On Target - Weekly Journal, Issue April 10, 2000

I	..	WHAT'S NEW Meetings
II		HISTORY OF MEDICINE Heart Disease
III		NATURAL PRODUCTS Walnuts and Cholesterol
IV		TISSUE ENGINEERING Dental Repair
V		UROLOGY PSA
VI		ANTIBIOTICS New Class of Drugs
VII		GENES AND DISEASE Pharmacogenetics
VIII		DIABETES Metformin and Rosiglitazone
IX		FDA MedWatch
X		TARGET HEALTH INC.

Dr. Jules T. Mitchel, President of Target Health, will be co-chairing the 4th Annual Orthopaedic Tissue Engineering Conference on April 13th and 14th at the Hilton Back Bay, Boston. Dr. Mitchel will be leading the session on "Proactive Approaches to FDA Relations During Device Development to Insure Successful Development Programs." A Q&A session with our friend and colleague Mr. Mark Citron (OSTEOTECH, Inc.) and Dr. Russ Pagano (CDRH, FDA) will follow the formal presentations.

Before 1900, very few people died of heart disease. Since then, heart disease has become the number one killer in the U.S. Before the Industrial Revolution, most people made their living through some sort of manual labor and walking was a major means of transportation. Laundry was scrubbed, stairs were climbed, carpets were beat, and butter was churned. With the arrival of automation, most manual labor was either replaced or assisted by machinery. Modern conveniences made physical activity unnecessary. Along with the change in lifestyle came a change in diet. Machines were built to homogenize milk, process cheese, churn butter, and make ice cream. Previously, such high-fat treats had to be made by hand. Fried foods, like potato chips, hamburgers, and french fries, became staples in many diets. The combination of a sedentary lifestyle and a rich diet led to an increase in cardiovascular events. The rate of heart disease increased so sharply between the 1940 and 1967 that the World Health Organization called it the world's most serious epidemic. Medical science immediately went to work studying heart disease including its causes and cures. In 1948, a thirty-year study began in Framingham, Massachusetts. The Framingham Study involved 5,127 people aged 30 to 62 who showed no signs of heart disease at the baseline visit. Every two years, the participants underwent a complete physical examination. The Study lasted thirty years and has provided priceless information about heart disease.

According to an article published in the Annals of Internal Medicine (Ann Intern Med 2000;132:538-546, replacing some of the mono-unsaturated fat in a Mediterranean diet with walnuts further reduces both total and low-density lipoprotein (LDL) cholesterol levels in patients with hypercholesterolemia. In a multicenter, the cholesterol-lowering effects of two diets, a control Mediterranean diet and a modified version in which walnuts were partially substituted for olive oil and other fatty foods, were compared. The diet included 8 to 11 walnuts a day, which contributed about 18% of total calories and 35% of total fat. Forty-nine men and women with serum cholesterol levels greater than 130 mg/dL and triglyceride concentrations lower than 250 mg/dL completed the crossover study. Patients followed each diet for 6 weeks with no washout period. Both diets were associated with decreases in total and LDL-cholesterol levels, but the declines were greater with the walnut diet. Mean total cholesterol levels dropped by 9.0% during the walnut diet, compared with a drop of 5.0% during the control diet. Mean LDL cholesterol declined by 11.2% during the walnut diet and 5.6% during the control diet. It was also report that the walnut diet resulted in a greater decline in lipoprotein(a) levels, 9.1% versus 3.4%. However, this drop was statistically significant only in men.

Repairing decayed teeth with natural materials, growing new teeth to replace lost ones, improved treatments for bone defects resulting from gum disease, and more rapid healing of oral wounds are some of the benefits dentistry is expected to reap from tissue engineering. According to an article published in The Journal of the American Dental Association, tissue engineering will affect dental practice significantly within the next 25 years. Less common, but still a treatment consideration, will be devices such as artificial salivary glands, and tongue muscles or mucosal grafts to replace tissues lost through surgery or trauma. According to the article, some of the earliest attempts at tissue replacement, dating back thousands of years, involved teeth. The article also states that dentistry has continued to place considerable emphasis on, and be a leader in, the study and use of biocompatible materials. Several current examples include passive approaches such as dental implants, and inductive approaches such as products which activate cells with specific molecular signals. The impetus for this latter approach was the discovery of growth factors that could lead to new bone and blood vessel formation.

