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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Peter Singleton who wrote (22191)	6/14/1998 7:07:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Peter, Here's what SBH had to say about Avandia SmithKline Beecham's Rosiglitazone Protects Insulin-Producing Cells In Type 2 Diabetes Pre-clinical Studies Show Compound Reduces Pancreatic Exhaustion and Prevents Progression to Diabetes ADVANCE FOR RELEASE AT 7 P.M. EDT MONDAY, JUNE 15/ ADVANCE/CHICAGO, June 15 /PRNewswire/ -- Two pre-clinical papers presented today at the American Diabetes Association (ADA) 58th Scientific Sessions show that the investigational oral diabetes medication rosiglitazone maleate (Avandia(R), SmithKline Beecham) protects the insulin-producing cells of the pancreas. In a pre-diabetic animal model, rosiglitazone prevented the pancreatic degeneration that otherwise would have led to diabetes. In a diabetic model, rosiglitazone allowed recovery of the pancreas already strained by producing too much insulin. Pancreatic exhaustion, in which the insulin-producing cells become overworked and decline in function, leads to steadily worsening diabetes. In humans, the corresponding condition often leads to dependence on insulin injections. Rosiglitazone is an investigational drug in a new class of oral diabetes medicines called thiazolidinediones (TZDs), or insulin sensitivity enhancers. It directly targets insulin resistance -- an underlying condition responsible for type 2 diabetes -- and works by enhancing the body's ability to use its own insulin more effectively. "Our results show that, in animal models, rosiglitazone can prevent pancreatic exhaustion by enhancing insulin sensitivity," says the lead author of one study, Diane T. Finegood, Ph.D., associate professor, School of Kinesiology at Simon Fraser University, Vancouver, Canada. "If replicated in humans, this may represent a major advance in treatment of the disease. By preventing pancreatic exhaustion, you can prevent progressively worsening diabetes, which often leads people with type 2 diabetes to become dependent on insulin injections." Pancreatic Size Maintained, Diabetes Prevented Led by Dr. Finegood, the study group began treating Zucker Diabetic Fatty (ZDF) rats shortly before the onset of diabetes and found that rosiglitazone prevented both diabetes and pancreatic exhaustion in rats when treatment began in the pre-diabetic stage. Genetically obese ZDF rats are considered a good model for human type 2 diabetes, since their obesity is associated with insulin resistance. As insulin resistance and failure of the pancreatic insulin-producing cells lead to elevated blood sugar levels, diabetes develops. Eventually these animals experience similar long-term diabetic complications to those in humans, such as eye and kidney damage. Rosiglitazone-treated animals were able to maintain normal blood sugar levels throughout the study. In fact, they were able to maintain blood sugar control with lower circulating insulin levels at the end of the study than at the beginning. This occurred because they were able to use their body's own insulin more efficiently. Moreover, while the mass of insulin-producing cells in untreated controls fell 48 percent during the final two weeks of the study, in rosiglitazone-treated animals the fall was prevented. Thus, rosiglitazone prevented diabetes and preserved not only these animals' ability to make insulin but the insulin-producing cells themselves. By contrast, in untreated controls, blood sugar levels rose as insulin output fell; by the end of the six-week study, insulin output was less than 20 percent of its starting value and the animals were overtly diabetic. "These results show that rosiglitazone prevents both diabetes and pancreatic exhaustion when treatment of ZDF rats begins in the pre-diabetic stage," comments Dr. Finegood. "Importantly, our study also demonstrates that rosiglitazone helps preserve the size and function of the pancreas' insulin-producing tissues -- a key factor in preventing pancreatic exhaustion and onset of diabetes." Pancreatic Recovery The second group presenting their rosiglitazone data at the ADA meeting studied genetically diabetic (db/db) mice who were already in the early stages of diabetes. The amount of insulin in their pancreas had fallen 70 percent compared to the lean, non-diabetic controls. In six days, mice treated with rosiglitazone normalized blood sugar levels. Within 10 days, the amount of insulin stored in the pancreas and the