BBI Contributing Editor

BOSTON, Massachusetts Rodman & Renshaw (New York) hosted the 5th annual Techvest Healthcare Conference here in the latter part of October, which encompassed a broad range of public and private pharmaceutical and biomedical product companies. Key areas were biomaterials for use in hard- and soft-tissue repair and as surgical accessories, stem cells for tissue and organ regeneration, and drug delivery technologies. Reviews of selected presenting companies are provided below with emphasis on recent developments.

Allografts for orthopedic applications:

Regeneration Technologies (Alachua, Florida) processes human musculoskeletal tissues which include bone, cartilage, tendon, ligament, pericardial and cardiovascular tissues. The allograft tissues are used to repair a wide range of bone and other tissue defects and are supplied in a variety of forms, including pastes, blocks, wedges and dowels.

The company's BioCleanse tissue preservation process is an innovation in tissue safety that allows for a sterile claim. It is a chemical and mechanical process that does not use excessive heat, irradiation or ethylene oxide.

Musculoskeletal Transplant Foundation (MTF; Edison, New Jersey), a leading supplier of demineralized bone matrices, is collaborating with Aastrom Biosciences (Ann Arbor, Michigan) to jointly develop treatments for the regeneration of bone and cartilage using Aastrom's stem cell technology.

MTF is the exclusive distributor of ceramic products from Switzerland's medArtis and has an agreement with Vertebron (Stratford, Connecticut) for product development and distribution of specific tissue allografts.

Biodegradable polymers for sealants, tissue repair, adhesion barrier and surgical aids:

Protein Polymer Technologies (San Diego, California) processes genetically engineered biomaterials into products with physical and biological characteristics matched to specific clinical requirements. The company is currently developing protein polymers to be used for surgical adhesives and sealants, soft tissue augmentation, wound healing and drug delivery devices, and has licensed its technology to Spine Wave (Stratford, Connecticut) for use as an injectable nucleus for spinal disc repair.

Products in clinical trials include a self-assembling silk-elastin hydrogel for treating female urinary stress incontinence and a dermal filler for repair of contour deficiencies.

Confluent Surgical (Waltham, Massachusetts) has developed an in situ polymerization process for transforming two streams of aqueous solutions into solid polymers. The resulting biocompatible polymers are hydrogels and can be used to reduce post-surgical scar formation and as surgical sealants.

The company's lead product, SprayGel, is an adhesion barrier for use after abdominopelvic surgery and is marketed in Europe and Australia. It is being evaluated in clinical trials in Europe for additional gynecological procedures, namely, hysteroscopic surgery and endometrial ablation.

DuraSeal, a surgical sealant, is sold in several European countries to seal cerebrospinal fluid leakage after cranial and spinal surgeries. It is in clinical trials in the U.S. and is being evaluated as a sealant in cardiac and vascular surgeries and for potential use as an adhesion barrier in spine surgery.

Fziomed (San Luis Obispo, California) has developed absorbable barrier adhesion products based on its Oxiplex polymer, which is comprised of polyethylene oxide and carboxymethylcellulose. Oxiplex can be formulated into gels, films, sponges and fluids.

Oxiplex/SP and Oxiplex/AP are bioabsorbable adhesion barrier gels for use after spine and abdominal/pelvic surgeries, respectively. The products have CE mark approval and are in clinical trials in the U.S. Oxiplex/SP is sold outside the U.S. by DePuy Acromed (Raynham, Massachusetts) and Medtronic Sofamor Danek (Memphis, Tennessee) for use in laminectomy, laminotomy and discectomy procedures. The European launch of Oxiplex/AP is planned for early next year.

Fziomed is conducting preclinical trials on additional adhesion barrier products, including Dynavisc for hand/tendon surgery and Oxiplex/CV for cardiac surgeries, as well as products for dural repair, tissue sealing and drug delivery.

