Graftskin - Apligraf; Human Skin Equivalent
Status: approved and marketed in U.S.
Organizations involved:
Organogenesis, Inc. – Manuf.; R&D; Tech.; World mark.
Sandoz Corp. – Former
Novartis Pharmaceutical Corp. – Parent; Former
Massachusetts Inst. of Technology (MIT) – Tech.
Cross ref.: See the entry for Dermagraft (#657), which is also cultured from neonatal foreskin. See also the other cultured skin products.
Description: Apligraf is a cultured, living, dual-layered, membrane human skin equivalent, composed of living human skin components cultured from neonatal foreskin, and designed to mimic human skin in structure, function, appearance and handling. The product is engrafted onto human skin to improve wound healing. The product is bi-layered, like human skin, with both an outer protective epidermis and inner dermis layer, with no polymeric matrix like some other cultured skin products (e.g. Integra Artificial Skin). The primary raw materials for manufacture of Apligraf are human keratinocytes, human fibroblasts, and type 1 bovine collagen.
Apligraf has two primary layers – an outer epidermal layer of living human keratinocytes, and an inner dermis layer of human fibroblasts interspersed in a bovine collagen type I matrix. Apligraf has four active components – a protective outer (after application to the skin) stratum corneum layer, epidermal keratinocytes, dermal fibroblasts, and an inner bovine extracellular collagen matrix/lattice. The upper/overlying cornified epidermal layer (stratum corneum), responsible for maintaining the skin’s permeability barrier, contains live human kera-tinocytes (the most common cell type in human epidermis stratum corneum), which form a well differentiated epidermal layer (cornified, flat, non-nucleated keratinocytes). The lower/inner dermis layer contains the skin’s most common structural protein, collagen (as bovine collagen), and the most common structural cell type in the human dermis, fibroblasts. Matrix proteins and cytokines found in human skin are present in Apligraf, but the product does not contain Langerhans cells, melanocytes, macrophages, lymphocytes, blood vessels, or hair follicles.
Apligraf is manufactured using patented organotypic three-dimensional cell culture technology which allows the cultured cells to self-establish their optimal, human skin-like, three-dimensional arrangement for normal skin function. The source human keratinocytes and dermal fibroblasts in Apligraf are derived from circumcised neonatal foreskin (with full informed consent from parents). Following serial cell culture and expansion, cultured human skin fibroblast cells are dispersed into a matrix of bovine-derived type I collagen, followed by addition of cultured human kera-tinocytes to form a well-differentiated epidermis and an underlying dermal layer. To maintain cell viability, the product is aseptically manufactured, but it is not terminally sterilized. Apligraf is shipped following a preliminary sterility test (like Carticel; see entry above) with a 48 hour incubation to determine the absence of microbial growth. The fibroblasts and keratinocytes for Apligraf are used within their first 2 to 3 in vitro passages. For further manufacturing information, see the manufacture section below. See also “Development of a Bilayered Living Skin Construct for Clinical Applications,” Biotechnol Bioeng. 1994;43:747-756.
Apligraf provides a means of delivering a functional epidermis with a stratum corneum (outer protective layer of cells) plus biosynthetically active fibroblasts within an extracellular matrix in a single procedure (i.e., it provides a living, cultured, equivalent of human skin). Apligraf provides the benefits of transplantation without rejection and donor matching, and without immune suppression treatments. Unlike Epicel (#653), it is not an autologous, custom-Manufactured product meant for use only by the source/donor patient. Apligraf can be engrafted (e.g., laid over leg ulcers) of heterologous patients without rejection, other adverse immunological reactions, and with no requirements for donor tissue matching or immune suppression of recipients. The product is left in place and is not removed after application. Apligraf can be handled like human skin, e.g., it can be sutured, stapled, meshed, and covered with topical antibiotics.
