Becaplermin Concentrate - platelet-derived growth factor, recombinant, for further manufacture
Status: an intermediate; not marketed
Organizations involved:
Chiron Corp. – Manuf.; R&D; Tech.
Novartis AG – Parent
OMJ Pharmaceuticals, Inc. – Manuf. other
Johnson & Johnson Co. – Parent
Washington Research Foundation (WRF) – Tech.
University of Washington – Tech.
Genentech, Inc. – Tech.
City of Hope National Medical Center – Tech.; Patent dispute.
ZymoGenetics, Inc. – Tech
Bristol-Myers Squib (BMS) – Parent
Novo Nordisk A/S – Parent; Former
Cross ref.: See the entry (#239) below for Becaplermin Gel (Regranex), which is manufactured from this intermediate.
Description: As more fully described in the Becaplermin Gel (Regranex) entry, becaplermin is recombinant platelet-derived growth factor (PDGF) B chain homodimer (rPDGF-BB) expressed in Saccharomyces cerevisiae (yeast) cells. Becaplermin is a homodimer, i.e., composed of two identical PDGF B chain polypeptide chains, each composed of 109 amino acids, linked covalently by disulfide bonds. Becaplermin has a molecular weight ~25 kDa.
Becaplermin Concentrate is rPDGF-BB manufactured by Chiron Corp. used exclusively as an intermediate for further manufacture of Becaplermin Gel by OMJ Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson Co. (J&J), marketed as Regranex in the U.S. by Ortho-McNeil Pharmaceutical, Inc., a J&J subsidiary.
Nomenclature: PDGF, rDNA conc. [BIO]; Becaplermin concentrate [FDA]; platelet-derived growth factor B, recombinant [CAS]; 165101-51-9 [CAS RN]; becaplermin [SY]; PDGF [SY]; rPDGF [SY]l rhPDGF-BB [SY]
Biological.: See the entry below for Becaplermin Gel (Regranex), which contains the same active agent, becaplermin (rhPDGF-BB), as GEM21S. Becaplermin has biological activity similar to endogenous human platelet-derived growth factor (PDGF). This includes promotion of chemotactic recruitment and proliferation of cells involved in wound repair, including bone precursor cells.
Companies.: Becaplermin concentrate was originally developed and is manufactured by Chiron Corp., CBER/FDA est. no. 1106. Chiron merged into Novartis AG in Oct. 2005. Becaplermin concentrate is used by OMJ Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson Co., for the manufacture of Becaplermin Gel (Regranex). It appears that Chiron receives about 50% or higher royalties from McNeil/J&J sales of Regranex
Becaplermin concentrate is manufactured at Chiron now Novartis, microbial manufacturing facilities in Vacaville, CA, apparently using the facility's 20,000 L bioreactor.
FDA class: Biologic BLA
CBER class: Biological Response Modifiers
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19971216; first approval, BLA
Indications: Becaplermin Concentrate is approved only for use in the manufacture of becaplermin (Manufactured by OMJ Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson Co.)
Status: The BLA was submitted on Dec. 16, 1996 and approved on Dec. 16, 1997 (review time of 12.0 months; 1.0 year).
Tech. transfer: Patents covering aspects of rPDGF-BB, licensed by Chiron, include U.S. 4,845,075, “Biologically active B-chain homodimers,” July 4, 1989, assigned to ZymoGenetics, Inc., then a subsidiary of Novo Nordisk A/S, later an independent company, now part of Bristol-Myers Squib (BMS; acquired in Oct. 2010); and U.S 5,045,633, “Expression of biologically active PDGF analogs in eucaryotic cells.”
Chiron has received rPDGF-BB patents, including U.S. 6,083,910, “Therapeutic uses of resolved intact or clipped native-sequence PDGF-BB dimers,” with claims including with at least about 80% of the PDGF-BB dimers being intact isoforms, single-clipped isoforms, or a mixture; and use for wound healing, including burns, ulcers, surgical wounds, and bone injuries.
Due to the time spent in FDA regulatory review (under USC §156), the expiration date of 4,845,075 was extended 1,578 days (4.32 years) to Oct. 29, 2010, with applying to both becaplermin concentrate and Regranex.
Yeast expression system technology used for manufacture was developed by the University of Washington and Genentech, Inc., and has been nonexclusively licensed to Chiron by the Washington Research Foundation (WRF), the licensing agent for this family of yeast expression patents. The patents, particularly the more recent ones, broadly claim processes and materials for expression of proteins in yeast. Patents include U.S. 5,854,018 and 5,856,123 (continuations of 5,618,676) concerning recombinant production of proteins in yeast expression systems including Saccharomyces, Kluyveromyces, Pichia and Hansenula. U.S. patent coverage expires in 2014.
The University of Kentucky has received U.S. patent with claims for PDGF BB homodimer expression in Pichia pastoris (yeast).
As discussed in the Recombinant DNA Product entry (at the beginning of this section), Genentech is appealing a $500+ million award to the City of Hope Medical Center (COH) arising from a 1976 contract and patent licensing dispute involving COH developing basic cloning technology for Genentech. Genentech is appealing to the California State Supreme Court.
Companies involvement:
Full monograph
238 PDGF, rDNA conc.
Nomenclature:
PDGF, rDNA conc. [BIO]
Becaplermin concentrate [FDA]
Platelet-derived growth factor B, recombinant [CAS]
165101-51-9 [CAS RN]
Becaplermin [FDA USAN INN]
PDGF [SY]
rhPDGF-BB [SY]
rPDGF [SY]
FDA Class: Biologic BLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19971216
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
growth factors, hematopoietic
intermediate/precursor products
recombinant DNA
yeast source materials
Saccharomyces cerevisiae (yeast)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
North American coral snake
Park-William no. 8, Corynebacterium diphtheriae
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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