Becaplermin - Regranex; Platelet-derived growth factor, recombinant; PDGF-BB
Status - approved; marketed
Organizations involved:
Healthpoint Biotherapeutics – R&D; Tech.; World mark.
DFB Pharmaceuticals Inc. – Parent
Systagenix Inc. – Former
Ortho Biotech Inc. – Former
OMJ Pharmaceuticals, Inc. – Manuf.
Ethicon, Inc. – Former
Johnson & Johnson Co. – Parent; Former
Knoll Pharmaceutical Co.– Former
Abbott Labs. – Parent; Former
Chiron Corp. – Manuf. other
Novartis AG – Parent
Janssen Pharmaceutica N.V. – Former
Cross ref.: See also the entry above for Becaplermin Concentrate from Chiron Corp., the source/intermediate material for manufacture of becaplermin (Regranex).
Description: Regranex is a topical aqueous gel formulation of recombinant becaplermin (rPDGF-BB) or two cross-linked platelet-derived growth factor (PDGF) B glcoprotein chains produced in a transformed Saccharomyces cerevisiae (yeast) cell line. Becaplermin is a homodimer composed of two identical antiparallel PDGF B chain polypeptide chains, each chain composed of 109 amino acids, linked covalently by two disulfide bridges at cystein residues 43 and 52. Post-translation modifications, including glycosylation, results in a mixture of homodimer rPDGF-BB species. Becaplermin has a molecular weight of approximately 24.5 kDa. Regranex Gel is manufactured from Becaplermin Concentrate (rPDGF-BB; see entry above) manufactured by Chiron Corp.
Regranex Gel is a non-sterile, low bioburden, colorless to straw-colored, gel packaged in 2, 7.5 (withdrawn in U.S. in 2005), and 15 gram tubes for topical application. The gel contains becaplermin at a concentration of 100 µg/gram (0.01%) formulated in an inert 0.01% sodium carboxymethylcellulose (NaCMC) water-based gel. Other inactive ingredients (excipients) in the U.S .formulation are sodium chloride; sodium acetate trihydrate; glacial acetic acid; Water for Injection; methylparaben, propylparaben, and m-cresol as preservatives (because it is a non-sterile, multi-use product); and l-lysine hydrochloride as a stabilizer. The European Product Assessment Report (EPAR) for Regranex reports another excipient in the European formulation - carmellose sodium. The gel is filled into tubes with a polyethylene liner.
Nomenclature: PDGF, rDNA/J&J [BIO] Regranex [TR] becaplermin [FDA USAN INN]; platelet-derived growth factor B, recombinant [CAS]; 165101-51-9 [CAS RN]; rhPDGF [SY]; PDGF [SY]; CTAP-III [SY]; RWJ 60235 [SY]; rPDGF-BB [SY]; rhPDGF-BB [SY]; PDGF-BB [SY]; NDC 0045-0810-02; NDC0045-0810-07; NDC 0045-0810-15 [NDC]
Biological.: Native human platelet-derived growth factor (PDGF) consists of two peptide chains, designated A and B. Human platelets contain all three isoforms of becaplermin - AA, BB (becaplermin) and AB. PDGF is present in low or undetectable levels in normal cells, but its expression level can be increased by factors released at the site of an injury (e.g., TGF-beta, TNF-alpha, and thrombin). PDGF receptors are found on mesenchymal cells, including fibroblasts, osteoclasts, chrodroblasts, smooth muscle cells, glial cells and some leukocytes and endothelial cells. A variety of tumor cells also present the PDGF receptor. Besides being mitogenic or inducing other factors with mitogenic activity, PDGF also is involved in cell-directed migration, cheomtaxis, modification of the cellular matrix and constituents, and vasodilation. PDGF activates mesenchymal cells to secrete collagen and collagenase, mediating wound healing and tissue repair.
PDGF-B has been shown to increase granulation tissue thickness, but not other factors involved in wound healing, and has little effect in most models of wound healing. Increased tissue granulation may explain becaplermin’s efficacy for treating diabetic ulcers.
PDGF and becaplermin act as cellular growth factors. Becaplermin has biological activity similar to and mimics endogenous human PDGF This includes promotion of chemotactic recruitment and proliferation of cells involved in wound repair. Native PDGF and becaplermin stimulate the migration of cells to the ulcer site, encouraging the body to grow new tissue that heals these open wounds.
