Efficacy, Safety and Tolerability of a New 10% Intravenous Immunoglobulin for the Treatment of Primary Immunodeficiencies

Abstract

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.

Low rates of headache and migraine associated with intravenous immunoglobulin infusion using a 15-minute rate escalation protocol in 123 patients with primary immunodeficiency

“…Almost all patients achieved the maximum infusion rate specified in the product labeling, utilizing an infusion protocol with 15-minute rate escalation increments. Recent trials of other IVIG products have reported achieving per-protocol infusion rates in >90% of infusions, but with longer rate escalation increments (30 minutes vs 15 minutes for the IVIG formulations used in this analysis) ( 22 , 24 ). In our study, subgroup analyses demonstrated differences in achievement of the maximum infusion rate by groups, with higher probabilities of achieving the maximum rate for adults vs pediatric patients, males vs females, and infusions every 28 days vs every 21 days.…”

“…The observed rates of product-related headache (6.1% of infusions, 28.5% of patients) and migraine (0.5% of infusions, 4.1% of patients) occurred with 94.6% of patients achieving the maximum infusion rate, and use of a 15-minute rate escalation protocol. To place these results in context, headache rates reported in recent studies of IVIG in PI range from 2% to 22% on a per-infusion basis, and from 8% to 50.8% on a per-patient basis ( 13 , 22 , 24 – 26 , 32 , 38 ). Our results cannot be compared directly with these trials due to differences in trial design, patient population, and other factors.…”

“…Because PI is rare, trials of IVIG in patients with PI tend to be small, with most late-phase clinical trials of these agents involving 50 or fewer patients (18,20,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). While these trials produce sufficient data to satisfy FDA requirements for safety and efficacy, the overall data sets are limited.…”

Cation exchange chromatography removes FXIa from a 10% intravenous immunoglobulin preparation

“…GC5107 is a 10% glycine-stabilized IVIG produced by GC Biopharma. Results of the phase 3 clinical trial in patients with primary immunodeficiency have been published previously (19). Here, we describe in detail the manufacturing process for GC5107 and demonstrate that cation exchange (CEX) chromatography is a robust means of removing FXIa from the final preparation, even in starting material spiked with high levels of FXIa.…”