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Belimumab is the first biological therapy to obtain a marketing authorisation in the past few decades for the treatment of active systemic lupus erythematosus
Albert Darque PharmD
Anna Elissalde Pharmacy Resident
Reine Kimbidima Pharmacy Resident
Guillaume Sicard Pharmacy Resident
Pharmacie, CHU Conception,
Assistance Publique-Hôpitaux de Marseille, France
Laurent Chiche MD
Service de Médecine Interne
Hôpital Européen Marseille
Belimumab (Benlysta, previously known as LymphoStat-B) is a human recombinant monoclonal antibody (anti-Blys) that targets and inhibits soluble B-lymphocyte stimulator, also known as B-cell activating factor (BAFF), a proliferation and survival factor for B-cells which are responsible for the immune response in autoimmune diseases like systemic lupus erythematosus (SLE).
SLE is a heterogeneous autoimmune disease with a complex pathophysiology involving B-cell dysregulation (hyperactivity) and presence of autoantibodies. The evolution of the disease is characterised by inflammatory flare-ups causing damage on several organs and phases of remission. The most severe clinical forms are nephritis lupus and CNS lupus. Clinical evaluation of SLE is carried out by different scores: the disease activity scores (such as SELENA-SLEDAI, BILAG, etc.), the damage score (such as SLICC/ACER damage index) and scores assessing the quality of life (such as SLE-QoL).
Current treatment armamentarium used to relieve symptoms and control the progression of SLE relies on antimalarial drugs (hydroxychloroquine), steroidal and non-steroidal anti-inflammatory agents, nonspecific immunosuppressive drugs, including methotrexate, azathioprine. Other drugs such as cyclophosphamide, cyclosporine, mycophenolate mofetil (MMF), and rituximab are used for treating more severe cases of SLE.1 These drugs have been associated with moderate to severe short-term and/or long-term adverse events, particularly the steroid agents.
Belimumab is the first biological therapy to obtain a marketing authorisation in 2011 for the past decades and is patented in Europe for the treatment of active SLE in the presence of hypocomplementaemia and anti-ds-DNA antibody positivity, in addition to the standard treatment regimen in adults. The recommended dose, derived from results of clinical trials, is 10mg/kg belimumab in one hour-infusion administration on day 0, 14 and 28, and once a month thereafter.
Main clinical trials of belimumab consisted in two randomised, double-blinded, Phase III studies (BLISS-52 and BLISS-76),2,3 comparing a dose of 1 or 10mg/kg of belimumab versus placebo in addition to a standard treatment of steroids and antimalarial drugs. These studies included a total of 1684 autoantibody seropositive adult patients (865 in BLISS-52 and in 819 BLISS-76) presenting a mild disease activity (SLEDAI score ≥6) and previously treated with standard of care within the 30 days prior to the first administration of the protocol drugs.
Using a novel composite score (SRI: SLE response index)4 specifically developed for these studies, both studies achieved their primary goal of demonstrating superiority over placebo at W52.
The clinical efficacy of belimumab on flares was evaluated with both Selena Flare Index (SFI) and British Isles Lupus Assessment Group (BILAG). In the BLISS-52 trial, using the SFI, belimumab 1mg/kg (n=288) and 10mg/kg (n=290) were superior to placebo (n=287) in flare rate reduction (70% and 71% versus 80%, respectively, p=0.003) while mean times to first flare were 126 and 119 days compared with 84 days with placebo (p values not provided).
Severe flares were lower in belimumab groups versus placebo: 18% and 14% versus 23%, the difference being significant only with the 10mg/kg (p=0.005). Prevalence of flare based on BILAG criteria was diminished with belimumab 1 and 10mg/kg (by 42% to 55%) versus placebo (both p<0.05) indicating a better stabilisation of disease. In the BLISS-76 trial, significant difference versus placebo (n=275) on prevalence of severe flares was maintained for the 10mg/kg (n=271) but not the 10mg/kg (n=273). There was no consistent dose-related effect of belimumab. Although significant, efficacy of belimumab in reducing flares in SLE was moderate, and the absence of sustained response at W76 might suggest a non-durable effect.
On the steroid dose reduction criteria, patients were classified in two groups according to a threshold dose of prednisone of 7.5mg/day at baseline. In BLISS-52 patients with a baseline dose of prednisone less than 7.5mg/day, increase rates to more than 7.5mg/day were lower in belimumab 1 and 10mg/kg compared to placebo at W52 (30% and 20%, versus 36%, p=0.558 and p=0.02). In patients with more than 7.5mg/day at baseline, a minimum of 25% decrease in prednisone dose to a dose of 7.5mg/day or less was reported for belimumab 1 and 10mg/kg groups over placebo between W40 and W52 (21%, 19% versus 12%, p=0.025 and p=0.053, respectively). Moreover, decrease in prednisone dose sustained for more than 12 weeks in patients with belimumab versus placebo (24% to 28% versus 15%, p<0.05).
