Cytomegalovirus Immune Globulin Intravenous -(Human) - CytoGam; CMV-IGIV
Status: approved; marketed
Organizations involved:
CSL Behring LLC – Manuf. other; USA mark.
CSL Behring AG – Intl mark.
CSL Ltd. – Parent
MedImmune, Inc. – Former
Massachusetts Biol. Labs. – Manuf.; R&D; Tech.
Massachusetts, State of – Parent
Sanofi Pasteur Inc. – Manuf. other
New York Blood Center, Inc. – Tech.
Genesis Bio-Pharmaceuticals, Inc. – Canada mark.
Connaught Laboratories, Inc. – Former
Dana Farber Cancer Institute – R&D
Harvard University – Parent
Bayer Corp. – Tech.
Cross ref: See Immune Globulin Products (#743).
Description: Cytomegalovirus Immune Globulin Intravenous (Human) or CytoGam is an aqueous immune globulin preparation containing a standardized amount of polyclonal antibodies to cytomegalovirus (CMV), with manufacture including solvent detergent viral inactivation. The purified immune globulin is derived from pooled adult human Plasma selected for high titers of CMV antibody using a specialized CMV antibody assay, with no selection for specific CMV strains. The donor pool for CytoGam is relatively small, about 3,000 persons with no relevant infectious diseases and high titers of CMV antibodies. CytoGam primarily contains immune globulin G (IgG) polyclonal antibodies in monomeric (non-polymerized) form.
Since first launched, the CMV antibody titers of CytoGam have averaged over 10,000 ELISA units/ml (based on CMV antigen from Massachusetts Biological Labs.). This is equivalent to CMV antibody titers 4- to 8-fold greater than standard intravenous immune globulin products. CytoGam also contains other diverse antibodies representative of those in the donor pool.
CytoGam is formulated in bottles containing sterile liquid stabilized with 5% sucrose and 1% Albumin (Human). Vials contain 2,250-2,750 mg of immune globulin/50 mL. CytoGam contains no preservatives. Each mL contains: 50 ± 10 mg of immunoglobulin, primarily IgG, and trace amount of IgA and IgM; 50 mg of sucrose; 10 mg of Albumin (Human). The sodium content is 20-30 mEq per liter, i.e., 0.4-0.6 mEq per 20 ml or 1.0-1.5 mEq per 50 ml. CytoGam should be stored at 2-8˚C (refrigerated), and has a shelf life of 36 months. The dating period (upon original approval) is 24 months from the date of manufacture (date of first sterile filtration of the bulk) when stored at 2-8˚C (refrigerated).
Nomenclature: CMV Immune Globulin/CSL [BIO]; CytoGam [TR]; Cytomegalovirus Immune Globulin Intravenous (Human) [FDA]; CytoGam Liquid Formulation Solvent Detergent Treated [FDA on insert/labeling]; CMV-IGIV [SY]; CytoMune-IV [TR former]; NDC 60574-3101-01 [NDC]
Biological.: CytoGam contains a high concentration of antibodies directed against cytomegalovirus (CMV) obtained from Plasma from selected healthy donors with high levels of CMV antibodies. CytoGam is used to raise levels of CMV-neutralizing antibodies levels in virus-exposed persons, e.g., CMV-seronegative persons receiving a transplant from a CMV-seropositive donor, to attenuate or prevent serious CMV disease.
CytoGam has a mean in vivo half-life of 21 days, although this is commonly shorter in immune suppressed transplant recipients (in whom CytoGam may have an immediate post-transplant half-life as short as 8 days). It is primarily eliminated by metabolic breakdown.
Companies.: Research leading to CytoGam was conducted by Dr. J. Zaia and coworkers, Dana Farber Cancer Institute, affiliated with Harvard University, in collaboration with the Massachusetts Dept. of Public Health.
CytoGam was developed and is manufactured by the Massachusetts Public Health Biologic Labs. (MPHBL; Boston, MA), FDA CBER est. no. 0064, now Massachusetts Biological Labs., State of Massachusetts. Sanofi Pasteur Inc. fills and packages the final product.
