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Daviddal, Yes, good point about Dr. Rogers still having a consulting role. Never having actually met Drs. Lynch or Rogers, they have taken on a near mythical status in my mind, so it's difficult to imagine the company without them. Perhaps with the various BP deals coming this year, Dr. Rogers figures that much of the new compound design work will be done by the BP scientists, leaving him with less to do.
It would be phenomenally great if he would be able to post here on I-Hub. I only have about a million questions for him :o) I can't imagine that happening, but it sure would be great.
Sigma-Aldrich (3-07) Launches MISSION(R) siRNA Druggable Genome Libraries
Tuesday March 6, 4:00 pm ET
>>> ST. LOUIS, March 6 /PRNewswire-FirstCall/ -- Sigma-Aldrich (Nasdaq: SIAL - News), a leading $1.8 billion Life Science and High Technology company, announced today the release of its first two MISSION siRNA Druggable Genome Libraries for Human and Rat (http://sigma.com/missionsirna) to address the needs of researchers to quickly and cost-effectively screen for gene function.
"MISSION siRNA Druggable Genome Libraries offer the most compelling siRNA collections available today by targeting genes of high therapeutic value as defined with input from major pharmaceutical companies," said Dr. David Smoller, Vice President of R&D at Sigma-Aldrich. "The flexible format of MISSION siRNA libraries facilitate research for life scientists who are interested in specific classes of genes as well as those who need to generate information across the entire druggable genome."
siRNA sequences comprising MISSION siRNA libraries have been optimized for performance in RNAi experiments using a best-in-class set of design rules developed by Rossetta Inpharmatics, a wholly owned subsidiary of Merck and Company, Inc., and a recognized leader in the field of bioinformatics. Specifically, design rules in the current Rosetta algorithm have been optimized with over three years of continuous development, leading to increased target specificity and improved knockdown of messages across the entire genome, as proven in use in drug discovery research.
"A good siRNA design reduces off-target effects and leads to down regulation of all types of genes, not just the historically easy-to-knock-down high expressors," said Dr. Peter Linsley, Executive Director of Biology at Rosetta Inpharmatics. "Using an siRNA of proven design saves time and money, enabling life science researchers to focus on downstream discovery instead of up-front validation work."
MISSION siRNA Druggable Genome Libraries have been sub-divided into 17 gene family panels using the most up-to-date gene information available, offering siRNA collections unique to the market with this level of gene-family classification. The druggable genome libraries are available for sale in their entirety, or may be purchased by individual gene-family panels.
About Sigma-Aldrich: Sigma-Aldrich is a leading Life Science and High Technology company. Its biochemical and organic chemical products and kits are used in scientific and genomic research, biotechnology, pharmaceutical development, the diagnosis of disease and as key components in pharmaceutical and other high technology manufacturing. The Company has customers in life science companies, university and government institutions, hospitals, and in industry. Over one million scientists and technologists use its products. Sigma-Aldrich operates in 35 countries and has 7,300 employees providing excellent service worldwide. Sigma-Aldrich is committed to Accelerating Customer Success through Leadership in Life Science, High Technology and Service. For more information about Sigma-Aldrich, please visit its award-winning Web site at sigma-aldrich.com. <<<
Some backround on Renovis -
>>> Renovis Tries to Right Itself
http://www.fool.com/investing/general/2007/01/25/renovis-tries-to-right-itself.aspx
Brian Lawler
January 25, 2007
It's just a fact of the industry that, inevitably, every year several development-stage biotechs implode after their lead compounds fail to pass muster in clinical trials. Unfortunately for shareholders in drug developer Renovis (Nasdaq: RNVS), it became one of those biotechs last year, after its lead drug failed in a pivotal phase 3 clinical trial.
If you recall, Renovis and partner AstraZeneca (NYSE: AZN) reported phase 3 results from their SAINT II clinical trial back in October for candidate NXY-059. The drug failed to show a statistically significant reduction (p-value of 0.33) in stroke-related disability compared to placebo, and it also missed its secondary endpoints. Considering the more than 3,000 patients in the trial, it's probably fair to say that these results were most likely not due to the trial being underpowered.
Investors had high hopes for NXY-059 after an earlier 1,700-person phase 3 trial, titled SAINT I, succeeded in the same primary endpoint (with a p-value of 0.038) but failed in its secondary endpoints. Either something went wrong with the second SAINT trial compared to this one, or else these first results may have been a statistical fluke. Remember, a p-value of 0.038 means there's nearly a 4% chance that the results could occur by chance. That's why the FDA almost always requires two successful phase 3 trials for a drug to gain marketing approval.
On Tuesday, Renovis partly outlined the steps it was taking in light of the failure of its stroke treatment NXY-059. It announced a 40% reduction in its workforce to conserve its $105 million in cash and equivalents, and also reiterated its commitment to the compounds in its pipeline. Really though, what other choice does Renovis have?