Apligraf sheets can be grown to any size or shape. However, Organogenesis currently packages it as a 3 inch (75 mm) diameter disk (a size familiar to and convenient for surgeons) with a thickness of 0.75 mm. Apligraf single-use sheets are packaged in a tray assembly holding four pieces of Apligraf in agarose medium in an atmosphere containing 10% carbon dioxide (CO2). The product is shipped overnight to surgeons. The tray unit and medium are sterile, further enclosed in a sterile plastic bag, and surrounded with insulation for shipping. Upon receipt, the whole package is placed in an incubator at 35-37˚C. Apligraf has a maximum shelf of 5 days. The agarose shipping medium contains agarose, L-glutamine, hydrocortisone, bovine serum albumin, bovine insulin, human transferrin, triiodothyronine, ethanolamine, O-phos-phoryl-ethanolamine, adenine, selenious acid, Dulbecco’s Modified Eagles Medium (DMEM) powder, HAM’s F-12 powder, sodium bicarbonate, calcium chloride, and water for injection. Bovine-derived components are obtained from countries not known to have cattle infected with BSE/TSE.
Note, Organogenesis also manufactures a related product, GraftPatch (not considered a biopharmaceutical product for this publication), which is regulated as a medical device, receiving 510(k) FDA approval in August 1997. This consists of patches of extracellular matrix material (bovine collagen) for reinforcement of soft tissue.
Nomenclature: Skin, Cultured/Apligraf [BIO]; Apligraf [TR formerly reg. to Novartis, now Organogenesis]; Apligraf Human Skin Equivalent [TR full name]; Graftskin [FDA TR formerly used by Organogenesis]; living skin equivalent [SY]; Human Living Skin Equivalent (HSE) [SY]; tissue engineered, living skin [SY]; HSE [SY]; NDC 09978-0078-99 [NDC]
Graftskin was the original trade name used by Organogenesis. This has been adopted by FDA as the proper name. Graftskin was dropped in favor of Apligraf after multinational market research by Novartis.
Biological.: The ideal skin replacement provides a semipermeable epidermal barrier and contain a supporting dermis to close the wound and prevent contraction and scarring. Living skin grafts act through a variety of mechanisms, including release of growth factors, and need not always “take” to promote healing. Apligraf has many of the properties of an ideal skin substitute. In clinical trials, Apligraf¨ has been shown to be more effective than the previous standard (compression therapy) in closing venous ulcers.
The epidermis, the top thin protective layer of human skin, is nourished by the thicker and more sensitive dermis below. Epidermal keratinocytes provide biologic wound closure and secrete growth factors and cytokines which promote development of new dermal tissue below. The keratinocytes in the epidermis produce the tough protein, e.g., keratin, and lipids that make the skin waterproof. The stratum corneum, the most outer/exposed portion of the epidermis, acts as a natural water-resistant barrier, protects the underlying cells, and provides feedback to the epidermis. As dead, flat, surface epidermal cells wear off, they are replaced by rapidly-dividing kera-tinocytes from the dermis below. The extracellular matrix (structural components) of skin, e.g., collagen, provides structural support for the epidermis, acts as a substrate for cellular ingrowth (e.g., blood vessels), and supports the formation of new tissue. The underlying dermis is primarily composed of fibroblasts and (in normal skin and fully engrafted Apligraf recipients) contains the skin blood vessels, lymph glands, nerves, and fibrous collagen protein (providing flexibility and support). Dermal fibroblasts contribute to the formation of new dermal tissue and support the persistence of the epidermis.
Diabetics can develop deficiencies in their dermis, and their dermis eventually loses its ability to secrete normal skin matrix proteins and growth factors. Skin collagen is abnormal due to non-enzymatic glycosylation of proteins. The glycosaminoglycans (GAGs) of the dermis are abnormal both in content and structure. Growth factor secretion and response are abnormal due to both early senescence of the fibroblasts and down-regulation of growth factor receptors. These factors, combined with venous insufficiency, make diabetics prone to skin extremity, e.g., foot, ulcers.
