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

William Stohl, Joan T Merrill, R John Looney, Jill Buyon, Daniel J Wallace, Michael H Weisman, Ellen M Ginzler, Blaire Cooke, Donna Holloway, Arunan Kaliyaperumal, Kameswara Rao Kuchimanchi, Tsui Chern Cheah, Erik Rasmussen, John Ferbas, Shelley S Belouski, Wayne Tsuji, Debra J Zack, William Stohl, Joan T Merrill, R John Looney, Jill Buyon, Daniel J Wallace, Michael H Weisman, Ellen M Ginzler, Blaire Cooke, Donna Holloway, Arunan Kaliyaperumal, Kameswara Rao Kuchimanchi, Tsui Chern Cheah, Erik Rasmussen, John Ferbas, Shelley S Belouski, Wayne Tsuji, Debra J Zack

Abstract

Introduction: Blisibimod 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).

Methods: SLE 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.

Results: All 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.

Conclusions: Blisibimod 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 registration: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.

Figures

Fig. 1
Fig. 1
Mean (SD) concentration-time profiles following administration of blisibimod in subjects with systemic lupus erythematosus. Subjects were treated with the indicated single doses of blisibimod IV (a), SC (b), or the indicated weekly doses (c) for 4 weeks. Abbreviations: IV intravenous, LOQ lower limit of quantification, SC subcutaneous, SD standard deviation
Fig. 2
Fig. 2
B cell subsets following administration of blisibimod to subjects with systemic lupus erythematosus treated with the four indicated weekly doses in the phase 1b study. B cell subsets are peripheral blood CD19+ CD20+ total B cells (a), IgD+ CD27- naïve B cells (b), IgD+ CD27+ memory B cells (c), and IgD- CD27+ memory B cells (d). Each symbol represents an individual patient at the indicated time point, and lines were generated by smoothing with a spline function

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