►2007 Regenerative Medicine Organization
        Conference Highlights

Prior Conference

Meeting Highlights and Synopsis
3rd Annual Regenerative Medicine Conference
February 20-22, 2006

“New Sciences for a Better Life”

Kauai, Hawaii

Meeting Highlights

A three day symposium sponsored by the Regenerative Medicine Organization entitled “New Science for a Better Life” brought together an international team of scientists, physicians and industry leaders to present the latest progress in efforts to extend and improve the quality of life through regenerative medicine.  A central focus of the meeting was to report on new therapies that regenerate tissues by bringing a fresh blood supply to tissues that have become injured or ischemic due to a lack of adequate blood perfusion. Several presentations, including those by Lynne Wagoner, M.D., University of Cincinnati Medical Center and Thomas Stegmann, M.D., CardioVascular BioTherapeutics, Las Vegas, NV, reviewed recent results that showed that regenerating new blood vessels, a process termed angiogenesis, could be a potential breakthrough therapy for patients suffering from coronary artery disease, peripheral vascular disease of the legs and stroke.  Equally important, new molecular imaging technologies that can identify, with very high sensitivity, areas of poor perfusion in these patients was reviewed by David Rollo, M.D., Philips Medical Systems.  He elaborated on the use of advanced imaging equipment and reagents to diagnose and manage patients who are undergoing treatment with a potent angiogenic agent, human fibroblast growth factor.

Other presenters at the Conference reviewed the promise of regenerating tissues with other approaches distinct from the growth of new blood vessels.  Michael Rosenblatt, M.D., Tufts University Medical School, presented how a naturally occurring hormone, parathyroid hormone, has been shown to regenerate new bone tissue and could become the treatment of choice for millions of women and men who suffer from osteoporosis.  Peter Hudson, Ph.D., CSIRO, Melbourne, Australia reviewed recent progress in the development of molecularly engineered antibodies that could be new therapies for the treatment of degenerative diseases such as rheumatoid arthritis. Finally, industry leaders discussed the economic impact of bringing these new therapies to the market and included presentations by Joseph Kaufman, M.D., Sierra Health Systems, Las Vegas, NV who focused his remarks on regenerating heart tissue in patients at risk, and Wei Chen, Ph. D., Phage Biotechnology Corporation, Irvine, CA who discussed that company’s promising portfolio of new biological drugs that are targeted to regenerative medicine.

Synopsis of Presentations: “New Science for a Better Life”

Day 1:

1.     Lynne Wagoner, M.D., University of Cincinnati Medical Center, “FGF-1 Treatment of No-Option Heart Patients: The U.S. Experience.”  Dr. Wagoner reviewed in her presentation the clinical results obtained to date which demonstrate the potential for Cardio Vascu-Grow™ (human FGF-1; fibroblast growth factor) to treat patients with advanced atherosclerotic disease of their coronary arteries. This treatment, which regenerates new blood vessels in the hearts of these patients, has been applied to 26 patients in the U.S. as well as to 40 patients in earlier trials in Europe, conducted by Thomas Stegmann, M.D.

To date, no significant adverse events attributable to the drug have been seen in  the treated patients, and all patients have reported a marked decrease in their primary clinical symptom, angina or chest pain.  In addition, Dr. Wagoner presented angiographic evidence from selected treated patients displaying the growth of new blood vessels in the injected regions of their hearts, as documented by angiography. A second, larger clinical trial for this medical indication is planned to commence this summer.

1. Kenneth Thomas, Ph. D., CardioVascular BioTherapeutics FGF-1

 Treatment Of  Diabetic Peripheral Vascular Disease and Dermal Ulcers.”  Dr. Thomas spoke on new clinical initiatives that CardioVascular BioTherapeutics is undertaking with its lead drug candidate, Cardio Vascu-Grow™, to treat patients suffering from dermal leg ulcers as well as patients who suffer intense leg pain resulting from peripheral vascular disease.  The wound healing study is an FDA-authorized trial that is scheduled to begin at the University of Pittsburgh Medical Center in patients with dermal leg and foot ulcers.  Preclinical data with Cardio Vascular-Grow™ showed it to be a highly effective agent in speeding up the healing rate of wounds in diabetic animals, and the growth factor was also shown to have a very favorable safety profile, with no toxicity seen in animal studies.
In addition to the wound healing studies, Dr. Thomas reviewed the pre-clinical
studies that have been completed to allow Cardio Vascu-Grow™ to progress into the clinic to be tested as a new treatment for peripheral vascular disease (PVD).  Dr. Thomas outlined the clinical protocol to treat PVD patients which has been developed in conjunction with medical researchers at Duke University and which will be submitted to the FDA as part of an Investigational New Drug (IND) application.  These clinical studies are planned to begin this spring.

