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From: Biomaven	3/4/2010 10:46:30 PM
	1 Recommendation of 40233

Study Identifies Key Cause of Chronic Leukemia Progression ScienceDaily (Mar. 5, 2010) — Researchers have discovered a key reason why a form of leukemia progresses from its more-treatable chronic phase to a life-threatening phase called blast crisis. The study, led by cancer researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James), indicates that chronic myeloid leukemia (CML) progresses when immature white blood cells lose a molecule called miR-328. Loss of the molecule traps the cells in a rapidly growing, immature state. The cells soon fill the bone marrow and spill into the bloodstream, a tell-tale sign that the disease has advanced to the blast crisis stage. The research, published in the March 5th issue of the journal Cell, should provide a better understanding of the blast-crisis stage of CML, and it suggests a possible new treatment strategy for the disease, the researchers say. "These findings indicate that the loss of miR-328 is probably essential for progression from the chronic phase of the disease to the blast crisis stage," says principal investigator Danilo Perrotti, associate professor of molecular virology, immunology and medical genetics and a member of the OSUCCC-James. "Our findings also suggest that maintaining the level of this microRNA might represent a new therapeutic strategy for CML blast crisis patients who do not benefit from targeted agents such as imatinib (Gleevec) and dasatinib (Sprycel)," Perrotti says The study also revealed a new function for microRNA. Researchers have known for some time that these molecules help regulate the kinds of proteins that cells make. But this study shows for the first time that microRNA molecules can also attach directly to protein molecules and alter their function. In this case, miR-328 binds to a protein that prevents immature blood cells from maturing. "We believe that it normally acts as a decoy molecule, tying up the protein and enabling the white blood cells to mature as they should," Perrotti says. During CML progression, however, the level of miR-328 drops, allowing the protein to be extremely active. This keeps the leukemic white blood cells from maturing and contributes to the transition from the chronic-disease phase to blast crisis phase. "These findings may help unravel novel pathways responsible for the initiation and progression of leukemia generally," Perrotti says. Funding from the National Cancer Institute and the U.S. Army, CML Research Program supported this research. Danilo Perrotti is a Scholar of The Leukemia and Lymphoma Society. Email or share this story: \| More Story Source: Adapted from materials provided by Ohio State University Medical Center, via EurekAlert!, a service of AAAS. Journal Reference: 1. Eiring et al. miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts. Cell, 2010; 140 (5): 652-665 DOI: 10.1016/j.cell.2010.01.007

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To: Biotech Jim who wrote (33751)	3/4/2010 11:16:18 PM
From: Biomaven	1 Recommendation of 40233

My dilemma is LGND Forgot to post this, but last week's NEJM had what I think is a significant article on Lasofoxifene - I think this has the potential to be a big drug - big enough to be one of the drivers for LGND even given their paltry royalty rate: Lasofoxifene in Postmenopausal Women with Osteoporosis Steven R. Cummings, ..., for the PEARL Study Investigators Background The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. Methods In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of –2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)–positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. Results Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group. Conclusions In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323 [ClinicalTrials.gov] .)

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To: Biomaven who wrote (33965)	3/4/2010 11:20:12 PM
From: Biomaven	of 40233