MacroPore Biosurgery (San Diego, California) has two technology platforms, bioresorbable implants made from polylactide polymer and adult stem cells for use in regenerative medicine. Its bioresorbable products include SurgiWrap film used for soft tissue support and for specific pelvic applications, CardioWrap film for repair of the pericardium and Hydrosorb used in spinal and reconstructive surgery. Hydrosorb is distributed by Medtromic Sofamor Danek.

MacroPore isolates adult stem cells from adipose tissues and makes them available for research and therapeutic purposes. The company has stem cell preservation capabilities and offers autologous stem cell banking.

Anika Therapeutics (Woburn, Massachusetts) has developed a line of therapeutic products for use in the repair, protection and healing of bone, cartilage and soft tissue that are based on hyaluronic acid. Its proprietary manufacturing process produces ultra-pure and high molecular weight hyaluronic acid. Orthovisc is used to treat the pain of osteoarthritis and is sold in Europe and Canada by multiple distributors. A premarket approval application for Orthovisc was filed with the FDA in May.

Anika manufactures a viscoelastic aid used in cataract surgery, which is marketed under several brand names by ophthalmic product companies. The company plans to conduct pilot clinical trials in Europe on chemically modified hyaluronan gel for reducing post-surgical fibrosis and as a dermal filler for correcting wrinkles and scars.

Life Medical Sciences (Little Silver, New Jersey) is developing bioresorbable copolymers for use as adhesion barrier products in cardiac and gynecologic surgeries. The copolymer is synthesized from hydrophilic and hydrophobic polymers. The most advanced product in its pipeline is CV-Resolve, a post-operative adhesion barrier that is in pivotal cardiac surgery trials. The company is conducting research on reverse thermal gel materials that can be injected or sprayed into surgical sites as liquids and, upon exposure to body temperature, convert into high viscosity gels for potential use as sealants, sustained delivery depots as well as adhesion prevention barriers.

Lifecell (Branchburg, New Jersey) has developed a line of products based on its proprietary regenerative tissue matrix, a complex 3-D structure that contains proteins, growth factors and human tissue. Lifecell markets AlloDerm for skin grafting of burn and cancer patients and reconstructive surgical procedures, and for periodontal surgery through BioHorizons (South Birmingham, Alabama).

Cymetra, a particulate form of AlloDerm, is used for correction of soft tissue defects and is sold by Lifecell and by OMP (Collegeville, Pennsylvania) under a co-promotion agreement.

Lifecell also supplies products that are sold under distribution agreements. These include Repliform for urologic and gynecologic procedures, sold by Boston Scientific (Natick, Massachusetts), AlloGraft DBM for bone grafting, sold by Stryker Howmedica Osteonics (Allendale, New Jersey), and Graft Jacket for periosteum and rotator cuff repair, sold by Wright Medical Technology (Arlington, Tennessee).

Products under development include the use of tissue matrix technology for vascular, nerve and orthopedic tissue repair and the investigation of human tissues as carriers for therapeutics.

Inion (Tampere, Finland) has developed biodegradable medical implants in a variety of shapes and forms (screw, pin, membrane, plate and mesh) for use in diverse applications including craniomaxillofacial surgery, periodontal surgery, orthopedic trauma, spinal surgery and sports medicine. These products have CE mark approvals and many of them also have been granted approval by the FDA under a 510(k) submission.

The Inion Optima biodegradable polymers are polylactides, polyglycolides and their copolymers. The strength and malleability of these polymers can be tailored by further incorporating trimethylene carbonate into the polymer backbone.

Production and therapeutic applications of stem cells:

Gamida-Cell's (Jerusalem, Israel) StemEx solution is being developed for use in large-scale, self-renewal of stem cells and progenitor cells. This technology can potentially be used for both umbilical cord blood stem cells as well as for stem cells from adult organs such as the liver and heart. It also has shown promise for expanding populations of skin, neural and pancreatic stem cells. A Phase I trial of StemEx is under way at the M.D. Anderson Cancer Center (Houston, Texas) to assess the safety and rate of hematopoietic reconstitution after high-dose chemotherapy.

