Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency

Abstract

PurposeTreatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies.MethodsSubjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule.ResultsEighty-three subjects (24 < 18 years; 59 ≥ 18 years) received 2729 infusions (excluding ramp-up) at a mean dose of 0.155 g/kg/week in the pivotal and 0.156 g/kg/week in the extension study. IGHy exposure exceeded 30 months in 48 subjects.During 187.7 subject-years of IGHy exposure, 2005 adverse events (AEs) (10.68 per subject-year) occurred. The rate of related systemic AEs during consecutive 1-year periods remained low; the rate of related local AEs decreased from 3.68/subject-year in months 1–12 to approximately 1.50/subject-year after 30 months of treatment. Fifteen subjects transiently developed anti-rHuPH20 binding antibody. There was no difference in AE rates in these subjects before and after the first titer increase to ≥1:160.The rate of infections during IGHy exposure was 2.99 per subject-year and did not increase during the studies. Annual infection rates were 3.02 in subjects <18 years and 2.98 in subjects ≥18 years.ConclusionsLong-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-016-0298-x) contains supplementary material, which is available to authorized users.

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

“…During an extension study (NCT01175213; Sponsored by Baxalta, Inc, now part of Shire), the dose and interval of IGHy were maintained for the first three infusions, after which patients could switch from a 3-or 4-week dose/interval to a 2-week interval (with 50% of the calculated 4-week dose) for ≤4 months in order to determine trough levels for the 2-week interval [39]. A total of 66 patients who completed the Phase III study entered the long-term extension study; 63 patients continued on IGHy and 3 continued on IVIG [39].…”

“…A total of 2729 infusions were administered during the Phase III study (1129, excluding ramp-up [initial 1-week dose of IGHy and increased until prestudy IVIG interval of 3 or 4 weeks was reached], and1600 in the extension study; Table 2) [39].…”

“…In the Phase III (excluding ramp-up) and extension studies, mean ± SD doses of IGHy were 0.155 ± 0.053 g/kg/week and 0.156 ± 0.051 g/kg/week, and mean IGHy treatment duration was 367.7 ± 103.9 days and 565.9 ± 211.8 days, respectively. A total of 48 patients were treated for >30 months [39].…”

“…By protocol, the minimum IgG trough level in the study was 500 mg/dl. The median steady-state IgG trough levels during IGHy infusions was 983 mg/dl (95% CI: 946-1070) during 4-week intervals; it was higher for the at 3-and 2-week interval recipients (1195 mg/dl [95% CI: 958-1530] and 1135 mg/dl [95% CI: 939-1440], respectively) [16,39].…”

“…During the Phase III and extension studies, there were five acute serious bacterial infections, all of which were pneumonias [39]. Overall, the rates of serious bacterial infections during IGHy treatment in the Phase III and extension studies were 0.025 (upper 99% CI limit: 0.046) and 0.03 (upper 99% CI limit: 0.05) per patient-year, respectively [16,39], which were substantially lower than the predefined rate threshold of <1.0 infection per personyear outlined by the FDA's Blood Products Advisory Committee for demonstration of efficacy of IgG replacement therapy [43].…”