Infasurf; bovine lung surfactant
Status: approved; marketed
Organizations involved:
ONY, Inc. – Manuf.; R&D; Tech.
Forest Pharmaceuticals, Inc. – USA mark.
Abbott Laboratories – Patent dispute
Mitsubishi-Tokyo Pharm. Co. – Patent dispute
Cross ref.: See Lung Surfactant Products (#940).
Description: Infasurf is an aqueous formulation of an organic solvent extract of bovine lung surfactant obtained by postmortem cell-free bronchoalveolar lavage (washing) of the lungs of calves followed by solvent-extraction purification. Infasurf is extracted using a chloroform-methanol-water separation process. Infasurf is a 35 mg/mL suspension containing: surfactant proteins (SP-B, 260 µg/mL; SP-C, 390 µg/mL), 1-3%; cholesterol, 5%; unsaturated phospholipids, 52%; dipalmitoyl-phos-phat-idyl-choline (DPPC), 40%; and palmitic acid, ≤ 2%. Infasurf is supplied sterile in single-use, rubber stoppered glass vials containing 6 mL off-white suspension at pH of 5.0-6.2 (target pH = 5.7).
The protein content and properties of Infasurf are similar to that of human lung surfactant. The surfactant protein most abundant in human lung surfactant, SP-A, is removed by the solvent extraction process. This lack of SP-A is adjusted for by mechanical dispersion (agitation, mixing) of the aqueous phase which results in properties (adsorption and dynamic surface activity) approaching that of endogenous human lung surfactant. Infasurf contains hydrophobic, chloroform-soluble lipids (92% phospholipid, 5% cholesterol) and proteins (1-3% surfactant proteins SP-B and SP-C). About 40% of the protein content is bovine SP-B by weight, with 60% as SP-C. SP-B and SP-C are the only peptide chains present. Infasurf is stored at 2-8˚C (refrigerated).
SP-B has a molecular weight of 6-8 kDa and SP-C of 3.7 kDa. These relatively small proteins are highly hydrophobic and have a high affinity for phospholipids. SP-B and SP-C increase the adsorption of DPPC and other phospholipids to the air-water interface in the bronchial alveoli. The proteins also facilitate the movement of gases within the interfacial film on the inner surface of lung alveoli. The composition of phospholipid head groups in calf lung surfactant are phosphatidylcholine, 82%; phosphatidylglycerol, 6%; phosphatidylethanolamine, 3%; phosphatidylinositol, 3%; sphingomyelin, 1%; and unknown, 5%.
Infasurf is prepared from postmortem lavage material of newborn calves bred solely in the U.S. All calves are less than 14 days of age when slaughtered. No microorganisms survive the solvent extraction process. The calves are not exposed to sources (e.g.,. animal feeds) that might transmit bovine spongiform encephalopathy (BSE).
Note, derived from dead tissue, with no live organisms or bioprocessing involved, Calfactant is not considered by this author to be a biopharmaceutical.
Nomenclature: Infasurf [TR]; calfactant [FDA]; bovine lung surfactant [SY]; NDC 0456-4600-06 [NDC]
Companies.: Calfactant was originally developed in the early 1980s by three physicians from western New York, Drs. E. Egan, R. Notter and D. Shapiro. Dr. Egan formed ONY, Inc. in 1985 to pursue commercialization of calfactant. Calfactant is manufactured by ONY, Inc. It is exclusively marketed in the U.S. by Forest Pharmaceuticals, Inc., which licenced marketing rights in 1991.
FDA class: Drug NDA
Approvals: Date = 19980702; first approval, NDA 20-521
Date = 20021202; NDA supplement; Indication = addition of 3 mL vial size and change of acceptance criteria for pH from 5.0-6.0 to 5.0-6.2 (target pH = 5.7)
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling]:
Infasurf is indicated for the prevention of Respiratory Distress Syndrome (RDS) in premature infants at high risk for RDS and for the treatment (“rescue”) of premature infants who develop RDS. Infasurf decreases the incidence of RDS, mortality due to RDS, and air leaks associated with RDS.
Prophylaxis: Prophylaxis therapy at birth with Infasurf is indicated for premature infants < 29 weeks of gestational age at significant risk for RDS. Infasurf prophylaxis should be administered as soon as possible, preferably within 30 minutes after birth.