TARGET HEALTH is very active in the area of Urology. A pre-IDE meeting in for a prostate cancer device has been completed and the final protocol is being sent to FDA for review. For another indication, a 12-center study is underway and the Target e*CRF is being used to monitor enrollment and safety. Please let us know if you will be attending the American Urology Association Meeting in Atlanta, April 30 -May 4, 2000.

According to an article published in the Journal of Urology (J Urol 2000;163:1085-1089), prostate-specific antigen (PSA) bounce occurs in 35% of patients 12 to 24 months after radiotherapy. The study followed 779 men who had stage T1T2N0 prostate cancer and who were treated with radioactive seed implantation followed by external beam radiation. PSA bounce, defined as an increase of 0.1 ng/mL or greater above the preceding PSA level, was seen in 273 patients. The bounce was most commonly a single event that disappeared at the next 3- or 6-month screening and was probably due to late-developing radiation prostatitis. The authors suggested that between 12 and 24 months after treatment, recurrent urinary symptoms may develop and that this time frame corresponds to the time that PSA bounce is most frequently observed. Other possible explanations included laboratory error and inconsistent laboratory practices. PSA bounce was not predictive of cancer recurrence and no significant difference in disease-free survival was seen between men with and without PSA bounce. It was suggested that physicians need to be aware of PSA bounce because it causes patient anxiety and can often result in premature initiation of diagnostic tests or treatments.

TARGET HEALTH is completing eight study reports for a Fortune 100 company in the area of antibiotics. Our writing team is lead by Anita Islam, Ph.D. with her team of Daisy Sun, M.S. and Sam Uretsky, Pharm.D.

Drug-resistant bacteria are a growing threat around the world as pathogens become resistant to antibiotics. Currently, vancomycin is an antibiotic that is considered the last line of defense against enterococcus bacteria, the organisms which cause deadly infections in the abdomen, urinary tract, post-surgical wounds and heart valves. According to an article recently published in the journal Nature, a molecule modeled on peptides, the natural proteins that organisms, ranging from plants to humans, use to kill bacteria has been shown to be effective in vitro. Up to now, peptides in development have become rapidly inactivated in vitro and have been toxic to both human cells as well as the microbes. However, a new synthetic version, called a beta-peptide, appears not to harm blood cells or break down within the body. In addition, in vitro, it has proved to be active against several drug-resistant bacteria, including strains of vancomycin-resistant enterococcus and methicillin-resistant staphylococcus (methicillin targets staphylococcus, which is responsible for infections of the skin, tissue, bones and joints. The beta-peptide seems to work by the same mechanism as the natural peptide, by punching holes in the bacteria's membrane. According to the authors, because the molecule works differently than traditional antibiotics, it would probably be harder for bacteria to evolve resistance to it. It was suggested that drugs already in advanced stages of development could be altered to incorporate the type of potent beta-peptide created by the research group. Last month, a government panel urged the Food and Drug Administration to approve Zyvox, a synthetic compound made by PHARMACIA & UPJOHN that has shown promise attacking drug-resistant bacteria. If approved, it would be the first entirely new antibiotic in 35 years.

While diet, environment, and lifestyle can all influence how a person responds to drug therapy, another key factor is one's genetic makeup. The National Institute of General Medical Sciences (NIGMS) and other components of the National Institutes of Health (NIH) are sponsoring a nationwide research effort to understand how one's genetic make-up determines the way drugs work, as well as what side effects a person might be prone to develop. This "pharmacogenetic" research approach focuses on linking the body's response to drugs with variations in particular genes. Many of these variations are expected to be "single-letter" differences, known as single-nucleotide polymorphisms or "SNPs." However, other genetic variations could be missing genes, or even extra genes. The research effort is designed to forge an interactive research network of investigators who will store data in a freely-shared information library. Other NIH centers are the National Cancer Institute (NCI); the National Heart, Lung, and Blood Institute (NHLBI); the National Human Genome Research Institute (NHGRI); the National Institute of Environmental Health Sciences (NIEHS); and the National Library of Medicine (NLM). Nine first-year awards, totaling $12.8 million, have been made.