Wound healing involves three phases: 1) inflammation – blood clots form, bacteria are attacked, and there is an orderly recruitment of key cells into the wound site; 2) proliferation – cells necessary for wound closure proliferate at the wound site to make new tissue and capillaries (“granulation” tissue); 3) remodeling – the wound is healed and the initial scar tissue is restructured. Many cell types are involved in wound healing, e.g., platelets, macrophages, and fibroblasts.
Platelets are the first cell components to invade the wound site and initiate the wound healing process by releasing growth factors, e.g., PDGF, which act as cytokines (proteins that act as intercellular signals allowing cells to communicate with one another). Growth factors are a subclass of cytokines that specifically stimulate the migration and proliferation of cells and synthesis of new tissues. PDGF and other growth factors are involved in all phases of wound healing. PDGF and other growth factors involved in wound healing attract useful cells and proteins to the wound, including immune cells to fight infection and other cells to form connective tissue; stimulate and increase production of connective tissue; and induce a new blood vessels (angiogenesis) to nourish the site.
Platelet-derived growth factor (PDGF) is a product of platelets and other cell types as well, including macrophages and endothelial cells. The function of PDGF is most evident at the proliferation stage in open wounds where granulation begins. Upon release at the wound site, PDGF stimulates migration and proliferation of cells important to the wound healing process, so that the wound fills with healthy tissue. Becaplermin exerts its biological activity in vitro in the range of 0.2 to 10.0 ng/ml.
Companies.: Regranex Gel was developed by the R.W. Johnson Pharmaceutical Research Institute (Ortho Biotech), a subsidiary of Johnson & Johnson Co. (J&J) Regranex Gel is manufactured by OMJ Pharmaceuticals, Inc., a subsidiary of J&J, in San German, PR; FDA CBER est. no. 0683. Regranex Gel is manufactured from Becaplermin Concentrate manufactured by Chiron Corp., and supplied to OMJ Pharmaceuticals under a shared manufacturing agreement. Chiron merged into Novartis AG in Oct. 2005.
Regranex was formerly co-marketed in the U.S. by Johnson & Johnson Wound Management, a division of Ethicon, Inc., a J&J subsidiary; and Knoll Pharmaceuticals, a subsidiary of Abbott Labs. Regranex was marketed internationally by J&J affiliates, with marketing in Japan handled by Fujisawa Pharmaceuticals, Inc., Ltd. In spring 2005, Fujisawa completed its merger with Yamanouchi Pharmaceutical Co. Ltd.. forming Astellas Pharma Inc. Regranex Gel is marketed in Europe by Janssen-Cilag NV, a subsidiary of Johnson & Johnson. Prior to March 2003, Regranex was co-marketed in the U.S. by Johnson & Johnson Wound Management and Ortho-McNeil Pharmaceutical, Inc., another J&J subsidiary.
In late 2008, Systagenix acquired Regranex Gel and related patents.
In June 2011, Healthpoint Biotherapeutics, a subsidiary or DFB Pharmaceuticals, Inc., acquired Regranex Gel, along with the corresponding intellectual property (including patents), from Systagenix.
Manufacture: Bulk rPDGF-BB (becaplermin) is manufactured at Chiron facilities in Vacaville, CA, and shipped to Chiron facilities in Emeryville, CA, for purification, concentration and filtration. This bulk is shipped to OMJ Pharmaceuticals, a subsidiary of Johnson & Johnson where the finished product is manufactured. Packing and labeling for the European market is performed by Cilag AG (Schaffhausen, Switzerland), subsidiary of Johnson & Johnson
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 (103691)
Date = 20050513; BLA supplement; Indication = add information to insert regarding venous stasis and pressure ulcers; add a Geriatric Use subsection; and withdrawal of 7.5 gram dose
Date = 20080606; BLA supplement; Indication = added information about cancer risk to product insert/labeling
Date = 20081006; BLA supplement; Indication = added information about increased risk of mortality, including a boxed warning
Date = 20111103; BLA supplement; Indication = apparently, a labeling modification (unspecified by FDA)
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling]:
Regranex is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. When used as an adjunct to, and not a substitute for, good ulcer care practices including initial sharp debridement, pressure relief and infection control, Regranex increases the incidence of complete healing of diabetic ulcers.
