Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis

Abstract

Objective: To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.

Methods: A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.

Results: Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.

Conclusions: Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.

Classification of evidence: This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.

Figure 1. Study flow diagram

Overview of number of patients screened and randomized over the efgartigimod and placebo treatment arms.

Figure 2. Schematic design of the phase 2 study of efgartigimod in patients with generalized myasthenia gravis

Arrows indicate time points of treatment administration; visit number and corresponding day after first administration are indicated. Only blood sampling at visits 9–16. Optional intermediate blood samplings at visit 2, visit 4, visit 6, and visit 8. *Visit window: ± 1 day. EoS = end of study; SoC = standard of care; V = visit.

Figure 3. Blood serum analyses

(A) Serum levels of efgartigimod. Values are mean ± SD. (B) Total immunoglobulin G (IgG) serum levels after efgartigimod and placebo treatment over the 11-week study. Values are mean ± standard error, and are expressed relative (%) to the respective IgG concentrations immediately prior to first dose at visit 1. (C) Individual serum anti–acetylcholine receptor (AChR) autoantibody profiles relative to baseline values. Values are individual values expressed relative (%) to the respective individual anti-AChR autoantibody concentrations immediately prior to first dose at visit 1; the anti-AChR autoantibody levels of patient 3 were below the limit of quantification. Arrows on the X-axis indicate time points of treatment administration. Ab = antibody; BLQ = below the limit of quantification; LLOQ = lower limit of quantification; T₀ = pre-first-dose time point.

Figure 4. Clinical efficacy

(A) Sensitivity analyses for clinical outcome measures. Values are mean ± standard error, and are expressed relative (point reduction) to the baseline zero value obtained immediately prior to first dose at visit 1; negative score is indicative of an improvement; dotted line delineates clinical significant zone, which is Myasthenia Gravis Activities of Daily Living (MG-ADL) ≥2 or Quantitative Myasthenia Gravis (QMG) ≥3; arrows on the X-axis indicate time points of treatment administration. *Statistically significant change from baseline (p ≤ 0.05). (B) Responder analyses for study days 29 and 36. Data are minimum point improvements on the outcome measures of the MG-ADL scale on days 29 and 36, which are the study days in the follow-up period where the pharmacodynamic effect was maximal; percentages of patients showing a clinical improvement of at least the specified value are indicated next to the bars. MG-QoL15r = 15-item Quality of Life scale for Myasthenia Gravis; MGC = Myasthenia Gravis Composite.