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

To: Peter Singleton who wrote (17860)	3/25/1998 2:28:00 PM
From: tonyt	Read Replies (1) \| Respond to of 32384

Dow just turned south -- down 44. NASDAQ up 13. LGND holding steady, down 1/4

To: Peter Singleton who wrote (17860)	3/25/1998 9:32:00 PM
From: Henry Niman	Respond to of 32384

A recent review of the Biotech sector can be found at: techstocks.com

To: Peter Singleton who wrote (17860)	3/26/1998 6:39:00 AM
From: Henry Niman	Respond to of 32384

The diabetes news that is being published today in Nature and NEJM is of interest. The leptin receptor defect should help the public understand animal models. Now human counterparts of the ob/ob mouse (doesn't make leptin) and the db/db mouse (leptin receptor is defective) have been found and the humans are similar to the mice (morbidly obese, diabetic, and undeveloped sexually). Earlier reports in the popular press had indicated that the role of leptin in humans wasn't as simple as its role in mice. The current paper indicates that the role is virtually identical, but the condition is rare (few humans fail to make leptin or have truncated receptors, but few mice also have those genotypes). The models merely show the effects of extreme conditions. There is a very good chance that obese individuals don't use leptin efficiently and there may be similarities between insulin resistance (type II diabetes) and leptin resistance (adult onset obesity?). Both may end up being treated with combinations of drugs that influence gene expression. Speaking of drug combos, the NEJM article indicates that troglitizone (Rezulin) works (reduces insulin resistances) in combination with Metformin (reduces glucose production). As posted previously, LLY will be testing Targretin in combination with Rezulin, insulin, Metformin, and sulfanylureas. As with cancer and AIDS, diabetes treatments will increasingly rely on drug combinations to increase efficacy and safety (as well as drug costs - but lower overall costs).

To: Peter Singleton who wrote (17860)	3/26/1998 6:53:00 AM
From: Henry Niman	Respond to of 32384

Looks like LGND related stories are popping up everywhere. Jesse Eisinger has a story on the LLY downgrade by Solomon Smith Barney. They cite lower than expected Evista sales and have also lowered earnings projections (role in breast cancer prevention remains to be proven and osteoporosis prevention is an embryonic market that is influence strongly by AHP's Premarin. On the analyst downgrade front, TSC suggest that LLY might even be for sale if things don't turn around: "The short-seller thinks that Merrill will downgrade LLY next, and then perhaps Morgan Stanley, at which point he would cover. However, if things got very gloomy for LLY, the company would be put up for sale and Morgan would angle seriously for the banking business, which might keep analyst Paul Brooke from lowering his LLY rating, this money manager thought. " Sounds like its time for LLY to crank up the Rexinoid clinical as well as preclincal programs. Prozac goes off patent in 2001 or 2003. All of the analysts that are projected to cut LLY's rating are on my short list of firms that I expect to initiate or reinitiate coverage of LGND.

To: Peter Singleton who wrote (17860)	3/26/1998 7:57:00 AM
From: Henry Niman	Respond to of 32384