Apligraf has three-dimensional structure like human skin — a stratum corneum, a granular cell layer, a spinous cell layer, a superbasilar layer, and a basilar layer. However, Apligraf differs from normal human skin in a number of respects. There are no blood vessels, endothelial cells, cells of hematopoietic origin, melanocytes, or lymphocytes. Particularly important, there are no antigen-presenting or Langerhans cells.
Engraftment with Apligraf allows regeneration of true full-thickness skin. The process by which healing occurs in Apligraf-treated patients is not entirely clear. Normal skin wound repair involves timed and balanced activity of inflammatory, vascular, connective tissue, and epithelial cells. Cytokines and growth factors produced by cellular constituents of the skin guide the process, while the extracellular matrix provides a framework for tissue repair. Normal human skin wounds often heal by formation of epithelialized scar tissue, rather than regeneration of true full-thickness skin.
Apligraf does not induce immunological responses. Apligraf does not contain antigen-presenting cells, which are necessary for activation of allogeneic T-cells and tissue rejection. Dedicated antigen-presenting cells of the skin include Langerhans cells, dermal dendritic cells, endothelial cells, and passenger leukocytes. Fibroblasts and keratinocytes usually do not function as antigen-presenting cells and do not activate unprimed allogeneic T-cells, because they do not express HLA class II and common costimulatory molecules, such as B-7, CD-40, and intercellular adhesion molecule (ICAM).
The type I bovine collagen matrix used in Apligraf is composed of heterotrimeric (3 different chain) molecules containing 2‹1 (I) chains and 1‹2 (I) chains. Type I collagen is weakly immunogenic, probably because collagen chains show little interspecies amino acid variability. Apligraf has been transplanted without adverse immune responses across histocompatibility barriers in a number of animal studies.
History: Compression dressings or bandages, originally developed in the 1800s, remain the main therapy for venous leg ulcers. Elastic and nonelastic compression bandages are made and applied in a variety of ways. Autologous split-thickness skin grafting and surgical reconstruction to correct or improve venous abnormalities often succeed where conservative therapy with compression bandages fail, but these procedures generally require hospitalization and are not commonly performed. Topical application of purified growth factors to accelerate the healing of venous ulcers has been studied, but this approach has been largely unsuccessful.
In early skin culture studies, the use of autologous sheets of kera-tinocytes for the treatment of chronic wounds including venous ulcers showed encouraging results. However, these clinical trials were small, and the need for autologous cells impeded further progress. Preparation of autologous keratinocyte sheets, involving culture of the patient’s own skin cells, requires isolation and expansion of cells from an initial biopsy specimen of the patient’s own skin. This takes several weeks, even in the hands of experienced and efficient specialized laboratory personnel (e.g., see Epicel; #653). Also, even when allogeneic cells are used to circumvent some of these problems, the resulting thin keratinocyte sheets may prove difficult to handle and apply to the wound.
In “A Method for Keratinocyte Culture,” Proceedings of the National Academy of Sciences, vol. 76, p. 5665-8, 1979, Dr. E. Bell, et al., Massachusetts Institute of Technology (MIT), and collaborators reported development of bilayer cultured human skin using a contracted collagen matrix and containing living fibroblasts overlaid with epidermal cells, and demonstrated engraftment in rats. Apligraf is based on this method. See also Bell, et al., “Living Tissue Formed In Vitro and Accepted as Skin-Equivalent Tissue of Full Thickness,” in Science. 1981; 211:1052-1054.
Companies.: Organogenesis, Inc developed and manufactures Apligraf. Sandoz AG, now merged into Novartis Pharma AG, obtained exclusive worldwide marketing rights from Organogenesis in Jan. 1996, and is responsible for all sales, marketing, and postmarketing studies. In the U.S., marketing of Apligraf is handled by the Wound Care Business Unit, Novar-tis Pharmaceuticals.
