Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency
J Clin Immunol
Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency
Richard L. Wasserman 0 1 2 3 4 6 7 8 10
Isaac Melamed 0 1 2 3 4 6 7 8 10
Mark R. Stein 0 1 2 3 4 6 7 8 10
Werner Engl 0 1 2 3 4 6 7 8 10
Marlies Sharkhawy 0 1 2 3 4 6 7 8 10
Heinz Leibl 0 1 2 3 4 6 7 8 10
Jennifer Puck 0 1 2 3 4 6 7 8 10
Arye Rubinstein 0 1 2 3 4 6 7 8 10
Lisa Kobrynski 0 1 2 3 4 6 7 8 10
Sudhir Gupta 0 1 2 3 4 6 7 8 10
Andrew J. Grant 0 1 2 3 4 6 7 8 10
Anoshie Ratnayake 0 1 2 3 4 6 7 8 10
Wendell G. Richmond 0 1 2 3 4 6 7 8 10
Joseph Church 0 1 2 3 4 6 7 8 9 10
Leman Yel 0 1 2 3 4 5 6 7 8 10
David Gelmont 0 1 2 3 4 6 7 8 10
0 IMMUNOe Clinical Research Center , Centennial, CO , USA
1 Allergy Partners of North Texas Research , Dallas, TX , USA
2 Allergy and Asthma Physicians , Hinsdale, IL , USA
3 West Coast Clinical Trials , Cypress, CA , USA
4 University of Texas Medical Branch , Galveston, TX , USA
5 Baxalta US Inc. , Cambridge, MA , USA
6 Allergy & Immunology Division, Montefiore Medical Center , Bronx, NY , USA
7 University of California San Francisco , San Francisco, CA , USA
8 Baxalta Innovations GmbH , Vienna , Austria
9 Children's Hospital Los Angeles , Los Angeles, CA , USA
10 Allergy Associates of the Palm Beaches , North Palm Beach, FL , USA
Purpose Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by in jection of r ec ombina nt human hya lu ronid ase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. Methods Subjects >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. This manuscript is dedicated to the memory of our esteemed colleague Dr. Richard Schiff, MD, PhD, whose untimely passing on 4 July 2014 left a permanent void. He touched the lives of many as a mentor, scholar, collaborator, and friend. Dr. Schiff was instrumental in the development of this product, and the creation and interpretation of the data included herein, and would have been senior author of this manuscript.
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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.
Conclusions Long-term replacement therapy with IGHy was
safe and effective in 83 pediatric and adult subjects with
PIDD.
A recent pivotal study in 83 subjects with PIDD
demonstrated that pre-infusion of rHuPH20 allowed SC
administration of large volumes of IgG in a single infusion site every 3–
4 weeks, comparable to an IV treatment schedule. SC infusion
of IgG facilitated by rHuPH20 (IGHy) was safe, effective, and
well tolerated despite high infusion volumes and rates [23].
Results after extended IGHy replacement therapy in the
pivotal and an extension study are reported here.
Study Design
Subcutaneous (SC) immunoglobulin (IgG) replacement
therapy in patients with primary immunodeficiency diseases
(PIDD) has been shown to be as efficacious as intravenous
(IV) treatment while causing fewer systemic adverse reactions
[1–4]. SC infusion proved to be beneficial specifically in
patients at risk of systemic reactions but also in patients,
including infants, in whom stable venous access is difficult to
maintain [3–10]. Because the incidence of systemic adverse
reactions is low and venous access is not required,
selfinfusion of IgG via the SC route can be performed by
patients at home providing greater ease and convenience
compared to IV administration in a hospital or infusion
center [3, 11–15].
The main disadvantages of SC therapy have been the
limited volume that can be infused in a single SC site and
the lower bioavailability of IgG after SC compared to IV
administration, necessitating the use of multiple infusion
sites on a weekly or every-other-week basis and an
increased dose compared to IV infusion in order to provide
the same exposure as measured by the area under the
time-concentration curve [16, 17].
Hyaluronan (hyaluronic acid), the main component of the
SC extracellular matrix (ECM), causes resistance to bulk fluid
flow through the SC tissue. Cleavage of hyaluronan by
subcutaneously injected hyaluronidase, a highly specific
glycosidase, increases the permeability of SC tissue. In the SC space,
hyaluronan is rapidly resynthesized, and the interstitial
viscosity is fully restored within 24 to 48 h [18]. Recombinant
human hyaluronidase (rHuPH20), a highly purified soluble form
of a naturally occurring human hyaluronidase suitable for
chronic use in humans, is (...truncated)