IVIG challenges

The need for more IVIG

Demand for IG replacement is outpacing supply.¹

IVIG, intravenous immunoglobulin;

PI, primary immunodeficiency.

INCREASING DEMAND

Global demand for IG treatment is increasing 6-8% per year,¹ driven by:

Increasing recognition
and diagnosis of PI¹

The chronic
nature of PI¹

Use of IVIG for other
disease states¹

At times, supply shortages have resulted in changes to patient prioritization and infusion schedules.² That’s why more IVIG products are critical to ensuring access to treatment for patients with PI.²

Why FXIa matters in IG treatments

While IG treatment is the gold standard of care for patients with PI and several other diseases,² thromboembolic events (TEEs) are a rare but serious potential adverse event.³

For nearly 30 years, it has been known that patients receiving IG treatment are at risk of developing TEEs^4-6
The most common IG-related TEEs include stroke and myocardial infarction, usually occurring within 24 hours of IVIG administration^4-6
With approximately 500,000 patients in the United States affected by PI,⁷ even at a small incidence rate, more patients may be at risk than realized

FXIa, activated coagulation factor XI.

FXIa has been identified as one of the root causes of IVIG-related TEEs.⁸

FXIa plays a key role in the activation of the intrinsic coagulation cascade⁹
Studies have confirmed that even small quantities of FXIa can result in significant thrombin generation⁹

A BRIEF HISTORY:

In 2010, the U.S. Food and Drug Administration (FDA) became aware of a cluster of TEEs associated with FXIa in IVIG⁸

In 2013, this led the FDA to place a mandatory boxed warning for risk of TEEs in all IG products¹⁰

Regulatory bodies across the world have implemented corrective actions, encouraging manufacturers to test products at lot release and to consider dedicated steps for removing FXIa⁸

At GC Biopharma, we have implemented the extra step of G-XI™ Technology, which utilizes cation exchange (CEX) chromatography, to help reduce FXIa levels below detectable limits³

The challenge with FXIa

A longstanding goal within the IG industry has been to remove FXIa, a plasma-based protein linked to IVIG-related thromboembolic events.³ But separating it in manufacturing can be a challenge.

THE STANDARD PROCESS FOR PURIFICATION

The manufacturing process for ALYGLO includes multiple steps, such as Cohn-Oncley cold ethanol fractionation, viral inactivation, and nanofiltration.³

A study demonstrated that coagulation factors II, VII, IX, and X are effectively removed during these steps, but residual FXI/FXIa remains in the intermediate solution.³

THE DIFFICULTY IN REMOVING FXIa

Since human IG and FXIa share a similar isoelectric point (pI), it can be difficult to separate FXIa from IG preparations using ethanol precipitation alone.³

Human IG: 6.4-9 pI

FXIa: 8.9-9.1 pI

Learn more about
G-XI^™ Technology

References:

Solís-Díez G, Turu-Pedrola M, Roig-Izquierdo M, Zara C, Vallano A, Pontes C. Dealing with immunoglobulin shortages: a rationalization plan from evidence-based and data collection. Front Public Health. 2022;10:893770.
Perez EE, Hébert J, Ellis AK, et al. Efficacy, safety and tolerability of a new 10% intravenous immunoglobulin for the treatment of primary immunodeficiencies. Front Immunol. 2021;12:707463.
Kang GB, Huber A, Lee J, et al. Cation exchange chromatography removes FXIa from a 10% intravenous immunoglobulin preparation. Front Cardiovasc Med. 2023;10:1253177.
Germishuizen WA, Gyure DC, Stubbings D, Burnouf T. Quantifying the thrombogenic potential of human plasma-derived immunoglobulin products. Biologicals. 2014;42(5):260-270.
Kapoor M, Spillane J, Englezou C, et al. Thromboembolic risk with IVIg: incidence and risk factors in patients with inflammatory neuropathy. Neurology. 2020;94(6):e635-e638.
Funk MB, Gross N, Gross S, et al. Thromboembolic events associated with immunoglobulin treatment. Vox Sang. 2013;105(1):54-64.
Primary immune deficiency diseases (PIDDs). National Institute of Allergy and Infectious Diseases. Accessed January 29, 2025. https://www.niaid.nih.gov/diseases-conditions/primary-immune-deficiency-diseases-pidds
Ovanesov MV, Menis MD, Scott DE, et al. Association of immune globulin intravenous and thromboembolic adverse events. Am J Hematol. 2017;92(4):E44-E45.
Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol. 2000;65(1):30-34.
Ammann EM, Haskins CB, Fillman KM, et al. Intravenous immune globulin and thromboembolic adverse events: a systematic review and meta-analysis of RCTs. Am J Hematol. 2016;91(6):594-605.

INDICATION

ALYGLO® is indicated for the treatment of primary humoral immunodeficiency (PI) in adults aged 17 years and older. This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

IMPORTANT SAFETY INFORMATION

WARNING: THROMBOSIS, RENAL DYSFUNCTION and ACUTE RENAL FAILURE

Thrombosis may occur with immune globulin intravenous (IGIV) products, including ALYGLO. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.
Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur with the administration of IGIV products in predisposed patients.
Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. ALYGLO does not contain sucrose.
For patients at risk of thrombosis, renal dysfunction or renal failure, administer ALYGLO at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Contraindications: ALYGLO is contraindicated in patients who have a history of anaphylactic or severe systemic reaction to the administration of human immune globulin and in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.
Hypersensitivity: In case of hypersensitivity, discontinue infusion immediately and institute appropriate treatment. Epinephrine should be available for immediate treatment of severe acute hypersensitivity reactions.
Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia: Hyperproteinemia, increased serum viscosity, and hyponatremia may occur.
Aseptic Meningitis Syndrome (AMS): Aseptic meningitis syndrome (AMS) may occur, especially with high doses or rapid infusion. AMS usually begins within several hours to 2 days following ALYGLO treatment. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.
Hemolysis: Delayed hemolytic anemia due to enhanced red blood cell (RBC) sequestration and acute hemolysis consistent with intravascular hemolysis have been reported. Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of IGIV. Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors.
Transfusion-Related Acute Lung Injury: Noncardiogenic pulmonary edema (transfusion-related acute lung injury [TRALI]) may occur. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Patients with TRALI may be managed using oxygen therapy with adequate ventilator support. Monitor patients for pulmonary adverse reactions.
Transmissible Infectious Agents: Because ALYGLO is made from human blood, it may carry a risk of transmitting infectious agents (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD] agent and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent).
Interference with Laboratory Tests: After infusion of immunoglobulin, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for a misleading interpretation.
Adverse reactions (observed in ≥ 5% of study subjects) were headache, nausea/vomiting, fatigue, nasal/sinus congestion, rash, arthralgia, diarrhea, muscle pain/aches, infusion site pain/swelling, abdominal pain/discomfort, cough, and dizziness.
It is recommended that ALYGLO be administered separately from other drugs or medications.

For more information about ALYGLO, please see full Prescribing Information.

Unaddressedneeds exist withIG treatments