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

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.

• Authors: 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
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 17 Pg. 215 (Aug 20 2015) ISSN: 1478-6362 [Electronic] England
• PMID: 26290435 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• AMG623 peptibody
• B-Cell Activating Factor
• Recombinant Fusion Proteins
• TNFSF13B protein, human

Topics

• Adult
• Area Under Curve
• B-Cell Activating Factor (antagonists & inhibitors, metabolism)
• B-Lymphocyte Subsets (drug effects, metabolism)
• Dizziness (chemically induced)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Headache (chemically induced)
• Humans
• Injections, Intravenous
• Injections, Subcutaneous
• Lupus Erythematosus, Systemic (drug therapy, metabolism)
• Lymphocyte Count
• Male
• Metabolic Clearance Rate
• Middle Aged
• Nausea (chemically induced)
• Recombinant Fusion Proteins (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Young Adult