Type 2 diabetes is characterized by decreased insulin secretion and insulin sensitivity in liver, adipose tissue, and skeletal muscle. Approximately 50% of patients treated with monotherapy require additional therapy. Rosiglitazone maleate (Avandia, SMITHKLINE BEECHAM) , a member of the thiazolidinedione class of anti-diabetic agents, targets insulin resistance by binding to the transcription factor peroxisome proliferator-activated receptor-beta, promoting synthesis of glucose transporters and activating adipocyte differentiation. Metformin hydrochloride works by reducing hepatic glucose production and gluconeogenesis, and by enhancing peripheral glucose uptake.

According to an article published in the Journal of the American Medical Association (JAMA. 2000;283:1695-1702), the combination treatment with once-daily metformin-rosiglitazone improves glycemic control, insulin sensitivity, and beta-cell function (BCF) more effectively than treatment with metformin alone. The study was performed to evaluate the efficacy and safety of adding 4 mg/d and 8 mg/d of rosiglitazone maleate to maximal-dosage of metformin in patients with poorly controlled type 2 diabetes. Efficacy was assessed by comparing the level changes in HbA(1c), fasting plasma glucose (FPG), fructosamine, serum insulin, free fatty acids (FFA), lipids, lactate, and estimates of insulin sensitivity and BCF between the treatment groups. The study was performed at 36 outpatient centers in the US with 348 patients aged 40 to 80 years. Randomized patients had baseline mean fasting plasma glucose level of 12.0 mmol/L (216 mg/dL), mean glycosylated hemoglobin level of 8.8%, and mean body mass index of 30.1 kg/m*m. Patients received either 2.5 g/d of metformin plus placebo (n = 116); 2.5 g/d of metformin plus 4 mg/d of rosiglitazone (n = 119); or 2.5 g/d of metformin and 8 mg/d of rosiglitazone (n = 113) for 26 weeks. Results showed that glycosylated hemoglobin levels, fasting plasma glucose levels, insulin sensitivity, and BCF improved significantly with metformin-rosiglitazone therapy in a dose-dependent manner. The mean levels of glycosylated hemoglobin decreased significantly by 1.0% in the 4 mg/d metformin-rosiglitazone group and by 1.2% in the 8 mg/d metformin-rosiglitazone group and fasting plasma glucose levels by 2.2 mmol/L (39.8 mg/dL) and 2.9 mmol/L (52.9 mg/dL) compared with the metformin-placebo group. Of patients receiving 8 mg/d of metformin-rosiglitazone, 28.1% achieved a glycosylated hemoglobin level of less than 7%. Significant dose-dependent increases in body weight and total and low-density lipoprotein cholesterol levels were observed for both rosiglitazone groups vs placebo. The proportion of patients reporting adverse experiences were comparable.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA. A pre-IND meeting is scheduled for the first week in October. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available. For additional information, please contact Dr. Jules T. Mitchel at TARGET HEALTH.

The FDA has announced that Norman Marks, M.D. will be Medical Director of MedWatch. Dr. Marks was a primary reviewer in the Division of Reproductive and Urological Drug Products (CDER). Dr. Marks received his medical degree from the University of Wisconsin Medical School in 1970 and completed a rotating internship at the Pennsylvania Hospital in Philadelphia in 1971. He spent two years as a Medical Officer with the Indian Health Service in Rapid City, S.D., and then completed his residency in Urological Surgery at the Medical College of Wisconsin in Milwaukee in 1977. He is a Diplomate, American Board of Urology, and a Fellow in the American College of Surgeons. Dr. Marks has a long-standing interest in how physicians make clinical decisions. His extensive experience should enable him to increase awareness of risks associated with the use of regulated medical products and to improve the MedWatch system.

TARGET HEALTH INC. is a full service CRO with full-time staff dedicated to all aspects of Regulatory Affairs, Clinical Research Management, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEALTH also has a group of specialized advisors in the areas of Toxicology, Analytical Methods Validation, Product and Process Development, Quality Assurance, Manufacturing and Animal Health. Let us be of help to you on your next project.

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Last modified: April 11, 2000