fraction of the pancreas devoted to insulin synthesis had also returned to normal. Significantly, the researchers found no increase in expression of the insulin gene, ruling out any rosiglitazone effect on insulin synthesis. "Rosiglitazone normalizes blood sugar without stimulating insulin output, as some older oral diabetes medications do," says study investigator Michael A. Cawthorne, Ph.D., professor, Metabolic Research, University of Buckingham, UK. "Our results document that this normalization of blood sugar not only spares the insulin-producing cells of the pancreas, but if begun early enough, actually allows these cells to recover from the effects of previous insulin overproduction. Assuming these results carry over to humans, they further underscore the importance of early diagnosis and treatment in type 2 diabetes." "We are very pleased with this preliminary data which suggest that rosiglitazone may preserve pancreatic size and function, and also attack the fundamental problem of insulin resistance in type 2 diabetes," says Jai Patel, M.D., group director, Diabetes and Metabolism, Clinical Research & Development, SmithKline Beecham. "Although it may be years before we have proof that pancreatic recovery is possible in humans, we are excited by the possibilities these two papers raise." Discovered and developed by SmithKline Beecham, rosiglitazone is currently in phase III clinical trials. SmithKline Beecham (NYSE: SBH) -- one of the world's leading health care companies -- discovers, develops, manufactures and markets pharmaceuticals, vaccines, over-the-counter medicines and health-related consumer products, and provides health care services including clinical laboratory testing, disease management, and pharmaceutical benefit management. SOURCE SmithKline Beecham CO: SmithKline Beecham ST: Illinois IN: MTC SU: PDT 06/12/98 17:14 EDT prnewswire.com

To: Peter Singleton who wrote (22191)	6/14/1998 7:09:00 AM
From: Henry Niman	Respond to of 32384

Here's more from SBH on Avandia: Study Demonstrates SmithKline Beecham's Rosiglitazone Lowers Blood Sugar Levels in Type 2 Diabetes Novel Diabetes Drug Attacks an Underlying Cause of the Disease ADVANCE FOR RELEASE AT 7:00 P.M. EDT SUNDAY, JUNE 14/ ADVANCE/ CHICAGO, June l4 /PRNewswire/ -- The investigational oral diabetes drug rosiglitazone maleate (Avandia(R), SmithKline Beecham) produces clinically and statistically significant lowering of blood sugar in type 2 diabetes patients, according to a study presented today at the annual meeting of the American Diabetes Association (ADA) 58th Annual Scientific Sessions. Blood sugar control is recognized by the ADA as the cornerstone for managing diabetes and preventing serious complications. In the multi-center, placebo-controlled, phase III clinical trial, rosiglitazone 8 mg/day when used alone reduced blood sugar levels by up to 76 milligrams, per deciliter (mg/dL) compared to the placebo group. "This 76 mg/dL drop in blood sugar levels is impressive. In trials of this type, it is rare to see a reduction in blood sugar levels greater than 60 mg/dL with any single drug," says Barry Goldstein, M.D., rosiglitazone study group investigator, and director, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Philadelphia, Pa. "Rosiglitazone's ability to improve blood sugar control may help patients better manage their disease. Improved control may delay or prevent some of the long-term complications of diabetes, such as blindness or kidney disease." Diabetes mellitus is a chronic disease characterized by high blood sugar levels that result from defects in the body's ability to use and/or produce insulin. It can lead to blindness, heart disease, kidney failure and limb amputation. There are two main types of diabetes: type 1 and type 2. People with type 1 diabetes are usually diagnosed when they are children or young adults. The pancreas of a person with type 1 diabetes makes little or no insulin and these patients must inject insulin every day to live. Most people with diabetes have type 2, in which the pancreas keeps making insulin for some time, but the body can't use it very well. Eventually, many patients with type 2 diabetes will require insulin injections. Rosiglitazone directly targets insulin resistance -- an underlying condition responsible for type 2 diabetes -- and is a member of a new class of diabetes agents called thiazolidinediones (TZDs), insulin sensitivity enhancers. In contrast to traditional type 2 diabetes medicines, which increase insulin production in the pancreas or decrease