And here (somewhat bizarrely) is an abstract that sets out at length the royalty rates that appear to apply: Drugs R D. 2005;6(1):56-60. Lasofoxifene: CP 336156, CP-336156. [No authors listed] Lasofoxifene [CP 336156] is a potent, nonsteroidal, tissue-selective estrogen receptor modulator (SERM). It has the bone-sparing and cardioprotective effects of estrogen, but lacks estrogen's uterine cancer risk. Lasofoxifene is under development with Ligand Pharmaceuticals and Pfizer (formerly Parke-Davis) for the prevention of postmenopausal osteoporosis and breast cancer. In June 2000, Parke-Davis' parent company, Warner-Lambert, merged with Pfizer. The resulting company retained the Pfizer name and Parke-Davis was integrated into Pfizer Global Research and Development. The discovery of lasofoxifene resulted from a research collaboration between Pfizer and Ligand Pharmaceuticals. There was a contract dispute between the two companies relating to their research agreement. Under a settlement of litigation, Ligand is entitled to milestone and royalty payments. If Pfizer is successful in developing the drug through to regulatory approval in the US, Ligand could receive royalty revenues from lasofoxifene as early as 2003-2004. The royalties will be equal to 6% of net sales and will be in addition to milestone payments for continuing development of the drug. However, on 6 March 2002, Ligand Pharmaceutical announced an agreement with Royalty Pharma in which the latter purchased the rights to a share of these future payments. Under the agreement, Ligand received US dollars 6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (lasofoxifene, bazedoxifene and bazedoxifene/Premarin) for a period of 10 years. Royalty Pharma retains the option to purchase, at escalating prices, additional rights (subject to timing restrictions) to extend this stake up to 1.0%, for a total of US dollars 56 million. In April 2002, Royalty Pharma exercised its first option to purchase an additional 0.125% of potential future sales of the three SERMS in exchange for US dollars 3 million. Subsequently, in December 2002, Royalty Pharma exercised an expanded option and agreed to pay Ligand US dollars 6.775 million for 0.1875% of potential future sales of SERM products. Royalty Pharma and Ligand Pharmaceutical amended their royalty agreement in October 2003 for the three SERM products. Under the amended agreement, Royalty Pharma exercised an option to pay Ligand US dollars 12.5 million, plus cumulative milestones of up to US dollars 2.5 million upon the launches of the three SERMs (provided they are approved by 30 September 2005), in exchange for 0.7% of potential future sales of the products for 10 years. In November 2004, Ligand Pharmaceuticals and Royalty Pharma further amended their existing royalty agreement for the three SERM products. Under the terms of the revised agreement, Royalty Pharma will purchase an additional 1.625% of the SERM products' net sales for US dollars 32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following the first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets will be paid to Ligand as earned and are not included in this amended agreement. In September 2004, Ligand Pharmaceuticals earned a milestone payment of approximately US dollars 2 million from Pfizer, payable in 181,818 shares of Ligand stock held by Pfizer. The payment was triggered by Pfizer's NDA submission for lasofoxifene in August 2004. Under the terms of the agreement between Ligand and Pfizer, Ligand is entitled to receive an additional milestone upon successful approval of lasofoxifene. On 19 August 2004, Pfizer filed an NDA with the US FDA for lasofoxifene for the prevention of osteoporosis in postmenopausal women. Product launch is forecasted to occur in 2006-2007. Ligand reported in January 2004 at the 22nd Annual JP Morgan Healthcare Conference that it anticipated the availability of phase III data and NDA filing sometime in 2004. Lasofoxifene has undergone two phase III studies with Pfizer in the US as an orally administered therapy for postmenopausal osteoporosis. In June 2003, Pfizer reported that enrolment was completed in a trial evaluating lasofoxifene in the prevention of bone loss. The trial also evaluated lasofoxifene's effect on lipid levels. The trial enrolled approximately 2000 postmenopausal women. Another trial was conducted among 8500 patients to investigate lasofoxifene in the treatment of fractures. In addition, Pfizer began a third worldwide phase III trial to evaluate whether lasofoxifene reduced the risk of vertebral fractures, breast cancer and cardiovascular disease. At the 10th Annual Meeting of the Biotechnology Industry Organization (BIO-2003), Ligand also confirmed that lasofoxifene was in phase III development for breast cancer. Lasofoxifene is under clinical evaluation as a treatment for vaginal atrophy. According to Pfizer's pipeline in November 2004, the company anticipates regulatory submission for vaginal atrophy by the end of 2004. In June 2002, Ligand estimated that lasofoxifene has the potential to reach sales of US dollars 1-2 billion, pending approval.

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From: Biomaven	3/5/2010 8:29:41 AM
	of 40233

ITMN briefing docs are up - much gentler than I would have anticipated and the market agrees. fda.gov Striking was the fact that there was a post-hoc survival benefit, with the FDA's only complaint about the adjudication of whether death was ipf-related or not. One thing that puzzles me - my recollection of the FVC graphs in the failed study (006) that ITMN has presented in the past differs from those they are presenting now. The old ones (as I recall them) show the drug doing better and then placebo suddenly improving near the end. The new ones show the placebo better pretty much throughout. Anyone else recall the graph from prior presentations (or have a copy of an old presentation)? Peter

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To: Biomaven who wrote (33969)	3/5/2010 10:09:45 AM
From: kenhott	1 Recommendation of 40233

There are in general 3 events now at the end of the FDA approval process. 1 is the docs, 2 is the meeting, and 3 is the FDA decision. A casual observer would lump them together but they are each and distinct trading opportunities. My opinion is that the docs are pretty much as expected (I didn't see a survival advantage other than a numerical edge. Please let me know if I am wrong.) and the market mispriced going into docs. The market had something like a $700m value on ITMN with both the IPF and the HCV drug. I can make an argument that there were too little value assigned to IPF. I think the docs are expected because of the severity of the disease and the fairly "clean cut" nature of the data and approvable problem. This was not a situation where the data showed a stop sign and a green light at the same time, for instance. When the phase 3 came out, I thought the chance of approval was like 36%. Recently I have been thinking that it is more like 40%. With the docs I am thinking a little more positive like 42/58. For the advisory decision, I am going to be out because I can't think of a way to play it. And a couple of comments. If someone is interested, he/she should really listen to the advisory meeting to get the feel for the FDA position. Because the FDA can still say NO if the Advisory say YES. Next we don't get a FDA decision till May 4th. This in between period is definitely playable.

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