L-Proline Stabilizer Used in the Intravenous Immunoglobulin Product Privigen® Shows No Neurological Side Effects Compared with Currently Used Stabilizers
Bern, Switzerland — 09 November 2007
CSL Behring announced new data today
that demonstrates that L-proline causes no neurological effects, including convulsive behaviour and spatial learning and memory, even at high doses, when compared with glycine, which is used in many current intravenous immunoglobulin (IVIg) products. L-proline is used as stabilizer in the new Immune Globulin Intravenous (human) 10% product (Privigenâ). The data were presented at the American Congress of Allergy, Asthma and Immunology (ACAAI) in Dallas, Texas.
The study aimed to assess the neurological safety of glycine and L-proline in two separate tests using rats. The neurobiological state was evaluated using the Irwin test, which assesses autonomic and sensorimotor functions, convulsive behaviour, and neurological side effects of drug administration. Spatial learning and memory were assessed using the Morris water maze task.
The Irwin test assessed the neurobiological state and convulsive behaviour of adult rats, upon daily intravenous infusion with doses of glycine or L-proline corresponding to IVIg doses of approximately two and five g IgG/kg bodyweight, over five days. This represents a multiple of the maximal dose applied to patients. It was found that L-proline did not significantly affect behaviour or any of the measured neurological parameters neither during nor after infusion when compared to the saline vehicle control. In comparison, rats infused with glycine showed behavioural changes including a significant decrease in spontaneous activity, decreased central nervous system (CNS) excitability and altered autonomic parameters.
Commenting on the data, CSL Behring lead researcher, Ulrich Kronthaler, PhD, said, “This data provides evidence of a neurological benefit when using L-proline, a naturally occurring amino acid stabilizer, over the currently used additives, such as glycine.”
The Morris water maze test assessed the spatial learning and memory in rats, which had been treated with glycine or L-proline as newborns with dosing schemes relevant for IVIg applications at the potentially most vulnerable phase of their brain development. The findings showed that no signs of acute neurotoxicity occurred during the treatment phase of the young rats and that as adults, their learning and memory abilities remained unimpaired.
IVIgs are used to treat several conditions, including immunodeficiencies and autoimmune diseases. IVIG solutions are often formulated with glycine, but such solutions are not stable for extended time at room temperature. The use of L-proline (250 mmol/L) at pH 4.8 has recently been demonstrated to allow storage of Privigen for at least three years at room temperature.
In July 2007, the U.S. Food and Drug Administration (FDA) granted marketing approval to CSL Behring for Privigen, an intravenous immunoglobulin (IVIg), for treating patients diagnosed with primary immunodeficiency (PI) and chronic immune thrombocytopenic purpura (ITP). CSL Behring plans to launch Privigen in the first quarter of 2008. The application is currently under review by European and Swiss Regulatory Authorities.
Important Safety Information
In clinical studies, Privigen has been shown to be safe. As with any medication, side effects may accompany treatment. The frequency of side effects was based on a review of 1,038 injections given during the clinical trial in the United States and Europe. Because Privigen is made from plasma, as are all commercial human polyvalent immunoglobulins, the risk of transmitting infectious agents, including viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.
Privigen is contraindicated in patients with known anaphylactic or severe hypersensitivity responses to Immune Globulin (Human). Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions.
As a class, Immune Globulin Intravenous Human (IVIg) products have been associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. While reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Privigen does not contain sucrose.
About Primary Immune Deficiencies
These are a group of predominantly genetic disorders that cause a malfunction in part or all of the immune system, keeping the patient from fighting off infections caused by everyday germs. For individuals with PI – many of them children – infections may not improve with treatment as expected, and may keep returning. As a result, patients may face repeated rounds of antibiotics or be hospitalized for treatment. Repeated infections can lead to organ damage, which, over time, can become life-threatening. In some severe cases of PI, infections may result in a patient being hospitalized repeatedly. Some infections, such as meningitis, may even result in death. Nearly 100 types of PIs exist. Most are inherited, but in some cases the cause is unknown.
No single treatment works for all of the different types of PI. Infusions of replacement antibodies (immune globulins or Ig) can help supplement the immune system to prevent infection in nearly three-quarters of those people living with PI whose disease is tied to an antibody deficiency.
Immune Thrombocytopenic Purpura, or ITP, is an autoimmune disease in which the immune system attacks and destroys the body's own platelets, the cells that prevent bleeding in blood vessels and facilitate clotting. There are two forms of ITP: acute ITP, which resolves within six months, and chronic ITP, which most often occurs in adults and by definition lasts six months or longer. The annual incidence of ITP is 100 to 115 in every one million people. In the U.S., approximately 200,000 people have the disorder. ITP is characterized by a low number of platelets (<30 x 109/L), usually caused by the body’s production of substances (antibodies) that coat the platelets and signal their elimination from the blood. Diagnosis of ITP is often made by excluding other possible causes of the low platelet count and bleeding. People with the disorder often have purple bruises on the skin called purpura, a sign that bleeding has occurred in small blood vessels under the skin. They can also have petechiae, small red splotches on the skin that resemble a rash.
About CSL Behring
CSL Behring is a global leader in the plasma protein biotherapeutics industry. Passionate about improving the quality of patients' lives, CSL Behring manufactures and markets a range of safe and effective plasma-derived and recombinant products and related services. The company's therapies are used in the treatment of immune deficiency disorders, hemophilia, von Willebrand disease, other bleeding disorders and inherited emphysema. Other products are used for the prevention of hemolytic disease in newborns, in cardiac surgery, organ transplantation and in the treatment of burns. The company also operates one of the world's largest plasma collection networks, ZLB Plasma. CSL Behring is a subsidiary of CSL Limited, a biopharmaceutical company with headquarters in Melbourne, Australia. For more information, visit www.CSLBehring.com.
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