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

To: medsunman who wrote (17223)	3/11/1998 2:55:00 PM
From: Henry Niman	Respond to of 32384

medsunman, I was running out the door and will work on a more detailed response. However, there is quite a bit of info under the LLY Alliance Table at home.att.net as well as the Clinical Trials table at home.att.net From the LLY/LGND alliance press release: The highlighted part relates to a rexinoid (like Panretin, Targretin, LGD1268, LGD1324 or another one from the lottery) and a SERM (like Evista or whatever 2nd or 3rd generation compound LLY has): Lilly will receive the following: Rights to TargretinTM, an oral therapy currently in early clinical development for Type II diabetes. Targretin is the first in a new class of oral diabetes therapies. Exclusive rights to two second generation oral diabetes compounds in preclinical development that could offer further improvements over currently available products. Exclusive rights to Ligand's metabolic disease technology to develop more advanced diabetes, cardiovascular and related therapies. Additional rights to use Ligand's technology to develop a compound in combination with a Selective Estrogen Receptor Modulator (SERM) in cancer. Ligand may qualify to receive the following: Up to $49 million in research funding over five years plus the potential for up to three additional years of research funding. $37.5 million in an equity investment at $17.23 per share. The price was calculated as a 20 percent premium to the market average on 20 days trading ending September 12 as defined in the contract. $12.5 million in upfront milestones. Up to $75 million in additional milestone payments paid over eight years assuming successful development of oral Targretin and five other compounds. Double-digit royalties for most advanced products and single-digit royalties on earlier compounds. An option to obtain select rights to one Lilly specialty pharmaceutical product in certain markets of interest to Ligand. The product would fit into an area of specific focus for Ligand, but not Lilly. Milestones, royalties and options to obtain certain codevelopment and copromotion rights for a Lilly-selected RXR compound in combination with a SERM. Raloxifene was the June, 1997 Molecule of the Month: prous.com

To: medsunman who wrote (17223)	3/11/1998 3:05:00 PM
From: Henry Niman	Respond to of 32384

Here's what LLY had to say about Evista (Raloxifene), second and third generation derivatives, and Tamoxifen: Proc Natl Acad Sci U S A 1997 Dec 9;94(25):14105-14110 Molecular determinants of tissue selectivity in estrogen receptor modulators. Grese TA, Sluka JP, Bryant HU, Cullinan GJ, Glasebrook AL, Jones CD, Matsumoto K, Palkowitz AD, Sato M, Termine JD, Winter MA, Yang NN, Dodge JA Endocrine Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. grese@lilly.com Interaction of the estrogen receptor/ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultimately, tissue-selective outcomes. The estrogen receptor ligands raloxifene and tamoxifen have demonstrated such tissue-specific estrogen agonist/antagonist effects. Both agents antagonize the effects of estrogen on mammary tissue while mimicking the actions of estrogen on bone. However, tamoxifen induces significant stimulation of uterine tissue whereas raloxifene does not. We postulate that structural differences between raloxifene and tamoxifen may influence the conformations of their respective receptor/ligand complexes, thereby affecting which estrogen-responsive genes are modulated in various tissues. These structural differences are 4-fold: (A) the presence of phenolic hydroxyls, (B) different substituents on the basic amine, (C) incorporation of the stilbene moiety into a cyclic benzothiophene framework, and (D) the imposition of a carbonyl "hinge" between the basic amine-containing side chain and the olefin. A series of raloxifene analogs that separately exemplify each of these differences have been prepared and evaluated in a series of in vitro and in vivo assays. This strategy has resulted in the development of a pharmacophore model that attributes the differences in effects on the uterus between raloxifene and tamoxifen to a low-energy conformational preference imparting an orthogonal orientation of the basic side chain with respect to the stilbene plane. This three-dimensional array is dictated by a single carbon atom in the hinge region of raloxifene. These data indicate that differences in tissue selective actions among benzothiophene and triarylethylene estrogen receptor modulators can be ascribed to discrete ligand conformations. PMID: 9391160, UI: 98054368

To: medsunman who wrote (17223)	3/11/1998 3:16:00 PM
From: Henry Niman	Respond to of 32384

