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

Journal of Clinical Immunology, May 2016

Purpose Treatment 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. 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. Results Eighty-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. Conclusions Long-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD.

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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. - 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)


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Richard L. Wasserman, Isaac Melamed, Mark R. Stein, Werner Engl, Marlies Sharkhawy, Heinz Leibl, Jennifer Puck, Arye Rubinstein, Lisa Kobrynski, Sudhir Gupta, Andrew J. Grant, Anoshie Ratnayake, Wendell G. Richmond, Joseph Church, Leman Yel, David Gelmont. Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency, Journal of Clinical Immunology, 2016, pp. 571-582, Volume 36, Issue 6, DOI: 10.1007/s10875-016-0298-x