The efficacy of Regranex for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue (Stage I or II, IAET staging classification) or ischemic diabetic ulcers has not been evaluated.
Status: The BLA was submitted on Dec. 16, 1996, received standard review, and was approved on Dec.16, 1997 (review time = 12.0 months; 1.0 year). The product was launched in the U.S. on April 16, 1998.
European Union approval was granted on March 29, 1999 to Janssen-Cilag NV.
On March 27, 2008, FDA issued an Ongoing Safety Review Communication for Regranex Gel based on study data suggesting there may be an increased risk of death from cancer in diabetic patients using Regranex Gel. This followed a long term safety study completed in 2001, where it was noted there were more cancers in people who used Regranex than in those who did not use it. A new study was performed using a health insurance database that covered the period from Jan. 1998 through June 2003. These data come from a retrospective study that compared cancer incidence and cancer mortality among 1,622 patients exposed to Regranex to 2,809 otherwise similar patients who were not exposed. The results were consistent with no overall increase in cancer incidence among the patients exposed to Regranex. However, there was a five-fold increased risk of cancer mortality in the group exposed to three or more tubes of Regranex. No single type of cancer was identified, but rather deaths from all types of cancer, combined were observed.
On June 6, 2008, FDA addes a boxed warning to the label of Regranex Gel to address the increased risk of cancer mortality in patients who use three or more tubes of the product.
In June 2010, the Committee for Medicinal Products for Human Use (CHMP) , European Medicines Agency, European Union, ruled that Regranex must not be used in patients who have any form of cancer. A similar restriction previously applied but only for patients who had a skin cancer close to the area where the gel was to be applied. The CHMP noted that while there was no firm evidence of a link between Regranex and cancer, there was also not enough evidence to rule out such a link.
Tech. transfer: See the entry above for PDGF, rDNA conc. for information about rhPDGF-BB patents and licensing.
The product insert cites U.S. 5,457,093, “Gel formulations containing growth factors,” Oct. 10, 1995, assigned to Ethicon, Inc., a subsidiary of Johnson & Johnson. This describes recombinant PDGF-BB stabilized gels providing a delivery system for treating wounds. In example 8, pharmaceutical grade sodium carboxymethylcellulose (CMC; Aqualon Co.) at a 1% concentration and a molecular weight of about 700 kDa is used to form a gel and stabilize PDGF-BB. Adsorption of PDGF-BB by the gel apparently involves the entrapment of the highly positively charged PDGF BB homodimer (containing 22 arginine residues and 14 lysine residues) within the negatively charged CMC matrix, which contains a large number of free carboxyl groups. An increase of PDGF stability in CMC gel is accomplished by minimizing its interaction with the reducing ends of the CMC by addition of competing positively or negatively charged counterions, e.g., lysine (0.5% w/w) which increases stability in CMC by more than 50%.
Due to the time spent in FDA regulatory review (under USC §156), the expiration date of this patent was extended 1,578 days (4.32 years) to Oct. 29, 2010. This extension is officially reported as applying to both becaplermin concentrate and Regranex.
Due to the time in European Union (EU) review, similar to the extension of the U.S. patent expiration date, the EU has granted Johnson & Johnson a SPC extending the expiration date of its patent, EP177957, to Oct. 9, 2010.
Trials: Clinical trials show that daily topical application of Regranex Gel as an adjunct to good ulcer care (including removal of dead tissue, daily dressing changes, pressure relief, and treatment of infection, if present) heals more serious diabetic ulcers (that extend into the subcutaneous tissue or beyond and have an adequate blood supply) than placebo gel plus good ulcer care. Regranex Gel is well tolerated. In trials, side effects were similar to placebo gel and/or good ulcer care alone. Regranex Gel has not been studied in superficial diabetic foot ulcers.
Chiron Corp. in fall 1999 suspended enrollment in a Phase III trial of becaplermin gel for the treatment of pressure ulcers after an interim data analysis did not support efficacy (as had been reported in a Phase II trial).