As part of its licensing agreement, Sandoz/Novartis agreed to provide Organogenesis with up to a total of $37.5 million in equity investments, milestone payments, and research support, including an initial $5 million equity investment and additional equity investment of $10.5 million upon achievement of specified milestones. The initial equity investment gave Sandoz (now Novartis) approximately 1.6% of the outstanding shares of Organogenesis. The agreement also provided for manufacturing payments and unspecified royalty revenues. Organogenesis receives two revenue streams from Novartis: a fixed per unit manufacturing payment and royalties based on sales (aside from R&D support, investments and other payments as part of its agreement with Novartis).
In March 2001, the 1996 agreement between Organogenesis and Sandoz/Novartis was modified. This included Organogenesis receiving higher royalty payments for Apligraf units, support for expansion of manufacturing facilities and trials of Apligraf for new indications:, and rights to sell Novartis $20 million in equity over three years, with Novartis obtaining exclusive options to license new living tissue (Vitrix) and dermal replacement products in development.
In Sept, 2002, Organogenesis and Novartis terminated their prior agreement, and Organogenesis filed for Chapter 11 bankruptcy reorganization. During reorganization, Organogenesis suspended sales of Apligraf, continued scaled-down operations (to preserve its cell lines and maintain FDA approval for its manufacturing facility), and searched for financing/partners to assure continued manufacture of Apligraf (i.e., it negotiated with Novartis for it to reacquire/renegotiate rights to Apligraf). Novartis was to continue to market and distribute Apli-graf until June 17, 2003, and would return marketing and distribution rights to Organogenesis after it completes its reorganization. Organogenesis had until Aug. 31, 2003 to complete its reorganization.
Organogenesis’ Chapter 11 bankruptcy reorganization was completed in fall 2003. This included renogotitating its relationship with Novartis. Organogenesis continues to manufacture Apligraf, but now has assumed all marketing responsibilities and assumed the Apligraf trademark from Novartis. From June 2003 to Jan. 12, 2004, Organogenesis contracted with PDI Inc., and PDI InServe (Upper Saddle River, NJ) for the sales, marketing and clinical support functions that had previously been provided by Novartis.
Manufacture: Apligraf is manufactured under aseptic conditions from human neonatal foreskin tissue from circumcised male infants. This tissue is usually discarded after circumcision. One foreskin, about the size of a postage stamp, can be expanded and cultured to produce about 200,000 units of Apligraf or about four acres of skin equivalent. This allows repeated use of preserved, well-characterized cells for consistent product manufacture. The foreskin tissue is treated with antibiotics, antifungals, and an ethanol rinse. The tissue is broken down mechanically and enzymatically dissociated to the cellular level, providing fibroblasts and keratinocytes. The fibroblasts are serially cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% newborn calf serum. Keratinocytes are obtained from either dissociated cells or explant outgrowths that are serially cultured. Prior to preparation of master cell banks, the blood of the infant donor’s mother and the neonatal foreskin tissue are screened for HIV-1, HIV-2, HTLV-1, HTLV-2, hepatitis A virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, syphilis, herpes simplex virus types 1 and 2 (HSV-1; HSV-2), and Epstein-Barr virus.
The fibroblast and keratinocyte cell banks, which are the source of the cells from which Apligraf is derived, are tested for human and animal viruses, retroviruses, herpesviruses, bacteria, fungi, yeast, mycoplasma, karyology, isoenzymes, and tumorgenicity. Each cell bank is also screened for tumor-genicity, chromosomal abnormalities, and genetic/biochemical defects. Upon removal from the master cell banks, cells are rescreened for bacteria, myco-plasma, chromosomal abnormalities, and genetic/biochemical defects. Testing of fibroblast and keratinocyte cell stocks includes: cytopathic effects in a sensitive indicator cell line; he-m-ag-glu-tination or hemad-sorption with red blood cells; in-oculation of suckling and adult mice, guinea pigs, and embryonic hens eggs; and screening for the presence of Langerhans cells (having MHC antigens). All reagents (cytokines, enzymes, etc.) used in manufacture are also screened for pathogens and contaminants.