Here's an older (but fairly comprehensive review of anti-estrogens as well as breast cancer prevention trials with Tamoxifen (which were subsequently halted or terminated): Breast Cancer Res Treat 1995;36(3):267-285 Third annual William L. McGuire Memorial Lecture. "Studies on the estrogen receptor in breast cancer"--20 years as a target for the treatment and prevention of cancer. Jordan VC Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611, USA. In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (ed) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.e., greater than one year) has proven efficacy to enhance the survival of breast cancer patients. In addition, because there is an associated 40% decrease in contralateral breast cancer during adjuvant tamoxifen therapy and tamoxifen maintains bone density and reduces fatal myocardial infarction, clinical trials to test the worth of tamoxifen as a preventive for breast cancer in high risk women have started in the United States, United Kingdom, and Italy. Initial concerns that long-term tamoxifen causes endometrial cancer have been placed in perspective and analyzed by a review of the literature. Tamoxifen only doubles the normal risk of detecting endometrial cancer (i.e., to 2 per 1,000 tamoxifen-treated women per year), and 80% of these cases are early stage, good prognosis disease. Annual gynecological examinations and education are essential to provide reassurance for patients. The success of tamoxifen has encouraged the development of new antiestrogens to exploit the estrogen receptor as a therapeutic target. Droloxifene and TAT-59 mimic the metabolite 4-hydroxytamoxifen in having a high affinity for the estrogen receptor (Jordan et al, J Endocrinol 75:305, 1977). These drugs appear to have a pharmacological profile similar to tamoxifen. In contrast, the new pure antiestrogens have a distinct mechanism of action and will be valuable either as a first line therapy for advanced breast cancer or as a second line endocrine therapy after the failure of long-term adjuvant tamoxifen therapy. Finally, a new strategy is being developed to exploit the target site specific action of antiestrogens. Raloxifene, an antiestrogen with high affinity for the estrogen receptor but only weak estrogenicity for the uterus, prevents rat mammary tumorigenesis and maintains bone density. The drug is to be evaluated as a treatment for osteoporosis, but may also prevent the development of breast and endometrial cancer in a broad group of treated subjects. The identification of the estrogen receptor as a target for therapeutic opportunities has proved to be extremely beneficial for the control of breast cancer and has the added potential to control osteoporosis and coronary heart disease in women. Publication Types: Review Review, tutorial PMID: 8573710, UI: 96111084

To: medsunman who wrote (17223)	3/12/1998 4:20:00 PM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

medsunman, I'll give a bit more detail on the molecular aspects of Rexinoid (Targretin) / SERM (Evista) synergies. Animal data has been quite encouraging. Although the various SERMs can have structural differences, they all target the estrogen receptor (ER). The compounds have been called anti-estrogens, but since their effect can vary, depending on the cell type, they have more recently been called TSEs (Tissue Specific Estrogens) or SERMs (Selective Estrogen Receptor Modulators). ER is a sex steroid and it is structurally related to the IRs that LGND targets (Retinoic Acid Receptor, RAR; Retinoic Acid X Receptor, RXR; Peroxisome Proliferation Activated Receptor, PPAR; Androgen Receptor, AR; Thyroid Hormone Receeptor, TR; Vitamin D Receptor, VDR; Gluccocorticoid Receptor, GR; etc). RXRs form heterdodimers with many of the receptors and the heterodimer is really the activated transcription factor, so it's pretty easy to understand why an RXR activator like Targretin would synergize with a PPAR activator like Rezulin. However, it's not clear that RXRs for heterodimers with ERs, so the synergy between Targretin or Panretin and Tamoxifen or Evista isn't as obvious from the molecular viewpoint. Howevere, the synergy has been demonstrated in many systems now. For breast cancer prevention in rats, Panretin has been shown to synergize with Tamoxifen and Evista. Targretin has also been shown to synergize with Tamoxifen in prevention trials. Moreover, Targretin has been shown to synergize with Tamoxifen to cause established breast tumors to disappear in rats. The above data is important because of the potential human applications. Panretin is in two Phase I/II trails with Tamoxifen to treat breast cancer. The upcoming presentation at ASCO is expected to show "Striking" prevention results for women treated for 3 years with Evista. LLY and LGND recognize this potential synergy for the treatment or prevention of breast cancer, so a research program targeting rexinoids and SERMs was set up under the recent LLY/LGND Alliance. Turk's info seems to also implicate LGGND with Evista based by the serum estrogen clues. It sounds like the media will be excited about the Evista prevention data to be presented at ASCO in May. By then, I suspect that more will be known about the LLY compound, and shortly thereafter, details about the implications for the research program may be more obvious.