1. David Rollo, M.D., Philips Medical Systems, “Application of Diagnostic

 Imaging to Assess the Efficacy of FGF-1 for the Diagnosis, Treatment and Management of Ischemia.”  Dr. David Rollo is the Chief Medical Officer of Philips Medical Systems, a company which develops, manufactures and markets advanced imaging equipment and diagnostic agents, and he spoke on the application of molecular imaging to assess the efficacy of FGF-1 for the diagnosis, treatment and management of ischemia.  Dr. Rollo’s talk focused on the recent development by Philips of imaging agents which can specifically visualize, at high sensitivity, ischemic areas of the heart, brain and other tissues.  Ischemia in these tissues results from poor blood perfusion which is a consequence of blocked arteries.  Dr. Rollo indicated that as FGF-1 is a potent inducer of new blood vessel growth, the new imaging agents could be utilized to first diagnose, and then assess the effect of FGF-1 given to patients with ischemic diseases.  He emphasized that combining new therapies, such as FGF-1, with powerful new imaging modalities will be critical for the successful management of patients who are undergoing regenerative treatment aimed at their cardiovascular systems.

4.         Thomas Stegmann, M.D., CardioVascular BioTherapeutics, “Human
 Life: Perfusion is All That Matters.”  In his presentation, Dr. Stegmann reviewed his earlier clinical trials in Germany in which he performed the first angiogenesis trials in humans where 40 no-option heart patients received injections of FGF-1 into their hearts. These very promising trials which were widely published in the medical literature and featured in a Wall Street Journal article on new treatments for heart disease led to the initiation of the current studies in the U.S.
            Dr. Stegmann then went on to enumerate a host of other medical conditions, similar to coronary artery disease in the heart, where blocked arteries lead to poor perfusion. Of particular note, in animal models of several of these diseases including peripheral vascular disease of the legs, stroke and diabetic leg ulcers, Cardio Vascu-Grow™ (human FGF-1) has already been demonstrated to be a well tolerated and effective treatment.
            Dr. Stegmann also discussed future medical indications, characterized by poor perfusion, where Cardio Vascu-Grow™ could have a high potential beneficial effect. This included lumbar ischemia, which results in chronic back pain and is caused by blockage of lumbar arteries; intestinal ischemia, where arteries in the small and large intestines become obstructed; and degenerative bone diseases caused by insufficient perfusion of bone, which can result in necrosis of the hip and other bone-associated conditions.  Dr. Stegmann concluded his talk by reviewing the very promising data that FGF-1 could also have a potential application for certain patients afflicted with diabetes by driving the proliferation and differentiation of the insulin-producing beta cells in the pancreas.     

Day 2: “New Science for a Better Life”

1. Jack Jacobs, Ph.D., CardioVascular BioTherapeutics, “FGF-1

for the Treatment of Stroke.”  Dr. Jacobs presented recent progress CardioVascular BioTherapeutics has made in its efforts to bring new therapeutics to the market for the treatment of stroke. He reviewed the promising data collected to date in which human FGF-1 has been tested in animal models of stroke. Human FGF-1, in addition to being a potent angiogenic protein, is also a powerful stimulator of new neuron growth and can protect neurons at risk, which is the situation observed in the brain immediately following a stroke. In animals receiving an experimental stroke, the FGF-1 protein decreased the area of the stroke, resulting in a significant decrease in neurological deficits in these animals. Of potential clinical significance, the FGF-1 could be administered to the animals up to 8 hours after the stroke was given, and a reduction in the stroke area and the number of neurological deficits was still observed. These data support FGF-1 as an appropriate candidate for clinical trials in patients suffering an acute stroke.
     Dr. Jacobs also reviewed progress that has been made with a new initiative that CardioVascular BioTherapeutics has launched in the area of stroke recovery. As human FGF-1 is a potent stimulator of new nerve growth, it has the potential to repopulate damaged areas of the brain with new neurons.  Preclinical experiments with FGF-1 in animals with a chronic stroke condition indicated a significant increase in neuronal density in the areas affected by the stroke.  Dr. Jacobs indicated these animals experiments will be pursued aggressively to best define a possible therapeutic intervention in humans who have been debilitated by stroke, and have no hope of recovery.

2.   Ginger Conway, MSN, RN, University of Cincinnati Medical Center, “A Patient’s Perspective While Participating in the FGF-1 Clinical Trial.” Ms. Conway’s presentation allowed insights into the trials and tribulations facing no-option heart patients as they seek entry into CardioVascular BioTherapeutics’ ongoing clinical trial.  These critically ill patients must undergo a battery of tests to ascertain if they are eligible for treatment with Cardio Vascu-Grow™ (human FGF-1).  These tests begin with simple clinical laboratory blood tests, but progress to tests of increasing complexity, including nuclear imaging tests and coronary angiograms.
    