Here's more on Evista: Lilly's Worldwide Trial to Assess the Efficacy of Evista in Preventing Heart Attacks PR Newswire - March 24, 1998 08:35 LLY %MTC V%PRN P%PRN Lilly Announces Investment to Further Explore Cardiovascular Profile of Evista, a SERM INDIANAPOLIS, March 24 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced the initiation of a large, prospective clinical trial, entitled Raloxifene Use for The Heart (RUTH), to determine the ability of Evista(R) (raloxifene hydrochloride) to prevent heart attacks and heart- related deaths in postmenopausal women. Evista is the first in a class of new drugs called selective estrogen receptor modulators (SERMs) to be approved by the FDA for the prevention of postmenopausal osteoporosis. In osteoporosis prevention studies, Evista has demonstrated the ability to preserve bone and have a favorable effect on lipids without stimulating reproductive tissues such as the breast and uterus. The RUTH trial, which will be managed by an executive steering committee independent of Lilly, will enroll in 25 countries approximately 10,000 postmenopausal women at risk of heart attack. The worldwide trial will last up to seven and one-half years. "We are proud to announce the initiation of this landmark clinical trial, one of the largest for postmenopausal women," said principal investigator Elizabeth Barrett-Connor, M.D., professor and chief, Division of Epidemiology, Department of Family and Preventive Medicine, University of California-San Diego. "I think it is remarkable that Lilly has committed to the RUTH trial early in the product's life to determine whether Evista can help protect against heart disease, the leading cause of death for American women." In previous osteoporosis clinical trials, Evista decreased serum cholesterol and certain blood-clotting factors. Evista produced significant reductions in LDL, or "bad" cholesterol, and total cholesterol, but did not increase HDL, or "good" cholesterol, when compared with placebo. Evista significantly reduced serum fibrinogen and did not increase triglycerides (fatty acids). "Based on these results, Lilly is eager to fully explore the cardiovascular profile of Evista," said Pamela Anderson, M.D., clinical research physician, Eli Lilly and Company. "The RUTH trial reflects both Lilly's belief in the potential of Evista and the company's commitment to improving women's cardiovascular health." Heart disease is the number-one killer of women in the U.S. and developed countries. According to the American Heart Association, more than one in three women over the age of 65 has some form of cardiovascular disease. "As the population ages, the public health impact of cardiovascular disease in women is likely to increase, pointing to a significant need to provide postmenopausal women with new, preventive options," said co-principal investigator Nanette Wenger, M.D., professor of medicine, Division of Cardiology, Emory University School of Medicine. "The RUTH trial will tell us if Evista may be such a choice for women after menopause," she said. The primary objective of RUTH is to assess whether chronic treatment with Evista reduces the incidence of coronary death and nonfatal myocardial infarction (heart attacks) in postmenopausal women at risk for cardiovascular events. The trial will also assess the effect of Evista on a variety of other important measures, including all-cause death, all-cause hospitalization, revascularization procedures, stroke and breast cancer. Outcomes in women taking Evista will be compared with those in women taking a placebo. To participate in the RUTH trial, women must be: * postmenopausal * over the age of 55 * at risk for heart attack or have coronary artery disease * able to understand and sign the informed consent document. Evista is currently available and indicated for the prevention of osteoporosis in postmenopausal women. To date, more than 12,800 postmenopausal women have participated in completed and ongoing Evista clinical trials. The effects of Evista on fracture risk are not yet known. Studies are ongoing to evaluate the ability of Evista to prevent fractures in postmenopausal women with established osteoporosis and involve more than 7,700 women worldwide. As with most drugs, Evista was associated with some side effects, the majority of which were reported as mild. The most commonly observed side effect was hot flashes (24.6 percent incidence among the Evista group versus 18.3 percent incidence among the placebo group); however, discontinuation rates due to hot flashes were about 2 percent in both groups. Women taking Evista also reported a higher rate of leg cramps than women taking placebo. The cramps, generally reported as "mild," did not cause women to discontinue Evista therapy. A rare but serious side effect associated with Evista was an increase in venous thromboembolic events (blood clots) similar to the rate seen with estrogen replacement therapies. Importantly, in studies up through two and one-half years, Evista did not increase the risk for breast cancer or cancer of the lining of the uterus. Eli Lilly and Company is a global research-based pharmaceutical corporation headquartered in Indianapolis, Ind., that is dedicated to creating and delivering innovative pharmaceutical-based health care solutions that enable people to live longer, healthier and more active lives. Women's health is a key area in which the company is focusing its efforts. For detailed information about Evista, visit Lilly's new website at evista.com. SOURCE Eli Lilly and Company /CONTACT: Angela Sekston of Eli Lilly, 317-276-6337; or Stacey Isaacs for Eli Lilly, 212-598-3636/ /Company News On-Call: prnewswire.com or fax, 800-758-5804, ext. 126236/ /Web site: lilly.com evista.com (LLY)

