Cangene
Vaccinia Immune Globulin Intravenous (Human) - VIGIV; C-VIG; VIG; CNJ-016
Status: FDA approved; in U.S. biodefense stockpile
Organizations involved:
Cangene Corp. – Manuf.; R&D; Tech.; USA mark.
Apotex Holdings Inc. – Parent
Centers for Disease Control and Prevention (CDC) – USA mark.
Acambis plc – Intl. mark.
Baxter Hyland Immuno – Intl. mark.
Serologicals Corp. – Manuf. other
New York Blood Center – Tech.
Cross ref.: See the entry above for Vaccinia Immune Globulin i.m. for background information about vaccinia immune globulin. See also the Vaccinia Immune Globulin, i.v./Cangene, concerning another VIVIG product that recently received FDA approval.
Description: VIGIV or CNJ-016 is an aqueous formulation of Vaccinia Immune Globulin Intravenous (Human) or high purity immune globulin (IgG) containing high levels of vaccinia virus neutralizing antibodies isolated from the pooled plasma of U.S. civilian donors having received immunization with the only currently FDA-licensed smallpox vaccine (Dryvax; live vaccinia virus; see related entry), with processing including solvent detergent viral inactivation and nanofiltration for viral reduction. This is the primary vaccinia immune globulin product for civilian (non-military) use.
VIGIV is packaged a 15 mL single dose vial containing ≥ 50,000 U/vial. The IgG is stabilized with 10% maltose and 0.03% polysorbate 80 (Tween 80). The pH is between 5.0 and 6.5). The product contains no preservative, and is stored at 2-8˚C (refrigerated). The dating period is 24 months from the date of manufacture when stored at 2–8°C (refrigerated). The date of manufacture is defined as the date of final sterile filtration of the formulated drug product. Following the final sterile filtration, no reprocessing/reworking is allowed without prior approval from FDA. The dating period for the bulk drug substance is 28 days when stored at 2-8°C.
Product potency (as determined by a plaque reduction neutralization test) is expressed in arbitrary units (U) by comparison to the FDA reference standard. Each vial contains approximately 40-70 mg/mL total protein and greater than 50,000 units of vaccinia antibody neutralizing activity. The product contains ≤ 40 µg/mL of Immunoglobulin A (IgA).
Nomenclature: Vaccinia Immune Globulin, i.v./Cangene [BIO]; Vaccinia Immune Globulin Intravenous (Human) [FDA]; CNJ-016 [TR]; Vaccinia Immune Globulin, i.v. [SY]; VIGIV [SY]; smallpox vaccine immune globulin [SY]; Vaccinia Immune Globulin (Human) [SY]; vaccinia virus immune globulin [SY]
Companies.: In summer 2002, the Centers for Disease Control and Prevention (CDC) granted five-year supply and development contracts to Cangene Corp. (82% owned by Apotex Holdings Inc.), CBER/FDA est. no. 1201, for development and supply of new VIG stocks. The supply contract is for a maximum of 100,000 doses of VIG, with an initial order of 15,000 doses to be delivered in early 2003, after which CDC will order VIG on an as-needed basis. Contract revenues were $60 million (Canadian) in Cangene’s FY2003. The CDC Centers seeks to develop and maintain stockpiles of VIGIV at a rate of 100 doses per million doses of stockpiled smallpox vaccine. Separately, Serologicals has received a five-year contract from CDC for the development and eventual supply of a new VIGIV product.
Serologicals Corp., a large U.S. blood collector and processor, supplies Cangene [under (sub)contract] with hyperimmune plasma from U.S. collection centers for manufacture of VIGIV (collecting blood from persons having received Dryvax vaccination). About 10,000 volunteers received smallpox vaccination and donated plasma.
In March 2003, Acambis plc concluded an agreement with Cangene for exclusive marketing rights for its new VIG product outside North America and Israel. This includes sales to other governments. Baxter, which is also Acambis’ partner in MVA3000 smallpox vaccine manufacture, collaborates with Acambis in international marketing (co-marketing). Cangene has retained marketing rights in the U.S. and Israel.
In March 2005, the Health Canada Centre for Emergency Preparedness and Response (Canadian government) awarded Cangene a $3.2 million contract for supply of VIGIV. Under the terms of the agreement, Cangene intends to seek Health Canada approval for the product.
