BIOPHARMA RSV Mab, rDNA (Synagis from MedImmune)

Cross ref.: See the Monoclonal Antibodies, Recombinant entry (#240). See also the entry for RSV Immune Globulin (RespiGam) in the human blood products section, which has been replaced by this product.

Description: Synagis is a lyophilized (freeze-dried) formulation of a recombinant humanized (chimeric murine-human) IgG1kappa monoclonal antibody glycoprotein (palivizumab) with specificity for an epitope in the A antigenic site of the F (fusion) protein of respiratory syncytial virus (RSV). Palivizumab is expressed from a stable murine (mouse) myeloma cell line (NS0). Synagis was the first monoclonal antibody product approved in the U.S. for an infectious disease indication. At the time, its initial launch was the most successful of any biopharmaceutical product, in terms of rapid gain of sales and market share. Palivizumab is composed of to heavy chains (50.6 kDa each) and two light chains (27.6 kDa each), contains 1-2% carbohydrate by weight and has a molecular weight of 147.7 kDa ± 1 kDa (MALDI-TOF). A new liquid formulation of Synagis was approved in July 2004, and is expected to be launched in time for the 2005/2006 RSV season.

Palivizumab is essentially a murine monoclonal antibody which has been "humanized" by replacement of comparable human for murine gene/protein sequences, while retaining the antibody-antigen affinity and active portions of Mab 1129, a murine RSV F protein-specific monoclonal antibody. See also the History and Patents sections for further information. The palivizumab molecule, originally designated MEDI-493, is a composite of murine (5%) and human (95%) antibody sequences. The configuration of the murine complementarity determining regions (CDRs; antigen-binding portion) into the human immunoglobulin (IgG1) framework shields the molecule from inducing significant human anti-mouse antibody (HAMA; immune rejection of murine IgG) reactions in clinical use. Simply stated, thee active RSV-neutralizing portions (CDRs) of the source mouse (murine) monoclonal antibody (Mab 1129) are spliced into a human antibody (immunoglobulin) constant framework. The human heavy chain sequence was derived from the constant domains of human immunoglobulin G1 (IgG1) and the variable framework regions of the VH genes Cor and Cess. The murine sequences were derived from murine Mab 1129 through a process which involved the grafting of the murine complementarity determining regions (CDRs) into the human antibody frameworks. The human light chain sequence was derived from the constant domain of the C-kappa and the variable framework regions of the VL gene K104 with J-kappa-4.

Humanization of the murine monoclonal antibody avoids human anti-mouse antibody (HAMA) reactions or recognition of the antibody as foreign, i.e., palivizumab presents itself as a human antibody. Humanized antibodies, such as Synagis, can have a longer in vivo half-life and be less immunogenic than conventional murine monoclonal antibodies. An article describing the development of Synagis was published in the Journal of Infectious Diseases (vol. 176, no. 5, p. 1215-24, November 1997).

Palivizumab specifically binds the F or fusion surface protein of respiratory syncytial virus (RSV). The F protein is required for fusion of RSV-infected cells with other infected cells, forming complexes of fused RSV-infected cells termed syncytia (syncytium is singular form). Syncytia are composed of masses of protoplasm with no cell membranes separating cell nuclei. The F protein, when expressed on the surface of RSV-infected cells, allows fusion with other the F proteins of other RSV-infected cells.

Synagis is supplied in a single use vial containing 100 mg of sterile lyophilized palivizumab for intramuscular injection after reconstitution with Sterile Water for Injection. After reconstitution, Synagis contains the following excipients: 47 mM histidine, 3.0 mM glycine and 5.6% mannitol. Synagis contains no preservatives. Synagis has a pH of 6 (range 5.0-7.0) and osmolality of 462 mmol/kg. The product should be stored at 2-8€C (refrigerated) and has a half-life of two years.

A new liquid formulation of Synagis, approved in July 2004, slated to replace the current lyophilized powder version, will be launched in fall 2004. This will be packaged in 50 mg and 100 single-use vials, with no preservatives

Each 100 mg vial contains 120 mg palivizumab (100 mg/mL), 4.7 mg histidine, and 0.1 mg glycine in 1.2 mL Water for Injection, for withdrawal and intramuscular injection of 100 mg palivizumab in 1 mL. Each 50 mg vial contains Á70 mg palivizumab (100 mg/mL), 2.6 mg histidine, and 0.08 mg glycine in 0.7 mL Water for Injection, for withdrawal and injection of 50 mg in 50 mL. There is an overfill in the vials to allow for withdrawal of the specified dose.