Status: The NDA was originally submitted on March 13, 1995. Due to orphan drug considerations for already-approved Survanta, the NDA filing was denied (refusal to file letter issued) on May 10, 1995, with FDA considering Infasurf and Survanta to be the “same” drug for purposes of orphan exclusivity and lack of clinical data showing superiority for Infasurf vs. Survanta. Ony and FDA met on July 6, and Ony presented data indicating that the products were different, with Infasurf containing higher levels of surfactant-associated protein B (SP-B) and that SP-B levels in Survanta were so low as to be inactive. On July 13, FDA allowed Ony to refile, based on submission of its SB-P data and redacted (censored by FDA) clinical studies, but obviously studies comparing the two products. On July 15, Ony refiled the NDA including this requested data [apparently, already having completed comparison trial(s), but not having submitted this as part of the original filing]. Howver, in April 1996, FDA informed Ony that the Infasurf and Survanta were to be considered the “same” (essentially generics) drug, and that Infasurf could not be approved until Survanta’s orphan exclusivity expired in July 1998. Ony was also encouraged to further differentiate the active components of Infasurf from those of Survanta. Ony pursued approval under these conditions, received an approvable letter on June 25, 1996, but encountered delays due to manufacturing facility inspection problems. Infasurf was eventually approved after expiration of Survanta’s orphan exclusivity; with its own orphan status as a new, unique product for an orphan indication (granted 9/5/2000).
Infasurf is marketed in various European and other countries.
Medical: Infasurf treatment is used with infants ≤ 72 hours of age with RDS (confirmed by clinical and radiologic findings) and requiring endotracheal intubation. Calfactant is more potent than Survanta in terms of lowering surface tension and assisting respiration. Despite differences between Survanta and Infasurf, only a modest difference in efficacy in the acute phase of RDS was observed in a comparative clinical trial.
Tech. transfer: U.S. patent 6,020,307, Egan, et al., Compositions and methods for isolating lung surfactant hydrophobic proteins SP-B and SP-C, February 1, 2000, assigned to ONY, “describes compositions of biologically active surfactant proteins SP-B and SP-C of high purity and high-yield methods for isolating SP-B and SP-C.”
In 2001, a patent infringement suit filed by Abbott Labs. and Tokyo Tanabe Co., Ltd., now Mitsubishi-Tokyo Pharmaceuticals, was successfully defended by Forest Labs. and ONY, Inc. Abbott and Tokyo Tanabe alleged that Infasurf infringed two Tokyo Tanabe U.S. patents exclusively licensed to Abbott, including U.S. 4,338,301, covering Survanta (see the Infasurf entry above, particularly the Tech. transfer section). FDA approval for Infasurf was granted while this suit was ongoing. In Feb. 2002, the Court of Appeals for the Federal Circuit affirmed a U.S. District Court ruling of noninfringement. Infringement of the first claim largely depended on interpretation of whether residual water in the formulation was merely a reference point for determining the concentration of other components and needed to be measured and taken into account or not. The court found that residual water needed to be measured along with other components, accepted the claim as granted, and ruled no infringement. [See Modern Drug Discovery, July 2001, p. 51-4].
Market: The 2007 Average Wholesale Price (AWP) is $413.64/3 mL vial and $732.12/6 mL vial (unchanged since 2004) (Red Book, 2007).
Companies involvement:
Full monograph
942 Calfactant
Nomenclature:
Infasurf [TR]
calfactant [FDA]
bovine lung surfactant [SY]
lung surfactant, bovine [SY]
NDC 0456-4600-06 [NDC]
FDA Class: Drug NDA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980702
(in format YYYYMMDD)
Index Terms:
bovine materials used<!-- bovinesource -->
bovine materials used<!-- bovinesource -->
lung surfactants
non-Hodgkin's lymphoma (NHL)
calves, postmortem lung lavage
bovine lung surfactants
chloroform
cholesterol
dipalmitoylphosphatidylcholine (DPPC)
methanol
palmitic acid
phospholipids
surfactant protein B (SP-B)
surfactant protein C (SP-C)
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
Copyright© 2020, Biotechnology Information Institute