       In Ms. Conway’s example, which was of a middle-aged man with severe coronary artery disease being treated at the University of Cincinnati Medical Center, the gentleman had successfully passed all of the entry criteria only to suffer a heart attach which made him ineligible for 6 months. After waiting the mandatory period of time, he again was schedule for treatment with CardioVascu-Grow only to have his surgery cancelled due to a blood clotting problem.  He finally was successfully treated and is responding very positively to the therapy. Ms. Conway indicated that with this class of patients, where no treatment is currently available, and who, in many cases, only have a 2 year life expectancy, there is a very real sense of urgency for them to be able to participate in this trial.  Because of this she added that the patients who do gain entry into the trial are exceptionally motivated and cooperative.

3.     Joseph Kaufmann, M.D., Sierra Health Services, “Coronary Artery Disease: The Continuum, The cost, The Opportunities.”  Dr. Kaufman, Chief Medical Officer of the managed health care group, Sierra Health Services, gave a presentation on the economic impact in caring for patients with coronary artery disease. He outlined the progression of coronary heart disease and the fact that these patients require an ever increasing amount of medical care, which includes very costly diagnostic testing.  As a representative of managed health care plan, he indicated the great economic stress such burgeoning costs put on these plans, and the challenge to try and control costs in this relatively sick class of patients. Dr. Kaufmann emphasized that as these patients age their coronary artery disease worsens and the disease becomes more costly to control.  The opportunity here, he indicated, would be to intervene at an earlier stage to slow or halt the progression of the disease, which would dramatically soften the economic impact of providing health care for these patients.

     Of particular promise, Dr. Kaufman noted, was the potential of angiogenesis therapy to treat coronary artery disease.  This treatment, which does not merely treat the symptoms of the disease, but can actually reverse the progression of the disease for a period of time, could have very important economic benefits for the patients, the health care providers and the payors of health care services for these patients.  He predicted that such new therapies, when combined with more sensitive imaging technologies to detect coronary artery disease at an earlier stage, will revolutionize the treatment of this disease and will permit substantial cost containment to occur in the care of this rapidly growing class of patients.           

1. Wei Chen, Ph. D., Phage Biotechnology Corporation, Manufacturing

Protein  Pharmaceuticals in the U.S.”  Dr. Chen discussed Phage Biotechnology’s portfolio of protein pharmaceuticals that would have direct application to the field of regenerative medicine. These include human growth hormone, which is regenerative for a number of tissues including bone, muscle and skin. Phage is also in pre-clinical development with parathyroid hormone, which is a potent regenerator of bone, and which was discussed in detail by Dr. Rosenblatt in Wednesday’s Conference session.  Dr. Chen indicated that as Phage Biotechnology is the sole manufacturer for human FGF-1 for CardioVascular BioTherapeutics clinical studies, it is currently in the process of leasing and then certifying a new biological manufacturing facility that could produce commercial lots of this protein once it is approved by the FDA.  Dr. Chen spoke of the lengthy testing and validation process that the FDA imposes upon such manufacturers and outlined a streamlined method to bring a manufacturing facility up to current good manufacturing practices known as cGMP’s.  He indicated the use of disposable bio-reactors and downstream processing equipment will enjoy wide spread use in future manufacturing facilities. He summarized other protein products in Phage’s pipeline including a number of longer-acting pegylated biologicals, as well as engineered antibodies, which enjoy a potential worldwide market in excess of $25 billion.

Day 3: “New Science for a Better Life”

1. Ralph Bradshaw, PH. D., University of California, Irvine, “Growth

 Factors as Therapeutic Targets.”  Dr. Bradshaw lectured on the rich diversity of growth factor families and used the fibroblast growth factor family as an example of how complex the biological activities of these proteins are in our bodies. He discussed the many cell surface receptors that interact with these growth factors and how they signal messages to the nucleus of the cell through a complex cascade of phosphorylation. FGF-1 was singled out as being the broadest acting member of the 22 member FGF family by virtue of its ability to interact with every known class of cell surface receptors for the FGF family.  This leads to a stimulation of a wide variety of cell types including skin, muscle and nerve cells, as well as FGF-1’s known effect on blood vessel proliferation.

     Dr. Bradshaw indicated that all of the proteins involved in sending the proliferation signal from the cell surface to the nucleus were potential drug products, and this could include antibodies that stimulate or block the receptor to small molecules that get inside the cell to interact with kinase enzymes responsible for the cascade of phosphorylation events. He speculated that designer drugs in the future will be able to precisely target a signaling protein in a specific cell type and could, for example, be used to turn off cell division in a targeted cancer cell or turn on cell division in areas of the body where repair is needed, such as the failing heart.