Nomenclature: RSV Mab, rDNA [BIO]; Synagis [TR]; Palivizumab [FDA USAN INN]; respiratory syncytial virus (RSV) monoclonal antibody [SY]; MEDI-493 [SY]; 60574-4111-01 [NDC]

Note, "Synagis" may best be used to refer to the product and "palivizumab" may best be used to refer to the active monoclonal antibody ingredient. However, both of these terms and synonyms are often used to refer to the product/formulation and/or active ingredient.

Biological: RSV was originally isolated from chimpanzees in 1956. RSV is a pleomorphic virus, a member of the family of Paramyxoviridae, comprising a single strand, sense-negative RNA genome, which is tightly associated with viral protein to form the nucleocapsid. RSV is comprised of two major groups (A and B). The RSV genome codes for three transmembrane surface proteins (F, G, and SH), 2 matrix proteins (M and M2), 3 nucleocapsid proteins (N; P and L) as well as for 2 non-structural (NS1 and NS2) proteins. The surface fusion (F) and attachment (G) proteins are the only viral components capable of inducing RSV-neutralizing antibodies.

The F protein, a 70 kDA disulfide linked heterodimer, mediates fusion of the viral envelope with the plasma membrane and syncytium formation; has a high degree of genetic and antigenic homology between RSV group A and RSV group B; and has been antigenically stable over years. Antibodies against the F protein neutralize both RSV group A and B isolates.

Palivizumab binds to the F surface protein of RSV - neutralizing RSV and also inhibiting spread by syncytia formation. Palivizumab was 50 to 100 times more potent than RSV immune globulin (RespiGam from MedImmune; see related entry #495) in a cotton rat model of RSV infection, with serum concentrations of > or = 40 µg/ml reducing RSV replication (viral load) about 100-fold greater. Neutralization activity in vitro has been demonstrated against 57 RSV isolates of both A and B strains.

Palivizumab has a pharmacokinetic profile in adults similar to that of human immune globulin (IgG1) with a mean half-life of 18 days and a half-life of 20 days in infants (<2 years old). As reported in the Journal of Infectious Diseases, December 1998, Synagis was shown to significantly reduce RSV titers in the tracheal secretions of severe RSV-infected intubated infants compared to placebo.

History: Respiratory syncytial virus (RSV) was first isolated in 1956. To date, efforts to produce an effective antigen-based prophylactic RSV vaccine have been unsuccessful. A major obstacle to development of such as vaccine has been safety. A formalin-inactivated RSV vaccine developed in the 1960s resulted in high seroconversion rates but caused an increased incidence of RSV lower respiratory tract disease and death in immunized children upon exposure to wild virus (Kapikian, A.Z., et al., Am. J. Epidemiol. 89:405, 1969) compared to patients receiving placebo.

Synagis is the result of about eight years of intensive development by MedImmune. Studies by Beeler and others in the mid-late 1980s established that RSV strains (serotypes A and B) share a common antigenic surface glycoprotein, particularly epitopes of the A antigenic site of the F (fusion) glycoprotein. Antibodies to this site were shown to neutralize RSV and/or inhibit RSV fusion (syncytia formation) activity. MedImmune then set out to identify and refine an IgG monoclonal antibody to this target (to take the place of RespiGam) First, mice were infected with human RSV strain A2 and their spleens were harvested to obtain B-cells primed to make RSV IgG antibody. Hybridoma cell lines for expression of monoclonal antibodies were developed by standard methods (Kohler, et al.; fusion with myeloma cells). Resulting monoclonal antibodies (Mab) were screened for antigen specificity. One murine monoclonal antibody (hybridoma), MAb 1129, was selected for its optimal specificity for an epitope of the A site in the RSV F glycoprotein.

