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BioSpecifics Technologies Corp. Annual Report Archive - See the 1997 Report SOME HIGHLIGHTS
It's been a good year. Our team delivered marketing and clinical advances that will profit patients as well as BioSpecifics in the years ahead. And, even with the increased expenditure associated with growth in our research and development effort, we still turned in a solid performance in earnings. Collagenase Santyl® is Now the Leader Ortho-McNeil/Knoll Agreement Filling Our Pipeline Elsewhere in this annual report we have invited three distinguished researchers to further acquaint you with their exciting work on collagenase's potential therapeutic applications in the areas of Dupuytren's disease, glaucoma, and wound healing. Last year, we told you about promising, though preliminary, research advancements being made particularly in our work on Dupuytren's disease and glaucoma. Since then, we have made significant progress in those two areas. I'd like to share some of this progress with you. Dupuytren's Disease These reports were based on open label studies by Drs. Marie Badalamente and Lawrence Hurst, Chairman of SUNY Stony Brook Department of Orthopaedics and involved patients who had severe enough symptoms to qualify for surgery. Once the proper dose was selected, a positive response was found in approximately 90% of the cases. A high percentage of patients regained full use of their fingers with a single injection of Cordase®. Complicated conditions may require repeated injections; thus far these have been well tolerated. Long term follow-up is ongoing and encouraging and a survey of hand surgeons indicates a highly positive attitude towards this approach to the disease. A Phase 2 trial is underway. Glaucoma Financial Strength Stock Buyback Sincerely,
This disorder is slowly progressive over the course of many years and often arises as "bumps or nodules" in the palm. Cells in these nodules called myofibroblasts synthesize excessive amounts of collagen. The collagen is deposited almost in the form of a rope extending from the palm up to the fingers and crossing the joint lines. When the rope crosses joint lines it permanently fixes the affected fingers in a chronic state of flexion and the patient is unable to extend the involved fingers. Most often the ring and little fingers are involved. The disease affects predominately older males, although females may also be affected notably former British Prime Minister Margaret Thatcher. Dupuytren's disease is strongly associated with people of Northern European descent, such as Irish, English, German and Scandinavian. The current standard form of treatment for Dupuytren's disease is surgery, which can be painful and involve lengthy post-operative physical rehabilitation. Although many forms of non-operative treatment have been tried in the past, none has proven successful. Recently, a clinical trial has begun in the Department of Orthopaedics, State University of New York at Stony Brook under the direction of Drs. Marie A. Badalamente and Lawrence C. Hurst to investigate a new non-operative therapy for Dupuytren's disease using injectable collagenase (Cordase®) which is manufactured by BioSpecifics Technologies Corporation, Lynbrook, NY. After pre-clinical laboratory studies were done, an open label trial was recently completed. Thirty-five patients were treated in this study, 32 males and 3 females with an average age of 65 years. Approximately 94% of the patients responded to Cordase® injection therapy, regaining full active extension of their affected fingers. This effect was seen within one day to two weeks after the injection. Some patients responded with only one injection while others required multiple injections with one patient receiving a total of five. In three patients who had flexion contracture of two joints in the same finger, the injection therapy corrected both joints. Similarly, in four patients who had flexion contractures in adjacent fingers, these patients also were restored to full active extension with Cordase® injection. The side effects of the injection therapy are minimal and include pain to pressure at the injection site, minimal swelling and minimal bruising. These effects appear to resolve within five days to two weeks of the injection. A randomized placebo controlled, double blind clinical trial is now ongoing. This trial is funded by the U.S. Food and Drug Administration, the State of New York Center for Advanced Technology in Biotechnology and BioSpecifics Technologies Corporation. The study will test the effects of Cordase® injection therapy against an inactive control, according to FDA guidelines. Based on the data now available, it appears that Cordase® injection therapy as a non-operative treatment for Dupuytren's disease has merit as a safe and effective alternative to surgery, which is not only cost effective but non-traumatic. Additional clinical trials need to be carried out to verify these results. After completing placebo controlled studies at the State University of New York, Stony Brook, the injection therapy will be further tested in multi center trials, in the United States and countries around the world.