Aastrom Biosciences is focused on the use of proprietary bone marrow stem cells for cell-based therapies. Its AastromReplicell system has the CE mark and uses ex vivo cell production technology to produce patient-specific cell products for stem cell tissue repair and regeneration, and for the treatment of cancer and infectious diseases.

As noted above, the company has a strategic alliance with the Musculoskeletal Transplant Foundation to jointly develop and market innovative treatments for tissue regeneration in bone grafting applications and for cartilage replacement.

Aastrom Biosciences has FDA approval of an investigational new drug application for conducting a multi-center trial of its OCG-I for treating tibial non-union fractures.

It also is in collaboration with Stanford University (Palo Alto, California) to develop a new immunotherapy approach for treating Hodgkin's disease, leukemia and lymphoma.

StemCells (Palo Alto, California) is developing applications of stem cells for treating disorders of the central nervous system, liver and pancreas. It isolates rare stem cells or progenitor cells from human fetal and adult tissue sources.

The company has a strong technology platform in the neural stem cell field with more than 30 issued patents. It recently reported positive results of a preclinical study using human neural stem cells to regenerate myelin, a nerve fiber insulator that is often damaged in spinal cord injuries, multiple sclerosis and certain genetic disorders. The ability of these human cells to prevent loss of neurons may also apply to other neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's.

The company recently licensed from StemCell Technologies (Vancouver, British Columbia) worldwide rights to manufacture and sell for research purposes certain proprietary mouse and rat neural cells and culture media for all mammalian neural stem cells.

Drug delivery technologies nasal, lingual, electroporation and polymer-linked:

Nastech Pharmaceutical (Bothell, Washington), a leader in nasal drug delivery, provided an update of its eight development programs. The most advanced intranasal products in its pipeline are calcitonin for osteoporosis and Nascobal vitamin B for which the company plans to submit to the FDA before year-end an ANDA and NDA, respectively. Competing nasal calcitonin products are Miacalcin from Novartis (Basel, Switzerland) and Fortical from Unigene Laboratories (Fairfield, New Jersey), for which an NDA was submitted to the FDA.

Phase II trials are under way using intranasal apomorphine for use in erectile dysfunction and for female sexual dysfunction. A recently initiated program is the nasal administration of the gut hormone, PYY for treating obesity, which recently entered a Phase I trial.

NovaDel Pharma (Flemington, New Jersey) is a drug delivery company that is converting 25 drugs into lingual spray formulations for faster onset of action, lower dose to reduce side effects and convenience to enhance compliance. The absorption of lingually sprayed drugs through the mucosal membranes of the oral cavity is rapid, minimizing GI tract degradation and first-pass metabolism. Many of the drugs being formulated as lingual sprays will come off patent in the next five years, thereby providing a means of extending their franchise life.

NovaDel's lead product is nitroglycerin lingual spray for which a new drug application will soon be filed with the FDA. The company is seeking to partner with pharmaceutical and biotechnology companies for furthering the development of lingual sprays. NovaDel entered into an agreement with Manhattan Pharmaceuticals (New York) for the development of the anesthetic propofol. The lingual spray technology is covered by six issued patents and 24 patent applications.

Genetronics Biomedical (San Diego, California) is developing therapeutic applications of electroporation (EPT) which uses pulsed electric fields to momentarily open pores in the cell membranes, allowing the entry of small amounts of drugs, vaccines or genes into the cell. Its lead product is the Medpulser EPT system, which is in Phase III trials for treating recurrent head and neck cancer with bleomycin. It already has received the CE mark in Europe.

The primary advantage of electroporation technology is that it selectively kills cancer cells with very little effect on healthy cells. EPT has demonstrated efficacy in a Phase I trial for treating assorted skin (cutaneous) cancers with 130 of 146 (89%) patients showing a complete response.

Other applications of EPT being investigated are for treating breast, prostate, pancreas and liver cancers. Genetronics is seeking a strategic partner in the area of oncology.

The company recently entered into an agreement with Vical (San Diego, California) for an exclusive worldwide license to its in vivo electroporation technology in combination with Vical's vaccine and DNA technology for undisclosed targets.