Using technology nonexclusively licensed from Protein Design Labs. (see Tech. transfer section), murine MAb 1129 was humanized. The MAb 1129 binding site, in the variable regions of the Fab fragment of the antibody, was sequenced to determine its Complimentary Determining Regions (CDRs). Six CDRs were found to be essential and by recombinant methods these were grafted to the variable framework of a human IgG1 antibody relying on the architecture of V domains (i.e., chimeric engineering of the variable regions). IgG1 was selected as the Fc fragment (constant human region) for the recombinant antibody because it has the optimal effector properties (pharmacokinetics, complement and cell-mediated killing) among all the IgG isotypes for this therapeutic use. DNA sequences for six desired CDRs were obtained from the murine B-cell that originally produced the MAb 1129 hybridoma, then spliced to DNA that encode for the variable (Fab) and constant (Fc) regions of a normal human IgG1 molecule. This involved use of human VH genes described by Cor and Cess for the heavy chain amino acid sequences, and VL genes K104 with Jk-4 for the light chain amino acid sequences (all of which comprise the entire IgG1 molecule.)

The chimeric gene containing the assembled DNA segments was synthesized via polymerase chain reaction (PCR), and the resultant gene was propagated as a plasmid in Escherichia coli (E. coli). The plasmid propagated in E. coli was isolated, mixed with murine myeloma NS0 cells (which are very efficient in expressing IgG antibody), and exposed to electroporation (high voltage electricity), allowing the DNA plasmid to enter the nucleus of the myeloma cell and become part of its chromosomal structure (transformation). Glutamine synthetase (GS) selection technology (licensed from Lonza; see Tech. transfer section) and amplification using methionine sulfoxine were used to select an optimally transformed murine NS0 cell line (hybridoma), which is capable of producing about 1 gram of monoclonal antibody/liter of culture. This cell line was expanded and preserved frozen in liquid nitrogen as the Working Cell Bank (WCB). Each myeloma cell derived from the WCB can produce significant quantities of palivizumab.

Companies: Synagis was developed by MedImmune, Inc., CBER/FDA est. no. 1252. Development was completed with only 3.5 years from time of submission of the first IND to FDA approval. As discussed below, Synagis is manufactured at facilities in the U.S. and Germany.

MedImmune and the Ross Products Div., Abbott Labs., co-promote Synagis in the U.S., and Abbott holds exclusive marketing rights outside of the U.S. MedImmuneÌs sales force concentrates on the 500 largest hospitals in the U.S. with neonatal intensive care units, while the Ross/Abbott sales force concentrates on the 2,000 hospitals with facilities for delivering babies and the 27,000 office-based pediatricians in the U.S. MedImmune is credited with all U.S. sales of Synagis by Ross/Abbott which receives a 32% commission on sales over an unspecified amount (an amount which MedImmune projected its own 60-person sales force could sell).

The original approval was for product manufactured by MedImmune, CBER/FDA est. no. 1252, at its Gaithersburg, MD, facility (not geared for large-scale manufacture). This was followed by supplemental approval of large-scale manufacture under contract to MedImmune by Boehringer Ingelheim Pharma KG (BI; Biberach/Riss, Germany), CBER/FDA est. no. 1251. BI also fills and packages Synagis produced at its facility. MedImmune paid Boehringer Ingelheim $14.3 million in 2001, $26.4 million in 2000, and $21.1 million in 1999 for production and scale-up of production. MedImmune has firm commitments with BI for production through March 2004 for approximately 43.7 million Euros.

In late 1999, MedImmune received supplemental approval allowing Synagis manufacture at the companyÌs new large-scale facility in Frederick, MD. Product manufactured at this facility supplements that manufactured by Boehringer Ingelheim (BI). Manufacture by MedImmune in Gaithersburg has ceased. MedImmune announced in July 2000 an increase in fermentation batch size from 10,000 to 12,500 liters. BI facilities are reported to have a maximum batch size of 45,000 vials of the 100 mg size and 93,000 of the 50 mg size vials. Even with enhanced yield improvements adopted in 2001, MedImmune will continue to rely upon BI for a portion of worldwide Synagis production for at least the next few years.

In April 1998, MedImmune contracted with Chiron Corp. for filling and packaging of Synagis produced at its Gaithersburg pilot plant and Frederick manufacturing plant. In 2001, this contract was extended for an additional three years.