Available sources suggest that glaucom a is responsible for 11% to 13% of existing blindness. The World Health Organization estimates the total worldwide number of suspect cases of glaucoma at around 105 million. Glaucoma and directly related conditions account for a direct cost of over $500 million, and over $2 billion in indirect health costs, in the United States. Glaucoma is treated conservatively by eye drops and by a multiplicity of surgical and semi-invasive approaches. The various treatments are characterized by complications, failures, systemic and local side effects. The development of a new ambulatory procedure with limited complications would represent an important therapeutic advantage. Scientists at the Weizmann Institute, in Israel, developed a specially designed delivery device, a micro-applicator to increase scleral permeability in a narrow area using BioSpecifics' highly purified collagenase. Increasing scleral permeability lowers the Intraocular Pressure. Studies in vitro showed selective action on the human sclera by collagenase as well as a clear correlation between the amount of collagenase used and the increase of scleral permeability. Preliminary studies in vivo on rabbits showed an immediate drop of over 40% of the Intraocular Pressure following the enzymatic treatment and a lasting effect of 30% over 21 days without adjuvant treatment. Since no systemic or ocular effects were noticed and purified Collagenase was known to be used in humans for vitrectomy, discolysis, and Peyronie's disease, approval of the procedure for limited experimental study in humans was granted by Review Boards at the Beilinson Medical Center, Israel, California Pacific Medical Center San Francisco CA, USA; Aravind Eye Hospital and L.V. Prasad Eye Institute India. The first clinical investigations evaluated the effect of collagenase when applied by means of the micro- applicator to the sclera of five phthisical eyes in five patients for 4-10 hours. Focal scleral excavation accompanied by percolation of fluid was seen in all cases. The next step in clinical investigations evaluated the IOP effect of enzymatic sclerostomy on eleven eyes of eleven patients with absolute glaucoma for 16-24 hours. Partial thickness sclerostomy accompanied by reduction of IOP with a mean of 44% was seen in all cases with open angle glaucoma. A further clinical investigation involved enzymatic application for 22 hours in a group of 15 eyes with absolute open angle glaucoma. These patients were followed for over 6 months and clinical appearance, pressure drop, and ease of application were evaluated. No difficulty was experienced by a glaucoma expert in performing the procedure. Appearance of the treated eyes showed various degrees of conjunctival hemorrhage and in one case full thickness scleral digestion was noted without vision threatening complications. The effect on IOP showed an average 44% immediate pressure drop and a lasting effect of 30% pressure drop for another 6 months. Enzymatic sclerostomy using a collagenase preparation, effectively reduced IOP in open angle glaucoma patients for at least 6 months with no vision threatening complications. Further follow-up of the treated patients and research for improvement in the method of collagenase delivery are in progress.
The central role these matrix-degrading enzymes play in tissue remodeling and wound healing directed us to test the hypothesis that supplementing the body's own collagenases with an added bacterial collagenase would influence the rate and extent of the epithelial cell response to injury, either under normal conditions or during abnormal wound healing. This notion is based on the observable and quantifiable differences seen when pharmaceutical quality clostridial collagenase is compared with mammalian collagenase in wound healing assays carried out on cells grown in tissue culture. While mammalian collagenase promotes wound healing in tissue culture, its migration-enhancing effects are only 20-30% of the stimulatory effects observed when comparable doses of pharmaceutical quality collagenase are used. Results from this work not only help to establish conclusively the important role that cell-extracellular matrix interactions play in modulating cellular responses to injury; but, these data also convincingly demonstrate the efficacy of clostridial pharmaceutical collagenase (over mammalian collagenase) in promoting wound healing in this model. In fact, recently published data using human keratinocytes (the major cell type of the epidermis) grown in tissue culture demonstrate that BioSpecifics' purified clostridial collagenase not only significantly promotes cell migration following injury, but also their growth. These observations are consistent with (1) published reports indicating that keratinocytes participating in post-injury re-epithelialization take on a collagenolytic phenotype and (2) that extracellular matrix turnover during wound healing is largely regulated via the metalloproteinases and their associated tissue inhibitors (TIMPs). If normal wound healing phenomena are typically mediated by a wide array of matrix-conditioning enzymes, including several classes of collagenases, then how is it that a bacterial enzyme is capable of stimulating the human enzymatic repertoire normally produced during cellular response to injury? One likely explanation rests in the substrate specificity of the bacterial versus the mammalian collagenases. Since the bacterial enzyme is more "promiscuous" in its ability to cleave interstitial and basement membrane collagens, it is not inconceivable to suggest that unique collagenolytic fragments are being generated following clostridial collagenase matrix digestion; these bioactive products would not normally be present or accumulate following the digestion of matrix with mammalian collagenase. Not only do these exciting findings suggest that clostridial collagenase should significantly accelerate normal wound healing phenomena by stimulating re- epithelialization; but, in addition, it seems highly likely that clostridial collagenase will also prove beneficial for healing chronic wounds. What Collagen is - Collagen is the fibrous protein constituent of skin, cartilage, bone, and other connective tissue. At BioSpecifics Technologies Corporation, we've built our Company on sinew, tendon, and connectivity. Collagen, the most important building block (by weight at least) in the entire animal world, is the tie that binds the animal kingdom together. In life's long march up from the primordial ooze, anything with more than one cell, from the simplest, oldest living creature to man, is knitted into whatever it is by collagen. The word collagen comes from the Greek, and means "glue producing". No