Status: approvals withdrawn; replaced by a recombinant product

Organizations involved:

MedImmune, Inc. – World mark.; Former

Abbott Labs. – USA mark.; Former

Massachusetts Biological Labs. – Manuf.; R&D; Tech.; Former

Massachusetts, State of – Parent; Former

Aventis Pasteur Inc. – Manuf. other; Former

Lederle Labs./Wyeth – USA mark.; Former

Wyeth Pharmaceuticals – Parent; Former

National Institute of Allergy and Infectious Diseases (NIAID) – R&D; Tech.; Former

National Institutes of Health – Parent; Former

New York Blood Center, Inc. – Tech.; Former

Cross ref: See the entry for Palivizumab (Synagis) (#245), a recombinant respiratory syncytial virus (RSV) monoclonal antibody (which has replaced this product) for RSV, disease, market, and other information. See the Immune Globulin Products entry (#743).

Description: RespiGam is an aqueous formulation of Respiratory Syncytial Virus Immune Globulin Intravenous (Human) or immunoglobulin G (IgG) fractionated and purified from pooled Plasma obtained from adult donors with high titers of neutralizing antibodies to respiratory syncytial virus (RSV; e.g., titers of at least 1:3,000) identified using a proprietary screening assay (see Tech. transfer section), with processing including solvent detergent viral inactivation. RespiGam has a neutralization titer greater than five-fold than conventional non-hyperimmune globulin products (e.g., IVIG). RespiGam contains IgG antibodies representative of the large number of normal healthy persons (with prior exposure to the virus) who contribute to the Plasma pool. The immune globulin is stabilized with 5% sucrose and 1% Albumin (Human).

RespiGam is packaged in 50 ml vials containing 2,500 ± 500 mg of immune globulin. Each mL contains 50 ± 10 mg immune globulin, primarily as IgG, and trace amounts of IgA and IgM; 50 mg sucrose; and 10 mg Albumin (Human). Respi-Gam contains no preservatives, and has a target pH of 5.5 (range 5.3-6.3). Each lot of RespiGam meets the minimum potency specifications when compared to a validated Reference Standard. The product is stored at 2-8˚C (refrigerated).

Nomenclature: RSV Immune Globulin [BIO]; RespiGam [TR]; Respiratory Syncytial Virus Immune Globulin Intravenous (Human) [FDA]; Respivir [TR former]; Hyperimmune RSV [TR former]; NDC 60574-2101-02 [NDC]

Biological.: In vitro tests have shown that antibodies in RespiGam neutralized each of 62 different RSV clinical isolates of both subgroup A (n=39) and subgroup B (n=23).

Companies.: RespiGam was developed and manufactured by the Massachusetts Public Health Biologic Labs.; CBER/FDA est. no. 1252. Aventis Pasteur Inc. filled and packaged Respi-Gam for MedImmune. Aventis Pasteur is merging into Sanofi-Aventis S.A. in summer 2004.

MedImmune markets RespiGam in the U.S. and internationally; and it was co-marketed in the U.S. by Abbott Labs. (Ross Products Div.). It was originally co-marketed in the U.S. by MedImmune and Lederle Labs., now Wyeth. A previous agreement by MedImmune with Baxter International for commercialization outside of North America was discontinued.

MedImmune originally had a strategic alliance with Lederle Labs., American Cyanamid Co., later acquired by American Home Products, now Wyeth, for the co-development and co-promotion of RespiGam. The agreement, entered into in Nov. 1993 and amended in Oct. 1995, provided for Lederle to fund a portion of the cost of the development of RespiGam and co-promote the product in the U.S., with the companies sharing in the profits and losses on RespiGam in the U.S. In Dec. 1999, much of this agreement was terminated, including co-promotion of RespiGam in the U.S. The parts calling for MedImmune to receive royalties on sales of a Wyeth candidate RSV subunit vaccine and for Wyeth to receive royalties on U.S. sales of Synagis (see entry #245) remained in effect.

In late 2003, MedImmune announced that manufacture of RespiGam would soon be halted, with sufficient supplies on hand for the 2003-2004 RSV season. MedImmune was acquired by AstaZeneca in spring 2007.

Manufacture: Immune globulin is purified from pooled adult human Plasma selected for high titers of neutralizing antibody against RSV using a proprietary screening assay (see Tech. transfer section). Pooled plasma lots are reported to include plasma from at least 2,000-5,000 donor units. All donor plasma and blood donors is tested for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies, normal liver enzymes (e.g., ALT), and normal VDRL (syphilis). The average RSV IgG titer for each donor is 1:1,500, yielding a final product with RSV IgG level of 1:7,000, which is consistent within and between lots.