Drug Royalty Corp. Inc. has purchased from undisclosed sources (apparently 2 different sources) for $9.25 million and later for $4.97 million undisclosed shares of future Synagis royalties

Manufacture: MedImmune uses a stirred-tank, fed-batch system for recombinant antibody manufacture. A stable cell line for large-scale production was developed from a murine myeloma cell line (NS0). Twenty-one candidate production cell lines were evaluated for growth rate and secretion of palivizumab. Selection of one cell line, suitable for large-scale production, was based on expression level, growth rate, and stability. The selected transformed cell line can produce about 1 gram paliviumab/liter of culture. The best candidate after cloning resulted in the generation of the Accession Cell Bank (ACB). Cells from one ACB vial were used to establish the Master Cell Bank (MCB). Each MCB vial can be used to prepare a Working Cell Bank (WCB). The MCB was characterized for identity, quality and safety measuring the following parameters: mouse antibody production, isoenzyme analysis, in vivo assay for adventitious viruses, in vitro assay for adventitious viruses, sterility, mycoplasma, extended S+L focus assay, extended XC plaque assay, DNA profiling, cDNA sequences of heavy & light IgG chains, and copy number. The WCB was characterized for sterility, DNA-fingerprinting, mycoplasma, and in vitro assay for adventitious viruses. No evidence of microbial contamination was found. The DNA profile was characterized and the profile was found to be similar to that of the MCB.

Media components are organic chemicals (e.g., amino acids and vitamins), recombinant products (e.g., recombinant yeast-expressed human Insulin), or are derived from bovine material obtained from U.S. or Canadian sources (considered BSE/TSE-free). The cell culture medium contains three bovine products: bovine serum albumin (BSA), transferrin, and lipoprotein fractions.

There are two parts to the fermentation process - T-Flask and spinner culture in which the volume (and number of cells) of the WCB is increased, and the larger-scale bioreactor process where the cell culture volume is increased incrementally to the final volume of 10,000 liters or more. At the start of each production run, a vial containing about 10 million frozen cells from the Working Cell Bank (WCB) is thawed and expanded through a series of flasks and bioreactors filled with cell culture media. The NS0 myeloma cells continuously secrete the palivizumab monoclonal antibody into the liquid medium throughout the fermentation process. About 18-22 days after inoculation of the production bioreactor, the cells and debris are removed and the pH and conductivity of the resulting cell-free conditioned media are adjusted for further processing and purification.

The first step in purification is microfiltration through a membrane that blocks large materials such as myeloma cells and debris but allows passage of proteins, such as antibodies, and other solubilized substances. The palivizumab is purified from the liquid phase via three-stage chromatography, acid treatment, and nanofiltration to remove process contaminants such as viruses, bovine serum albumin, transferrin, and endotoxin. The final product is formulated by stabilization at pH 6.0 with histidine, glycine, and mannitol. Bulk Synagis is passed through a 0.22 micron filter and filled in glass vials. The resulting sterile product is then lyophilized (freeze-dried). Every lot is validated for purity, potency and sterility. The palivizumab purification process includes several (unspecified) virus removal/inactivation steps (probably referring to nanofiltration, acid treatment and, perhaps, the chromatography steps). In-process controls include testing of samples for fill volume and integrity testing of sterilization filters. Validation is performed according to standard procedures. Viral clearance studies are conducted throughout the Synagis manufacturing operation.

Routine testing on the finished product includes appearance of the lyophilized powder and reconstituted solution, pH, moisture, total protein, biological potency, identity, size exclusion chromatography, endotoxins, sterility, and uniformity of content. SDS PAGE and RSV Microneutralization assays have been validated and are used for quality control. Palivizumab reference standards have been developed. The characterization of the reference standard includes a series of analytical tests to confirm that its structural identity and biological activity are consistent with the set criteria.

During the course of Phase I through III trials, palivizumab was manufactured by MedImmune in various bioreactor sizes including 20, 45, 100, and 200 liters. This was further scaled-up and three consistency lots were manufactured by MedImmune in 500 liter bioreactors. Combined data from 20-500 liter lots were used to support approval. Boehringer Ingelheim further scaled-up the process from 400 to 10,000 liter bioreactors, and testing showed materials produced by both companies and all lot sizes were comparable using a variety of analytical methods [see "Comparabilty Testing of a Humanized Monoclonal Antibody (Synagis) to Support Cell Line Stability, Process Validation, and Scale-Up for Manufacturing," Biologicals, 27, p. 203-15, 1999].

