Belimumab (anti-BLys)
Belimumab is a human immunoglobulin G1λ monoclonal antibody which blocks thebinding of the soluble form of the cytokine B-lymphocyte stimulator (B-Lys), alsoknown as B cell activating factor (BAFF), to the transmembrane activator/calciummodulator/cyclophilin ligand interactor (TACI) receptor, B-cell maturation (BCMA)receptor and BAFF receptor 3 (BR3) on B cells and thus interrupts the B cellsurvival role of B-Lys [
21].
BAFF/BLys is expressed by several cells including dendritic cells, monocytes,activated neutrophils and T cells. It is vital in facilitating the maturation andsurvival of B cells via signaling through the BAFF-R, BCMA and TACI receptors withhigh, intermediate and low affinity respectively. APRIL, a BAFF homologueproliferation-inducing ligand binds with higher affinity to the TACI receptor thanBAFF [
22]. Dimerization of BAFF and APRILto the BCMA receptor is required to support the maturation of plasma cells[
22]. A strong interaction of BAFFto the BAFF-R propagates the maturation and survival of naive B cells and theinteraction of BAFF/BLys, APRIL and TACI to the TACI-R facilitates immunoglobulin(Ig) gene class switching in the germinal center [
22].
In the presence of an excess amount of BAFF/BLys, low-affinity self-reactive Bcells may survive and mature into self-reactive auto-antibody secreting plasmacells implicated in autoimmune disease pathogenesis. As a result, it has beendeduced that the inhibition of BAFF/BLys by belimumab has therapeutic implicationsin SLE.
In March 2011 the United States Food and Drug Administration (FDA) and theEuropean Medicines Evaluation Agency (EMEA) licensed belimumab as the first newdrug in over 50 years for SLE. Belimumab was licensed as a biologic agent to beprescribed with standard therapy for autoantibody-positive adult SLE patientsexcluding those with active lupus nephritis and central nervous systemmanifestations of SLE.
Belimumab is administered on a weight-based dosing schedule of belimumab 10 mg/kgas an hour long intravenous infusion fortnightly for three infusions then monthlythereafter.
A phase III randomized placebo-controlled trial Belimumab International SLE Study(BLISS-52) conducted between May 2007 and July 2009 included 865 SLE patientsenrolled in Central and Eastern Europe, Latin America, and Asia Pacific[
19]. A phase III randomizedplacebo-controlled trial Belimumab International SLE Study (BLISS-76) wasconducted between February 2007 and February 2010 enrolling 819 patients in NorthAmerica and Western and Central Europe [
23]. These studies used the composite SRI outcome measurewhich requires improvement in the SELENA-SLEDAI but no worsening in the BILAG andPhysician Global Assessment scores.
The trial outcome at 52 weeks in BLISS-52 reported positive clinical response in44% of those treated with placebo with standard therapy, 51% of those treated withbelimumab 1 mg/kg with standard therapy and 58% of those treated with belimumab 10mg/kg with standard therapy (
P = 0.013 and
P = 0.0006,respectively) [
23].
The trial outcome at 52 weeks in BLISS-76 reported positive clinical response in34% of those treated with placebo with standard therapy, 41% of those treated withbelimumab 1 mg/kg with standard therapy and 43% of those treated with belimumab 10mg/kg with standard therapy (
P = 0.10 and
P = 0.021,respectively) [
23]. However, at 76 weeks,there was no significant difference in responder rates between the belimumab andplacebo groups.
The BLISS-52 and BLISS-76 clinical trials both excluded patients with active lupusnephritis. BLISS-LN is a phase III, randomized, double-blind, placebo-controlledstudy to evaluate the efficacy and safety of belimumab plus standard of careversus placebo plus standard of care in adult subjects with active lupus nephritiswhich will provide clinically relevant information about the use of belimumab inlupus nephritis NCT01639339 (
http://www.clinicaltrials.gov).
An exploratory analysis of belimumab use in patients of black ethnicity in theBLISS-52 and BLISS-76 trials (n = 148) reported lower clinical effectiveness inthis group as compared to other ethnic groups.
A phase III/IV multi-center, randomized, double-blind, placebo-controlled, 52-weekstudy to evaluate the efficacy and safety of belimumab in adult subjects of blackrace with SLE is planned as a future study NCT01632241(
http://www.clinicaltrials.gov).
Belimumab may be more effective in specific sub-groups of lupus patients.Published data indicate that belimumab is significantly more efficacious in SLEpatients who are ds-DNA positive, hypocomplementemic or have high disease activityas measured by SELENA-SLEDAI score >10 [
24].
In 2012, fatal anaphylaxis was reported in a patient treated with belimumab and itis now known that there is a risk of a delayed acute hypersensitivity reaction tobelimumab, especially in patients with multiple drug allergies. Long-termobservational data will provide further safety and tolerability data on belimumab.At present the FDA Center for Drug Evaluation and Research has reviewed the safetylabeling for belimumab(
http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm299628).
The increased susceptibility to infection after belimumab treatment may be as aconsequence of alterations in the signaling pathways involving BAFF/BLys and theTACI receptor. The TACI molecule has a complex role in host immunity involvingactivation of B cells and T cell independent immune regulation; however, this isyet to be completely understood [
25]. Inlight of this, it has been postulated that the post-belimumab low BAFF/BLys levelsresult in a reduction in TACI signaling and hamper the host immune defensesagainst pathogens, such as polysaccharide encapsulated bacteria. Patients treatedwith belimumab have an increased susceptibility to infection, the commonest beingpharyngitis, bronchitis, cystitis and viral gastroenteritis [
23]. In the clinical trials serious infectionshave been reported in 6% of belimumab-treated patients as compared to 5.2% inplacebo controls but there have been no reports to date of PML in belimumabtreated patients [
26].
Although belimumab received regulatory approval from the US FDA and the EMEA, itsuse in some countries has been restricted until approval by national drugevaluation organizations. The German Institute for Quality and Efficiency inHealth Care (IQWiG) has recommended evaluation of belimumab for additional benefitover optimized immune-suppression rather than over standard therapy prior to fullapproval (
http://www.iqwig.de).
In 2012 The National Institute for Health and Clinical Excellence (NICE) provideda draft national guidance on the use of belimumab for SLE in the United Kingdom.NICE did not recommend belimumab within its licensed indication as add-on therapyto standard immune-suppressive drugs in adult patients with active auto-antibodypositive SLE. In making this decision, NICE considered the clinical trialevidence, clinical specialist and patient opinions. NICE concluded that the use ofbelimumab was not sufficiently cost-effective to the National Health Service (NHS)in relation to its reported clinical effectiveness. A final decision will beexpected after the appeals process has been concluded(
http://www.nice.org.uk).