In Nov. 2005, Cangene received a C$17 million contract from the U.K. Department of Health for supply of VIGIV.
Manufacture: This VIGIV is manufactured from plasma collected from healthy, screened donors with high titers of anti-vaccinia antibody (meeting minimum potency specifications). Purification includes anion-exchange column chromatography. Several steps in the manufacturing process have been validated for their ability to remove/inactivate viruses that may not have been detected in the Source Plasma, including both a Planova 35 N virus filtration (nanofiltration) step and a solvent detergent treatment step using tri-n-butyl phosphate (TNBP) and Triton X-100 (octoxynol).
Virus spiking and other validation studies have shown the 35 nm filtration (nanofiltration) to reduce the log10 of virus titers by ≥6.0 for HIV-1; 4.4 to ≥6.4 for bovine viral diarrhea virus (BVDV; a model virus for hepatitis C virus and West Nile virus); and ≥6.8 for pseudorabies virus (PRV; a model for large enveloped DNA viruses, including herpes and hepatitis B viruses). The solvent detergent viral inactivation process has been shown to reduce the log10 of virus titers by >10.7 for HIV-1; ≥11.0 for BVDV; and ≥11.8 for PRV. Further contributing to the overall viral clearance capacity for small, non-lipid enveloped viruses is the the anion-exchange chromatographic step with a clearance of 3.4 log10 of murine minute virus (MMV; a model for parvovirus B-19) and 2.3 log10 for hepatitis A virus. The nanofiltration step yields a clearance of 4.25 log10 of poliovirus, a model for hepatitis A virus.
For reduction of vaccinia virus, the 35 nm nanofiltration step is expected to remove the vaccinia virus, based on the large size of this virus (200-450 nm long x 140-460 nm wide), and on the results obtained for BVDV (50-70 nm). However, no validation studies have been performed for this step specifically using vaccinia virus. Further clearance is obtained by the solvent and detergent step, which was validated for a 3.7 log10 reduction of the vaccinia virus. Also, the presence of anti-vaccinia antibodies in the product is also expected to inactivate any vaccinia virus in the product.
FDA class: Biologic BLA
Approvals: Date = 20050503; BLA
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]
Vaccinia Immune Globulin Intravenous (Human) (VIGIV) is indicated for the treatment and/or modification of the following conditions: Eczema vaccinatum; Progressive vaccinia; Severe generalized vaccinia; Vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy; or in individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions; Aberrant infections induced by vaccinia virus that include its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard.
Treatment of complications that include vaccinia keratitis with VIGIV should be performed with caution since a single study in rabbits has demonstrated increased corneal scarring with intramuscular VIG administration. 6 VIGIV is not considered to be effective in the treatment of postvaccinial encephalitis.
Prospective clinical studies to evaluate the efficacy and safety of any VIG IM/IV product in patients suffering complications of vaccinia vaccination have not been conducted.
Status: In July 2004, Cangene submitted a BLA for accelerated approval of its VIGIV for treatment of adverse effects of smallpox vaccination, with Fast Track designation. Approval was granted on May 3, 2005, with orphan designation. Approval was based on demonstration of comparable efficacy, as shown by vaccinia-neutralizing antibody titers, with that of VIG (the previous intramuscular vaccinia immune globulin from Baxter; see #788). Presumably, like the other recently approved VIGIV product, this product was approved with orphan status.
Available stocks of VIGIV from Cangene are held in CDC’s biodefense stockpiles, and are available for use (in emergencies) through preapproved INDs.
As part of the approval, Cangene must conduct post-approval studies including the collection of clinical data from the first 100 patients treated with VIGIV for complications of vaccinia infection, including descriptions of treatment and clinical course. The purpose of data collection is to verify the ultimate clinical benefits of VIGIV, to further study the relationship of the surrogate endpoint (anti-vaccinia antibody levels day 5 post-infusion) to clinical benefit, and to provide information about adverse events in patients with vaccinia infection treated with VIGIV. Cangene must also collect serum samples prior to VIGIV treatment and 5 days after treatment in the first 50 patients, which will subsequently be analyzed to determine anti-vaccinia antibody levels at both timepoints. These data will be analyzed to assess the correlation between day 5 antibody levels and clinical improvement for each complication. Cangene agreed to work with FDA, and other public health agencies to design and implement a clinical study protocol to include VIGIV dose ranging, when such a study is feasible, due to the actual or impending widespread use of VIGIV.
