Under the Skin Is in

IT WAS 1979, and the 24-year-old woman with a long history of severe and life-threatening infections — including episodes of sinusitis, otitis media, sepsis and pneumonia — was again in serious trouble. Unable to tolerate the pain of injections of large volumes of intramuscular immunoglobulin (IMIG) needed to raise her serum IgG to a protective range, her serum immunoglobulin (Ig) levels were undetectable when she was admitted to the hospital with cellulitis and fever.

With intravenous immunoglobulin (IVIG) not yet available, Dr. Melvin Berger and colleagues at the National Institutes of Health (NIH) promptly administered a loading dose of IMIG, and followed with more IM injections that brought her serum IgG level up to only 270 mg/dL, well below protective levels.¹ Meanwhile, a chronic pulmonary infection and culture-positive sinusitis would not clear up. The NIH team decided to resort to a different approach: The young woman was trained to self-administer small, slow subcutaneous infusions of standard 16% IMIG on a daily basis.

While IgG clumps and fragments in IMIG cause severe anaphylactic reactions when given by the IV route, the patient tolerated the product quite well. Her sinopulmonary and sepsis problems disappeared. She continued her daily subcutaneous infusions right through a normal full-term pregnancy shortly thereafter, boosting her dose along the way to maintain a protective IgG level. Other patients were started on subcutaneous therapy with IMIG.

But a few years later, intravenous immunoglobulin (IVIG) became available, and with it the ability to dose large quantities of IgG antibody in a single infusion every three to four weeks. Suddenly, the subcutaneous route for Ig infusions in patients with primary immunodeficiency disorders (PIDDs) all but disappeared in the United States.

You Can’t Keep a Good Delivery Option Down

While these preparations of largely intact IgG monomers and dimers were heralded for being the first to allow administration of very large doses, physicians and infusion nurses quickly learned that IVIG products are not without their own tolerability issues. Despite mitigation strategies that include pre-hydration, pre-medication, slowing the infusion rate and switching product brands, some patients may still experience non-serious but unpleasant adverse effects such as headache and nausea. Very infrequently, more severe reactions can occur, including anaphylaxis and aseptic meningitis. An entirely separate challenge may be posed by immunodeficient children in particular who have poor IV access.

Taking note of the long experience of Scandinavian physicians treating PIDD patients with subcutaneous Ig,^2,3 in 1998, Dr. E. Richard Stiehm and colleagues at the University of California Los Angeles reported successful use of the subcutaneous route for administration of IVIG in eight patients with venous access problems, a history of IVIG-related anaphylaxis or rapid IVIG catabolism.⁴

Finally in 2006, CSL Behring introduced Vivaglobin, a 16% subcutaneous immunoglobulin (SCIG), providing physicians with their first FDAapproved option after years of prescribing off-label subcutaneous use of licensed IVIG products. Vivaglobin has now been replaced by Hizentra, an even more concentrated 20% product approved in March 2010. Further expanding the choices, the FDA has recently approved subcutaneous administration of three licensed 10% IVIG products: Grifols’ Gamunex-C, Baxter’s Gammagard Liquid and Kedrion’s Gammaked.

Today, patients are trained to perform their subcutaneous infusions using convenient mechanical and batterypowered syringe pumps and administration sets that allow product delivery to one, two, three, four or more adequately spaced sites (typically the abdomen, lateral hip, thigh and/or upper arm). Infusions are performed on a weekly basis (or sometimes more often), and typically can be completed in an hour or less. Local redness and swelling at the infusion site is common, but in most patients, it dissipates within a few hours and tends to diminish with more procedures over time. Very importantly, the frequency of severe systemic adverse reactions, and specifically in patients who experienced these reactions with IVIG, is extremely low. This is immediately attributable to a much lower peak serum IgG level than IVIG administered directly into the circulation.

Other Benefits of Subcutaneous Delivery

Self-administering Ig at home is not for everyone with PIDD.Careful selection of patients who are both capable and motivated is critical. But for those who can comfortably manage the SCIG home self-infusion procedure, there are clear quality-of-life-related advantages over scheduled visits for IVIG infusions:⁵

• No missed school/work days. The patient does not need to miss school or work to receive infusions at a clinic typically open only during normal business hours.
• Scheduling flexibility. SCIG infusions can be completed whenever the patient desires, except when engaged in sports or exercise activity.
• No venous access issues. For patients with difficult IV access, there is no need for surgical implantation or maintenance of venous access devices.
• Patient autonomy. Self-infusion promotes a positive sense of personal control over the patient’s lifelong immunodeficiency disorder.

Further, because subcutaneous IgG distributes gradually from the infusion site(s), patients experience far less fluctuation in serum IgG levels than with IVIG infusions every three to four weeks (see Figure 1). For similar doses, the trough IgG level for a patient on SCIG therapy is usually marginally higher than the trough level on IVIG, but the overall quantity of circulating IgG over time — the so-called “area under the curve” — favors IVIG. At present, there is no substantive evidence that either delivery route yields a lower serious bacterial infection risk.

In Development: Much More, Much Less Often

For many PIDD patients who tolerate IVIG infusions well, the potential advantages of SCIG — including time flexibility and freedom from a clinic IV infusion session — are outweighed by the need to set up and self-infuse SCIG at least every week. But soon, this barrier could be eliminated if a new “facilitated” SCIG currently being co-developed by Baxter Healthcare and Halozyme Therapeutics proves safe and effective.

Dubbed “HyQ,” this investigational product involves two sequential phases. First, recombinant hyaluronidase is infused subcutaneously. This synthetic version of a naturally-occurring human enzyme increases connective tissue permeability by digesting hyaluronic acid, a carbohydrate polymer present throughout the extracellular space that acts to “cement” cells together. This facilitates dispersion and absorption of the 10% IgG protein solution that follows. The objective of this novel approach is to enable patients to self-administer a single large dose of SCIG every three or four weeks, using only one or two infusion sites. Preliminary results of a Phase III study of “HyQ” in 89 patients with PIDD appear encouraging; the acute serious bacterial infection rate was just 0.025 per patient per year, far below the required threshold for regulatory approval. Baxter submitted a Biologics License Application for “HyQ” earlier this year.

More Diagnoses Under the SCIG Tent?

Interest in the advantages of SCIG has prompted a number of investigators here and abroad to evaluate this alternative to IVIG in certain other disorders where Ig therapy is needed on a protracted basis. Recent small studies and case reports suggest that SCIG therapy may be safe and therapeutically equivalent to IVIG infusions in properly selected patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 6 multifocal motor neuropathy (MMN)7,8 and polymyositis and dermatomyositis.

SCIG Past and Future

Back in 1952, Dr.Ogden Bruton, a pediatrician at Walter Reed Army Hospital, described the first case of PIDD: an 8-year-old boy with profoundly depressed serum immunoglobulin levels later shown to be X-linked agammaglobulinemia. Dr. Bruton treated that first case of PIDD with subcutaneous doses of immunoglobulin.

Over the decades that followed, physicians returned to subcutaneous delivery to provide protective Ig replacement therapy for patients who could not tolerate painful IMIG injections, or who had specific contraindications to IVIG therapy. Today, thousands of patients with PIDD self-manage their condition using one of the four licensed, wellproven SCIG product options.

There’s no question about it: Ig delivery under the skin is in, and all indications suggest it will become the choice of increasing numbers of patients who require chronic Ig replacement therapy.