CytoGam from MPHBL was originally marketed in the U.S. by Connaught Labs. (now Sanofi Pasteur) as CytoMune-IV from late 1991-1994. MedImmune acquired the U.S. marketing rights and launched the product as CytoGam in 1992. In Dec. 2002, MedImmune received approval for processing hyperimmune plasma at new Frederick, MD, facilities for manufacture of CMV immune globulin intermediate paste (concentrate) for further manufacture of CytoGam by MPHBL. MedImmune, Inc. exclusively marketed CytoGam in the U.S.
In Dec. 2006, ZLB Behring, now CSL Behring LLC, a subsidiary of CSL Ltd., completed acquisition of CytoGam from MedImmune, which received $50 million, with potential for up to $70 million in milestone payments. Although CytoGam was MedImmune’s first marketed product, it no longer fit in with the its other products (recombinant proteins) and strategy. MedImmune was acquired by AstraZeneca plc in April 2007. Presumably, the CSL acquisition included MedImmune’s facility for manufacture of CMV immune globulin paste (concentrate) and contracts for further manufacture of CytoGam.
CytoGam is now marketed in the U.S. by CSL Behring LLC, a subsidiary of CSL Behring AG, which markets it internationally and which is a subsidiary of CSL Ltd.
CytoGam is marketed by Genesis Bio-Pharmaceuticals, Inc. in Canada.
Manufacture: Each source Plasma unit is tested, including for HIV-1, HIV-2, HIV-1 p24 antigen, syphilis (VDRL), hepatitis B surface antigen (HBsAg), and alanine aminotransferase (ALT; a liver enzyme elevated in persons with viral hepatitis). Source material (Plasma) for fractionation may be obtained from another U.S. licensed manufacturer. Plasma is screened and assayed for CMV IgG content with a patented ELISA immunoassay produced using CMV Davis strain. Only plasma containing over CMV IgG titers ≥ 1:1,000 (reciprocal of dilution) as shown by this assay is used. Typically, only 15%-20% of units of volunteer source plasma qualify. Intermediate CMV immune globulin paste manufactured by MedImmune is also used for further manufacture of CytoGam by MPHBL. [CMV High Titer Fraction II+III Paste (For Further Manufacturing Use) (#750), manufactured by Baxter Healthcare, may also be used for manufacture of CytoGam].
Plasma is pooled, reportedly using from 2,000-5,000 donor units/lot, and fractionated by Cohn-Oncley cold ethanol precipitation of coagulation factors and certain other proteins. Cohn method 6 yields Fraction II + III precipitate, which is subjected to Oncley method 9 processing. The resulting fluid (effluent III) fraction is subjected to ultrafiltration (to remove ethanol by diafiltration with 0.02% sodium phosphate buffer). The IgG solution is concentrated to 6% and stabilizers are added – 1% Albumin (Human) and 5% sucrose (excipients) – followed by dilution to 5% IgG solution, forming an intermediate antibody/IgG-rich raw material. This is subjected to solvent detergent inactivation, e.g., using the solvent tri-n-butyl phosphate and detergent(s), e.g., octoxynol-9 (Triton X-100) and/or polysorbate 80 (Tween 80). This process for viral inactivation (primarily enveloped viruses, e.g., HIV, hepatitis B and C viruses) was added to the manufacture process in 1993. See the entry for Plasma SD (#799) for further information about solvent detergent viral inactivation. Even before addition of solvent/detergent viral inactivation, an overall reduction of 11 logs (1011) in tissue culture infective dose50 (TCID50) of HIV-1 was demonstrated for the manufacturing process. Solvent, detergent, and dissociated viral components are removed by ion-exchange chromatography. The IgG is ultrafiltered and formulated by the addition of stabilizers [sucrose, Albumin (Human), and sodium chloride]. The product is then filled and packaged.
A proprietary immunoassay developed by MPHBL using the CMV Davis strain, the same immunoassay used to select high CMV antibody donors, is used to assure that the final product contains titers ≥ 1:7,000. Production lots must have a potency ratio of at least 0.8 (ratio of CMV antibody titers compared to a CMV immune globulin/CytoGam standard). MedImmune reports that CMV antibody titers of CytoGam lots have averaged 10,052 ELISA units/mL since its U.S. launch, a level 4-8 fold higher than typical pooled intravenous immune globulin products. Final product testing includes sterility, residual moisture, antibody potency (anti-CMV), pyrogenicity, safety, heat stability, protein aggregation (by HPLC), pH, electrophoretic purity, anticomp-lementary activity (AC), prekallikrein activator (PKA) activity, kallikrein activity, and hepatitis B surface antigen. FDA concluded that the overall manufacturing “process caused very little change in the physical and chemical properties of the IgG molecules...and appears to be pharmacologically similar to IgG that normally circulates in the plasma.”