Access Pharmaceuticals (Dallas, Texas) is utilizing a proprietary polymer drug delivery system for site-specific delivery of drugs with initial focus on platinum-based cancer drugs. A Phase I trial on polymer-cisplatin for treating ovarian cancer showed dramatic tumor inhibition and is now in a Phase II trial. A Phase I trial of polymer-oxaliplatin for treating colorectal cancer is under way.

The company is developing a bioerodible mucoadhesive disc for treating aphthous ulcers (canker sores) and a mucoadhesive liquid for preventing mucositis. Also under investigation are nanoparticle aggregate technology for controlled release of proteins and a vitamin-mediated oral delivery system.

Microcapsules used for embolization therapy and islet cell transplants:

BioSphere Medical (Rockland, Massachusetts) markets embolization therapy products in North America, Europe and Australia. This minimally invasive treatment of uterine fibroids, hypervascularized tumors and vascular malformations uses microspheres that are delivered by a catheter into the targeted vessel, blocking the blood flow that feeds these growths and causing them to shrink.

BioSphere Medical sells Embosphere microspheres and EmbolGold visible microspheres. The microspheres are precisely calibrated, hydrophilic, microporous beads made of an acrylic copolymer which is crosslinked with gelatin. The EmboCath infusion catheter and Segway guidewire are used to deliver the microspheres.

Competing embolization products are sold by Boston Scientific and by Terumo (Tokyo) in Europe under a distribution agreement with Biocompatibles (Farnham, UK).

Microislet (San Diego, California) uses proprietary microencapsulation technology in its development of transplanted porcine islet cells for use in treating insulin-dependent diabetes. Microislet is collaborating with the Scripps Research Institute (La Jolla, California), and they plan to conduct preclinical studies. The advantages of this approach are a near-limitless supply of islet cells, islet durability and functionality, no need for immunosuppressive drugs and simple administration by injection into the peritoneal cavity.

Celsion (Columbia, Maryland) has submitted a PMA for use of focused microwave heating for treating benign prostatic hyperplasia and is awaiting market clearance from the FDA for its Microwave Uretheroplasty 800 BPH system, which will be marketed by Boston Scientific. Its focused heating technology is being evaluated in two pivotal Phase II clinical trials for treating breast cancer and in a Phase I study for treating prostate cancer.

The company has licensed from Duke University (Durham, North Carolina) a proprietary formulation of thermo-liposomes for encapsulating heat-activated drugs for targeted release. This technology is in preclinical evaluation for treating prostate and liver cancers. The objective is to enhance efficacy and reduce side effects of chemotherapy. Celsion also licensed from Duke an advanced phase array radio frequency heating system for use with chemotherapeutic drugs for hyperthermia treatment of advanced breast cancer.

Celsion recently announced that it has acquired from the National Institutes of Health (Bethesda, Maryland) exclusive rights to develop heat-sensitive gene therapy products activated by microwave heat energy.

Diagnostics based on oral specimens:

OraSure Technologies (Bethlehem, Pennsylvania) markets OraQuick, a 20-minute, point-of-care (POC) test for detection of antibodies to HIV-1 in fingerstick or venipuncture blood specimens. The company is seeking FDA approval for use of this test to detect HIV-1 antibodies in oral fluids. A rapid POC test is of vital importance for detecting HIV-1 in mothers during childbirth in order to prevent transmission to the newborn.

OraSure also is seeking FDA approval for its Uplink analyzer and oral fluid assays for the rapid, POC detection of five common drugs of abuse, as identified by the National Institute of Drug Abuse (Bethesda, Maryland), known as NIDA-5. Uplink is OraSure's product platform based on the company's proprietary Up-Converting Phosphor technology. This technology uses phosphor particles that convert light from low energy (infrared) to high-energy visible light and is being jointly developed with SRI International (Menlo Park, California). OraSure already markets laboratory-based oral fluid tests for detecting HIV-1 and NIDA-5.

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