Efficacy, Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America

Abstract

Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3–83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year (p < 0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4–180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0327-9) contains supplementary material, which is available to authorized users.

Recombinant Human Hyaluronidase-Facilitated Subcutaneous Immunoglobulin Infusion in Primary Immunodeficiency Diseases

“…This is in contrast to conventional subcutaneous infusions, in which hyaluronan limits the permeability of the ECM, and the deliverable volume of drug that can be infused in a single site. The volume of conventional SCIG infusions has been limited to 20-60 ml/site depending on the SCIG formulation [21,22], necessitating frequent infusions and the use of multiple infusion sites because infusion of larger volumes resulted in significant induration, reduced absorption of IgG and pain. Preclinical studies have demonstrated that rHuPH20 is fast acting and safe.…”

Response to the Letter to the Editor Regarding “Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials”

“…We welcome the recommendation to standardize the collection of study data to allow for more straightforward data comparisons. However, our comparative discussion made no assertion of superiority and instead stated that IG20Gly treatment was well tolerated, despite the higher infusion rates and volumes per site than those previously reported with other subcutaneous IG products [ 2 ]. The discussion of manufacturing processes, excipients, and infusion supplies in the Suez et al publication was in reference to reasons the high infusion rates and volumes up to 60 mL/h/site and 60 mL/site, respectively, were achievable with IG20Gly.…”

“…In the recent letter to the editor, “Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials” [ 1 ], Ballow et al discuss the inappropriateness of making comparisons of adverse event (AE) and tolerability data from different clinical trials of subcutaneous immunoglobulins (IGs) unless the products are studied contemporaneously within the same study using the same methodology, the same investigators, and the same patient populations. The authors conclude that “given the current difficulties in standardizing methodologies across sites and studies, comparisons of tolerability of different products in reported clinical trials should be avoided.” Their letter focuses on the recent phase 3 clinical trial publication of IG20Gly (Cuvitru®, SCIG 20%, Baxalta US Inc., Westlake Village, CA, USA) by Suez et al, which reports the infusion administration parameters and rates of AEs, and discusses the results within the framework of reported data for other available subcutaneous IG products [ 2 ].…”

“…In addition, although we agree that drawing conclusions regarding the superiority of a product from direct comparisons of data acquired in trials with different study designs, populations, and methodology is not appropriate, we maintain that it is appropriate to make comparisons of data among trials, with acknowledgment of the limitations, in order to provide reference points to contextualize the results. Indeed, the discussion section of the Suez et al publication includes a disclaimer, “differences in study design and product concentration may limit direct comparison” [ 2 ]. The Borte et al publication, which reported similar data for IG20Gly in a European patient population, also included such a statement [ 3 ].…”

Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies

“…To overcome the drawbacks of multiple site injections and the limitations of volume per infusion, a 20% IgG product containing L-proline as a stabilizing agent (Hizentra) was introduced in 2010 (35). In 2016, based on a phase II/III study in PID (36), the glycine-stabilized 20% IgG product Cuvitru was approved by the Food and Drug Administration. These products are only for s.c. use and have the advantage of delivering a higher dose of Ig in a lower volume.…”