To: Peter Singleton who wrote (17860)	3/26/1998 8:01:00 AM
From: Henry Niman	Respond to of 32384

Here's more on the diabetes combo: March 26, 1998 Diabetes Drugs Called Effective In Combination By THE ASSOICATED PRESS combination of two new diabetes drugs has proved a powerful means of controlling hard-to-treat cases of the disease, according to a study reported today in The New England Journal of Medicine. The drugs are troglitazone, approved by the Food and Drug Administration last year, and metformin, approved two years ago. Both are for adult-onset diabetes, a disease of high blood sugar that afflicts millions of Americans and can lead to kidney damage, blindness, heart disease and other complications. While diet and exercise can control blood sugar levels in these people, most will eventually need insulin, the hormone that helps the muscles convert blood sugar into energy. But insulin shots and some older diabetes drugs do not work well in many patients. Troglitazone and metformin have previously been shown to be especially useful in these patients, troglitazone by making muscles more sensitive to insulin, and metformin by reducing the blood sugar produced by the liver. The new study found that the drugs work even better in combination than they do alone. The study was paid for by the Public Health Service and by the Warner-Lambert Company, which sells troglitazone as Rezulin. Metformin is sold as Glucophage by Bristol-Myers Squibb . In the study, led by Dr. Silvio Inzucchi of Yale University, 29 patients with moderate adult-onset, or type II, diabetes were randomly assigned to take either metformin or troglitazone for three months. Then all were given both drugs for three more months. Taken individually, metformin and troglitazone each reduced the patients' after-meal blood-sugar levels by 25 percent on average. Taken together, the drugs yielded a 41 percent drop. Troglitazone can cause liver failure and even death, so patients must be carefully watched for signs of liver damage. But in an editorial accompanying the study, Dr. Hiroo Imura of Kyoto University in Japan wrote, "Troglitazone might well be the first-choice drug for patients with mild type II diabetes."

To: Peter Singleton who wrote (17860)	3/26/1998 8:05:00 AM
From: Henry Niman	Respond to of 32384

Here's the abstract for one of the NEJM articles: Efficacy and Metabolic Effects of Metformin and Troglitazone in Type II Diabetes Mellitus Silvio E. Inzucchi, David G. Maggs, Geralyn R. Spollett, Stephanie L. Page, Frances S. Rife, Veronika Walton, Gerald I. Shulman Abstract Background. Combination therapy is logical for patients with non-insulin-dependent (type II) diabetes mellitus, because they often have poor responses to single-drug therapy. We studied the efficacy and physiologic effects of metformin and troglitazone alone and in combination in patients with type II diabetes. Methods. We randomly assigned 29 patients to receive either metformin or troglitazone for three months, after which they were given both drugs for another three months. Plasma glucose concentrations during fasting and postprandially and glycosylated hemoglobin values were measured periodically during both treatments. Endogenous glucose production and peripheral glucose disposal were measured at base line and after three and six months. Results. During metformin therapy, fasting and postprandial plasma glucose concentrations decreased by 20 percent (58 mg per deciliter [3.2 mmol per liter], P<0.001) and 25 percent (87 mg per deciliter [4.8 mmol per liter], P<0.001), respectively. The corresponding decreases during troglitazone therapy were 20 percent (54 mg per deciliter [2.9 mmol per liter], P = 0.01) and 25 percent (83 mg per deciliter [4.6 mmol per liter], P<0.001). Endogenous glucose production decreased during metformin therapy by a mean of 19 percent (P = 0.001), whereas it was unchanged by troglitazone therapy (P = 0.04 for the comparison between groups). The mean rate of glucose disposal increased by 54 percent during troglitazone therapy (P = 0.006) and 13 percent during metformin therapy (P = 0.03 for the comparison within the group and between groups). In combination, metformin and troglitazone further lowered fasting and postprandial plasma glucose concentrations by 18 percent (41 mg per deciliter [2.3 mmol per liter], P = 0.001) and 21 percent (54 mg per deciliter [3.0 mmol per liter], P<0.001), respectively, and the mean glycosylated hemoglobin value decreased 1.2 percentage points. Conclusions. Metformin and troglitazone have equal and additive beneficial effects on glycemic control in patients with type II diabetes. Metformin acts primarily by decreasing endogenous glucose production, and troglitazone by increasing the rate of peripheral glucose disposal. (N Engl J Med 1998;338:867-72.) Source Information From the Section of Endocrinology, Yale University School of Medicine (S.E.I., D.G.M., G.R.S., S.L.P., F.S.R., V.W., G.I.S.), and the Howard Hughes Medical Institute (G.I.S.), both in New Haven, Conn. Address reprint requests to Dr. Inzucchi at the Section of Endocrinology, TMP 5, Yale University School of Medicine, Box 208020, New Haven, CT 06520.

