DB08879 BELIMUMAB C 6358 H 9904 N 1728 O 2010 S 44 147 kDa CATEGORY Monoclonal antibodies

DESCRIPTION Belimumab is an intravenous immunosupressant for the adjunctive treatment of systemic lupus erythematosus (SLE). More specifically, it is a fully human recombinant IgG1λ monoclonal antibody produced from a recombinant NS0 cell line stably transfected with the belimumab heavy chain and light chain genes. It is the first biological treatment approved for the indication of SLE. Concomitant use with live or inactivated vaccines must be avoided. Belimumab was FDA approved on March 9, 2011. Belimumab consists of 2 heavy chains, and 2 light chains of the lambda subclass. Each heavy chain contains 452 amino acid residues and each light chain contains 214 amino acid residues. There are 3 post-translational modifications: a conserved N-linked glycosylation on the CH2 domain at Asn 303 of the heavy chain, the conversion of the N-terminal glutamine residue of the heavy chain into pyroglutamate, and loss of C-terminal lysine residue of the heavy chain.

INDICATION Adjunct treatment for auto-antibody-positive active systemic lupus erythematosus. PHARMACODYNAMICS By the 52nd week of treatment with belimumab, a reduction in CD19+, CD20+, naive and activated B cells, plasma cells, plasmacytoid cells, and SLE B-cell subset can be observed. Reductions in plasma cells and SLE B-cell subset can be seen by the eighth week and these levels were maintained to week 52. Belimumab also reduced levels of IgG and anti-dsDNA.

MECHANISM OF ACTION Belimumab selectively binds to soluble human B lymphocyte stimulator protein (BLyS) so that BLyS is unable to bind to receptors on B lymphocytes. The binding of BLyS to its receptor is essential for the survival of B lymphocytes. Consequently, belimumab reduces B-cell mediated immunity and the autoimmune response. ABSORPTION Cmax, 10 mg/kg, SLE patients = 313 µg/mL; AUC (0-∞), 10 mg/kg, SLE patients = 3083. VOLUME OF DISTRIBUTION 10 mg/kg, SLE patients = 5.29 L

METABOLISM Because belimumab is a protein, it is expected that it is degraded into peptides and amino acids by proteolytic enzymes. HALF LIFE Terminal elimination half-life, 10 mg/kg, SLE patients= 19.4 days; Distribution half-life, 10 mg/kg, SLE patients = 1.75 days. CLEARANCE Systemic clearance, 10 mg/kg, SLE patients = 215 mL/day. TOXICITY The most commonly-reported adverse reactions, occurring in ≥5% of patients in clinical trials were nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis. The most common serious adverse reactions were serious infections

DRUG INTERACTIONS Abatacept Avoid combination due to enhanced adverse effects of belimumab. ado-trastuzumab emtansine Avoid combination due to the increased risk of belimumab associated side effects. Belatacept Belimumab increases the immunosupressive effect. Interaction is significant so monitor closely. Bevacizumab Avoid combination due to enhanced adverse effects of bevacizumab Cyclophosphamide Avoid combination due to enhanced toxic effects of cyclophosphamide. Denosumab Belimumab increases the immunosupressive effect. Interaction is significant so monitor closely. Etanercept Avoid combination because of enhanced adverse effects of belimumab. Etanercept Avoid combination due to enhanced toxic effects of belimumab. Fingolimod Belimumab increases the immunosupressive effect. Interaction is significant so monitor closely. Gemtuzumab ozogamicin Avoid combination due to enhanced adverse effects of belimumab. golimumab Avoid combination with belimumab due to the increased chance of belimumab associated side effects. Hydroxyurea Belimumab increases the immunosupressive effect. Interaction is significant so monitor closely. Ibritumomab Avoid combination due to enhanced adverse effects of belimumab. Leflunomide Consider modifying therapy as belimumab may enhance the adverse effects of leflunomide, such as hematologic toxicities. Natalizumab Avoid combination due to enhance adverse effects of natalizumab such as the risk of concurrent infections. Obinutuzumab Avoid combination due to enhanced toxic effects of monoclonal antibody. Omalizumab Avoid combination due to enhanced toxic effects of monoclonal antibodies. Pimecrolimus Avoid combination due to enhanced toxic effects of immunosuppressants. Roflumilast Consider therapy modification due to enhanced immunosuppressive effect. Sipuleucel-T Monitor therapy due to decreased therapeutic effect of sipuleucel-t. Tacrolimus Avoid combination due to enhanced adverse effects of immunosuppressants. Tofacitinib Avoid combination due to enhanced immunosuppressive effect of tofacitinib.

Benlysta IV infusion BENLYSTA is a prescription medication used to treat adults with active systemic lupus erythematosus (SLE or lupus) who are receiving other lupus medicines. It is not known if BENLYSTA is safe and effective in people with severe active lupus nephritis or severe active central nervous system lupus, and it has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of BENLYSTA is not recommended in these situations. BENLYSTA (belimumab) is a human IgG1λ monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weight of approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a mammalian cell expression system.

VIAL: BENLYSTA is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous infusion. Upon reconstitution with Sterile Water for Injection, USP [see DOSAGE AND ADMINISTRATION], each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric acid, 0.4 mg/mL polysorbate 80, 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with a pH of 6.5. DOSAGE: 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter ADVERSE REACTION: Nausea, diarrhea, or trouble sleeping Clearance: 215 mL/day Half-life :19.4 days

PATENTS Country Patent Number Approved Expires (estimated) Canada 2266439 2009-06-16 2016-10-25 Canada 2407910 2009-06-16 2021-06-15

REFERENCES Scott LJ, Burness CB, McCormack PL: Belimumab: a guide to its use in systemic lupus erythematosus. BioDrugs. 2012 Jun 1;26(3):195-9 http://www.ncbi.nlm.nih.gov/pubmed/25396065 http://www.ncbi.nlm.nih.gov/pubmed/25303323 http://www.ncbi.nlm.nih.gov/pubmed/25243173 http://www.ncbi.nlm.nih.gov/pubmed/25205827 http://www.ncbi.nlm.nih.gov/pubmed/25201862 http://www.ncbi.nlm.nih.gov/pubmed/25107935 http://www.ncbi.nlm.nih.gov/pubmed/25034159 http://www.ncbi.nlm.nih.gov/pubmed/25005336 http://www.ncbi.nlm.nih.gov/pubmed/22593633 http://www.ncbi.nlm.nih.gov/pubmed/22097430 http://www.ncbi.nlm.nih.gov/pubmed/21659968 http://www.ncbi.nlm.nih.gov/pubmed/21553691 http://www.ncbi.nlm.nih.gov/pubmed/21309405 http://www.ncbi.nlm.nih.gov/pubmed/20509716