All bovine materials are obtained from countries (U.S.) free from bovine spongiform encephalopathy (BSE), from a slaughterhouse in compliance with USDA regulations. Product manufacture includes media/reagents derived from animal materials including bovine pituitary extract and other bovine products. All animal-derived reagents are tested for viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma before use. The bovine collagen used in Apligraf is tested for bovine poly-o-mavirus, bovine papillomavirus, and other bovine viruses.
To manufacture Apligraf, the dermal layer is formed first, followed by epidermal layer formation, and development of the stratum corneum. Fibroblasts and keratinocytes are removed from the master cell banks, thawed, and expanded in culture. Organo-typic culture or three-dimensional tissue culture (see also the Tech. transfer section) is performed in three steps:
1) An acidic solution of bovine type I collagen plus neutralizing medium is poured into a flat polycarbonate mold, e.g., a 3 inch (76.3 mm) diameter disk, that later fixes the collagen layer in place to limit lateral contrac-tion and has a porous membrane bottom. The collagen is neutralized, mixed with fibroblasts, and cultured for six days. The mixing of fibroblasts throughout the collagen acts to condense the collagen fibers, reducing the volume of the collagen, squeezing out fluids and concentrating the collagen about 30-fold to form a dense collagen lattice or matt (the underlying dermis component). The gel that forms as a result of collagen polymerization and fluid trapping is contracted uniformly in all dimensions and secured at its ends and edges in the mold in which it is cast. The fibroblast cells are biosynthetically active and enrich the matrix to different degrees with secretory products.
2) A suspension of serially passaged epidermal keratinocytes is poured (seeded) on top of this matrix in minimally supplemented culture medium and left to culture to confluence. This results in formation of consistent sheets of about four kera-tinocyte cell layers on top of the collagen/fibroblast dermal matrix. Distinct epidermal and dermal layers form within four days of incubation.
3) The bi-layered sheet is raised by lowering the level of culture medium, which is replaced with a high-calcium concentration maintenance medium, and the sheet is exposed to a carbon dioxide (CO2)-enriched atmosphere, which promotes stratification and cornification of the epidermis. This leads to full differentiation of the epidermis and formation of the outermost protective layer of the skin (stratum corneum). After about 7-10 days of culture under these conditions at the CO2 atmosphere-liquid interface (i.e., floating on top of the medium), a dermal lattice about 0.5-1.0 mm thick is formed with multiple layers of live keratinocytes in the epidermis and a stratum corneum similar to human skin. The barrier properties of Apli-graf increase with time during culture, reaching a permeability to water of less than 2%-hour after approximately 2 weeks at the air-liquid interface. However, this is still about 30-fold more water-permeable than normal human skin.
Apligraf may be harvested and shipped between days 20 and 31 after start of manufacturing. From days 20-31, it is maintained with a maintenance media, which is replaced with a sterile nutrient containing agarose that maintains product viability during transport and storage. Apligraf may then be stored in cryogenic units under liquid nitrogen and thawed prior to shipping. The final product is tested for morphology, cell viability, epidermal coverage, sterility, mycoplasma, and physical container integrity.
FDA class: Medical device PMA
Approvals: Date = 19980522; first approval, PMA; Indication = for the treatment of non-infected partial and full-thickness skin ulcers
Date = 20000620; supplemental approval; Indication = for use with conventional diabetic foot ulcer care in the treatment of diabetic foot ulcers
Indications: [full text of “INTENDED USE/indications:” section of product insert/labeling]:
Apligraf is indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than 1 month duration and which have not adequately responded to conventional ulcer therapy.