Note, although substantially the same and used for the same indications:, but with differently worded indications:, both VIGIV from Cangene and DVC have orphan designation from FDA.
Tech. transfer: Solvent detergent viral inactivation was developed by and nonexclusively licensed from the New York Blood Center. For example, see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) (#799) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Trials: Cangene filed an IND for VIGIV in June 2000, and a Phase IIB clinical trial began in July 2000. Development of a validated assay for VIG potency, a requirement for approval, has been completed.
A Phase I, randomized, double-blind study was conducted in which 60 healthy volunteers received either 6,000 U/kg or 9,000 U/kg VIGIV. After intravenous administration of 6,000 U/kg, a mean peak plasma concentration of 161 U/mL was achieved within 2 hours. The half-life of VIGIV was 30 days (range of 13-67 days) and the volume of distribution was 6,630 L. Pharmacokinetic parameters were calculated based on antibody levels determined by an ELISA. The binding capacity and neutralizing antibody activity of anti-vaccinia antibody in these subjects 5 days after administration of VIGIV (both 6000 U/kg and 9000 U/kg dosages) were at least as high as the theoretical values that would be achieved following the administration of the comparator Vaccinia Immune Globulin (VIG intramuscular from Baxter; #788). Five days represents the approximate time of peak serum anti-vaccinia antibody concentration following intramuscular administration of other Immune Globulin (Human) products. No historical pharmacokinetic data are available for the comparator, intramuscular VIG. Nor are there any pharmacodynamic or efficacy data from controlled trials available for any VIG IM or IV product.
A pilot Phase I double blind pharmacodynamic study was conducted in which 32 healthy volunteers were randomized to receive vaccinia vaccination with or without VIGIV. The objectives of the study were to assess the effects of VIGIV upon the local and immunological response to vaccinia vaccination and to further characterize the safety of VIGIV. When VIGIV was administered prior to or concurrently with vaccinia vaccination, the safety of VIGIV was consistent with the pharmacokinetic study.
Ongoing studies are evaluating the effects of concurrent administration of VIGIV with vaccinia vaccine on the pharmacokinetics of the vaccine-induced antibody response, on local vaccination site reaction, and on safety.
Medical: Dosage is based on body weight, usually 6,000 U/kg (adult and pediatric dose), with an upper limit of 9,000 U/kg. With each 15 mL vial containing 50,000 units, an average 50 kg adult would require 300,000 U or 6 vials. VIGIV from Cangene is administered as a starting dose of 6000 U/kg at an infusion rate of 0.01-0.02 mL/kg/min for 30 min. If no adverse reactions occur, the rate of infusion may be gradually increased to a maximum of 0.06 mL/kg/min. This may be repeated every 2-3 days as needed. The administration of higher doses (e.g. 9000 U/kg) may be considered in the event that the patient does not respond to the initial 6000 U/kg dose.
Market: With VIG’s only use being to treat side effect from smallpox vaccination and with it being a strategic commodity, the only purchasers are governments, which stockpile the product for emergencies arising from use of smallpox vaccines.
Companies involvement:
Full monograph
789 Vaccinia Immune Globulin, i.v./
Nomenclature:
Vaccinia Immune Globulin, i.v./Cangene [BIO]
CNJ-016 [TR]
Vaccinia Immune Globulin Intravenous (Human) [FDA, upon approval]
smallpox vaccine immune globulin [SY]
Vaccinia Immune Globulin (Human) [SY]
Vaccinia Immune Globulin, i.v. [SY]
vaccinia virus immune globulin [SY]
VIGIV [SY]
FDA Class: Biologic BLA
Year of approval (FDA) = 2005
Date of 1st FDA approval = 20050502
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
DNA, mammalian
vaccinia virus vaccine
Namalva cells
octoxynol (Triton X-100)
Planova 35 nm Virus Filter
Plasma (Human)
polysorbate 80 (Tween 80)
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)
BHK-21 (C-13)
conjugates
implants
North American coral snake
orphan status
EU000 Not yet/Never filed with EU
UM100 Controlled/Gov't Distribution in US
US666 Biodefense stockpile
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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