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

To: Machaon who wrote (22072)	6/11/1998 9:35:00 AM
From: TomOrt	Respond to of 32384

Thursday June 11, 9:01 am Eastern Time Company Press Release SOURCE: Front Line Strategic Management Consulting, Inc. 0steoporosis Therapeutic and Diagnostic Markets Are Expected to Experience Increased Competition and Sales Into the Next Decade FOSTER CITY, Calif., June 11 /PRNewswire/ -- The osteoporosis therapeutic and diagnostic markets are comprised of many players, each vying to develop differentiated products in a competitive but prosperous market. So prosperous that in 2000, worldwide therapeutic sales are projected to be $5.5 billion and worldwide diagnostic sales are estimated to reach $396.6 million. Growth will be driven by an expected worldwide patient population of 220 million and the introduction of several hopeful blockbuster products, according to a new study published by Front Line Strategic Management Consulting, Inc. Osteoporosis treatment at this time relies primarily on hormone replacement due to its high efficacy and low cost. This class currently holds 69% of the market and is expected to capture 63% in 2005. Wyeth-Ayerst will hold a commanding market share in 1998 due to the success of Premarin. However, this share is expected to shrink by 2005 as Eli Lilly's Evista, Merck's Fosamax, and Procter & Gamble's Actonel become leading products. Novartis' market share is also expected to slip because the company competes in the smaller therapeutic classes of calcitonins and estrogen patches. Some of the other companies trying to obtain market share in this therapeutic market include Astra AB [NYSE:A - news], Celtrix Pharmaceuticals, Chugai, Cortecs International, Hoechst AG [NYSE:HOE - news], Hoffmann-La Roche, Inhale Therapeutic Systems [Nasdaq:INHL - news], Ligand Pharmaceuticals, Novo Nordisk A/S [NYSE:NVO - news], SmithKline Beecham, and Warner-Lambert. Other industry participants such as Allelix, Astra, Teijin, Haemopep and Korea Green Cross are developing emerging products like parathyroid hormone and vitamin D3. Various other companies with emerging technologies are players such as Arris, Scotia Pharmaceuticals, Ariad and Nycomed. Front Line Strategic Management Consulting, Inc., is a strategy and market consultancy specializing in the pharmaceutical and biotechnology industries, providing clients with technology and market evaluations, strategic and tactical recommendations and business opportunity assessments. This research was obtained and analyzed in its 1998 report, ''Osteoporosis Therapeutics and Diagnostics, A Worldwide Strategic Evaluation.'' Free executive summaries of Front Line's studies are available to the press and free tables of contents are available to industry. SOURCE: Front Line Strategic Management Consulting, Inc. --------------------------------------------------------------------------------

To: Machaon who wrote (22072)	6/11/1998 9:57:00 AM
From: Henry Niman	Respond to of 32384

Bob, I haven't seen the new applications (Basal and squamous cell carcinoma applications for Panretin gel) in print yet. The news came from Robinson's remarks at the recent San Diego field trip.

To: Machaon who wrote (22072)	6/11/1998 10:09:00 AM
From: Henry Niman	Read Replies (2) \| Respond to of 32384

Speaking of LGND info, they have at least three presentations at the diabetes meeting this week on Rexinoids and TZDs. Here's one: Abstract #: 0111 Abstract Type: Orals Abstract Category: Islet Secretion, Sensitization and Senescence Presentation Time: 4:15-6:15 PM Presentation Date: 6/14/97 Activation of RXR with Rexinoids (RXR Selective Ligands) Function as Insulin Sensitizers in Type II Diabetic Mice DIANE L. CROMBIE 1,2, JAMES R. PATERNITI 1,2, RICHARD A. HEYMAN1,2, San Diego, CA, USA. Receptors for retinoic acid (RAR), thyroid hormone (TR) and peroxisome proliferator activated receptors (PPARs) preferentially bind to DNA to regulate transcription as heterodimers with the common partner, retinoid X receptor (RXR). This raises the question whether rexinoids may replicate the activity of ligands for several of these receptors. We have identified a series of synthetic RXR selecive ligands that are potent transcriptional activators of the RXRs. These RXR selective ligands, function as RXR heterodimer selective agonists activating the RXR:PPARg dimer. Since PPARg is a target for antidiabetic agents such as the thiazolidinediones, we investigated whether RXR ligands would alter insulin and glucose signaling. In mouse models of non-insulin dependent diabetes mellitus (NIDDM) and obesity, including the ob/ob and db/db mice, RXR agonists function as insulin sensitizers decreasing hyperglycemia, hypertriglyceridemia and hyperinsulinemia. Combination treatment with the thiazolidinedione, BRL49653, further enhances the maximal response of either agent alone. When RXR agonists are used during early stages of insulin resistance they block the progression of NIDDM. At late stages of insulin resistance, these agents signficantly reduce the amount of exogenous insulin required to reduce the hyperglyemic state to the euglycemic levels. These data suggest that activation of the RXR:PPARg heterodimer with rexinoids may provide a new therapeutic approach as monotherapy or combination therapy for the treatment of insulin resistance.