FDA class: Biologic BLA

CBER class: Viral And Rickettsial Vaccines

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19980619; first approval; BLA 97-1359; for product manufactured at MedImmune's Gaithersburg, MD, facility

Date = 19990908; BLA supplement; Indication = approval of manufacture by Boehringer Ingelheim Pharma KG under contract to MedImmune

Date = 19991217; BLA supplement; Indication = approval of manufacture at MedImmune's new facilities in Frederick, MD, to augment product manufactured by Boehringer Ingelheim. The approval acknowledged the therapeutic and other equivalence of palivizumab produced by MedImmune and Boehringer Ingelheim.

Date = 20010000 (sometime in 2001); Indication = approval for manufacture using ÏEnhanced Yield ProcessÓ (EYP), which improves Synagis fermentation yields by over 300%

Date = 20030916; BLA supplement; Indication = addition to product insert/labeling of findings supporting use in young children with hemodynamically significant congenital heart disease (CHD) to prevent hospitalization caused by RSV.

Date = 20040724; BLA supplement; Indication = new liquid formulation

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

Synagis (palivizumab) is indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. Safety and efficacy were established in infants with bronchopulmonary dysplasia (BPD) and infants with a history of prematurity (Á 35 weeks gestational age). (See Clinical Studies section).

Status: The BLA was filed on December 19, 1997, received priority review, and was approved by FDA on June 19, 1998; an on-target approval time of six months (0.5 year). Product sales began on September 15, 1998. This allowed for production and product launch in time for the fall 1998 RSV season in the U.S. The FDA approved Synagis without the usual review and recommendation by an advisory committee, in this case the Vaccines and Related Biological Products Advisory Committee.

Synagis was approved on August 13, 1999 in the European Union (EU) "For the prevention of serious lower respiratory tract disease requiring hospitalization as caused by respiratory syncytial virus (RSV) in children who are born at 35 weeks of gestation or less and were less than 6 months of age at the onset of the RSV season, or in children who are less than 2 years of age and had required treatment for bronchopulmonary dysplasia within the last 6 months." On Oct. 30, 2003, EU supplemental approval was granted "for use in infants less than two years of age born with hemodynamically significant congenital heart disease (CHD) to prevent serious lower respiratory tract infection (LRTI) hospitalisation caused by respiratory syncytial virus (RSV)."

On July 2004, a new liquid formulation was approved. This offers improved convenience. The lyophilized formulation requires reconstitution with sterile water, a process that takes ~20 minutes, and the product must be used within the next six hours. MedImmune plans to end production of the lyophilized formulation for the U.S. on October 2004, and to begin manufacturing liquid Synagis, which is expected to be launched later in the U.S. later in 2004, in time for the 2005-2006 RSV season.

Tech. transfer: U.S. patent, 5,824,307, "Human-murine chimeric antibodies against respiratory syncytial virus," Oct. 20, 1998, assigned to MedImmune, Inc., covers palivizumab (see also EP 0783525). This composition of matter patent protects Synagis through October 20, 2015. The official abstract states: "This invention relates to a human antibody which contains the one CDR from each variable heavy and variable light chain of at least one murine monoclonal antibody, against respiratory syncytial virus which is MAb1129 and the use thereof for the prevention and/or treatment of RSV infection." The exemplary claim (no. 1) states, "A neutralizing antibody against RSV, comprising: a human constant region and a variable region, said variable region comprising heavy and light chain framework regions and heavy and light chain CDRs, at least a portion of the heavy and light chain framework regions being derived from a human antibody, said neutralizing antibody against respiratory syncytial virus binding to the same epitope as an antibody comprising three heavy chain CDRs comprising amino acids 31-37, 52-67 and 100-109 of SEQ ID NO:31, and three light-chain CDRs comprising amino acids 24-33, 51-56 and 89-96 of SEQ ID NO:3." Additional patent applications which could provide even broader and longer protection are pending. DataMonitor and ABN Amro report that U.S. patent protection for Synagis expires in 2004, although the source patent for this is not readily apparent.

