Introduction This trial evaluated the safety, biologic activity, and pharmacokinetics of belimumab, a fully human monoclonal antibody that inhibits the biologic activity of the soluble form of the essential B-cell survival factor B-lymphocyte stimulator (BLyS) in patients with systemic lupus erythematosus (SLE).

The tolerability, pharmacodynamic effects, and pharmacokinetics of belimumab (LymphoStat-B) were evaluated in cynomolgus monkeys. Belimumab is a fully human IgG1lambda antibody directed against B-lymphocyte stimulator (BLyS) protein. BLyS is a TNF family member that supports B-lymphocyte maturation and survival and has been implicated in the pathogenesis of autoimmune diseases and B-lymphocyte malignancies. Belimumab was developed to antagonize BLyS activity in autoimmune diseases and B-lymphocyte malignancies, where undesirable effects of B-lymphocyte activity may cause or contribute to disease. Pharmacodynamic effects of belimumab were monitored by immunophenotyping of peripheral blood. Pathology end points, including tissue immunophenotyping, are described after 13 and 26 weeks of treatment and after a 34-week treatment-free (recovery) period. Belimumab was safe and well tolerated in repeat-dose toxicology studies at 5-50 mg/kg for up to 26 weeks. Monkeys exposed to belimumab had significant decreases in peripheral blood B lymphocytes by 13 weeks of exposure, continuing into the recovery period, despite total lymphocyte counts similar to the controls. There were concomitant decreases in spleen and lymph node B-lymphocyte representation after 13 or 26 weeks of treatment with belimumab. Microscopically, monkeys treated with belimumab for 13 or 26 weeks had decreases in the number and size of lymphoid follicles in the white pulp of the spleen. All findings were generally reversible within a 34-week recovery period. These data confirm the specific pharmacologic activity of belimumab in reducing B lymphocytes in the cynomolgus monkey. The favorable safety profile and lack of treatment-related infections also support continued clinical development of belimumab.

The population pharmacokinetics (PK) of belimumab were characterized in 1,603 patients with systemic lupus erythematosus receiving belimumab 1, 4, 10, or 20 mg/kg doses in Phase 1-3 trials. Belimumab PK were well described with a linear two-compartment model, with clearance from the central compartment (CL). Belimumab exposure was approximately dose-proportional. The estimated population terminal half-life was 19.4 days and steady-state volume of distribution (Vss) was 5.29 L for the currently approved 10 mg/kg dose used in the Phase 3 trials, with an estimated CL of 215 mL/day. No effects of age, sex, race, disease activity, co-medications, or baseline characteristics on belimumab PK were found to alter exposure in a manner requiring dose adjustment. An association observed between increasing baseline proteinuria and increasing CL may be clinically relevant in nephropathy with very high proteinuria levels. No evidence of target-mediated clearance was observed. Clinically relevant effects of body size (increased CL and V1 with increased body weight, and reduced V1 with increased body mass index) have been accounted for in current weight-normalized belimumab dosing.

HGS004 is safe and well tolerated and demonstrates meaningful antiviral activity when administered to patients infected with CCR5-tropic HIV-1.

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