To: Peter Singleton who wrote (17860)	3/26/1998 8:08:00 AM
From: Henry Niman	Respond to of 32384

Here's the other NEJM abstract: Effect of Troglitazone in Insulin-Treated Patients with Type II Diabetes Mellitus Sherwyn Schwartz, Philip Raskin, Vivian Fonseca, Jane F. Graveline, for the Troglitazone and Exogenous Insulin Study Group Abstract Background. Troglitazone is a new oral antidiabetic drug that increases the sensitivity of peripheral tissues to insulin. It may therefore increase the efficacy of exogenous insulin in patients with insulin-resistant diabetes mellitus. Methods. We studied the effect of troglitazone or placebo in 350 patients with poorly controlled non-insulin-dependent (type II) diabetes mellitus (glycosylated hemoglobin values, 8 to 12 percent; normal, 4.3 to 6.1 percent) despite therapy with at least 30 U of insulin daily. The patients were randomly assigned to receive 200 mg of troglitazone (116 patients), 600 mg of troglitazone (116 patients), or placebo (118 patients) daily for 26 weeks. Insulin doses were not increased and were reduced only to prevent hypoglycemia. Glycosylated hemoglobin, serum glucose while fasting, serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured 5 times during an 8-week base-line period and 10 times during the 26-week treatment period. Daily insulin doses were recorded during both periods. Results. Ninety percent of the patients completed the study. The adjusted mean glycosylated hemoglobin values decreased by 0.8 and 1.4 percentage points, respectively, in the group given 200 mg of troglitazone and the group given 600 mg of troglitazone, and fasting serum glucose concentrations decreased by 35 and 49 mg per deciliter (1.9 and 2.7 mmol per liter), respectively, despite decreases in the insulin dose of 11 percent and 29 percent (P<0.001 for all comparisons with the placebo group). Serum total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations increased slightly and serum triglyceride concentrations decreased slightly in the troglitazone-treated patients. Conclusions. When given in conjunction with insulin, troglitazone improves glycemic control in patients with type II diabetes mellitus. (N Engl J Med 1998;338:861-6.) Source Information From the Diabetes and Glandular Diseases Clinic, San Antonio, Tex. (S.S.); the University of Texas Southwestern Medical School, Dallas (P.R.); the University of Arkansas for Medical Sciences and John L. McClellan Memorial Veterans' Hospital, Little Rock (V.F.); and Sankyo U.S.A., New York (J.F.G.). Address reprint requests to Ms. Graveline at Sankyo U.S.A., 780 Third Ave., Suite 4700, New York, NY 10017. The other members of the Troglitazone and Exogenous Insulin Study Group are listed in the Appendix. Appendix In addition to the authors, the Troglitazone and Exogenous Insulin Study Group includes the following investigators: T. Blevins, Austin, Tex.; J. Blodgett, San Antonio, Tex.; P. Dandona, Buffalo, N.Y.; B. Draznin, Denver; J. Drucker and S. Plevin, Palm Harbor, Fla.; L. Fish, Minneapolis; B. Francis, Seattle; R. Guthrie, New Orleans; B. Haag, Springfield, Mass.; B. Henson, Kansas City, Mo.; J. Levine, Nashville; W. Mitchell, Albuquerque, N.M.; W. Nicholas, Jackson, Miss.; M. Nolte, San Francisco; S. Pek, Ann Arbor, Mich.; A. Peters and M. Davidson, Los Angeles; P. Ross, Fairfax, Va.; R. Suwannasri, St. Louis; and R. Teague, Birmingham, Ala.