Apligraf is also indicated for use with standard diabetic foot ulcer care for the treatment of full-thickness neuropathic diabetic foot ulcers of greater than three weeks duration which have not adequately responded to conventional ulcer therapy and which extend through the dermis but without tendon, muscle, capsule or bone exposure.
Status: The original Product Marketing Application (PMA) was filed on Oct. 4, 1995, accepted for filing in Dec. 1995, received priority review (target within six months), and approval was granted on May 26, 1998 (review time = ~2.5 years). A supplemental PMA was filed by Organogenesis Inc., for use in diabetic foot ulcers on Dec. 23, 1999.
Organogenesis was the first company to gain major regulatory approval for a manufactured living organ.
Regulatory uncertainties and inconsistencies have made development and approvals for Apligraf and other tissue engineered products difficult. For example, Apligraf (and also TranCyte) is regulated in the U.S. and Canada as a class III medical device, as a medicinal drug in the Europe Union, and as transplant products in Australia and New Zealand. Even after approvals are obtained, problems and delays have been encountered in obtaining reimbursement from government and private health plans.
Tech. transfer: Organogenesis has licensed certain patents from the Massachusetts Institute of Technology (MIT) and pays a royalty ranging from 3%-4.5% on Apligraf sales. Licensed patents include U.S. 4,485,096, “Tissue-equivalent and method for preparation thereof,” and 4,539,716, “Fabrication of Living Blood Vessels and Glandular Tissues,” by E. Bell, assigned to MIT. More recent patents concerning the fabrication and manufacturing process include U.S. 5,536,656 assigned to Organogenesis and including Dr. Bell as an inventor. See also U.S. 4,604,346, “Skin-equivalent prepared by the use of punch biopsy.”
Based on time during clinical trials and FDA regulatory review (under 35 USC §156), the expiration date of U.S. 4,485,096 was extended five years to Nov. 27, 2006.
Critical aspects of the manufacturing of Apligraf include the minimally supplemented basal medium (MSBM), cell culture methods, and contracted collagen gel matrices developed by Orga-nogenesis and MIT. Cells from one well-characterized foreskin can be stored (cryopreserved) and used for manufacture of multiple product lots, for optimal quality and consistency of the product. The defined MSBM has a high calcium concentration (1.88 mM), and allows rapid cell culture expansion and maintenance. MSBM enables maintenance and storage of large numbers of cells, providing a reliable and consistent source of graftable human cells which can be induced to develop a mature epidermis. The MSBM-based method can routinely be used to manufacture over 10 square meters of graftable skin from a single human foreskin in about three weeks. Three passages in culture provide about 1010 (10 billion) cells for cryostorage as a cell bank. Subsequent culture of these cells for one passage increases cell numbers by tenfold, and can produce about 100-200 m2 of living skin equivalent from a single source.
Trials: Results of the pivotal clinical trial supporting original approval were published in “Rapid Healing of Venous Ulcers and Lack of Clinical Rejection with an Allogeneic Cultured Human Skin Equivalent,” Archives of Dermatology, March 1998, p. 293-300. This was a prospective, randomized, multicenter study in the outpatient setting. Each of 293 patients with a lower extremity (leg) venous ulcer for a year or longer due to venous insufficiency randomly received either conventional compression therapy alone or compression therapy plus treatment with Apligraf. The patients were evaluated for Apligraf safety, complete (100%) ulcer healing, time to wound closure, wound recurrence, and immune response. End points were prospectively set at 6 months, with an additional 6 months for further safety evaluation. The average number of Apligraf applications for each patient was 3.34.
The investigators concluded Apligraf provided complete wound closure in one-third of the time of compression therapy alone, without evidence of rejection of or sensitization to Apli-graf antigens. Apligraf-treated subjects enjoyed a greater number of wound-free days than the control-treated subjects, and Apligraf was particularly effective in difficult-to-heal ulcers, including those that were large, deep, or of long duration. The frequency of ulcer recurrence and the number of adverse events did not differ between control and Apligraf groups. Apligraf provided the benefits of transplantation without rejection and donor matching, and without immune suppression treatments.
