Treatment of systemic lupus erythematosus patients with the BAFF antagonist “peptibody” blisibimod (AMG 623/A-623): results from randomized, double-blind phase 1a and phase 1b trials

Abstract

IntroductionBlisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE).MethodsSLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed.ResultsAll subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for ≥ 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naïve B cells (24–76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD-CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0–6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects.ConclusionsBlisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0–6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases.Trial registrationClinicaltrials.gov NCT02443506. Registered 11 May 2015. NCT02411136 Registered 7 April 2015.

Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial

“…Blisibimod (A-623, AMG 623) is a potent and selective BAFF inhibitor composed of a tetrameric BAFF binding domain fused to a human IgG1 Fc region 9. Although the phase II Placebo-controlled Evaluation of A‑623 Response in Lupus (PEARL-SC) trial with blisibimod in SLE failed to meet the primary efficacy end point, SLE Responder Index-5 (SRI-5), it corroborated the observations from larger Phase III trials in that better treatment effect was observed in subjects with higher disease activity, taking corticosteroids, who had abnormalities in anti-dsDNA and/or complement 10.…”

Update on Biologic Therapies for Systemic Lupus Erythematosus

“…One of them is blisibimod, a Bpeptibody^made of four BAFF binding domains linked to the Fc domain of human IgG1 and which, unlike belimumab, binds to both membrane-bound and soluble BAFF. In phase I RCTs, this agent was well tolerated and led to decreases in total B cell counts, reductions in the naïve B cells, and transient increases in the memory B cells [74].…”

Therapeutic options for cutaneous lupus erythematosus: recent advances and future prospects

“…Recent treatments that have been reported but are in need of further study include lenalidomide, a thalidomide derivative [77–79]; octreotide, a peptide analog of somatostatin [112]; mizoribine, an immunosuppressive [113]; and blisibimod, a biologic BAFF inhibitor [114], among others. Likewise, treatments such as intravenous immunoglobulin therapy [115], mesenchymal stem cell transplantation [116], and regulatory T cell therapy [117] that have shown success in other diseases are now being applied to CLE in exploratory studies.…”