glucose output through the liver, rosiglitazone reduces the amount of insulin needed while improving glycemic control. In other studies, rosiglitazone has also been shown to have no clinically significant drug interactions with acarbose, digoxin, metformin, ranitidine, warfarin, and cytochrome P450-metabolized drugs, such as nifedipine and one of the most commonly prescribed oral contraceptives. Rosiglitazone Lowers Blood Sugar The 26-week study included 493 patients, most of whom were receiving another oral diabetes drug at the time of study entry. Study participants were assigned to one of three groups: placebo, rosiglitazone 8 mg/day or rosiglitazone 4 mg/day. The study included periodic measurements of blood sugar and hemoglobin A1c (HbA1c) levels, which reflect average amounts of blood sugar over the preceding two to three months and are directly related to the risks of long-term complications. Compared to placebo, blood sugar levels were reduced by up to 76 mg/dL in the group receiving the highest dose of rosiglitazone (8 mg/day). Results for the group receiving the lower dose (4 mg/day) demonstrated a 58 mg/dL reduction in blood sugar levels. The effectiveness of rosiglitazone was further confirmed by measurement of HbA1c levels. In the study, HbA1c levels were reduced by 1.54 percent and 1.21 percent of total hemoglobin in the 8 mg/day and 4 mg/day dose, respectively. "It is very exciting that we may soon have a new treatment option for type 2 diabetes," says Dr. Goldstein. "This treatment alternative -- which helps the body more effectively use its natural insulin -- may assist patients in managing their disease." "This is a statistically and clinically significant drop in blood sugar levels, and may help patients meet the ADA treatment goals for blood sugar control," says James Gavin, M.D., past ADA president and senior scientific officer of the Howard Hughes Medical Institute, Chevy Chase, Md. "Both patients and physicians recognize the importance of meeting the ADA goals, however, this has been difficult with current single-agent treatment regimens." Rosiglitazone Is Well Tolerated Rosiglitazone was well tolerated. Overall, reported side effects occurred at similar frequencies in the placebo group and the rosiglitazone treatment groups. The most common adverse events reported in both groups included upper respiratory tract infections and headache. As is common practice, patients in the clinical trial were routinely tested for blood enzyme elevations that might suggest liver damage. "There have been no reported cases of idiosyncratic drug reaction, leading to jaundice or liver failure in any of the ongoing phase III clinical trials," says Jai Patel, M.D., group director, Diabetes and Metabolism, Clinical Research & Development, SmithKline Beecham. Of the nearly 5,500 type 2 diabetes patients enrolled in these trials, approximately 2,500 received rosiglitazone for a minimum of six months, with 1,400 receiving the drug for more than one year. "In the study, rosiglitazone appeared to be free of clinically significant liver side effects," says Harold Lebovitz, M.D., rosiglitazone study group investigator, and professor of medicine, chief, Endocrinology and Metabolism/Diabetes, and director of the Diabetes, Diagnostic and Treatment Center at State University of New York Health Science Center in Brooklyn. "This could potentially eliminate the need to perform costly and routine liver function tests on patients, if additional and continuing studies do not show evidence of any significant liver toxicity." Discovered and developed by SmithKline Beecham, rosiglitazone is currently in phase III clinical trials. SmithKline Beecham (NYSE: SBH) -- one of the world's leading health care companies -- discovers, develops, manufactures and markets pharmaceuticals, vaccines, over-the-counter medicines and health-related consumer products, and provides health care services including clinical laboratory testing, disease management and pharmaceutical benefit management. SOURCE SmithKline Beecham CO: SmithKline-Beecham ST: Illinois IN: MTC SU: 06/12/98 16:43 EDT prnewswire.com

To: Peter Singleton who wrote (22191)	6/14/1998 7:24:00 AM
From: Henry Niman	Respond to of 32384

