Chronic IG Therapy Options: They Just Keep Getting Better

TRADE-OFFS. They’ve always been there for people who are prescribed immunoglobulin (IG) therapy, particularly those with primary immunodeficiency disorders (PIDD) who require chronic dosing to keep serious infections at bay. Only a few decades ago, PIDD patients faced the unhappy trade-off between frequent, very painful deep intramuscular injections of 16% immune serum globulin or the prospect of being overcome by a potentially life-threatening bacterial infection such as pneumonia. When the first intravenous immunoglobulin (IVIG) products arrived in the 1980s, requiring less frequent and far more comfortable injections, the misery of intramuscular injections became a thing of the past.

But as generally safe and effective as it is, IVIG therapy isn’t without risks or limitations.Many patients can recurrently experience a spectrum of mild or moderate adverse reactions such as fatigue, headache, fever, chills, dizziness, nausea and vomiting. And, a far more serious IVIG-related issue concerns the small share of patients whose health problems dictate that overall administered fluid volume be minimized to the extent possible. This includes patients with renal dysfunction or impaired cardiac function resulting from a prior myocardial infarction or congestive heart failure.

IVIG Volume Heads Down

One way to reduce the infused volume is to administer divided doses on different days. But a better and far more convenient solution is to simply concentrate the product. Three manufacturers — Baxter Healthcare, CSL Behring and Talecris Biotherapeutics — have done just that by reformulating their original 5% IVIG products to a 10% concentration, effectively cutting the infused volume by half. Two others — Grifols and Octapharma — expect their new 10% formulations to be approved shortly.

Another benefit of a more concentrated IVIG product is less time needed to infuse it, which can translate into cost savingsfrom reduced nursing and infusion room time.

Suddenly, Under the Skin Is In

Over the years, physicians infusing IVIG preparations have learned how to reduce the frequency and extent of nonserious adverse events by slowing the rate of infusion and by premedicating with drugs such as acetaminophen, antihistamines or corticosteroids.² But for patients with persistent tolerability problems, physicians discovered long ago that protective levels of IG could be administered subcutaneously with fewer systemic side effects. So few, in fact, that the first subcutaneous immunoglobulin (SCIG) introduced in 2006 — CSL Behring’s 16% Vivaglobin product — can be self-administered at home. But, again, there are trade-offs.

While IVIG is usually infused only once every three to four weeks in PIDD patients, SCIG must be administered at least weekly due to the fact that only a very limited volume can be injected under the skin during a single session. These subcutaneous volume restrictions also necessitate two or more needle sticks at a session, as well as patient training on the use of a syringe pump, specialized tubing and proper methods to safely deliver the product. Itching or burning at the injection site is common, but can be either prevented or effectively treated with antihistamines.

Not surprisingly, four years after the launch of Vivaglobin, roughly threefourths of PIDD patients remain on the simpler and much less frequent IVIG therapy option.

Innovation May Yield Better Product

Options Like so many times before, immunoglobulin manufacturers are addressing these drawbacks head on with product innovation. CSL Behring has recently introduced a 25 percent more concentrated SCIG preparation called Hizentra. Talecris Biotherapeutics is expected to introduce its own product in the near future. But, arguably, Baxter is now working on the biggest potential leap for patients now on SCIG or considering SCIG therapy. Acquired from Halozyme Therapeutics in 2007, Baxter’s novel “Enhanze Technology” is designed to allowthe patient to self-administer a lot more SCIG in a single session — enough, in fact, to permit the same frequency of administration as IVIG.

Enhanze is a recombinant version of the naturally occurring human enzyme hyaluronidase, which breaks down a space-filling gel-like substance called hyaluronic acid (HA), which is found in tissues throughout our body. The job of this man-made hyaluronidase injected under the skin prior to SCIG infusion is to temporarily digest HA, thereby enhancing penetration and diffusion of much more SCIG than would otherwise be possible.

In a Phase I/II trial, 10 PIDD patients received monthly subcutaneous infusions with Enhanze HA followed by Gammagard Liquid 10% IVIG in doses ranging from 25.5 to 61.2 grams (255 to 612 mL) in a single site. Patients were infused at rates between 120 to 300 mL per hour, similar to IVIG administration rates.A Phase III trial in 80 adults and children with PIDD is now nearing completion. FDA approval will hinge on demonstrating safety and tolerability; if successful, we could see this exciting new product within the next two years.

Meanwhile, manufacturers also continue to strive for improvements to their IVIG offerings. Octapharma, for example, recently announced the first of a series of pivotal studies to evaluate a novel 10% “high purity” IVIG preparation. “Pre-clinical studies and initial clinical experiences have confirmed that a favorable tolerability profile may be expected,” according to the study’s coordinating investigator. A Phase III trial in PIDD patients is now under way.

Weighing IG Therapy Choices

Today and in the future, PIDD patients and their physicians will continue to weigh differences in time, convenience, treatment setting and adverse event profiles that apply for SCIG and IVIG to try to decide which product is best for them. As they improve and the trade-offs between these two product options diminish, that choice could become more difficult. I think we can all agree that would be a very pleasant new challenge to face.