The situation concerning recombinant monoclonal antibody patents, licensing, cross-licensing and disputes is very complex. This includes an extended patent dispute between Genentech and Celltech Group (being acquired by UCB Bioproducts in mid-2004) concerning basic recombinant monoclonal antibody design and expression technologies. See the "Tech. transfer (rDNA)" section of the Monoclonal Antibodies, Recombinant entry (#240) for further information. This includes Celltech receiving its "Boss" U.S. patent (expiration in 2006) and Genentech receiving its original "Cabilly" patent (expiration in 2006), both on the same day; Celltech's Boss patent later revoked; and Genentech later receiving its "New Cabilly" patent (6,331,415; expiration in 2018), including claims copied from the revoked Celltech "Boss" patent. Genentech and Celltech later settled their disputes and cross-licensed their patents, with Genentech taking the lead in licensing. As a result, in some respects, Celltech's U.S. "Boss" patent (licensed by MedImmune for Synagis) was essentially broadened and its expiration extended by over a decade, from 2006 to 2018.

In Oct. 2000, Celltech Chiroscience Ltd., now Celltech Group plc filed a suit in the U.K. alleging that MedImmune failed to pay royalties on sales of Synagis as required by a license agreement concluded in January 1998. Under this agreement, MedImmune obtained a worldwide license to Celltech's "Boss" patent (and related applications) concerning recombinant chimeric/humanized monoclonal antibody co-expression technology. Subsequently, with Genentech's "New Cabilly" patent and the cross-licensing between Celltech and Genentech, Genentech is now demanding royalties from MedImmune on sales of Synagis.

MedImmune, Inc. responded to the Genentech-Celltech cross-licensing agreement by filing suits in federal court alleging antitrust violations between Genentech and Celltech, and challenging the "New Cabilly" patent (6,331,415). MedImmune alleged that Genentech and Celltech conspired to gain a monopoly, with Celltech agreeing to abandon defense of its 2006-expiring Boss patent in exchange for continuing (through 2018) (cross)licensing revenue from Genentech's licensing of its New Cabilly patent and access (through cross-licensing) to the New Cabilly patent for its own products. MedImmune asserted that the Genentech-Celltech agreement resulted in 29 years of patent protection for the same technology. In May 2004, a U.S. District Court dismissed MedImmune's suit, with the Genentech/Celltech patents and agreements remaining intact. The judge ruled in favor of Genentech, because a U.S. District Court judge had previously approved the Genentech-Celltech agreement. Challenges to 6,331,415 ("New Cabilly") have been resolved yet.

Antibody humanization design/construction technology for palivizumab has also been nonexclusively licensed by MedImmune from Protein Design Labs. (PDL). Based on a Jan. 2003 CIBC World Markets Report on PDL, the company receives royalties of 2.85%, a rate similar to what the company receives from other licensed manufacturers of humanized Mabs. The basic technology for PDL's antibody humanization is disclosed by Queen, et al., in 5,530,101 and related patents and Winter, et al., in U.S. patent 5,225,539 and related patents. See the Tech. transfer (rDNA) section of the Monoclonal Antibodies entry (#240) for further information.

Manufacture of palivizumab entails use of the glutamine synthetase (GS) recombinant mammalian cell selection, amplification and expression system developed by Celltech Biologics plc, now Lonza Biologics plc, a subsidiary of Alusuise-Lonza Group. Lonza Biologics receives unspecified royalties from MedImmune on sales of Synagis from licensing of its patents covering the GS gene expression system. GS technology involves dominant selectable markers for use in amplification of genes and transforming host cell lines to glutamine independence. See related patents including U.S. 5,770,359 and 5,747,308. The technology is coassigned to the University of Glasgow. The glutamine synthetase gene is used in recombinant vectors as a marker along with (an)other desired gene(s) for expression, with only successfully transformed mammalian cells (normally deficient in glutamine synthetase) being capable of producing their own GS and surviving in glutamine-deficient culture media. Over forty companies have licensed GS System technology for various uses.

