Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia

Abstract

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count (<100 × 109 /L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function, resulting in increased risk of bleeding and impaired quality of life. Efgartigimod is a human IgG1 antibody Fc-fragment, a natural ligand of the neonatal Fc receptor (FcRn), engineered for increased affinity to FcRn, while preserving its characteristic pH-dependent binding. Efgartigimod blocks FcRn, preventing IgG recycling, and causing targeted IgG degradation. In this Phase 2 study, 38 patients were randomized 1:1:1 to receive four weekly intravenous infusions of either placebo (N = 12) or efgartigimod at a dose of 5 mg/kg (N = 13) or 10 mg/kg (N = 13). This short treatment cycle of efgartigimod in patients with ITP, predominantly refractory to previous lines of therapy, was shown to be well tolerated, and demonstrated a favorable safety profile consistent with Phase 1 data. Efgartigimod induced a rapid reduction of total IgG levels (up to 63.7% mean change from baseline), which was associated with clinically relevant increases in platelet counts (46% patients on efgartigimod vs 25% on placebo achieved a platelet count of ≥50 × 109 /L on at least two occasions, and 38% vs 0% achieved ≥50 × 109 /L for at least 10 cumulative days), and a reduced proportion of patients with bleeding. Taken together, these data warrant further evaluation of FcRn antagonism as a novel therapeutic approach in ITP.

Conflict of interest statement

Adrian C. Newland: consultant for Amgen, Angle, argenx, Dova, Novartis, Ono, Rigel, and Shionogi; received funding from Amgen, Novartis, and Rigel; received honoraria directly from Amgen, Angle, argenx, Dova, Novartis, Ono, Rigel, and Shionogi; and paid expert testimony from argenx and Rigel. Blanca Sánchez‐González: received honoraria directly and paid expert testimony from Novartis, Takeda, Amgen, Alexion, Gilead and Shire; and Board of Directors or its advisory committees at Novartis, Takeda, Amgen. László Rejtő, Miklos Egyed, and Nataliya Romanyuk: none. E. Sally Ward: receives funding and royalty payments from argenx, and has equity ownership in argenx. Marc Michel: consultant for Novartis, Amgen, and Rigel. Howard A. Liebman: consultant for argenx, Novartis, Rigel, Pfizer, Dova, and received funding from Janssen and Bristol‐Myers. David J. Kuter: consultant for Actelion (Syntimmune), Agios, Alnylam, Amgen, argenx, Bristol Myers Squibb (BMS), Caremark, Daiichi Sankyo, Dova, Kyowa‐Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Platelet Disorder Support Association, Principia, Protalex, Protalix, Rigel, Sanofi, Genzyme, Shionogi, Shire, Takeda (Bioverativ), UCB, Up‐To‐Date, Zafgen; and received funding from Actelion (Syntimmune), Agios, Alnylam, Amgen, argenx, Bristol Myers Squibb (BMS), Kezar, Principia, Protalex, Rigel, and Takeda (Bioverativ). Katrien Verschueren: consultant for argenx. Marie Godar, Domenica Gandini, Peter Ulrichts, Jon Beauchamp, Torsten Dreier, Hans de Haard, and Nicolas Leupin: employees and equity ownership in argenx.

© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.

Figures

Figure 1

Proportion of patients achieving increasing thresholds of platelet count assessed per treatment group during the main study. Patients receiving rescue medication were excluded from the analysis from the day of rescue. n, number of patients achieving the threshold

Figure 2

Mean platelet count ±SEM (×109/L, circles), mean percentage change from baseline of total IgGs ±SEM (triangles), and percentage of patients with total WHO score >0 (squares) assessed per treatment group during the main study. (A) Placebo, (B) efgartigimod 5 mg/kg, and (C) efgartigimod 10 mg/kg. Patients receiving rescue medication were excluded from the analysis from the day of rescue (as indicated in the table below the figure). Arrows on the X‐axis indicate time points of treatment administration