The Expanding Role of Immune Globulin Treatment in Diseases: Utilization and Growth

Sales of immune globulin (IG) are up. According to the Marketing Research Bureau (MRB), manufacturer-level sales of intravenous IG (IVIG) in grams grew more than 10 percent in 2023 compared to 2022.¹ Matthew Hotchko, president of MRB, explained that the various disruptions related to the COVID-19 pandemic caused IG demand to drop in 2021 and recover in 2022 and 2023. “The particularly high 10 percent-plus growth rate in IG demand that we saw in 2023 may partly reflect a catch-up effect, as undiagnosed patients whose access to specialist care was delayed by the pandemic finally received their diagnoses and prescriptions for IG therapy,” he says.

Hogan Lovells, a global law firm specializing in commercial, regulatory and legal issues, conducted a roundtable discussion focused on access to and use of IG therapies and published its conclusions in the Hogan Lovells Roundtable Report in May 2022. The report found that each year in the United States, approximately 275,000 patients are treated with IVIG and subcutaneous IG (SCIG) therapies for a variety of conditions. “In 2020, roughly 110 million grams of IG were used to treat patients,” according to the report. “These patients have conditions in more than eight medical specialties and receive treatment for hundreds of indications.”² Categories of conditions treated with IG therapy include primary immune deficiency (PI) — 30 percent or about 400 conditions; secondary immune deficiency (SID) — 17.5 percent or about 200 conditions; neurology — 40 percent or about 50 conditions; and all others — 12.5 percent or about 300 conditions.²

IG therapy is a medicine made from human blood plasma. The plasma is processed from donated human blood and contains antibodies that protect the body against diseases. Recently, the role of IG has expanded both in its utilization and growth, meaning more patients can benefit from IG therapy, which is often the only treatment for many rare, life-threatening chronic diseases and genetic conditions. IG therapy increases the chances of regular access to plasma medicines, which contributes to the improvement of health outcomes for patients.

Indications

According to Terry Harville, MD, PhD, a professor of pathology and laboratory services and internal medicine at the University of Arkansas for Medical Sciences, IG therapy can be used as either 1) replacement therapy for people who are deficient in immunoglobulin (antibodies) or 2) immune modulation. “The initial intended use of IG therapy was for patients with antibody deficiencies to replace [the antibodies] they were missing,” he explained. “The earliest documented use was in patients with X-linked agammaglobulinemia, a [PI] affecting males who are unable to produce B lymphocytes and are thereby unable to make antibodies. Yet, this is considered a rare disorder, perhaps one in 1,000,000 live births. More commonly, IG replacement is used for patients diagnosed with CVID [common variable immune deficiency], of which some registries may have as many as one in 3,000 people, although most textbooks suggest one in 10,000 to 50,000 people.

“As with many new medications, for example, when cortisol became available, it was tried in many conditions which did not have better treatment options. One of the earliest was Kawasaki disease, where a total dose of two grams per kilogram of body weight infused over two to five days demonstrated benefit. From there, similar dosing has been used to treat thrombocytopenia and other hematologic cytopenias. Subsequently, it was tried for Guillain-Barré syndrome, where it was found to be as efficacious as undergoing plasmapheresis. Subsequently still, a variety of neurologic disorders, which for the most part can be considered some form of autoimmune encephalopathy, have had beneficial results. Related conditions such as PANDAS/PANS have benefit. We recently reported the use in patients with catatonia, which may be one of the rarest usages.”