To: Machaon who wrote (22072)	6/11/1998 10:13:00 AM
From: Henry Niman	Respond to of 32384

Here's another: Abstract #: 1099 Abstract Type: Posters Abstract Category: Metabolism, in vivo, animals Presentation Time: 12:15-2:15 PM Presentation Date: 6/13/97 Rexinoid x Receptor Agonists Improve Insulin Sensitivity and have Anti-obesity Effects in Zucker fa/fa Rats YONG-LING LIU 2, MATTHEW V. SENNITT 2, DAVID C. HISLOP 1, DIANE L. CROMBIE 1, RICHARD A. HEYMAN 2, MICHAEL A. CAWTHORNE 2* Buckingham, UK; La Jolla, CA, USA. The thiazolidinedione insulin sensitizer drugs are believed to act via activation of a PPARg nuclear receptor. PPARg forms heterodimers with retinoid x receptors and it has been shown previously that RXR-selective ligands (rexinoids) have antihyperglycemic activity in ob/ob and db/db mice. In the current experiments the effects of two rexinoids (LG 100268 and LG 100324) and the thiazolidinedione BRL 49653 were examined in Zucker fa/fa rats. The rats were given either the rexinoids (20mg/kg p.o.) or BRL 49653 (3mg/kg p.o.) for 14 days prior to a hyperinsulinemic, cuglycemic clamp. Treatment with rexinoids resulted in a significant reduction in food intake and growth rate, whereas food intake and growth rate of rats given BRL 49653 did not differ from controls. The rexinoids produced significant reductions in the fed and 5h-fasted plasma insulin concentrations. For the hyperinsulinemic clamp, insulin was infused at the rate of 10mU/kg body wt/min for 120 min. The whole body glucose utilization rate under steady state conditions and the hepatic glucose output did not differ significantly between rexinoid-treated rats, BRL 49653-treated rats and controls but the steady state plasma insulin concentration in the rexinoid-treated rats and BRL 49653-treated rats were respectively 3.80 ñ 0.53, 5.67 ñ 0.07, 5.00 ñ 0.40 as against 6.93 ñ 1.01 nmol/l in control rats. Thus whole body insulin sensitivity of glucose utilization was significantly increased by both the rexinoids, particularly LG 100268, and BRL 49653. Insulin sensitivity of 2-deoxyglucose uptake in vivo in muscle and brown adipose tissue was also increased by the treatments. However, LG 100268 had no effect on white adipose tissue insulin sensitivity. Thus, treatment of Zucker rats with rexinoid selective agonists improves insulin sensitivity and reduces food intake and obesity. Rexinoids may provide a new approach to insolin sensitizer drugs with the additional advantage of anti-obesity action. \|

To: Machaon who wrote (22072)	6/11/1998 10:16:00 AM
From: Henry Niman	Respond to of 32384

New diet pill?Abstract #: 1152 Abstract Type: Posters Abstract Category: Metabolism, in vivo, animals Presentation Time: 12:15-2:15 PM Presentation Date: 6/13/97 The RXR-Selective Agonist LGD1268 Improves Insulin Sensitivity and Reduces Body Weight Gain in the Female Zucker Fatty Rat KATHLEEN M. OGILVIE 1,2, DIANE L. CROMBIE 1,2, JAMES R. PATERNITI 1,2, RICHARD A. HEYMAN 1,2, La Jolla, CA, USA. In rodent models of insulin resistance or humans with type 2 diabetes, thiazolidinediones (TZDs) act as insulin sensitizers via peroxisome proliferator activated receptor gamma (PPARg). Regulation of transcription by PPARg relies on the formation of a heterodimer with retinoid x receptor (RXR). We recently showed that treatment of ob/ob and db/db mice with an RXR-selective agonist (LGD1268) reduced levels of glucose and insulin levels measured 3 hours after dosing and improved glucose tolerance, data that support the hypothesis that activation of the RXR:PPARg heterodimer via either receptor improves insulin sensitivity. We report here that oral treatment of female Zucker fatty rats (fa/fa) with LGD1268 (3-100 mg/kg/d) or the TZD BRL49653 (3 mg/kg/d) reduced insulin levels within 7 days (controls, 2.9ñ0.6 ng/ml; all treated animals < 1.15 ng/ml; p < 0.05), indicating improved insulin sensitivity in these animals. However, after 6 weeks, rats treated with BRL49653 weighed significantly more than control (492ñ7g vs. 401ñ9g, p < 0.0001). In contrast, LGD1268 did not effect (3 mg/kg/d, 432ñ11g; 10 mg/kg/d , 409ñ14g) or reduced (30 mg/kg/d, 350ñ10g; 100 mg/kg/d, 348ñ17g) body weight after 6 weeks of dosing. Since rats weighed 249ñ6g at the beginning of treatment, this change was due to restrained body weight gain, rather than weight loss. Importantly, LGD1268 (100 mg/kg/d) did not reduce body weight gain in lean littermates (207ñ7g vs. 214ñ7g for controls, p = 0.42). Altered body weight gain is likely due to changes in cumulative food consumed which is increased by BRL49653 (1262ñ33g vs. 954ñ42g for controls) and reduced in animals treated with 30 mg/kg/d (749ñ27g) or 100 mg/kg/d (797ñ52g) LGD1268. These data show that RXR-selective compounds improve insulin sensitivity in the Zucker fatty rat, but do so without exacerbating weight gain and therefore provide a new opportunity in the treatment of type 2 diabetes.

