patient-years (95% CI 0.16 -- 0.83) that is below the published mortality rate for SLE patients, which is 1.63/100 patient-years [18]. Clinical practice experience of adverse events in North America and Europe
2.2.7
To date, there have been two spontaneous cases of progressive multifocal leukoencephalopathy (PML) in SLE patients treated with belimumab. One was a reported fatality related to PML that developed in a 40-year-old female lupus patient treated with belimumab and standard immunosuppressant drugs. She had initially been diagnosed with CNS lupus based on her neurological decline and MRI brain images. The belimumab was discontinued, she was treated with high-dose corticosteroids and two cycles of intravenous cyclophosphamide but her condition deteriorated and she was transferred to another institution where a repeat MRI brain scan showed multifocal, confluent areas of T2 hyperintensity in the cerebral white matter bilaterally and cerebrospinal fluid PCR was positive for JC virus, thus confirming that she had PML. She had received a total of 10 monthly belimumab
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infusions in addition of mycophenolate mofetil and low-dose prednisolone and had relatively mild lupus at the time of neurological deterioration, therefore the conclusion made by her physicians was that the PML was associated with immunosuppressant drug therapy [19].
the UK, the National Institute of Clinical Excellence (NICE) has not approved belimumab for SLE patients, therefore individual funding requests are required to treat SLE patients in the UK with belimumab. 3.
Current clinical trials in belimumab 2.3.1 Lupus nephritis
Conclusion
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2.3
BLISS-LN study is a Phase III, randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of belimumab plus standard of care versus placebo plus standard of care in adult subjects with active lupus nephritis, which will provide clinically relevant information about the use of belimumab in lupus nephritis NCT01639339 (www. clinicaltrials.gov). A post hoc analysis of 267 SLE patients with renal disease at baseline in the BLISS trials indicated the possibility that belimumab in combination with mycophenolate mofetil could result in renal organ disease improvement [20]. The BLISS-LN study is powered to evaluate the efficacy of belimumab in active lupus nephritis. African ancestry A Phase III/IV multicentre, randomised, double-blind, placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab in adult subjects of black race with SLE is planned as a new clinical trial NCT01632241 (www. clinicaltrials.gov). An exploratory analysis of the data from 148 black patients in the BLISS trials reported lower clinical effectiveness in this group of patients compared with other ethnic groups. This new clinical trial will be powered to evaluate this further and provide data that will be of use in clinical practice. 2.3.2
Subcutaneous belimumab BLISS-SC study is a Phase III, randomised, double-blind, placebo-controlled, 52-week study to evaluate the efficacy and safety of belimumab administered subcutaneously NCT014 84496 (www.clinicaltrials.gov). If positive, this study will reduce infusion costs and will be more acceptable to patients and clinicians. 2.3.3
Regulatory affairs The FDA and EMEA licensed and approved belimumab for the management of autoantibody-positive SLE patients who lack a clinical response to standard treatment. Regulatory bodies and health insurance companies may require fulfilment of these criteria prior to initiation of belimumab. At present, standard treatment is defined by the physician’s clinical judgement and usually consists of corticosteroids, an anti-malarial drug and one additional immunosuppressant: azathioprine, methotrexate or mycophenolate mofetil. Regulatory bodies often require objective documentation of the response to belimumab therapy to justify continuation of the treatment. This is usually recorded at 6 months post-initiation of belimumab. The cost of belimumab is a limiting factor in some regions. In 2.4
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The longitudinal long-term continuation study of SLE patients enrolled in the Phase II belimumab plus standard immunosuppressant therapy trial is evaluating the efficacy and safety of this therapeutic intervention beyond the 52-week randomised, double-blind, placebo-controlled clinical trial period, and the 24-week open-label extension period is ongoing. Observational clinical data from medical practice show that belimumab in combination with standard immunosuppressant drugs is efficacious and generally well tolerated for the long-term maintenance of clinical remission in SLE patients. 4.