The cost effectiveness of Apligraf for outpatient treatment of venous ulcers has been studied by Dr. G. Sibbald, Univ. of Toronto. Over 12 weeks, mean time to healing was 56 days for conventional bandage and 26 days with Apligraf. This reduction in time to healing significantly reduced total costs, including the costs for managing infections and complications, physician assessments, nursing care, bandages and dressings, and patients’ lost time. Unlike conventional compression bandage treatment, Apligraf only requires weekly assessments for the first three weeks and intermittent checks thereafter.
Medical: Apligraf is engrafted directly to wounds, much the same as a conventional autologous skin graft. Apligraf is placed over and made to conform to the surface of the ulcer or wound. Excess tissue is trimmed off and a nonadherent dressing is applied over Apligraf, followed by a bolster of folded or rolled gauze or foam. The bolster is immobilized with tape. An elastic wrap is then applied.
Apligraf is able to heal persistent ulcers and wounds that remain unhealed with standard treatment because the living cells in Apligraf actively contribute to wound healing. The product has advantages over other wound covers and grafts. Bandages must rely on the patient’s own wound healing abilities, which can be compromised in persistently unhealed wounds. Autologous cultured skin grafts, e.g., Epicel, require 3-4 weeks for cell propagation and usually lack a functional dermis. Cultured allogeneic keratinocyte grafts act as wound coverings and do not generally cause immunologic reactions, but they lack a dermis, so they are unstable and subject to wound contracture and blistering. Acellular collagen matrices are effective for covering and treatment of burns, but they usually require 2-step applications, and the artificial matrices may inhibit drainage. Apligraf is the first skin construct containing both dermal and epidermal layers and, thus, closely mimics human skin.
Disease: An estimated 14 million individuals worldwide with chronic wounds not responding well to standard treatments may be candidates for Apligraf. This includes patients with diabetic ulcers, pressure sores, burn victims, and individuals undergoing dermatologic surgery for conditions such as removal of skin cancers and birthmarks. Some of these additional indications: are being studied in clinical trials.
Venous ulcers are chronic wounds associated with long-standing venous hypertension of the lower extremities. Ulcerations are the most frequently occurring chronic wounds in the lower extremity. This complication is a potential cause of amputation, and is the most frequent cause of hospitalization among people with diabetes. Approximately 1,000 amputations are performed on people with diabetes each week in the U.S. Venous ulcers are a major cause of morbidity, and their care is costly, require frequent visits to physicians and by visiting nurses, cause loss of productivity in the young and increased frailty in the elderly, require patients to deal with bulky and malodorous dressings, and commonly lead to hospitalization for often life-threatening cellulitis. Until Apligraf, no substantive advances had been made in the way venous ulcers were treated.
In addition to diabetes mellitus, other conditions may lead to impaired wound healing and leg/foot ulcers, including venous insufficiency (especially of the lower limbs) and cerebrovascular accidents. Many of these conditions have a high incidence in elderly people. About 7 million people in the U.S. have chronic venous insufficiency.
Organogenesis estimates about 900,000-1.5 million people in the U.S. and four million globally suffer from venous ulcers. In Europe, the overall prevalence of patients with leg and foot ulceration is between 0.15 and 0.3%, rising to 4.7 - 6% in the population over 65 years of age. In a 1992 study in Australia, the prevalence of chronic ulceration of the leg was 1.1/100,000 population, with venous insufficiency the sole or a contributing cause of 67% cases. Venous ulcers associated with venous insufficiency occur in about 10/1,000 (1%) of persons in the U.S. over age 80. The prevalence of venous ulcers will increase in the U.S. and other developed countries as the population matures.