To: Machaon who wrote (22072)	6/11/1998 10:25:00 AM
From: Henry Niman	Respond to of 32384

Here's one on Panretin (9-cis retinoic acid) as well as an RXR (LG100154) specific (rexinoid)compound on increasing insulin secretion from beta cells: Abstract #: 1036 Abstract Type: Posters Abstract Category: Islet Biology: Signal/Synthesis/Secretion Presentation Time: 12:00-2:00 PM Presentation Date: 6/14/97 Effects of 9-cis and All-trans Retinoic Acid and Receptor-Selective Retinoids on bTC6-7 Cell Insulin Secretion, Content and Growth BRUCE S. CHERTOW, HENRY K. DRISCOLL, DONALD A. PRIMERANO, KIMBERLY A. MATTHEWS, Huntington, WV, USA. Previous studies show all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9CRA) stimulate insulin release and inhibit proliferation of RINm5F cells. These effects are mediated through homo- and heterodimers of ATRA (RAR) and 9CRA (RXR) nuclear receptors. To determine whether retinoids affect secretion from a glucose-responsive insulin-secreting cell line and whether effects are mediated through RXR/RXR homodimers or RAR/RXR heterodimers, b TC6-7 cells were tested for effects of ATRA, 9CRA, LG100153 (RXR-selective retinoid) and TTNPB (RAR-selective retinoid). Cells were cultured for 2-7 days without and with retinoids, 1-1000 nM, and then stimulated with glucose 0.5, 2.8, 7, and 11 mM. In the absence of retinoids, glucose, 11 mM, induced insulin secretion 4-fold. Whereas ATRA stimulated release at most to 1.5-fold, increased insulin content 1.2-fold, and decreased growth by 25%, 9CRA, 70-100 nM, increased secretion consistently from 1.4- to 2.7-fold, increased insulin content to 1.9-fold, and decreased growth by 75%. RXR-selective retinoids stimulated basal secretion and inhibited cell growth more than RAR-selective retinoids. Glucose-responsive secretion was affected more by a combination of RAR- and RXR-selective retinoids. These findings using a physiologically responsive b-cell line show: 1) 9CRA increases basal insulin secretion and content and restrains growth more than ATRA; 2) RXR and RAR receptors mediate these effects; and 3) RXR homodimers may be more important than RAR/RXRs for basal secretion, and RXR/RARs may be more important than RXR homodimers in glucose-induced secretion.

To: Machaon who wrote (22072)	6/11/1998 12:35:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

H&Q came out with a LGND report this morning. They reiterated their BUY rec and had this to say about topical Panretin: NDA Filing for Panretin On Schedule ú On May 27, Ligand announced that it had filed its first new drug application (NDA) for topical Panretin fir treating patients with AIDS-related Kaposi's sarcoma. The NDA package included clinical data from the international and North American pivotal Phase III trials. We believe that potential approval of the product could come by year-end 1998. ú The international Phase III data demonstrated an overall response rate of 37.1% (23 of 62 patients) in the treatment arm versus a response rate of 6.9% (5 of 72 patients) in the placebo arm (p value=0.00003). The international Phase III data were consistent with the results from the North American Phase III trial announced in December 1997. These results showed an overall response rate of 35.1% (47 of 134) in the treatment arm compared with 17.9% (24 of 134) in the placebo arm ( p value=0.002). ú Given the favorable safety profile and efficacy demonstrated thus far, Panretin may become the first treatment of choice for AIDS patients with early stage KS. We believe that Panretin represents a $20-40 million opportunity for Ligand which would help bring the company to profitability in 1999.