Barring an acquisition -- a possibility to which Renovis seemed open in its third-quarter financial release -- the company also guided for its cash stockpile to last it until "at least" the end of 2009. Considering that all the drug candidates in Renovis' pipeline are in the preclinical stage -- except for a partnered pain drug with Pfizer (NYSE: PFE) that is just entering phase 1 testing -- this rate of cash burn sounds reasonable.
It's way too soon for me to make any judgment on the value of Renovis' pipeline, since none of the compounds have any clinical trial results attached to them. By 2008, Renovis expects to have three drugs in phase 1 testing. If there is any meaningful value in these compounds then shares of Renovis might be a deal right now, just considering the breakup value of the company.
As of last year's third quarter, Renovis had net cash and equivalents of approximately $105 million. Even with a couple of million dollars in cash burn for the fourth quarter, it's now barely trading above its cash level. Considering the other opportunities out there in this sector, though, it's tough to generate any interest for a biotech whose products have so many unknowns attached to them. <<<
CombinatoRx (3-07) Reports Financial Results for the Fourth Quarter and Year End 2006
Tuesday March 6, 7:30 am ET
>>> Clinical Data Demonstrates Power of Drug Discovery Approach --
CAMBRIDGE, Mass.--(BUSINESS WIRE)--CombinatoRx, Incorporated (NASDAQ: CRXX - News), today reported financial results for the fourth quarter and year ended December 31, 2006 and goals and guidance for 2007.
"2006 was a substantial year for CombinatoRx as we demonstrated the validity of our drug discovery approach with strong proof-of-concept clinical data across four product candidates, the selection of two programs to advance into further development, the selection of three additional programs to initiate clinical studies and two new discovery and development collaborations providing product rights," commented Alexis Borisy, President and CEO of CombinatoRx. "This momentum will continue in 2007 as we expect to report clinical data from multiple product candidates, advance programs into later stage clinical development and add new candidates to the clinical pipeline. In particular, clinical data for the product candidates CRx-139, CRx-150 and CRx-191 are expected during 2007."
For the fourth quarter of 2006, CombinatoRx reported a net loss of $10.0 million as compared to $7.0 million for the same period last year. For the year ended December 31, 2006, CombinatoRx reported a net loss of $34.3 million compared with a net loss of $29.5 million for the same period last year. At December 31, 2006, CombinatoRx had cash, cash equivalents, restricted cash and short-term investments of $121.1 million compared to $102.4 million on December 31, 2005.
2006 and Recent Accomplishments
Product Pipeline Advancements:
Presented three positive phase 2 results for CRx-102. CRx-102, an oral synergistic combination containing the cardiovascular drug dipyridamole and an unconventionally low dose of the glucocorticoid steroid prednisolone, demonstrated powerful anti-inflammatory effects and rapid onset of action in both hand osteoarthritis and rheumatoid arthritis:
-- In hand osteoarthritis, CRx-102 met its primary and
secondary endpoints with statistically significant 31%
reduction in pain, as well as improvements in stiffness,
patient global, and tender and swollen joints.
-- In rheumatoid arthritis, CRx-102 met its primary and
secondary endpoints with a statistically significant 63%
ACR 20 response compared to 30% with control.
-- In a biomarker study, CRx-102 met its primary endpoint with
a statistically significant reduction in C-reactive protein
(CRP) compared to placebo
Based on this positive data, CRx-102 has been selected for further development with phase 2b clinical trials in rheumatoid arthritis and osteoarthritis expected to begin in 2007. A proprietary modified-release commercial formulation of CRx-102 is expected to be complete by the end of the year.
Demonstrated clinical activity of a CRx-170 combination in a phase 2 proof-of-concept asthma trial where the individual components did not show activity. CRx-170 has also shown synergistic efficacy in a number of preclinical pain models. CRx-170, an oral synergistic combination drug candidate combining the analgesic activity of nortriptyline with the anti-inflammatory activity of prednisolone, has been selected for further development in chronic pain with a phase 2 clinical trial in chronic lower back pain expected to begin in the second half of 2007.
Completed patient accrual in a 210 subject phase 2 clinical trial of CRx-139 in rheumatoid arthritis. In this study, CRx-139, an oral synergistic combination drug candidate containing low doses of the glucocorticoid steroid prednisolone and the anti-depressant paroxetine, is being evaluated in comparison to low dose prednisolone alone. Data from this study is anticipated this spring.
Presented clinical inflammatory biomarker data on CRx-150 at the Gordon Conference on Periodontal Disease. CRx-150, a synergistic cytokine modulator containing the anti-depressant amoxapine and the cardiovascular drug dipyridamole, reduced acute release of CRP and exhibited a trend toward reduction of TNF-alpha and IL-6 in this study. Data from a phase 2 clinical trial of CRx-150 in rheumatoid arthritis is expected in the second quarter of 2007.
