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.
BACKGROUND
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.


BACKGROUND
Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.
Los Angeles County and University of Southern California Medical Center and University of Southern California Keck School of Medicine, 1975 Zonal Ave., Los Angeles, CA, 90033, USA. stohl@usc.edu.|Division of Rheumatology, Los Angeles County + University of Southern California Medical Center and Keck School of Medicine of the University of Southern California, 2011 Zonal Ave., Los Angeles, CA, 90033, USA. stohl@usc.edu.
William
W
Stohl
Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK, 73104, USA. JTMmail@aol.com.
Joan T
JT
Merrill
University of Rochester, 252 Elmwood Ave., Rochester, NY, 14627, USA. John_Looney@URMC.Rochester.edu.
R John
RJ
Looney
Hospital for Joint Disease, 301 E 17th St., New York, NY, 10003, USA. Jbuyonic@aol.com.
Jill
J
Buyon
Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA. drdanielwallace@gmail.com.
Daniel J
DJ
Wallace
Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA, 90048, USA. Michael.Weisman@cshs.org.
Michael H
MH
Weisman
SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY, 11203, USA. ELLEN.GINZLER@downstate.edu.
Ellen M
EM
Ginzler
Amgen Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. bcooke@amgen.com.
Blaire
B
Cooke
Formerly of Amgen, Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. donnalholloway@yahoo.com.
Donna
D
Holloway
Amgen Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. arunank@amgen.com.
Arunan
A
Kaliyaperumal
Formerly of Amgen, Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. Kamesh.Kuchimanchi@baxalta.com.
Kameswara Rao
KR
Kuchimanchi
Amgen Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. tcheah@amgen.com.
Tsui Chern
TC
Cheah
Amgen Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. hansr@amgen.com.
Erik
E
Rasmussen
Amgen Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. jferbas@amgen.com.
John
J
Ferbas
Formerly of Amgen, Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. sbelouski@yahoo.com.
Shelley S
SS
Belouski
Amgen Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. tsujiw@amgen.com.
Wayne
W
Tsuji
Formerly of Amgen, Inc., 1 Amgen Center Dr., Thousand Oaks, CA, 91320, USA. djzk3tk@msn.com.
Debra J
DJ
Zack
D000328:Adult; D019540:Area Under Curve; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism*; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000378:metabolism*; D018655:Lymphocyte Count; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
C573858:AMG623 peptibody; D053264:B-Cell Activating Factor; D011993:Recombinant Fusion Proteins; C505719:TNFSF13B protein, human