Whatever the classes of prednisone baseline dose, differences for both belimumab doses versus placebo were not statistically different in BLISS-76 either in increase or decrease of prednisone. As for reduction of flares, effect of belimumab in reducing steroid doses in SLE was moderate and seemed delayed. In regard of the span of glucocorticoid reduction (a few milligrams) and the time (several months) needed to achieve it, the effect may have sparse clinical relevance
Tolerance was not statistically different between placebo and treatment arms, on both global and dose-dependent severe adverse events, in terms of occurrence, severity (including infections), laboratory abnormalities, and discontinuations due to adverse events. The most commonly reported adverse events were headache, upper respiratory tract infection, arthralgia, urinary tract infection, influenza, diarrhoea, nasopharyngitis, nausea, hypotension and fatigue. Twelve patients died during the clinical trials. More deaths were reported with belimumab at 1 and 10mg/kg than with a placebo (4 and 5 versus 3, respectively). Causes of death were infection, lupus related deaths, cardiovascular, tumour and suicide with no predominance of cause.
These studies present some flaws limiting the extension of their conclusion into the daily practice. The main concern was that the adaptation of standard therapy was only possible to a limited extent since the study protocols explicitly restricted the possibilities for adapting the administration of glucocorticoids. Without restriction on adapting the standard therapy, differences in the effects observed between belimumab and comparator groups might have been smaller or indeed absent.
Patient’s quality of life was not a part of the primary endpoint in none of these studies, and the SRI specifically developed for these studies seems difficult to use routinely. Long-term efficacy data are still missing, and evidence of correlation between SRI and survival has not been established. Concerns also rose as belimumab was marginally effective, and with the fact that there were more deaths in the treatment groups. It is therefore difficult to specify the place of this new molecule in the real life where data are still sparse.
In the post-marketing era, a study conducted by Andreoli et al.5 reported a decrease in prednisone dose from 66.3mg/week (18 patients) to 46.9mg/week (11 patients) after nine months of treatment but provided no data on flare rates. Another study from Askanase et al.6 over a time period of two years reported a mean improvement of SLEDAI scores from baseline to 6 and 12 months (4.4 ± 4.32; 3.09 ± 3.41 p<0.05; 2.3 ± 2.79 p<0.01, respectively). A significant improvement of PGA score was also observed between baseline and 6 or 12 months of follow-up although the steroid sparing was not statistically significant.
Limits of use
Clinical trials of belimumab have not been conducted in patients with severe lupus, in particular in those with kidney and neurological complications. A Phase III study for SLE patients with kidney disease is recruiting. A number of case reports or case series suggest an efficacious use of belimumab with mycophenolate7 or rituximab8 as maintenance therapy in patients with lupus nephritis, who achieved a clinical response consisting in an improvement of SLEDAI, autoantibody level decrease, improvement of complement usage within six months after starting treatment.
Even in SLE patients eligible to this treatment, beneficiary patients seem to be not yet well identified. As an example, a subgroup analysis showed that belimumab appeared to be ineffective in black-skinned patients and the FDA has requested ongoing studies in this specific population. In the current state of knowledge and funding resources, it is critical to carefully select patients to whom this treatment could be beneficial, and to participate in the evaluation of its place in real life.
In France, health authorities have qualified the improvement of the medical service due to belimumab as minor.9 Approval in Europe is more restrictive than in the USA, as belimumab is being indicated only in second-line of treatment in adult patients with biologically active disease and in association with the standard of care.
Due to the risk of severe allergic reactions, administration of belimumab has to take place in a hospital setting, on a monthly basis, which can represent a constraint for the long-term treatment as well as a major factor of cost. Moreover, disease progression and accumulated damage are the main factors contributing to SLE costs, which direct and indirect costs are driven by nephritis/neuropsychiatric lupus and flares. Therefore, prevention of relapses and control of disease activity are targets of choice for saving large amounts of costs. Belimumab is an expensive drug as it costs around €13,000 per patient for the first year of treatment and assessing its cost effectiveness is challenging. Economic studies in SLE are difficult to perform since the disease is of low prevalence along with a high variability in clinical manifestations, comorbidities, and long-term progression.10
Specchia et al. performed a cost effectiveness analysis11 on a lifetime microsimulation model comparing belimumab to standard of care in Italy. The authors support the use of belimumab for treatment of SLE in Italy, based on the calculation that belimumab with standard of care may prevent 4742 flares in three years, making it cost effective with an incremental cost effectiveness ratio (ICER) of €32,859 per quality adjusted life year gained (QALY).
Nevertheless, an assessment from the UK National Institute for Health and Care Excellence (NICE)12 concluded that belimumab was not cost effective in comparison to standard of care and highlighted methodological concerns impairing a reliable estimation of ICER. NICE calculated the cost of belimumab at £61,200 (€92,000) per QALY, which is more than the normally accepted £20–30,000 (approximately €35–45,000). The drug was firstly rejected in 2012, and another guidance published in 2013 still did not recommend belimumab as an add-on therapy in adults with active, autoantibody-positive SLE.
Belimumab presented moderate efficacy and good tolerance in treating SLE. Nevertheless, it has not been evaluated in the severe forms of the disease such as lupus nephritis or neuropsychiatric lupus. The lack of consensus on efficacy criteria, variability on the course of disease and concomitant therapy, temper the enthusiasm driven around the availability of this expected new class in the treatment of SLE. Due to its high cost and the lack of solid comparison to standard of care, pharmacoeconomic analyses qualify it as not cost effective. Based on these statements and the results currently available, belimumab cannot be considered a major improvement in the treatment of SLE, neither an affordable one.