Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies

M Borte, G Kriván, B Derfalvi, L Maródi, T Harrer, S Jolles, C Bourgeois, W Engl, H Leibl, B McCoy, D Gelmont, L Yel, M Borte, G Kriván, B Derfalvi, L Maródi, T Harrer, S Jolles, C Bourgeois, W Engl, H Leibl, B McCoy, D Gelmont, L Yel

Abstract

A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient-year, P < 0·0001); the rate of all infections was 4·38/patient-year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3-4·1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.

Keywords: 20% immunoglobulin; immunoglobulin replacement therapy; pharmacokinetics; primary immunodeficiency diseases; subcutaneous administration.

© 2016 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology, Clinical and Experimental Immunology.

Figures

Figure 1
Figure 1
Study design. i.v. = intravenous; s.c. = subcutaneous; IGIV 10% = 10% immunoglobulin (Ig) treatment administered i.v.; IgGSC 16% = 16% Ig treatment administered s.c.; PK = pharmacokinetics.
Figure 2
Figure 2
Related local adverse events (AEs) reported over time during immunoglobulin (Ig) treatment administered subcutaneously (IGSC) 20% treatment. Annualized rate of related local AEs over time for the planned treatment period (52 weeks). Annualized rate of causally related local AEs = number of causally related local AEs divided by the total number of patient‐years under IGSC 20% treatment.
Figure 3
Figure 3
Tolerability of immunoglobulin (Ig) treatment administered subcutaneously (IGSC) 20% infusions. (a) Infusion volumes; (b) Infusion rates. Numbers above the bars indicate the number of infusions associated with a causally related local AE and numbers inside the bars indicate the number of infusions not associated with any causally related local adverse event (AE). Only infusions with complete infusion histories (n = 2338) have been considered for these analyses.
Figure 4
Figure 4
Pharmacokinetic of immunoglobulin (Ig)G levels during the course of a treatment interval. Samples were collected on day 0 within 60 min prior to the first immunoglobulin (Ig) treatment administered subcutaneously (IGSC) 20% infusion and on days 1, 3, 5 and 7 post‐infusion (± 6 h from infusion start). Plotted are the mean serum IgG concentrations in patients aged 12 years and older treated with IGSC 20%; minimum, 28 patients per time‐point. Vertical bars represent standard deviations.
Figure 5
Figure 5
Patients who chose to continue with immunoglobulin (Ig) treatment administered subcutaneously (IGSC) 20% at the end of the study. Treatment preference was analysed separately for the age groups 2–13 years (observer: parent) and 14 years and older (observer: patient) at the ‘end‐of‐study’ visit (n = 48). Plotted are the number of patients who declared that they would continue with immunoglobulin (Ig) treatment administered subcutaneously (IGSC) 20% treatment (black bar) and the number of patients who would choose an alternative IgG replacement therapy (grey bar); the proportion of subjects in each category (%) is indicated above the bars.

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