Source material for fractionation may be obtained from other U.S.-licensed manufacturer(s). Pooled plasma is fractionated by cold ethanol precipitation of the proteins according to Cohn Method 6 and Oncley Method 9. Human plasma is converted to an intermediate antibody/IgG-rich raw material, Fraction II+III paste, from which RespiGam is manufactured. IgG is isolated from effluent III by ultrafiltration and then stabilized with sucrose and Albumin (Human). The solvent detergent viral inactivation process, e.g., with tri-n-butyl phosphate (TNBP) and polysorbate 80 (Tween 80), particularly to inactivate enveloped viruses. See the Plasma SD entry (#799) for further information about solvent detergent viral inactivation.

FDA class: Biologic PLA

Approvals: Date = 19960118, first approval, PLA, granted to Massachusetts Public Health Biologic Labs.; orphan designation (granted 09/27/1990; expired 1/18/2003)

Indications: [full text of the "INDICATIONS AND USAGE” section from recent product insert/labeling]:

RespiGam is indicated for the prevention of serious lower respiratory tract infection caused by RSV in children under 24 months of age with bronchopulmonary dysplasia (BPD) or a history of premature birth (less than or equal to 35 weeks gestation). RespiGam has been demonstrated to be safe and effective in reducing the incidence and duration of RSV hospitalization and the severity of RSV illness in these high risk infants.

Status: RespiGam has been replaced by palivizumab (Synagis), a recombinant humanized RSV monoclonal antibody, from MedImmune. FDA approval has been voluntarily withdrawn since mid-2005.

Upon the initial launch of Synagis, RespiGam stocks were recalled and/or purchasers allowed to return the product for credit (exchange), and MedImmune projected about $12.5 million in potential returns. However, in May 2000, the Massachusetts Public Health Biologic Labs. reported continued demand and sales of RespiGam to MedImmune, enough demand to require obtaining redating authorization from CBER for some product on hand and the manufacture of another production lot. In late 2003, MedImmune announced that RespiGam would soon no longer be manufactured, with sufficient supplies on hand for the 2003-2004 RSV season.

This product no longer appears on CBER/FDA approval lists, indicating that its approval was recently voluntarily withdrawn. Other approvals have, presumably, been withdrawn.

Tech. transfer: Exemplary patents assigned to the Massachusetts Public Health Research Institute, now Massachusetts Biological Labs., include U.S. 5,582,827 and 5,412,077 covering methods for identifying plasma units containing high RSV antibody titers (over 1:3,000). Only about 8% of normal donors have RSV neutralizing antibody titers high enough to qualify for the production of RSV hyperimmune globulin. See also “Protective Activity of a Human Respiratory Syncytial Virus Immune Globulin Prepared from Donors Screened by Microneutralization Assay,” J. Inf. Dis., 165:456-63, 1992.

Molecular Vaccines, Inc., now MedImmune, nonexclusively licensed U.S. 4,800,078, “Treatment of respiratory disease caused by RSV using human gamma globulin,” invented by researchers with the National Institute of Allergy and Infectious Diseases (NIAID) and assigned to the National Institutes of Health (NIH). This patent concerns RSV monoclonal antibody and polyclonal immune globulin preparations and inhalation delivery methods useful for passive immunization prevention and treatment of RSV infections.

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 further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).

Trials: In the pivotal Phase III trial (PREVENT), monthly doses of 750 mg/kg resulted in geometric mean serum RSV-neutralizing antibody of 1:297 ± 38 one month after first infusion; 1:477 ± 85 one month after a second infusion; 1:490 ± 61 one month after a third infusion; and 1:429 ± 23 one month after a fourth infusion. For results from PREVENT trial, see Groothius, J.R., et al., Prophylactic Administration of Respiratory Syncytial Virus Immune Globulin to High-Risk Infants and Young Children, New England Journal of Medicine, vol. 329, p. 1524-30, 1993.

Medical: RespiGam is used for passive immunization, to provide transient, near immediate immunity against infection with RSV. RespiGam is not effective for treatment of RSV infections. The mechanism of action of RespiGam is based on the high titers of RSV-neutralizing antibodies contained in the product. The in vivo half life of RSV neutralizing antibodies after RespiGam administration is 22-28 days. Specific protective levels of RSV antibodies have not been established.

RespiGam is administered by intravenous infusion using an infusion pump, with the total dose per month generally 750 mg/kg. In RSV-susceptible infants, a primary dose may be administered at the start of the RSV season, followed by monthly doses during the RSV season. The RSV season in the Northern Hemisphere is usually about November-April.

Competition: Compared to palivizumab (Synagis; recombinant RSV monoclonal antibody; see related entry) also from MedImmune, Respi-Gam has a number of drawbacks, including requiring intravenous infusion in infants with limited venous access because of prior intensive therapy; the large volume of RespiGam infusion required for protection, particularly since most candidate infants have compromised cardiopulmonary function; intravenous infusion necessitates monthly hospital visits during the RSV season which places the infants at risk of nosocomial RSV infection; and the difficulty in selecting sufficient donors to produce RSV hyperimmune globulin. RespiGam also, theoretically, entails a risk of blood-borne infection.

Market: The 2004 Average Wholesale Price (AWP) was $1,030.10/vial (Red Book, 2004; last year was listed).