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

To: celeryroot.com who wrote (27084)	12/31/1998 7:08:00 AM
From: Henry Niman	Respond to of 32384

on CNBC, WSJ writer summarized most important medical news for 1998. Cloning was the top story, with validation of Dolly by many including South Korean study with human cells. Predicted a human clone would be created in 2-3 years (when Dolly news broke, I had said that human clone would be born by the year 2000, and I'll stick with my prediction that clone will be born in the next two years). Stem cell research was mentioned next with reference to GERN and growing replacement parts. Next came GNE's HER2/neu for breast cancer treatment as well as potential treatments for prevention. RA advances such as IMNX's Enbrel were then mentioned in the context of biggest advance since steroid treatments discovered decades ago. Viagra was then mentioned to fill out 1998. For 1999, COX-2 inhibitors such as MTC/PFE's Celebrex and MRK's Vioxx were mentioned as new pain killers.

To: celeryroot.com who wrote (27084)	12/31/1998 7:31:00 AM
From: Henry Niman	Respond to of 32384

The breast cancer prevention referred to tamoxifen which is now in head to head trials with LLY's Evista (a SERM). LGND is looking at combinations of rexinoids with LLY's next generation of SERMs. The San Antonio conference on breast cancer included an abstract summarized as follows: LY353381 -- An "Ideal" Endocrine Therapy for Breast Cancer? Another new hormone currently in clinical trials is the selective estrogen receptor modulator(SERM) LY353381. This compound was developed as an "ideal" endocrine therapy for breast cancer as it has a beneficial effect on breast, bone and lipids, but is devoid of intrinsic estrogen-agonist activity which makes its stimulatory effect on the uterus negligible. Hudis and colleagues presented data on the efficacy and toxicity of the SERM LY353381 when given to 32 patients who had failed prior hormone therapy for metastatic breast cancer [9]. The objectives of this Phase I trial were to determine the safety and toxicity profile, the pharmacokinetics, and the antitumor activity of LY353381. Four separate daily dose levels were evaluated: 10 mg, 20 mg, 50 mg, and 100 mg. Of the initial 32 patients one achieved a minor response (3%) and 28% have achieved stable disease with the remaining 69% having progressive disease as the best response to therapy. The compound was well tolerated at all dose levels. Multi-institutional phase II trials comparing 20 mg and 50 mg/day are ongoing in metastatic breast cancer patients who have had adjuvant chemotherapy alone, adjuvant tamoxifen alone, or in patients with prior response or stable disease with tamoxifen. Whether this new compound proves equivalent or superior to the gold standard tamoxifen awaits the results of these Phase II and future Phase III trials.

To: celeryroot.com who wrote (27084)	12/31/1998 9:36:00 AM
From: Henry Niman	Respond to of 32384

Here's a LLY abstract on their next generation SERM, which for some applications is more potent than Evista (Raloxifene): J Pharmacol Exp Ther 1998 Oct;287(1):1-7 LY353381.HCl: a novel raloxifene analog with improved SERM potency and efficacy in vivo. Sato M, Turner CH, Wang T, Adrian MD, Rowley E, Bryant HU Department of Endocrine Research, Lilly Corporate Center, Indianapolis, Indiana, USA. Sato_Masahiko@Lily.com Body weight, uteri, serum cholesterol and bones were shown previously in vivo to be sensitive to circulating levels of estrogen, as well as to synthetic, nonsteroidal ligands termed selective estrogen receptor modulators (SERM). In this study, we examined the in vivo effects of a new potent SERM on these tissues in 6-month-old, ovariectomized rats that were orally dosed with 0.0001-10 mg/kg/day LY353381.HCl for 5 weeks. LY353381.HCl prevented the ovariectomy-induced increase in body weight and serum cholesterol levels of treated rats and lowered them to below sham levels in a dose dependent manner, with maximum efficacy similar to estrogen or raloxifene. However, LY353381.HCl was consistently more potent than raloxifene, with a half maximal efficacious dose of 0.001 mg/kg for the reduction of body weight and cholesterol. In the uterus, LY353381.HCl had marginal effects on uterine weight compared to ovariectomized controls (OVX) like raloxifene, but unlike estrogen. Histological examination of uterine epithelial cell height showed little to no stimulatory effect of LY353381.HCl on the endometrium. Quantitative computed tomographic analyses (pQCT) of tibiae showed that LY353381.HCl prevented loss of bone due to ovariectomy with an ED50 of about 0.01 mg/kg with maximal efficacy observed at 0.1-1 mg/kg/day. Maximally attainable bone mineral density and content with LY353381.HCl were not significantly different from Sham or ovariectomized rats treated with estrogen or raloxifene. Interestingly, assessment of bone quality by biomechanical analyses showed that LY353381.HCl preserved the strength of the femora neck and midshaft, while improving the Young's modulus of cortical bone to beyond estrogen, raloxifene or sham levels. In uteri of immature rats treated with estrogen, LY353381.HCl antagonized the estrogen-induced elevation in uterine weight down to vehicle-dosed control levels with ED50 of 0.03 mg/kg/day. Therefore, LY353381.HCl was 30-100 times more potent than raloxifene in preventing ovariectomy effects on body weight, serum cholesterol and bone, while maintaining estrogen antagonist effects on the uterus. These animal data suggest that LY353381.HCl may have advantages over estrogen or raloxifene in the prevention of bone loss and treatment of other tissues in postmenopausal women. PMID: 9765314, UI: 98438605

