Immune deficiencies, infection, and systemic immune disorders
Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency

https://doi.org/10.1016/j.jaci.2012.06.021Get rights and content

Background

Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site.

Objective

This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI.

Methods

In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals.

Results

The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV.

Conclusion

IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates.

Section snippets

Study products

A 10% preparation of normal human immunoglobulin stabilized with glycine (GAMMAGARD LIQUID in the United States/Canada; elsewhere KIOVIG; Baxter Healthcare Corporation, Westlake Village, Calif) was administered intravenously (hereafter referred to as IGIV) and subcutaneously in combination with rHuPH20 (IGHy). The rHuPH20 (Halozyme Therapeutics, Inc, San Diego, Calif) component of IGHy is a preparation of purified soluble human hyaluronidase produced in Chinese hamster ovary cells formulated at

Results

Eighty-nine (89) patients with PI were enrolled; 87 aged 4 to 78 years received IGIV and 83 received IGHy. The majority presented with common variable immune deficiency (n = 49) or hypogammaglobulinemia associated with antibody deficiency (n = 17; Table E2). Participants were distributed evenly with respect to sex (see Table E3 in this article's Online Repository at www.jacionline.org). IGIV was administered for a median of 91 days and IGHy for a median of 366 days per subject during the

Discussion

The present phase III, open-label, multicenter study was conducted to investigate a novel approach to IgG replacement in patients with PI that would allow self-administration of facilitated SC Immune Globulin Infusion with rHuPH20 using the same volume and frequency as IGIV, in a single site.

The rate of acute SBIs was similar to other IGIV and IGSC products.11, 23, 24, 25 The rate of all infections for IGHy was 2.97 (95% CI, 2.51-3.47) per subject-year during the 12-month efficacy observation

References (35)

  • A. Gardulf

    Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route

    BioDrugs

    (2007)
  • S. Misbah et al.

    Subcutaneous immunoglobulin: opportunities and outlook

    Clin Exp Immunol

    (2009)
  • R. Gustafson et al.

    Rapid subcutaneous immunoglobulin administration every second week results in high and stable serum immunoglobulin G levels in patients with primary antibody deficiencies

    Clin Exp Immunol

    (2008)
  • A. Gardulf et al.

    Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies–a prospective multi-national study

    J Clin Immunol

    (2006)
  • S. Jolles et al.

    Subcutaneous immunoglobulin replacement therapy with Hizentra(R), the first 20% SCIG preparation: a practical approach

    Adv Ther

    (2011)
  • R.L. Wasserman et al.

    Efficacy, safety, and pharmacokinetics of a 10% liquid immune globulin preparation (GAMMAGARD LIQUID, 10%) administered subcutaneously in subjects with primary immunodeficiency disease

    J Clin Immunol

    (2011)
  • R.L. Wasserman et al.

    Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease

    Clin Exp Immunol

    (2010)
  • Cited by (117)

    • Long-term follow-up of facilitated subcutaneous immunoglobulin therapy in multifocal motor neuropathy

      2021, Journal of the Neurological Sciences
      Citation Excerpt :

      The mechanism is primarily attributed to increased plasma viscosity following plasma IgG surge, administration of daily doses larger than 35 g being a significant risk factor [19]. Treatment associated with thromboembolic events following subcutaneous immunoglobulin has not been reported, neither following conventional nor facilitated SCIG [2,3,20,21]. Most larger studies are, however, conducted in young patients receiving low dose fSCIG for primary immunodeficiency disease [21,22].

    View all citing articles on Scopus

    Supported by Baxter Healthcare Corporation; conducted in part at the pediatric research center at the University of California, San Francisco (UCSF; study site J. Puck) supported by the National Institutes of Health (NIH grant UL1 RR024131) to the UCSF Clinical and Translational Science Institute; and conducted in part in facilities (study site A. Rubenstein) supported by Clinical and Translational Service Awards (grants UL1RR025750, TL1RR025748, and KL2RR025749; and UL1TR000086, TL1TR000087, and KL2TR000088).

    Disclosure of potential conflict of interest: R. L. Wasserman has served as a consultant and/or speaker for Baxter International, CSL Behring, and Grifols; has served as an investigator for Baxter, CSL Behring, the Korean Green Cross, and Biotest; and has served as a consultant for Biotest. I. Melamed has received one or more payments for speaking from Baxter and has served as a principal investigator for Baxter, CSL Behring, Biotest, Octapharma, and Gammaplex. M. R. Stein has received funding from Baxter International and from CSL Behring and has consultancy arrangements with and/or has provided expert testimony for Baxter International, CSL Behring, and Grifols. S. Gupta has received one or more payments for speaking from Baxter. J. Puck has received funding from Baxter for an immunoglobin clinical trial. H. Leibl is a shareholder and holds stock options in Baxter. B. McCoy is a shareholder in Baxter. The rest of the authors declare that they have no relevant conflicts of interest.

    Names and affiliations of the IGSC, 10% with rHuPH20 Study Group are provided in this article's Online Repository.

    View full text