Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans

Abstract

Background: Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs.

Methods: A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys.

Results: Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG, and no serious adverse events related to efgartigimod infusion were observed.

Conclusion: Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases.

Trial registration: Clinicaltrials.gov NCT03457649.

Funding: argenx BVBA.

Keywords: Autoimmune diseases; Autoimmunity; Immunoglobulins; Therapeutics.

Conflict of interest statement

Conflict of interest: PU, AG, TD, VH, EH, BV, PV, NO, VL, FJE, HDH, and NL are or used to be full-time employees of argenx BVBA. TVB is a consultant to argenx BVBA. ESW, RJO, and JC are supported in part by a research grant funded by argenx BVBA.

Figures

Figure 1. The location of the residues targeted for mutation in efgartigimod.

X-ray crystallographic structure of hIgG1-derived Fc (54) with locations of residues that are mutated in efgartigimod shown in color (Met252 to Tyr, Ser254 to Thr, Thr256 to Glu, His433 to Lys, and Asn434 to Phe). Residues playing a central role in hIgG1:FcRn interaction are indicated in black (Ile253, His310, and His435) (55). The figure was generated using PyMOL (PyMOL Molecular Graphics System, version 2.0, Schrödinger LLC).

Figure 2. Differences in subcellular trafficking behavior between efgartigimod and anti-FcRn Ab.

(A) HMEC-1 cells expressing hFcRn-GFP were pulse-chased with Alexa Fluor 647–labeled efgartigimod, isotype control (HEL-specific hIgG1), or anti-FcRn Ab at concentrations of 25, 200, and 75 μg/ml, respectively, for 30 minutes and chased for 0, 30, and 120 minutes. Levels of cell-associated Alexa Fluor 647 were determined using flow cytometry. Representative histogram plots for 2 independent experiments are shown. (B) Cell-associated fluorescence levels for analyses carried out as in panel A, displayed as the percentage of fluorescence remaining at different chase times relative to the pulse-only samples. For chase times of 30 and 120 minutes, means of 4 samples (2 samples per experiment, 2 experiments) are shown. Error bars indicate SEM, and statistical significance of the difference between efgartigimod and hIgG1 following a 30-minute chase is indicated. *P < 0.05, 1-way ANOVA. (C) HMEC-1 cells expressing human FcRn-GFP were pulse-chased with 500 μg/ml Alexa Fluor 555–labeled dextran and then pulse-chased (30-minute pulse, 0- or 16-hour chase) with Alexa Fluor 647–labeled efgartigimod (25 μg/ml) or anti-FcRn Ab (75 μg/ml). Images of representative cells are shown, with arrowheads in the anti-FcRn panel (16 hours) indicating Ab that is localized in dextran-positive compartments. Data for Alexa Fluor 647–labeled efgartigimod or Alexa Fluor 647–labeled anti-FcRn and FcRn-GFP are displayed as acquired. The lysosomes in boxed regions (labeled 1 and 2 for each inhibitor) are cropped and expanded (lower panels), and pixel intensities along the dotted lines are shown. Intensities are normalized against the highest pixel value in each 16-hour image (Alexa Fluor 555) or for both 16-hour images (Alexa Fluor 647). GFP, Alexa Fluor 555, and Alexa Fluor 647 are pseudocolored blue, red, and green, respectively. Scale bars: 3 μm (upper panels); 1 μm (cropped lysosomes). Microscopy data are representative of at least 2 independent experiments.

Figure 3. Effect of efgartigimod and IVIg on tracer IgG levels in cynomolgus monkeys.

Animals (n = 2/group) were injected with 1 mg/kg of the tracer Ab FR70-hIgG1, followed 2 days later with i.v. infusion of 70 mg/kg efgartigimod or 2 g/kg IVIg. Tracer levels in serum, detected by murine CD70-binding ELISA, were plotted relative to predose levels. Values are shown as mean ± SEM. %T0, percentage change from baseline.

Figure 4. Efgartigimod dose-escalation study in cynomolgus monkeys.

Animals (n = 2/group) were injected with 1 mg/kg of the tracer Ab FR70-hIgG1, followed 2 days later with i.v. infusion of 0.2 to 200 mg/kg efgartigimod or vehicle. Tracer levels in serum (A) are detected by murine CD70-binding ELISA. Endogenous IgG levels in serum (B) were plotted relative to predose levels. Cyno, cynomolgus. Values are shown as mean ± SEM.

Figure 5. Endogenous IgG levels in multiple dose study in cynomolgus monkeys.

Animals (n = 2/group) were injected i.v. with 20 mg/kg efgartigimod every day during the first 4 days or once every 4 days (arrows indicate drug administration). Endogenous IgG levels in serum were plotted relative to predose levels. Values are shown as mean ± SEM.

Figure 6. Flow chart of SAD part of first-in-human study of efgartigimod in healthy volunteers.

n, number of subjects. *One subject who did not originally fulfill the in- and exclusion criteria was rescreened at a later stage and was subsequently listed as a reserve subject. **An optional sixth cohort was not initiated.

Figure 7. Flow chart of MAD part of first-in-human study of efgartigimod in healthy volunteers.

n, number of subjects. *Subject withdrew consent. **Dosing of all subjects in cohort 8 was discontinued early because of 1 subject experiencing a SAE. At that time, 4 subjects in this cohort had received 2 doses of the study drug and 4 subjects, including the subject with the SAE, had received 1 dose. After further investigation, it was considered unlikely that the SAE was related to the study drug.

Figure 8. Efgartigimod serum concentration in the SAD part of first-in-human study.

Healthy subjects (n = 6/group) were dosed with 0.2, 2, 10, 25, or 50 mg/kg efgartigimod or placebo (i.e., cohorts 1–5). Efgartigimod or placebo (randomized at a 4:2 ratio) was administered i.v. in a 2-hour infusion. Values are shown as mean ± SD. LLOQ, lower limit of quantification.

Figure 9. Efgartigimod serum concentration in the MAD part of first-in-human study.

Healthy subjects (n = 8/group) were dosed with 10 mg/kg efgartigimod or placebo q4d on 6 occasions (cohort 7), 10 mg/kg efgartigimod or placebo q7d on 4 occasions (cohort 9), or 25 mg/kg efgartigimod or placebo q7d on 4 occasions (cohort 10). Efgartigimod or placebo (randomized at a 6:2 ratio) was administered i.v. in a 2-hour infusion. Values are shown as mean ± SD.

Figure 10. Serum levels of IgG subclasses over time in the SAD part of first-in-human study.

Healthy subjects (n = 6/group) were dosed with 0.2, 2, 10, 25, or 50 mg/kg efgartigimod or placebo (i.e., cohort 1-5). Efgartigimod or placebo (randomized at a 4:2 ratio) was administered i.v. in a 2-hour infusion. Percentage change versus baseline in IgGsubclass serum concentration (%T0) is shown. Values are shown as mean ± SD.

Figure 11. Serum levels of IgG subclasses over time in the MAD part of first-in-human study.

Healthy subjects (n = 8/group) were dosed with 10 mg/kg efgartigimod or placebo q4d on 6 occasions (cohort 7), 10 mg/kg efgartigimod or placebo q7d on 4 occasions (cohort 9), or 25 mg/kg efgartigimod or placebo q7d on 4 occasions (cohort 10). Efgartigimod or placebo (randomized at a 6:2 ratio) was administered i.v. in a 2-hour infusion. Percentage change versus baseline in IgGsubclass serum concentration (%T0) is shown. Values are shown as mean ± SD.