MedImmune currently holds a Biological Materials License (BML) from the National Institutes of Health (NIH) for an unspecified biological material. Molecular Vaccines, Inc., now MedImmune, in the early 1990s also nonexclusively licensed U.S. 4,800,078, invented by researchers with the National Institute of Allergy and Infectious Diseases (NIAID), NIH. This license is no longer active. The patent's single claim concerns RSV monoclonal antibodies and immune globulins delivered by inhalation aerosol (while Synagis is administered by intramuscular injection).

Medical: The recommended dosage is 15 mg/kg (with palivizumab containing 100 mg/ml) administered once monthly throughout the RSV season (generally Nov.-April). The first dose is best administered starting prior to commencement of the RSV season, generally in the fall and winter months, but the season may begin earlier or persist later in certain communities. The safety and efficacy of Synagis have not been demonstrated for treatment of established (chronic) RSV disease.

Disease:: RSV is a common disease among infants and children, but can be particularly harmful, including causing death, in infants born prematurely or with underlying respiratory disease (bronchopulmonary disorders). RSV is responsible for the largest proportion of respiratory infections in infants and children. Because premature birth interrupts the final stages of fetal development, each premature infant is at risk for contracting serious RSV disease, such as bronchiolitis or pneumonia due to RSV. Premature infants do not have a normal immune response or the lung capacity of full-term children to resist lower respiratory tract infections. Recent data indicate that compared to normal birth weight children, those born at a low birth weight are five times as likely to die with bronchiolitis. The risk of serious RSV infection and hospitalization increases with risk factors such as premature birth, chronic lung disease, congenital heart disease, low birthweight, passive smoke exposure, daycare attendance, multiple birth, family history of asthma, and birth within six months of the onset of RSV season.

RSV is generally transmissible by direct or close contact, probably inhalation of respiratory aerosol droplets. RSV can live on tissues and surfaces, e.g., counter tops, for 4 to 7 hours, and the virus can survive on the hands for about 0.5 hour. Nosocomial (hospital-associated) infections are common in infants and medical staff. The incubation period for RSV disease (respiratory symptoms) is 2-8 days. Live virus is usually shed for about 3-8 days, but this may last 3-4 weeks in infected infants with low or no neutralizing antibody titers. Infants born premature and others with suppressed immune systems are particularly susceptible to RSV infection.

An estimated one-third of the 12.2 million respiratory infections that occur in children under age five is attributed to RSV. Half of all children develop RSV infection by the age of one year and, by the age of two, virtually all children have been infected. For most otherwise healthy children over age four, RSV usually amounts to little more than a cold. In children under age four, it can cause lower respiratory tract infection. Most RSV infections start with a low-grade fever, a runny nose, and cough, which may be accompanied by difficulty in breathing and wheezing. The infection may last as long as two to three weeks.

A small percentage of infants and children who contract RSV are at high-risk for hospitalization, particularly premature infants and others with bronchopulmonary disorders. The largest proportion of Synagis is used for treatment of infants born prematurely.

RSV is the most common cause of lower respiratory tract infection in children under five years of age and the number one reason for hospitalization of children under the age of one. The Centers for Disease Control and Prevention (CDC) now estimates that each year up to 125,000 children under the age of five are hospitalized with serious RSV disease (primarily during the RSV season - from fall through spring). Only a few years ago, about 4,500 deaths annually are attributed to the disease. An article in the October 20, 1999 issue of the Journal of the American Medical Association reported that an increasing number of children in the U.S. are being hospitalized for bronchiolitis, often caused by RSV infection, with over half of hospitalizations among infants under six months of age and 81% among those under 1 year old. Between 1980 and 1996, there were an estimated 1.65 million hospitalizations for bronchiolitis among children under age five, for a total of seven million in-patient days.

The rate of births of premature babies is on the rise, providing a growing market for Synagis. Between 1981 and 2001, the annual rate of premature births rose more than 27% (from 9.4% to 11.0%). Prematurity now affects one out of every eight babies. In an average week in the U.S., there are 9,159 babies born before the 37th week of gestation and 1,493 babies are born at less than 32 weeks of gestation.

Blacks and Hispanics in the U.S. both have high rates of premature and low birth weight babies. However, despite the increased risk for RSV, many mothers do not know about RSV. A recent survey conducted by Harris Interactive found that nearly 90% of Black and Hispanic mothers were not aware that RSV is a serious infectious illness that affects infants and young children. Even fewer knew that RSV could put babies with risk factors such as prematurity, low birth weight, or daycare attendance at risk for hospitalization, or worse.