Presented preclinical data on CRx-401, a novel insulin sensitizer with anti-diabetic activity, at the American Diabetes Association meeting in which CRx-401 resulted in synergistic anti-diabetic activity by reducing fasting blood glucose and improving insulin resistance without promoting body weight gain. Based on this encouraging preclinical data, CRx-401, a novel synergistic combination containing the cholesterol agent bezafibrate and a low dose of the analgesic diflunisal, has been selected as a clinical product candidate with a phase 2a clinical trial in type 2 diabetes expected to begin mid-2007.
Selected CRx-191 to enter clinical development for topical dermatology in 2007. CRx-191, a novel synergistic combination containing the mid-potency glucocorticoid steroid mometasone and the anti-depressant nortriptyline co-formulated as a topical cream, has the target product profile of providing the efficacy of a high-potency topical steroid with the safety of a mid-potency one. CRx-191 is expected to initiate a phase 2 clinical trial for the treatment of psoriasis in mid-2007 with data becoming available later this year.
Selected CRx-197 to enter clinical development for topical dermatology in 2007. CRx-197 is a selective cytokine modulator containing low concentrations of the allergy drug loratadine and the anti-depressant nortriptyline, which has been shown to act synergistically in preclinical models of inflammation. CRx-197 is expected to initiate a phase 2 clinical trial as a topical cream for the treatment of psoriasis in the second half of 2007.
Research Progress:
Presented data at the American College of Rheumatology conference showing insights into the molecular mechanism of action for CRx-102 and CRx-139. The separate posters indicate differences in the activities and mechanisms of action between the two selective steroid amplifier product candidates.
Additional data on CRx-102 was presented by Tore K. Kvien, MD, Professor of Rheumatology, Diakonhjemmet Hospital, Oslo Norway, and principal investigator of the CRx-102 phase 2a clinical study in hand osteoarthritis, at the European League Against Rheumatism (EULAR) Annual Congress of Rheumatology meeting. This poster, entitled "Efficacy and Safety of a Novel Syncretic Drug Candidate - CRx-102 - in Hand Osteoarthritis" reported that CRx-102 treated subjects experienced improvements in a number of clinically meaningful secondary endpoints including stiffness, physical function, joint pain and patient global assessment scores, in addition to the previously reported statistically significant mean improvement in pain relief, the primary endpoint of the study.
Presented in vitro data on novel synergistic combination drug candidates for glioblastoma multiforme (GBM) at the 97th annual meeting of the American Association for Cancer Research. The rapid identification and delivery of these novel synergistic combinations for GBM represents the successful completion of the discovery research collaboration with Accelerate Brain Cancer Cure (ABC2), a non-profit foundation dedicated to accelerating therapies leading to a cure for brain cancer.
Continued CombinatoRx leadership in the field of combination systems biology with the publication, "Chemical Combination Effects Predict Connectivity in Biological Systems", Lehar, et.al. in the online journal Molecular Systems Biology, a NATURE Publishing Group journal.
Business Accomplishments:
Entered into a collaboration with Cystic Fibrosis Foundation Therapeutics (CFFT) to develop novel therapeutics to treat cystic fibrosis built from synergistic combination pharmaceuticals by leveraging the CombinatoRx drug discovery technology with the significant disease-specific expertise at CFFT:
-- CFFT will fund up to approximately $13.8 million of
research at CombinatoRx and up to 75% of the clinical
development expenses through phase 2a.
-- CombinatoRx retains worldwide commercialization rights for
any product candidates discovered under the collaboration
and is eligible for certain clinical and regulatory
milestones. CFFT will receive a royalty on net sales of any
approved products.
Entered into a collaboration with Fovea Pharmaceuticals SA for the potential development and commercialization of synergistic combination pharmaceuticals to treat ophthalmic diseases, uniting CombinatoRx leadership in combination drug discovery with Fovea's drug development resources and expertise in the field of ophthalmic therapeutics:
-- Fovea will conduct, at its own expense, development of
selected product candidates from our portfolio for certain
ophthalmic indications, including creating ophthalmic
formulations for these selected candidates.
-- CombinatoRx will retain the rights to any resulting
products in North America while granting Fovea exclusive
rights for ophthalmic indications in Europe.
Built further depth in the CombinatoRx management team with the addition of Lynn Baird, Ph.D., Senior Vice President, Regulatory, Quality and Clinical Operations and Theresa Podrebarac, MD, Vice President, Clinical Research as well as the promotion of Daniel Grau to Chief Operating Officer.
Included in the Russell 3000 Index and the small-cap Russell 2000® Index.
2007 Goals and Financial Guidance
Advance the pipeline with two product candidates moving into later stage clinical development.
