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Randomized Controlled Trial
. 2019 Apr;105(4):1031-1039.
doi: 10.1002/cpt.1276. Epub 2018 Dec 4.

M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study

Leona E Ling  1 , Jan L Hillson  1 , Renger G Tiessen  2 , Tjerk Bosje  2 , Mattheus Paulus van Iersel  2 , Darrell J Nix  3 , Lynn Markowitz  1 , Nicholas A Cilfone  1 , Jay Duffner  1 , James B Streisand  1 , Anthony M Manning  1 , Santiago Arroyo  1
Affiliations
Randomized Controlled Trial

M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study

Leona E Ling et al. Clin Pharmacol Ther. 2019 Apr.

Abstract

M281 is a fully human, anti-neonatal Fc receptor (FcRn) antibody that inhibits FcRn-mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double-blind, placebo-controlled, first-in-human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose-dependent serum IgG reductions, which were similar across all IgG subclasses. Multiple weekly doses of 15 or 30 mg/kg achieved mean IgG reductions of ≈85% from baseline and maintained IgG reductions ≥75% from baseline for up to 24 days. M281 was well tolerated, with no serious or severe adverse events (AEs), few moderate AEs, and a low incidence of infection-related AEs similar to placebo treatment. The tolerability and consistency of M281 pharmacokinetics and pharmacodynamics support further evaluation of M281 in diseases mediated by pathogenic IgG.

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Conflict of interest statement

L.E.L., L.M., J.D., A.M.M., and S.A. are full‐time employees of Momenta Pharmaceuticals and may own stock or stock options. J.L.H. was an employee of Momenta Pharmaceuticals when the study was designed and conducted and subsequently a paid consultant of Momenta Pharmaceuticals and may own stock or stock options of Momenta Pharmaceuticals. N.A.C. was a full‐time employee of Momenta Pharmaceuticals during the execution of the study and subsequently a paid consultant of Momenta Pharmaceuticals, and owned stock, restricted stock, and stock options in Momenta Pharmaceuticals during manuscript preparation. R.G.T., T.B., and M.P.v.I. are full‐time employees of PRA Health Sciences and may own stock or stock options in PRA Health Sciences. D.J.N. was principal of Drug Development Consulting, currently is a full‐time employee of Certara Strategic Consulting and is a paid consultant of Momenta Pharmaceuticals. J.B.S. is principal at Streisand Biomedical Consulting and a paid consultant of Momenta Pharmaceuticals.

Figures

Figure 1
Figure 1
Single ascending dose receptor occupancy and serum IgG. Values are shown as mean (SD). (a) M281 receptor occupancy, as measured by percentage unoccupied FcRn compared with baseline in monocytes. (b) Serum immunoglobulin G (IgG) percentage relative to baseline. M281‐treated cohorts are represented by n = 3 (0.3 or 3 mg/kg), n = 6 (30 mg/kg), and n = 5 (60 mg/kg). Placebo controls from each single‐dose cohort were combined (n = 10).
Figure 2
Figure 2
Multiple‐dose receptor occupancy and serum IgG after 4 once weekly doses of M281 of 15 or 30 mg/kg. Values are shown as mean (SD). (a) M281 receptor occupancy, as measured by percentage unoccupied FcRn compared with baseline in monocytes. (b) Serum immunoglobulin G (IgG) percentage relative to baseline. Each M281‐treated cohort is represented by n = 3. Placebo controls from each multiple‐dose cohort were combined (n = 4).
Figure 3
Figure 3
Serum immunoglobulin G subclasses after four once weekly doses of M281 (30 mg/kg). Values are shown as mean (SD). IgG1 (a), IgG2 (b), IgG3 (c), and IgG4 (d) percentage relative to baseline. Each M281‐treated cohort is represented by n = 3, and placebo controls from the same cohort are represented by n = 2.
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