Utilization

The Hogan Lovells Roundtable Report showed that approximately 65 percent of IG use in the United States is on-label use, meaning it is prescribed to treat conditions for which the U.S. Food and Drug Administration (FDA) has granted approval. The other 35 percent is prescribed for off-label use to treat conditions for which it is medically acceptable according to existing treatment guidelines and evidence-based, real-world use.²

A study that described U.S. IG utilization patterns from 2009 to 2019 showed growth in both commercial and Medicare populations. Respectively, IG administrations per 100,000 person-years increased by 120 percent and 144 percent; IG recipients per 100,000 enrollees grew by 71 percent and 102 percent; average annual administrations per recipient rose by 28 percent and 19 percent; and average annual dose (grams) per recipient increased by 29 percent and 34 percent.³ The study also showed that IG administrations associated with immune deficiency per 100,000 person-years increased by 154 percent and 176 percent. Autoimmune and neurologic conditions were associated with higher annual average administrations and doses than other conditions.³

In contrast to the Hogan Lovells Roundtable Report, there is a consistent increase of non-specific IG use in Québec, Canada, according to Héma-Québec, a nonprofit organization that supplies blood and other human biological products to local hospitals. Québec’s Ministry of Health’s data for the use of IG reports that more than two million grams were administered at an average of 349.6 grams per user, or 232.⁴ grams per 1,000 people. The rate of Quebecers who have received IG is 67 recipients per 100,000 people. Nearly half of the IG used was administered for a neurological indication; nearly a third was administered for an immunological indication; and just under 10 percent was administered for hematological indications. PI was the medical condition for which IG was administered to the largest number of users (20.1 percent); chronic inflammatory demyelinating polyneuropathy (CIDP) was the medical condition for which the highest amount of IG was administered (21.6 percent or an average of 671.1 grams per patient); and in nearly 20 percent of users, IG was either administered for an unclear indication at 14.3 percent or absent at 4.7 percent. In total, this represents 15 percent of the quantities of IG.⁴

Keith Berman, MPH, MBA, founder of Health Research Associates and plasma industry consultant, says there are currently 12 unique licensed IVIG products, three of which are approved for SC administration. Three of the 12 IVIG products are available in both 5 percent and 10 percent IgG concentrations. There are also five unique licensed SCIG products, including HYQVIA, which is co-administered with a special agent that facilitates SC delivery of substantially increased doses of IG into the infusion site, thereby reducing infusion frequency.

Over the last year, two new 10 percent IVIG products have received FDA marketing approval — Yimmugo and ALYGLO. Manufactured by Grifols’ Biotest subsidiary, Yimmugo is expected to be available through Kedrion Biopharma in the first quarter of 2025. The Korean plasma products manufacturer GC Biopharma initiated its first shipments of ALYGLO in July 2024.

“Like other licensed IG preparations, these new IVIG products will likely be used as well for a wide range of off-label uses, including treatment of SIDs, as well as numerous immune-mediated hematological, neurological, neuromuscular, rheumatologic and other disorders,” says Berman.

Berman also notes that government health authorities in other countries — notably Australia and the United Kingdom — have published guidance for the clinical use of IG products based on the robustness of the evidence for effectiveness and safety. “The Australian national guidance indicates that IG has an established therapeutic role for the treatment of immune thrombocytopenic purpura in adults. In the example of bullous pemphigoid, IG has an emerging therapeutic role, indicating that there’s already some available evidence of benefit. But for other disorders, such as relapsing-remitting multiple sclerosis (RRMS), the guidance says IG use should be reserved for exceptional circumstances only,” said Berman.

Growth

Dr. Harville says the growth of IG treatment for different disease states can be attributed to solving the challenge of not suppressing the immune system: “An ideal IG therapy would provide only benefit and create no harm. With autoimmune disorders, the typical approach is to suppress the immune system. Therefore, the patient becomes susceptible to infections and can even be at risk for developing malignancies. Immune modulation via infusion of IG does not suppress immunity, taking away these risks. Furthermore, providing a large antibody experience from the donors can enhance the immune protection of the patient. Therefore, we can achieve benefit with low risk for harm to the patient.”

Dr. Harville also says the types of disease states that are seeing the most growth in IG treatment use include neurological disorders: “Initially used for demyelinating conditions with benefit, IG is now used for other autoimmune encephalopathies. As we obtain more information and gain a better understanding, we have found a large variety of autoimmune antibodies in the central nervous system. Therefore, modulation of these autoimmune antibodies can and do provide benefit to patients with neurological disorders.”