Peter, I think that you are correct about the future markets in SERMs and Rexinoids. LGND is well placed in both areas. In SERMs they have three products that they characterized that have now moved into the clinic. The most advanced is Droloxifene, discovered under the PFE osteoporosis alliance. The back-up selection, CP-366,156 has also entered the clinic and I believe that it has now progressed to Phase II. A new clinical product is TSE424, identified under the AHP women's health alliance. In addition to the 3 SERMs listed above, LGND is working with LLY to look at treatment of breast cancer with a combination approach using LLY's second generation SERMs (their first is Evista, aka Raloxifene), and LGND's second generation rexinoids such as LGD1268 or LGD1324 (the first generation is Targretin). On the diabetes front, LGND is also moving forward aggressively. Targretin is in the clinic in Europe and should be entering US trials soon (at the Phase II level). One of their second generation products (either LGD1268 or LGD1324) should be entering US trials soon also (as an IND). These rexinoids have been shown to be affective in animal (mouse and rat) models of diabetes and they synergize with SERMs such as Rezulin and Avandia. LGND of course also has its own PPAR program going to come up with even better TZDs. the above progress can be seen at home.att.net Of course this all requires capital, and up to this point, those funds have been generated through alliances and equity positions by partners. In addition to these partnered programs, LGND claims to have the largest androgen program in the world (including pharmas) and I suspect that their progress with small molecule mimic of polypeptide hormones has been spectacular.

To: Peter Singleton who wrote (22191)	6/17/1998 6:58:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Peter, Although LGND's alliance with SBH centers on hematopoietic growth factors (mimics for Epogen, Neupogen, and Leptin), the top two clinical compounds listed by SBH in their pipeline report were a TZD and SERM (both classes of drugs synergize with Targretin and other rexinoids such as LGD1268 and LGD1324): Tuesday April 14, 8:31 am Eastern Time Company Press Release SOURCE: SmithKline Beecham SmithKline Beecham's Expanding Portfolio of Drugs and Vaccines - 'Deep, Diversified and Innovative' NEW YORK, April 14 /PRNewswire/ -- SmithKline Beecham's (NYSE: SBH - news) expanding portfolio of drugs and vaccines is ''deep, diversified and innovative and will translate into sustained growth for the company well into the next millennium,'' SB President and Chief Operating Officer Dr. Jean-Pierre Garnier said today. In an update to securities analysts covering an array of more than 60 new chemical entities, new indications and vaccines in SB's pipeline, Dr. Garnier noted that ''product candidates now moving through clinical trials promise to sustain over the next several years the steady flow of new pharmaceuticals that SB has introduced to the healthcare marketplace throughout the 1990s. The pace at which these compounds are moving through the clinic reflects SB's commitment to value creation in its drug-development program. ''Looking still further into the future, we see unprecedented drug-discovery opportunities offered by rapid advances in molecular biology. To secure success, we have strengthened not only our in-house capabilities, but also our network of alliances with both academic institutions and biotechnology companies,'' Dr. Garnier said. Product candidates currently moving through clinical trials include: NEW CHEMICAL ENTITIES Avandia (rosiglitazone), for treating type 2 diabetes. Avandia, a potent and selective member of the glitazone drug class, has progressed to Phase III in an extensive clinical program intended to develop the drug for use both as first-line monotherapy and in combination with conventional therapy. Avandia attacks the fundamental defect underlying type 2 diabetes, the resistance of cells to the action of insulin, by activating nuclear hormone receptors. In trials to date, the drug has demonstrated sustained glycemic control without drug-drug interactions and with no evidence of hepatic side effects. New drug applications for Avandia are scheduled to be filed in the U.S. and Europe within 12 months. Idoxifene, a selective estrogen-receptor modulator (SERM). Idoxifene is in Phase III for the prevention of osteoporosis and Phase II for the treatment of advanced breast cancer. Preliminary studies suggest that idoxifene favorably influences lipid levels. Additional studies will examine the potential benefits of idoxifene in treating or preventing cognitive disorders. In clinical trials, idoxifene has been well tolerated after up to one year of treatment with low incidence of hot flashes and no evidence of patterns of increased venous thromboembolism or leg cramps.