In the Nov.-Dec. 2005 edition of Wound Repair and Regeneration, results were published concerning the effectiveness of Regranex in actual clinical practice. Diabetic neuropathic foot ulcers treated with Regranex were 32% more likely to heal within 20 weeks than those treated by other methods (802/2394 vs 5806/22504). This retrospective patient cohort study utilized a claims database to evaluate more than 24,000 patients with neuropathic diabetic foot ulcers who were treated at specialty wound clinics between 1998 and 2004. These results were similar to the results of previous randomized controlled trials of Regranex Gel.
Regranex Gel has not been evaluated for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue (Stage I or II, IAET staging classification) or ischemic diabetic ulcers.
Disease: Foot ulcers commonly develop among persons with diabetes. These wounds extend through the top layer of skin, sometimes deep into the tissue. Foot ulcers often go undiagnosed since other ailments associated with diabetes, such as nerve damage and vision problems, may make it difficult for patients to feel or see the ulcer, and/or patients with other severe symptoms may not seek treatment for foot ulcers. Complications of foot ulcers can include infection, hospitalization and, in some cases, amputation.
Among the more than 16 million individuals with diabetes, 15% develop foot ulcers at some point in their lifetime. Over two million people with diabetes will develop foot ulcers during their lifetime. According to the National Institutes of Health (NIH), more than 67,000 people undergo lower limb amputations each year due to diabetes.
Medical: Regranex Gel is applied daily until the ulcer heals. The gel is applied topically to ulcers using a formulae/charts provided in the product insert to determine dosage. Each square inch of ulcer surface requires an ~0.6 inch length of gel squeezed from a 15g or 7.5g tube, or ~ 1.3 inch length of the gel from the 2g tube. For example, if the ulcer measures 1 x 2 inches, a 1-1/4 inch length of gel should be used for 15g or 7.5g tubes (1 x 2 x 0.6 = 1.25) and 2-3/4 inch gel length should be used for the 2g tube (1 x 2 x 1.3=2.75). The weight of Regranex Gel from 7.5g and 15g tubes is 0.65g per inch length. This should cover the ulcer with a 1/16th inch coating of gel.
Market: Johnson & Johnson does not report annual sales of Regranex. Total sales of Regranex were reported to have been about $160 million in 2004, and were $72 million in 1999. Sales were expected to increase.
The author’s rough/crude guess for 2006 sales is in the range of $250 million.
The 2007 Average Wholesale Price (AWP) is $585.792/15 gr tube, with a Direct Price (discount price) of $5321.09 (Red Book, 2007). The 2005 AWP was $537.42/15 gr tube ($511.92 in 2004).
Companies involvement:
Full monograph
239 PDGF, rDNA/J&J
Nomenclature:
PDGF, rDNA/J&J [BIO]
Regranex [TR]
Becaplermin [FDA USAN INN]
Platelet-derived growth factor B, recombinant [CAS]
165101-51-9 [CAS RN]
CTAP-III [SY]
PDGF [SY]
PDGF-BB [SY]
rhPDGF-BB [SY]
rPDGF [SY]
RWJ 60235 [SY]
NDC 0045-0810-02; NDC0045-0810-07; NDC 0045-0810-15 [NDC] [NDX]
molecular weight (kDa) = 24.5
FDA Class: Biologic BLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19971216
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2012, based on 5,457,093; 4,845,075 had been extended to Oct. 2010 |
U.S. Patent Expiration Year: | 2012 |
U.S. Biosimilars Data Exclusivity Expiration: | 2009 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2004 |
U.S. Biosimilars Launchability Year: | 2012 |
U.S. Biobetters Launchability Year: | 2012 |
Biosimilars/biobetters-related EU Patents: | 2011, based on EP 0539523; 2010, based on an SPC for EP177957; 2011 (based on EP 0539523) |
EU Patent Expiration Year: | 2011 |
EU Biosimilars Data Exclusivity Expiration: | 2009 |
EU Biosimilars Orphan Exclusivity Expiration: | 2009 |
EU Biosimilars Launchability Year: | 2011 |
EU Biobetters Launchability Year: | 2011 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
recombinant DNA
yeast source materials
Saccharomyces cerevisiae (yeast)
acetic acid
cresol, meta-
lysine hydrochloride
methylparaben
propylparaben
sodium acetate
sodium carboxymethylcellulose
sodium chloride
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
Park-William no. 8, Corynebacterium diphtheriae
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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