The most growth seen in IG treatment, he says, is in the subcutaneous infusion of replacement IG because it can reduce infusion-related side effects: “High-dose IG treatment is impractical subcutaneously because too much volume needs to be infused. Although, for some neurologic conditions such as CIDP, lower dosing and subcutaneous infusions work. Similarly, treatment of pemphigus may need doses less than used for IG replacement and may be amenable for SCIG infusion. Anti-phospholipid disease may also require lower dosing amenable for SCIG infusion.

Continued studies are needed to determine which disorders require the high pulse serum level of IG for efficacy, which could only be provided by intravenous infusion, versus those whereby other mechanisms of IG are helpful, such as the presence of anti-cytokine antibodies or anti-idiotypic antibodies, which are modulating immune function. In the latter, perhaps the slower introduction of IG via SC infusion may actually be of more benefit. Which poses the question: Is this why SCIG works well for CIDP treatment?”

Berman added that, both in the United States and abroad, growth in utilization of IG continues to be driven by the publication of new research documenting its therapeutic benefit in an ever-widening range of autoimmune, and in the case of transplantation alloimmune, disease states, as well as by growing numbers of patients diagnosed with secondary humoral immunodeficiency resulting from the growing use of B cell-depleting drugs that induce hypogammaglobulinemia (low IgG level).

“Over the last five years, the average annual growth rate in IG demand has exceeded seven percent, continuing nearly uninterrupted year-over-year growth that extends all the way back to the mid-1980s,” Berman explained. “The explanation for this remarkable growth begins with the fact that IG is the purified concentrate of many thousands of immunoregulatory and anti-infectious IgG antibodies, which makes it a vastly different kind of product than any drug or single-molecule biotherapeutic agent.”

Challenges to Utilization and Growth

According to Dr. Harville, broad use of IG therapy still has not been achieved because it has only a small number of FDA-approved indications, and IG therapy is expensive.

“When an autoimmune process is present, which could have theoretic benefit from IG infusion, it would be nice for third-party payers to allow a test usage. However, this raises a conflict if an infant with XLA may need five grams of IVIG a month whereas an adult with a neurological disease may need 200 grams of IVIG infusion several times,” Dr. Harville explained. “Therefore, one adult treatment could use an amount of IG which could treat 16 infants with XLA for a year. While all patients deserve the best treatment available, the high amounts used in adults with neurological diseases could result in less availability for ongoing treatment of patients with PI, especially if a manufacturing shortage was to occur.”

Advances Contributing to the Growing Need of IG Treatment

Representing more than 1,000 human plasma collection centers in North America and Europe, as well as the manufacturers of plasma protein therapies, the Plasma Protein Therapeutics Association (PPTA) says its members produce approximately 80 percent of the plasma protein therapies in the United States and 60 percent of those manufactured in Europe.

The PPTA’s “Statement on Immunoglobulin Use to Meet Clinical Need” reports several advances are contributing to the growing clinical need of IG therapy: “Advances in the diagnosis, treatment and identification of many diseases has led to an increase in the number of patients treated with IG and other plasma-derived medicinal products (PDMP) in the past several years, particularly in Europe. These diseases include immune deficiencies, immune-mediated peripheral neuropathies, hereditary angioedema, alpha 1-antitrypsin deficiency, hemophilia and other bleeding disorders. In many cases, PDMPs are the only treatment option for these rare and serious diseases. Without these treatments, many patients might not survive or would have a substantially diminished quality of life.

“Improved diagnostic techniques, better awareness among physicians and greater use in emerging markets are further contributing to the growing clinical need for PDMPs. IGs have been proven to prevent or delay the development of comorbidities, positively affect a range of physician- and patient-reported outcomes, including improved quality of life, and are even cost-saving for certain conditions.

“Focused on addressing the growing clinical need for PDMPs, the growth in plasma collection over the past 10 years has mainly come from the private sector and its efficient plasmapheresis programs.”⁵