2.   Myung Park, Ph.D., BiopolyMed, Inc., “The Potential of New Pegylated Proteins.”  Dr. Park spoke on the progress that she and her company have made in creating second generation biological drugs, that are characterized by a much longer duration of action in the human body, and which have direct application to regenerative medicine.  These drugs are created by attaching a long chain sugar molecule to the protein, a process termed pegylation, which in some cases can increase the resident time of the protein in the blood circulation by 10-11 fold.  Dr. Park and BiopolyMed have teamed up with Phage Biotechnology to convert Phage’s first generation protein products into longer acting, second generation drugs.
     Dr. Park reported on the success she has had in pre-clinical experiments with three (3) Phage proteins.  With human growth hormone, her patented pegylation technology has permitted once a week administration of the hormone versus daily injections with native growth hormone, to achieve similar growth rates in animals.  With human granulocyte colony stimulating factor (G-CSF, marketed by Amgen and Neupogen ® and Neulasta®) she was able to demonstrate that pegylated GCSF made with her technology was as active and as long lasting in the circulation as Neulasta®.  Finally, pegylated-alpha interferon which was synthesized with her technology showed a very favorable activity profile and resident time in the circulation when compared to the two marketed products, Pegasys® manufactured by Roche, and Peg-Intron A® manufactured by Schering. All of these pegylated products have a multi-billion dollar market potential according to Dr. Park, and because these new pegylated proteins will enjoy patent production, they should provide Phage and BioPolyMed with a very attractive portfolio of new pegylated proteins.

1. Michael Rosenblatt, M.D., Dean, Tufts University School of Medicine 

Osteoporosis, Regenerating Bone, and Parathyroid Hormone.”  Dr. Rosenblatt lectured on the high potential of parathyroid hormone (PTH) as a potential new protein drug to regenerate bone for application in patients with osteoporosis.  He reviewed the alarming statistics on the increase incidence of osteoporosis in both men and women as our life spans are increased.  He mentioned that current drugs that are approved for the treatment of osteoporosis, including Merck’s Fosamax®, merely decrease the rate of bone destruction (bone re-absorption) and have no anabolic effect on regenerating bone. Parathyroid hormone is a potent regenerator of bone tissue and can actually increase bone mass in patient with osteoporosis.  The hormone is also involved in the daily repair and maintenance of our bones, and he gave a remarkable statistic that we gain a completely new skeleton every 10 years.
     Dr. Rosenblatt also spoke on a promising new protein call parathyroid hormone-related protein or PTHrp.  This protein shares many of the same biological properties with PTH but lacks one very important side-effect of PTH.  At higher levels, PTH actually destroys bone and can raise calcium levels to abnormal levels, and PTHrp does not appear to have this activity based on recent evidence from early clinical studies.  Dr. Rosenblatt indicated it was his opinion that the PTH products could eventually dominate the current $5 billion dollar market for osteoporosis, and that companies that are developing such therapeutics, including Phage Biotechnology Corp., could be able to exploit the very attractive bone regenerating properties of PTH over the currently prescribed Fosamax®-type drugs.

1. Peter Hudson, Ph.D., CSIRO, Australia, “Engineered Antibodies as Novel

 Drugs and Diagnostics.”   Dr. Hudson reviewed the exploding field of antibody therapeutics and the progression of these therapies from the 15-year-old mouse monoclonal antibodies to the recently approved fully humanized monoclonal antibodies. He cited over 15 currently marketed monoclonal antibody products with annual U.S. sales approaching $10 billion. Most of these therapeutics either target a specific cancer indication or are aimed at rheumatoid arthritis.  Dr. Hudson went on to predict that the future of this field would be to take these exciting antibodies and design better drugs by molecular engineering. He emphasized the approach taken in his laboratory where they have simplified the complex structure of a monoclonal antibody to a single chain or a diabody structure (so called nano-bodies).  They then use new mutagenesis technologies to convert the nano-bodies into much tighter binding antibodies, which would create, theoretically superior drugs.  The great advantage of this technology is that the single chain antibodies can be produced in bacteria, whereas monoclonal antibodies must be produced in mammalian cells, a much more time consuming and expensive way to produce protein products.

     Dr. Hudson is using the engineered antibodies he has produced in his lab to image, in an exquisitely sensitive manner, specific tumor types.  These same antibodies, if loaded with a toxic compound, can be used as tumor seeking agents to selectively bind and kill cancer cells. The one current drawback with the single chain antibodies is that they are small and leave the blood circulation faster than the larger monoclonal antibodies.  Dr. Hudson felt that pegylation technologies, such as discussed by Dr. Park in her earlier talk, would be the key to extending the half-life of these compounds in the circulation and turn them into very promising new drug candidates.       

 

Prepared for the Regenerative Medicine Organization by:
Jack Jacobs, Ph.D., CardioVascular BioTherapeutics, Inc.
February 27, 2006