In June 2002, the Marketing Research Bureau reported that the average price paid by plasma fractionators for purchase of plasma with high titer of CMV antibodies was $135-$140/L. CMV antibody-rich plasma has other uses besides manufacture of CytoGam, e.g., for diagnostics/reagents and for export.
FDA class: Biologic PLA BLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19900417, first approval; PLA ref. no. 86-0472, ELA ref. no. 87-0525, granted to Massachusetts Public Health Biologic Labs.; orphan designation (expired 4/17/1997); Indication = for the attenuation of primary cytomegalovirus (CMV) disease associated with kidney transplantation. Specifically, the product is indicated for all kidney transplant recipients who are seronegative for CMV and who receive a kidney from a CMV seropositive donor
Date = 19981209; PLA supplement; orphan designation (expires 12/9/2005); Indiction = prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas and heart. In transplants of these organs other than kidney from CMV seropositive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir
Date = 20001222; supplemental approval granted to Massachusetts Public Health Biologic Labs. for plasma processing at MedImmune’s new Frederick, MD, facilities for manufacture of CMV immune globulin-rich intermediate (Fraction II+III paste) for further manufacture of CytoGam (by the Massachusetts Biological Labs.)
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling; ganciclovir (Cytovene) is an anti-CMV drug from Hoffmann-La Roche]:
For the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas and heart. In transplants of these organs other than kidney from CMV sero-positive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.
Status: CytoGam has orphan product-based U.S. market exclusivity for use in lung, liver, pancreas, and heart transplants until Dec. 2005. Exclusivity for its original kidney transplant CMV prophylaxis indication expired in 1997.
CytoGam is approved and marketed in Argentina, Canada, Turkey, and South Korea. It is also available on a named patient basis in other countries. MedImmune reported that it was evaluating the potential to expand CytoGam distribution into Europe and Mexico.
Tech. transfer: Miles Labs./Bayer Corp. (now Talecris Biotherapeutics Inc.) received U.S. 4,617,379, “High Titer Cytomegalovirus Immune Serum Globulin,” in October 1986. This patent broadly claims methods for the identification of donated plasma with high titers of CMV antibodies, manufacture of CMV immune globulin, and its use to raise serum levels of CMV antibody. MedImmune does not report having licensed this patent for CytoGam (although it could have been licensed by MPHBL), and this patent likely expired in 2003.
Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center, e.g., see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) (#799) for information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Disease: The incidence rate for CMV infection (persons seropositive or having antibodies to CMV) in most developed countries is 60-80% (i.e., most persons have latent/asymptomatic infection), while incidence approaches 100% in lesser developed countries. CMV, like other herpesviruses, can establish latent, asymptomatic, lifelong, infection in nervous tissue and be reactivated (induction of active viral replication) at any later time. Most individuals contract CMV infection through mucosal contact with body secretions known to carry CMV, including urine, saliva, breast milk, semen, and cervical secretions. Intrauterine infection of fetuses may also occur, and from 1-2% of newborn infants are infected with CMV, which may lead to severe neurological disorders and even death. However, nearly all healthy persons develop and maintain antibody protection and responses to CMV, and CMV disease is rare and generally associated with immune suppression.
Adults at the greatest risk for CMV disease (and candidates for CytoGam) include organ transplant recipients, generally receiving treatment with immune suppressant drug to prevent transplant rejection, and symptomatic HIV (AIDS) patients. CMV infection is one of the opportunistic infections defining advancement to AIDS in HIV-infected patients. With the high incidence rate for CMV infection in the general population, most organs for transplantation are likely to be infected with CMV. Either receipt of infected organs or reactivation of latent CMV infection may lead to active infection and disease in immune suppressed patients lacking sufficiently protective levels of CMV antibodies.