To: Peter Singleton who wrote (17860)	3/26/1998 8:12:00 AM
From: Henry Niman	Respond to of 32384

Here's the NEJM editorial: A Novel Antidiabetic Drug, Troglitazone -- Reason for Hope and Concern Type II (non-insulin-dependent) diabetes mellitus is characterized by insulin resistance, increased hepatic glucose production, and impaired secretion of insulin by pancreatic beta cells. Although the primary defect underlying these abnormalities is still not known, previous longitudinal studies have indicated that insulin resistance precedes any evidence of glucose intolerance in most patients. The goal of oral therapy with antidiabetic drugs is to lower blood glucose concentrations toward normal by improving the pathophysiologic abnormalities. Several classes of drugs are now available for the management of type II diabetes mellitus. The oldest are the sulfonylurea compounds. Although they may have some extrapancreatic actions, their chief action is to stimulate insulin secretion through binding to sulfonylurea receptors on the membrane of beta cells. Hypoglycemia is therefore one of the untoward effects of these drugs. The second class of drugs is the biguanides, principally metformin. They act mainly by decreasing hepatic glucose production, but they may act peripherally as well. The third class of drugs inhibits (alpha)-glucosidase. They delay the digestion of carbohydrates and therefore the absorption of glucose, thus blunting the postprandial increase in blood glucose concentrations. More recently, considerable effort has been devoted to the search for drugs that would reduce peripheral insulin resistance. This effort led to the development of a series of thiazolidinedione derivatives that correct hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in animals with type II diabetes. (1,2) These drugs therefore decrease the insulin resistance that is such an important initial event in the pathogenesis of type II diabetes. An interesting feature of thiazolidinedione compounds is that they bind to the (gamma) isoform of the peroxisome proliferator-activated receptor. (3) This receptor, a member of the nuclear-receptor superfamily, is a transcription factor that enhances the differentiation of fibroblasts into adipose cells and the expression of genes involved in intermediary metabolism. (3) In humans, the receptor predominates in adipose tissue, muscle, and large intestine. (4) Thiazolidinediones appear to reduce insulin resistance at least in part by increasing peripheral glucose uptake, but their exact mechanism of action is not known. (5) Among the thiazolidinedione compounds, troglitazone was the first to become widely available, and clinical trials of this drug have been conducted in the United States, Europe, and Japan. In these trials, troglitazone significantly lowered blood glucose concentrations. In this issue of the Journal, Schwartz et al. (6) report the results of a multiinstitutional, double-blind study of the efficacy of troglitazone in 350 patients with type II diabetes that was not well controlled by insulin therapy. Troglitazone significantly decreased blood glucose concentrations and glycosylated hemoglobin values, with nadirs at 4 to 8 weeks and 16 weeks, respectively, and allowed a reduction in the patients' daily doses of insulin. Similar results were obtained in a study in Japan. (5) Troglitazone is also effective in patients whose hyperglycemia is not adequately controlled by sulfonylurea therapy, and as reported by Inzucchi et al. (7) in this issue of the Journal, it further lowers blood glucose concentrations in patients who are taking metformin. Troglitazone is also effective as sole therapy in patients with type II diabetes. (7,8) Taken together, these results indicate that troglitazone is useful either alone or in combination with other drugs for glycemic control in patients with type II diabetes. To understand the mechanism of action of troglitazone, Inzucchi et al. (7) performed hyperinsulinemic-euglycemic clamp studies. They found that troglitazone increased insulin-mediated peripheral glucose disposal by muscle, which accounted for the entire glucose-lowering effect associated with a dose of 400 mg daily. Inzucchi et al. did not find that troglitazone affected endogenous glucose production, in contrast to previous studies. On the other hand, metformin lowered blood glucose concentrations as much as troglitazone did, primarily by decreasing endogenous glucose production. The effects of troglitazone on lipid metabolism are of interest, since a major target of its action is adipose tissue. Serum total, high-density lipoprotein, and low-density lipoprotein cholesterol concentrations either did not change or increased slightly during treatment with troglitazone, whereas serum concentrations of triglycerides and free fatty acids tended to decrease. (5,6) Body weight increased slightly in many studies. The discovery of the thiazolidinediones has renewed optimism that patients with type II diabetes can be treated more effectively. These drugs are the first that sensitize peripheral tissue to the action of insulin, and they thus reduce the need for insulin. Therefore, unlike the sulfonylurea drugs, they are not likely to lead to beta-cell exhaustion after long-term treatment. Unfortunately, troglitazone has a propensity to cause hepatic dysfunction, which in several instances has been fatal. These findings led Watkins and Whitcomb (9) to review the North American clinical trials of troglitazone. Among 2510 patients who received troglitazone, 48 patients (1.9 percent) had hepatic dysfunction, defined as serum aminotransferase concentrations that were more than three times the upper limit of normal, as compared with 3 of 475 patients who received placebo (0.6 percent). The changes were reversible in all the patients. Liver biopsies performed in two patients revealed hepatocellular injury. As Watkins and Whitcomb noted, patients who are taking troglitazone need to be monitored frequently. Troglitazone might well be the first-choice drug for patients with mild type II diabetes, especially obese patients with marked insulin resistance. It can also be given in conjunction with other oral antidiabetic drugs or insulin in patients with more severe hyperglycemia. Because of the possibility of drug-induced hepatic dysfunction, however, therapy with troglitazone should be limited to patients who can be evaluated frequently until the incidence and severity of hepatic dysfunction with this drug become clearer. Hiroo Imura, M.D. Kyoto University Kyoto 606-8501, Japan