Expert opinion
B cells play a crucial role in the immunopathogenesis of SLE as they develop into plasma cells that secrete pathogenic autoantibodies that lead to immune complex deposition. In addition, patients with autoimmune diseases such as SLE have significantly elevated serum B-LyS levels, therefore the inhibition of the B cell survival factor B-LyS, by belimumab, is a logical therapeutic intervention. There is a role for belimumab in the management of SLE patients. The serological improvement and normalisation of complement in the majority of SLE patients treated with belimumab parallels the overall improvement in disease activity scores and reduction in the SFI in belimumab-treated patients. The longitudinal continuation study data and clinical observational data report the clinical efficacy of belimumab in combination with standard immunosuppressant drugs in autoantibody-positive SLE patients who have active disease despite optimised standard therapy. In our opinion, this will remain the main indication for belimumab therapy. It is yet to be determined whether or not belimumab has a role as a first-line remission induction immunosuppressant therapy. In our opinion, belimumab may be beneficial early in the management of SLE after induction of disease remission as the significant reduction of the corticosteroid cumulative dose and lupus flare rates attributed to belimumab may limit damage accrual related to recurrent flares and corticosteroid use. The exact cohort of SLE patients who would benefit most from belimumab is being established. In our opinion, autoantibody-positive SLE patients with high dsDNA titres, low complement levels, active disease in predominantly mucocutaneous or musculoskeletal domains will benefit significantly from belimumab therapy, as evidenced by the clinical trial data. However, the question remains whether
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Belimumab
belimumab will be beneficial in autoantibody-negative SLE patients long term. This is mainly because unexpectedly the long-term continuation study data show evidence of clinical responsiveness to belimumab in years 3 -- 7 in the autoantibody-negative patients, which is numerically slightly superior to the autoantibody-positive patients as assessed by SRI and PGA. It is important to take into account when interpreting the long-term continuation study data that the patients were assessed for evidence of disease activity or flare once every 16 weeks after the end of the 76-week clinical trial period. This limits the opportunity to record flares or evidence of disease activity to these specific clinic visits, thereby increasing the chances of underreporting of SLE disease activity or flares. The role of belimumab in the management of severe systemic manifestations of SLE is being investigated. The current belimumab trial in severe lupus nephritis may provide information that will determine whether or not belimumab is beneficial in lupus nephritis. At present, belimumab is not recommended in cerebral lupus as it has not been evaluated in clinical trials and there are insufficient data to provide evidence of its efficacy in this situation. The ongoing clinical trials in SLE patients of African ancestry may provide useful information pertaining to the efficacy and safety of this drug in this ethnic group. Overall the belimumab safety profile is acceptable, with the long-term continuation study data complementing the clinical trial data in terms of low incidence of serious infections, malignancies and death. The occurrence of two cases of progressive multifocal leukoencephalopathy over the 7 years of belimumab treatment should be highlighted and physicians should remain vigilant in reporting this adverse event. It is likely that this indicates the susceptibility of heavily immunosuppressed patients to the reactivation of JC virus than a specific adverse event unique to belimumab as PML has been reported with rituximab and mycophenolate mofetil use. To date, there have not been any specific opportunistic infections or pattern to infections that have emerged from the 7-year study data to raise alarm. The level of hypogammaglobulinemia and lymphopenia has not been directly linked to the incidence of infections, although there has been a trend to discontinue belimumab in cases of severe hypogammaglobulinemia.
Bearing in mind the level of immunosuppression SLE patients generally experience, it may be worth investigating the possibility of using belimumab with anti-malarial drugs alone to ascertain the clinical effectiveness of this combination compared with the standard belimumab with conventional immunosuppressant combination. The question concerning duration of belimumab treatment is yet to be answered. However, the 7-year long-term continuation data indicate an increase in efficacy of belimumab with time, which is associated with an improvement in lupus biomarkers and a reduction in the corticosteroid dose or usage. Belimumab also reduces the incidence and severity of flares overall; therefore, at present, the general consensus is to continue belimumab therapy unless there are any adverse events or contraindications that would preclude continuation. In our opinion, the maintenance of clinical remission with belimumab and the subsequent reduction in damage associated with recurrent lupus flares and high-dose steroids are desirable outcomes that may influence the physician’s decision to continue belimumab therapy long term. In our opinion, the observational real-world data are useful in providing further information about the role of belimumab in clinical practice. Although it is limited by lack of controls for comparison and may have selection or reporting bias, it is still important to consider all information pertaining to this new drug. Belimumab is currently being used in clinical practice, and over the next 5 years data will accumulate from clinical trials, observational studies, case series and case reports that could determine the place for belimumab in SLE management.
Declaration of interest DP D’Cruz reports participation in Advisory Boards and Consultancies for Human Genome Sciences and has received consulting fees and/or has participated in clinical trials for GlaxoSmithKline, Bristol Myers Squibb, and Eli-Lilly. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation
Pamela MK Lutalo1 & David P D’Cruz†2 † Author for correspondence 1 St Thomas’ Hospital, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, Louise Coote Lupus Unit, Westminster Bridge Road, London SE1 7EH, UK 2 Professor, St Thomas’ Hospital, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, Louise Coote Lupus Unit, Westminster Bridge Road, London SE1 7EH, UK E-mail: david.d’[email protected]