The incidence of diabetic ulcers is estimated at 600,000-800,000 cases/year in the U.S. (likely an underestimate in view of the increasing age of the population), with about 10% eventually requiring amputation. Up to 15% of diabetic patients develop foot ulcers, leading to 50,000 amputations per year in the U.S. Almost half die or loose the opposite leg within 3 years. Diabetic foot ulcers are conservatively estimated to cost the U.S. healthcare system over $1 billion per year.
Market: The 2007 Average Wholesale Price (AWP) is $1,362.50/sheet (no change from 2004) (Red Book, 2007)
Customers include 1,100 centers having purchased Apli-graf, and over 625 having reordered the product from Novartis. Organogenesis originally projected worldwide sales of about $41 million in 1998, $172 million in 1999, $276 million in 2000 and $317 million in 2001. However, sales have been disappointing, and Organogenesis is only now starting to recover from bankruptcy.
The Medicare outpatient reimbursement price for Apligraf (CMS Hospital Outpatient prospective Payment System, Addendum B Update, effective April 1, 2005) is $1,130.88. In 2004, Medicare reimbursement for Apligraf had increased to $1,199 in the outpatient setting; and office-based setting reimbursement was set at $1,153 per unit. With this increase and financial disincentives removed, clinicians may now base their decisions exclusively on patient necessity, and U.S. sales may be expected to increase.
Competition: Apligraf primarily competes with compression dressing treatment, autologous skin grafts, and other conventional venous insufficiency ulcer treatments, which are generally labor intensive and have other disadvantages. Autologous skin grafting can be effective for treatment of venous ulcers, but is invasive, requires surgery including anesthesia to remove and apply the graft, and can often require six or more months. Besides being more effective than conventional compression, autologous skin grafts and other treatments for chronic leg ulcers, Apligraf does not require harvesting skin from the patient and does not require hospitalization. Apligraf does not require ultra-cold storage facilities or complex thawing regimens – the physician simply schedules the patient, orders the product, and it is delivered ready-to-use.
R&D: In May 2004, Organogenesis began an ambitious clinical development program with Apligraf, targeting eventual FDA approval for three new indications: over the next several years, and initiating several multi-center Phase IV studies to further refine the profile within its existing FDA indications: (venous leg ulcers and diabetic foot ulcers).
Companies involvement:
Full monograph
651 Skin, Cultured/Apligraf
Nomenclature:
Skin, Cultured/Apligraf [BIO]
Apligraf [TR reg. to Novartis]
Apligraf Human Skin Equivalent [TR full commercial name]
Graftskin [FDA TR former, used by Organogenesis]
HSE [SY]
Human Living Skin Equivalent (HSE) [SY]
living skin equivalent [SY]
tissue engineered, living skin [SY]
NDC 09978-0078-99 [NDC]
FDA Class: Medical device PMA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980526
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
human materials used<!-- humansource -->
skin replacements
adenine
agarose
albumin, bovine serum
bovine insulin
bovine serum albumin (BSA)
calcium chloride
carbon dioxide
cells, human <!-- humancellculture -->
collagen matrix, bovine
Dulbecco's Modified Eagles Medium (DMEM)
fibroblasts, human
glutamate
HAM's F-12 medium
high-calcium medium
human fibroblast cells
human keratinocytes
human neonatal foreskins
human transferrin
hydrocortisone
insulin, bovine
Kawasaki Syndrome
mammalian cell culture
minimally supplemented basal medium (MSBM)
O-phosphorylethanolamine
polycarbonate molds
selenious acid
stratum corneum, human
three-demensional cell culture
tissue culture, three-dimensional
transferrin, human
triiodothyronine
albumin, bovine
bovine collagen
bovine extracellular collagen matrix
bovine pituitary extract
bovine serum albumin (BSA)
carbon dioxide (CO2 gas; dry ice)
ethanolamine
nitrogen (gas and liquid)
pituitary extract, bovine
serum, fetal calf
sodium bicarbonate
stratum corneum
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
Park-William no. 8, Corynebacterium diphtheriae
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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