To: Peter Singleton who wrote (17860)	3/26/1998 9:53:00 AM
From: Henry Niman	Respond to of 32384

Here's what UPI had to say about the deformed frogs and obese humans: DEFORMED FROGS Scientists have concluded that chemicals related to vitamin A in the water are most likely the cause of deformities that have been showing up in frogs. At a weekend forum in Milwaukee, scientists said the compounds retinoids _ appear to be to blame for such deformities as extra or missing limbs...misplaced eyes...webbed skin...and other defects. Deformed frogs were first discovered by a grade school class examining a lake in Minnesota nearly two years ago. Since then, the same problems have been reported in dozens of states and Canada. Michael Lannoo of Ball State University in Muncie, Indiana, says (in the Minneapolis Star-Tribune) although ultraviolet rays and parasites might be responsible for some of the defects...only chemicals could account for all of them. Bruce Blumberg of the Salk Institute for Biological Studies in LaJolla, California, says it's unclear how the chemicals mimic hormones. ..causing the malformations. He's also studying the insecticide methoprene...which acts like a retinoid. OBESITY BREAKTHROUGH Medical researchers in Boston say they've discovered a molecule in the brains of animals that may cause obesity. The doctors at Beth Israel Deaconess Medical Center say the chemical compound inhibits the body's use of a hormone known as leptin...which helps protect both animals and people from becoming too fat. The researchers have labeled the newly discovered molecule SOCS-3...and they say if new drugs can be developed to counter its effects, it could help many obese people get their weight under control for the first time. Leptin signals the brain that it's stored enough fat and that it's time to stop eating. The research (published in the journal Molecular Cell) found that the SOCS-3 molecule somehow keeps leptin from doing its job...leaving the test animals chronically hungry and prompting them to overeat. (Thanks to UPI's Phil Reed in Boston)