To: celeryroot.com who wrote (27084)	12/31/1998 9:41:00 AM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's another abstract on bone loss: Endocrinology 1998 Nov;139(11):4642-51 LY353381 x HCl: an improved benzothiophene analog with bone efficacy complementary to parathyroid hormone-(1-34). Sato M, Zeng GQ, Rowley E, Turner CH Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285, USA. sato_masahiko@lilly.com LY353381 x HCl is a benzothiophene analog that is structurally related to raloxifene with potent selective estrogen receptor modulator activity in the ovariectomized rat model of postmenopausal osteoporosis. The effects of LY353381 x HCl on bones, body weight, and uterine weight were evaluated in 7-month-old rats with osteopenia that was induced by ovariectomizing animals for 1 month before initiation of treatment with several agents individually, in combination, or in sequence. LY353381 x HCl was administered daily by itself for 90 days, in combination with the amino-terminal fragment of PTH-(1-34) (PTH) for 90 days, or sequentially after PTH when PTH was discontinued after 45 days of treatment. Additionally, comparisons were made of animals treated with PTH alone, 17alpha-ethynyl estradiol alone, equine estrogens (Premarin) alone, raloxifene alone, or combinations of PTH and equine estrogens or raloxifene. Ovariectomy induced increases in the rate of bone turnover and body weight while decreasing bone mineral density, bone mineral content, bone strength, trabecular bone volume, trabecular thickness, trabecular number, and uterine weight. LY353381 x HCl at 0.01-1 mg/kg had marginal effects on body weight and no effect on uterine weight compared with those in ovariectomized controls, in contrast to 17alpha-ethynyl estradiol or equine estrogens. LY353381 x HCl prevented further bone loss due to ovariectomy in tibia, femora, and lumbar vertebra, like 17-alpha-ethynyl estradiol but unlike equine estrogens. LY353381 x HCl prevented the resorption of trabecular bone spicules, like 7alpha-ethynyl estradiol, but inhibited bone formation activity to a lesser extent than 17alpha-ethynyl estradiol. In this model, 7alpha-ethynyl estradiol appeared to be more efficacious after 3 months of treatment than equine estrogens in the proximal tibia metaphysis, suggesting efficacy differences between metabolites of 17beta-estradiol in bone. PTH at 10 microg/kg had no effect on body weight or uterine weight, but significantly increased bone mass to beyond those in sham-operated controls, baseline controls, and groups receiving other individual treatments at both axial and appendicular sites. The combination of LY353381 x HCl and PTH increased bone mass at a faster rate and to a greater extent than PTH alone or the combinations of equine estrogens/PTH and raloxifene/PTH at trabecular bone sites. The LY353381 x HCl/PTH combination improved bone mass and quality beyond any agent alone in regions enriched for cancellous bone, but was not significantly better than PTH alone on cortical bone. Additionally, when PTH was discontinued at 45 days, LY353381 x HCl prevented the rapid loss of bone observed in controls. Therefore, LY353381 x HCl appears to be useful by itself, in combination, or in sequence with PTH to replace lost bone in postmenopausal women. PMID: 9794476, UI: 99008607