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

To: Skeeter Bug who wrote (25792)	9/28/1998 7:21:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

sb, The number of CTCL patients is small (I think that it's something like 10,000 current patients with about 2000 new patients per year in the US. However, I believe that LGND plans to charge about $40,000 for a treatment course. For KS, there are about 25,000 patients in the US and and equal number in Europe. I think that a treatment course for topical Panretin is closer to $5,000. As far as off label prescription are concerned, once a drug is approved, any MD can prescribe it for anything that would benefit the patient. Restrictions are on the company's promotion. I think that the FDA modernization act allows for off label promotion after two peer reviewed publications for the off label indication. However, a recent federal court ruling indicated that off label promotion was covered by free speech, and companies could promote without meeting FDA off label requirements: paradise-web.com As far as combinations with Targretin and SERMs or TZDs are concerned, oral Targretin approval is projected for next year as is Avandia and Actos. SERMs that are already available include Tamoxifen and Evista, while Rezulin is an approved TZD. Peer reviewed off label applications for diabetes could happen next year if the European data is publishable. Similarly, Targretin for cancers other than CTCL could also be published next year. I haven't heard anything new about a Targretn breast cancer trial, but initial data on Panretin combined with tamoxifen for breast cancer could also be published next year. Of course abstracts on initial data could be published sooner than peer reviewed papers. Of interest, the British Medical journal just came out with an editorial on breast cancer prevention using COX-2 inhibitors: paradise-web.com which would also suggest use of TZD's for breast cancer in addition to diabetes.

To: Skeeter Bug who wrote (25792)	9/29/1998 8:53:00 AM
From: Henry Niman	Respond to of 32384

Interesting article on estrogen, PPARalpha and energy metabolism. PPARalpha knockout mice (mice genetically engineered to be missing the PPARaplha gene) die because they can't metabolize fat. However, the deaths were largely restricted to males and they could survive if they received estrogen: paradise-web.com Experiment suggest that estrogen may also be involved in energy metabolism and my help explain synergies seen between Targretin and SERMs or TZDs. LGND of course has major SERM and TZD programs.

To: Skeeter Bug who wrote (25792)	9/29/1998 8:58:00 AM
From: Henry Niman	Respond to of 32384

Here's the abstract: J. Clin. Invest. Volume 102, Number 6, September 1998, 1083-1091 A Gender-related Defect in Lipid Metabolism and Glucose Homeostasis in Peroxisome Proliferator- activated Receptor - deficient Mice Fatima Djouadi, Carla J. Weinheimer, Jeffrey E. Saffitz§, Clovis Pitchford, Jean Bastin, Frank J. Gonzalez, and Daniel P. Kelly¶ * INSERM U319, Université Paris 7, Paris, France; Department of Medicine, § Department of Pathology, and ¶ Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 The peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPAR is activated as a component of the cellular lipid homeostatic response, the expression of PPAR target genes was characterized in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPAR target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPAR (PPAR/), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female PPAR/ mice. The metabolic phenotype of male PPAR/ mice was rescued by a 2-wk pretreatment with -estradiol. These results demonstrate a pivotal role for PPAR in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism. (J. Clin. Invest. 1998. 102:1083-1091.) Key words: fatty acids; estrogens; myocardial diseases; hypoglycemia; cytoplasmic and nuclear receptors

To: Skeeter Bug who wrote (25792)	9/30/1998 1:25:00 AM
From: Henry Niman	Respond to of 32384

Recent reports indicate that protease treatments of AIDS are failing when tried for a second time: paradise-web.com

To: Skeeter Bug who wrote (25792)	10/1/1998 6:37:00 AM
From: Henry Niman	Respond to of 32384

Today's NEJM has an article on PPARgamma mutations and obesity: paradise-web.com Looks like anti-TZDs could have an application here.

To: Skeeter Bug who wrote (25792)	10/1/1998 6:43:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's the NEJM abstract: The New England Journal of Medicine -- October 1, 1998 -- Volume 339, Number 14 Obesity Associated with a Mutation in a Genetic Regulator of Adipocyte Differentiation Michael Ristow, Dirk Muller-Wieland, Andreas Pfeiffer, Wilhelm Krone, C. Ronald Kahn Abstract Background. There is increasing evidence of genetic factors leading to obesity, but the exact genes involved have not been defined. Peroxisome-proliferator-activated receptor (gamma)2 (PPAR(gamma)2) is a transcription factor that has a key role in adipocyte differentiation, and therefore mutations of the gene for this factor might predispose people to obesity. Methods. We studied 358 unrelated German subjects, including 121 obese subjects (defined as those with a body-mass index [the weight in kilograms divided by the square of the height in meters] of more than 29). We evaluated these subjects for mutations in the gene for PPAR(gamma)2 at or near a site of serine phosphorylation at position 114 that negatively regulates the transcriptional activity of the protein, using a polymerase-chain-reaction-based assay coupled with specific endonuclease digestion. The activity of the mutation identified was analyzed by retroviral transfection and overexpression in murine fibroblasts. Results. Four of the 121 obese subjects had a missense mutation in the gene for PPAR(gamma)2 that resulted in the conversion of proline to glutamine at position 115, as compared with none of the 237 subjects of normal weight (P=0.01). All the subjects with the mutant allele were markedly obese, with body-mass-index values ranging from 37.9 to 47.3, as compared with a mean of 33.6 in the other obese subjects. Overexpression of the mutant gene in murine fibroblasts led to the production of a protein in which the phosphorylation of serine at position 114 was defective, as well as to accelerated differentiation of the cells into adipocytes and greater cellular accumulation of triglyceride than with the wild-type PPAR(gamma)2. These effects were similar to those of an in vitro mutation created directly at the Ser114 phosphorylation site. Conclusions. A Pro115Gln mutation in PPAR(gamma)2 accelerates the differentiation of adipocytes and may cause obesity. (N Engl J Med 1998;339:953-9.) Source Information From the Joslin Diabetes Center and Harvard Medical School, Boston (M.R., C.R.K.); the Klinik II und Poliklinik fur Innere Medizin, Universitat zu Koln, Cologne, Germany (M.R., D.M.-W., W.K.); and the Medizinische Klinik und Poliklinik, Bergmannsheil, Ruhr-Universitat Bochum, Bochum, Germany (A.P.). Address reprint requests to Dr. Kahn at the Joslin Diabetes Center, Research Division, Section on Cellular and Molecular Physiology, 1 Joslin Pl., Boston, MA 02215.