wonder the popular name for collagen is connective tissue. You might say that Mother Nature had to invent collagen in order to start the evolutionary march upward from a single cell. The science of medicine is a continuing journey into ever smaller territory. From the body as a whole to its separate systems and parts. Only a generation ago, medical science studied the human body by examining cells and how they were seen to work. As our microscopes and methods kept getting stronger, new techniques and devices appeared. And now biotechnologists gain their latest insights by going deep below the cellular level. Below and beyond. Down to the molecules: the bricks and mortar of every living thing in the universe. We used to think creatures were collections of cells, many different from each other, but most bound together cheek by jowl like pieces in a jigsaw puzzle. Now we know that life outside the cell performs essential functions. And the term 'connective tissue' has taken on an even broader meaning. Just as connective tissue binds various parts of the body together, muscle to bone, vertebrae to vertebrae... collagens are essential for tying cell to cell. To hang together, cells need a scaffold, a matrix. Like the mesh in a screen. Cells fill the holes in the mesh. The mesh itself is primarily collagen - the tie that binds. Life is a string of complex molecules: polymers. And Nature's most abundant protein polymer is collagen. More than a third of all the protein molecules in our bodies are collagens. Some parts have even more. Collagen makes up 75% of our skin. The more science learns about the body, the more miraculous we see collagen to be. At this stage of our knowledge, we've found 13 kinds of vertebrate collagen, plus some smaller molecules looking like collagen spare parts. Members of the family, we suspect. Each type has evolved to serve a distinct purpose. Collagen varies depending on the anatomical region. From muscle to bone to cartilage to blood vessels to nerves to various parts of the skin, the largest organ in the body. The differences among these collagen siblings come at the ends of each collagen molecule. It's as though Nature created specified arms able to share their fingertips with the tips of different molecules in appropriate cells. That's how they connect. But all collagen middles are the same. Three strands of repeating amino acids coil themselves, left-handed, into the unique collagen triple helix. Then these coils weave themselves right-handed into a cable, like small steel wires braided into the cables of a mighty suspension bridge. In fact, collagen has a greater tensile strength than steel. When the body needs to build any new cellular structure as in the healing process, for example, collagen and/or collagen fragments play a central role. Although the role of collagen as a scaffolding has been known for some time, we now know that collagen controls cell shape and differentiation, migration, and the synthesis of a number of proteins. This is why broken bones regenerate and wounds heal. Why blood vessels grow to feed healing areas. The collagen mesh provides the blueprint, the road map and the way. Why Collagenase - Anything so wide-spread in the body as collagen is bound to develop problems. Our bodies can build too much of it. Or produce it in the wrong places. Or keep it after the proper time to leave. Healing processes can go awry Ñ producing pain, sores, dead or dying tissue of various kinds, and sites for infection: bedsores, keloid scarring, wounds that won't heal, herniated spinal discs and a variety of localized ailments up and down the body. In order to correct these conditions, collagen has to be resculpted: reduced and controlled. But this is not easy. Collagen is tough. It's hard to remodel collagen without killing other necessary molecules and cells. And here is where modern biotechnology and BioSpecifics Technologies come in. If we liken the collagen molecule to a train with amino acids as the train cars, these cars can be uncoupled by the action of collagenase. The living process is constant, with amino acid train cars shunted off a living polymer molecule by de-coupling. Nature does this with a remarkable protein enzyme we call collagenase. Collagenase works by clamping onto a particular spot in the molecular train car, in essence its coupling, and dissolving it. Only the coupling. Nothing else. Sometimes the body's collagenase production is adequate, and sometimes not. When it isn't, and collagen needs to be resculpted and regrown, it needs a helping hand from additional collagenase. The body makes collagenase naturally. BioSpecifics Technologies has learned how to make it in a concentrated, purified form. This is the technology we own. Our bacterial collagenase dissolves only the couplings of the collagen molecule train. The collagenase produced by the body does it one coupling per train; our bacterial collagenase dissolves the amino acid couplings at multiple sites along the collagen triple helix. Safely. You may have seen reports on the constantly growing body of clinical evidence showing how useful and important our collagenase can be. More and more doctors use collagenase for cleaning out charred, dead tissue when treating severe burns. Once collagenase reduces the tough dead collagen, germ-killing medicines can reach more of the area to ward off infection while new collagen and tissue form more quickly. It's the same with bedsores, one of the terrors of bedridden patients in or out of hospitals. Before collagenase, treating bedsores was frustrating and inefficient because the body's dead collagen got in the way of the healing process. Now, dead collagen can be effectively and conveniently removed with collagenase to improve wound management. Remember collagen is 75% of the skin. That means in general it is also 75% of any non-viable tissue in a lesion. Ordinary enzymes don't work to remove collagen. That is why to cleanse the wound for healing, you need a collagenase. Clinical trials for collagenase treatment of localized ailments like keloids, hypertrophic scars, Peyronie's disease and Dupuytren's disease are in progress in the United States. Elsewhere in this annual report, Dr. Jacob Dan discusses early clinical evidence of collagenase's value in treating glaucoma, an eye disease that can cause blindness. And fascinatingly, more and more evidence is coming to light showing how collagenase itself speeds the healing process in all kinds of wounds. Research goes on to discover additional uses. Careful research, because we're dealing with the processes of human life. Our leadership position in this area of biochemical research is developing even further. |
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