Congenital heart defects are structural problems of the heart that are present at birth, having occurred during development. About 32,000 children are born in the U.S. each year with CHD, of which there are many different types with varying degrees of severity. Children born with serious CHD who have decreased cardiac or pulmonary reserve are at highest risk of serious RSV infection. These children require intensive care and use mechanical ventilation with RSV infection more frequently than children who do not have CHD. Further, children with CHD who are hospitalized with RSV have a fatality rate that is 2-6 times greater than those having RSV without CHD. Synagis is an important preventative option for children with significant CHD.

Market: Worldwide sales of Synagis were $849 in 2003; $668 million in 2002, $516.4 million in 2001, $427 million in 2000, $352 million for the 1999/2000 RSV season, and $227 million for the 1998/1999 season. U.S. sales were $480 million in 2001, and $399 million in 2000.

MedImmune reports sales of Synagis in 2004 are expected to grow only 10% above 2003 levels, to $915.6 million, including $830.4 million in the U.S. and $85.2 million ex-U.S. The slowing growth in sales reflects market saturation, and sales are expected to grow even less in 2005. Friedman Billings Ramsey (FBR) analysts project 2004 sales of $916 million; with 2005 sales of $984.3 million, including $884.6 million in the U.S.

The 2004 Average Wholesale Price (AWP) is $654.59/50 mg vial and $1,311.00/100 mg vial (Red Book, 2004). MedImmune has reported that Synagis provided an ~17%-25% cost savings compared to RespiGam, including the cost of administration of i.v. fluids, influsion pump, and nursing time.

During the 2003/2004 RSV season, an averageof 4.1 doses were administered to each treated infant, with this in line with prior use and showing that new dosing guidelines from the American Academy of Pediatrics (AAP) recommending limiting use to five doses have not significantly affected use of the product.

The launch of Synagis in the 1998/1999 RSV season was the most successful introduction of any biopharmaceutical product to date. MedImmune estimates that Synagis was used in its first season in the U.S. by 15 to 20% of the children who could potentially benefit from its use. Over 150,000 infants received Synagis from its launch in Sept. 1998 through the 1999/2000 RSV season.

Synagis has largely replaced blood plasma-derived Respiratory Syncytial Virus Immune Globulin (RespiGam; RSVIG; entry #495) from MedImmune. Synagis offers a number of advantages over RespiGam. A major advance is that Synagis can be administered by simple intramuscular (IM) injection vs. 2-4 hour intravenous infusion.. Besides the improved safety offered by a recombinant vs. a blood-derived product, Synagis offers improved convenience, requiring only about 1 mL/dose which is administered by simple intramuscular injection, while RespiGam requires 100 mL/dose and intravenous infusion over a four-hour period. For MedImmune, Synagis offers higher profit margins, e.g., the Cost of Goods (COG; manufacturing cost) for RespiGam, which is manufactured by another organization, has been reported to be about 50% while the COG for Synagis is about 10%.

Synagis currently has little or no competition. Aerosolized ribavirin (Virazole) from Ribapharm, a subsidiary of ICN Pharmaceuticals, is marketed in the U.S. for treatment (not prevention) of infant RSV infection, but its use is limited by the prolonged aerosol administration required and safety concerns including potential exposure of pregnant women to ribavirin. No vaccines are available for prevention of RSV.

R&D: MedImmune is developing a next-generation humanized RSV Mab with trade name NuMax, which entered trials in late 2003. Applied Molecular Evolution, Inc. (San Diego, CA) used its SelectAME screening technology to identify molecules with faster association rates and increased potency, compared to palivizumab. MedImmune project U.S. launch in the 2008/2009 RSV season. A Phase I safety and pharmacokinetic trial in 30 healthy volunteers was recently completed. A 160-patient pediatric trial and a safety trial of hospitalized infants are currently (summer 2004) enrolling patients in the Southern hemisphere.

MedImmune concluded an agreement with Alkermes Inc. in June 2000 for the development and licensing of inhaled formulations of palivizumab (or NuMax) using its AIR pulmonary delivery technology.

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