CMV infection and disease are associated with kidney, lung, liver, pancreas, and heart transplantation (due to use of immune suppressant drugs and, sometime transplant of an organ from a CMV-infected donor), and contribute significantly to morbidity and mortality. CMV can cause severe pneumonia and other organ complications related to invasive CMV disease which, if not successfully treated, can lead to organ failure. CMV infection has also been shown to cause increased susceptibility to bacterial and fungal infections, and has been associated with an increased risk of rejection of the transplanted organ.
MedImmune estimated that there are about 20,000 kidney, lung, liver, pancreas, and heart transplants annually in the U.S. The original indication applied to about 2,000 kidney transplants annually in the U.S. from CMV-seropositive organ donors to CMV-seronegative recipients.
A large proportion, 25% or more, of AIDS patients eventually develop CMV retinitis, with CMV infecting the retina of the eye and often leading to impairment or loss of vision. However, CytoGam is not specifically approved or used extensively for CMV retinitis prophylaxis or treatment (and the number of HIV-infected patients with AIDS has been decreasing with improved combination HIV drug treatment regimens and viral resistance testing).
Medical: CytoGam is used for passive immunization or replacement therapy – replacing missing or supplementing CMV antibodies in immune suppressed patients, particularly those receiving immune suppressant drugs to prevent rejection of an organ transplant. It is used for prophylaxis and treatment of CMV disease (including CMV pneumonia and systemic infection). As with other immune globulins, onset of activity is immediate, as soon as the product is infused into the bloodstream.
Clinical studies have shown a 50% reduction in CMV disease in kidney transplant patients given CytoGam, and a 56% reduction in serious CMV disease in liver transplant patients. CytoGam prophylaxis is associated with increased survival in liver transplant recipients.
For prevention and attenuation of CMV disease in immune suppressed organ transplant recipients, such as those receiving bone marrow (BMT), kidney or liver transplants, CytoGam is generally administered before transplant operations, or within 72 hours after. Dosages vary based on the type of transplant. CytoGam is further administered at weeks 2, 4, 6, and 8 after transplantation, and optionally at weeks 12 and 16. CytoGam is administered by intravenous infusion using an infusion pump, generally at a dose of 150 mg/kg for the first infusion and 100 mg/kg at weeks 2, 4, 6, and 8, and at 50 mg/kg at weeks 12 and 16. Infusions generally start at a rate of 15 mg/kg/hr and are increased to 60 mg/kg/hr if tolerated.
Anti-CMV drug therapy, such as ganciclovir, valganciclovir or foscarnet, may be combined with CytoGam. Off-label (unapproved) uses of CytoGam include treatment of immune compromised patients (e.g., AIDS patients) with CMV pneumonia. CytoGam is not approved or used for treatment of CMV retinitis.
Market: The 2007 Average Wholesale Price (AWP) is $1,057.51/vial (Red Book, 2007).
The author’s rough guess (with no additional information to work from) for 2005 sales is in the range of $25-$35 million. This presumes a fairly constant market, but sales could very well have decreased precipitously in recent years [(as suggested by claims for market leadership by Cytotect (see entry below)]. MedImmune has not reported sales in recent years. Sales of CytoGam in the U.S. were $28 million in 2001 and $4 million outside the U.S. Sales were $36.5 million in 2000, $34.7 million in 1999, and $32.9 million in 1998.
With its acquisition of CytoGam, CSL had about 80 sales reps in the U.S., and planned to modestly increase the sales force supporting CytoGam.
Companies involvement:
Full monograph
748 CMV Immune Globulin/CSL
Nomenclature:
CMV Immune Globulin/CSL [BIO]
CytoGam [TR]
CytoGam Liquid Formulation Solvent Detergent Treated [FDA [label]]
Cytomegalovirus Immune Globulin Intravenous (Human) [FDA]
CMV-IGIV [SY]
CytoMune-IV [TR former]
NDC 60574-3101-01 [NUM NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1990
Date of 1st FDA approval = 19900417
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
cytomegalovirus (CMV)
Davis strain, cytomegalovirus (CMV)
Albumin (Human)
Cytomegalovirus Immune Globulin Paste
ethanol
immune globulin (IgM)
immune globulin A (IgA)
octoxynol (Triton X-100)
Plasma (Human)
polysorbate 80 (Tween 80)
sodium phosphate
sucrose
tri-n-butyl phosphate (TNBP)
viral inactivation, solvent detergent
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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