-- Initiate later-stage clinical trials with CRx-102 in
osteoarthritis and rheumatoid arthritis and CRx-170 in
chronic lower back pain based on positive proof-of-concept
data.
Refresh the pipeline with three new product candidates dosed in humans.
-- Initiate proof-of-concept clinical studies for CRx-191 in
topical dermatology, CRx-197 in topical dermatology and
CRx-401 in type 2 diabetes.
Reload the late preclinical pipeline from research engine.
-- Multiple opportunities available from preclinical and
research programs.
Introduce next generation product candidates.
-- Including second generation opportunities for current
CombinatoRx product candidates with potential for improved
product profiles as well as new combinations of highly
targeted agents.
Maintain financial strength.
-- CombinatoRx expects to end 2007, based on current operating
plans, with revenue between $13.0 and $15.0 million, a net
loss in the range of $48.0 million to $53.0 million and
cash, cash equivalents and short-term investments of
between $70.0 and $80.0 million.
2006 Financial Results (Unaudited):
As of December 31, 2006, CombinatoRx had cash, cash equivalents, restricted cash and short-term investments of $121.1 million compared to $102.4 million on December 31, 2005.
Total revenue was $3.4 million in the fourth quarter of 2006, an increase from the $3.0 million reported in the fourth quarter of 2005. For the year ended December 31, 2006, revenue was $13.3 million compared to $4.7 million for the same period last year. The increase is due primarily to a full year of revenue recognition related to the Company's collaboration with Angiotech Pharmaceuticals.
Net loss for the quarter ended December 31, 2006 was $10.0 million or $0.35 per share as compared to $7.0 million or $0.13 per share in the fourth quarter of 2005. For the year ended December 31, 2006, net loss was $34.3 million, or $1.26 per share, compared to a net loss of $29.5 million for the year ended December 31, 2005.
Research and development expenses totaled $9.7 million in the fourth quarter of 2006 compared to $7.2 million in the fourth quarter of 2005. R&D expenses were $34.1 million for the year ended December 31, 2006, compared to $24.1 million for the year ended December 31, 2005. The increase in R&D expense for the fourth quarter and the full year is due primarily to costs associated with additional research and development collaborations, an increase in personnel-related expenses to support expanded research, clinical and regulatory activities associated with an advancing pipeline of product candidates and facilities-related expenses resulting from the Company's move to Cambridge, Massachusetts.
General and administrative expenses were $5.1 million in the fourth quarter of 2006 compared to $3.1 million in the fourth quarter of 2005. General and administrative expenses were $18.6 million for the year ended December 31, 2006, compared to $10.6 million for the year ended December 31, 2005. The increase in general and administrative expense is due primarily to personnel-related expenses to support operations as a publicly traded company as well as the expansion of our commercial development capabilities and increased stock-based compensation expense under SFAS No. 123R.
Conference Call Information:
CombinatoRx management will provide an update on the company, discuss fourth quarter and year end results, and discuss goals and milestones for 2007 via conference call at 8:30 a.m. ET on Tuesday, March 6, 2007. To access the call, please dial 866.362.4832 (domestic) or 617.597.5364 (international) five minutes prior to the start time and provide the passcode 34085392. A replay of the call will be available from 9:30 a.m. ET on March 6, 2007 until March 20, 2007. To access the replay, please dial 888-286-8010 (domestic) or 617-801-6888 (international), and provide the passcode 22923287. A live audio webcast of the call will also be available on the "Investors" section of the company's website, www.combinatorx.com. An archived webcast will be available on the CombinatoRx website approximately two hours after the event and will be archived for 14 days.
About CombinatoRx
CombinatoRx, Incorporated (CRXX) is pioneering the new field of synergistic combination pharmaceuticals and has a broad product portfolio in phase 2 clinical development. Going beyond traditional combinations, CombinatoRx creates product candidates with novel mechanisms of action striking at the biological complexities of human disease. The lead programs in the CombinatoRx portfolio are advancing into later stage clinical trials based on the strength of multiple positive phase 2a results. This portfolio is internally generated from the CombinatoRx proprietary drug discovery technology which provides a renewable and previously untapped source of novel drug candidates. The Company was founded in 2000 and is located in Cambridge, Massachusetts. To learn more about CombinatoRx please visit www.combinatorx.com. <<<
Neuro, board, Anyone know if Dr. Rogers gets to keep his options, and if so, for how long? Thanks.
Dr. Stoll's heir apparent, Dr. Varney, also has an early UK Merck connection, fwiw -
>>> Mark Varney, Ph.D.,
Chief Operating Officer and Chief Scientific Officer
Dr. Varney has spent over 15 years in the pharmaceutical industry, holding senior level positions at Sepracor, Inc., where he was Vice President and head of Discovery, and at Bionomics, Ltd., where he was Vice President of Drug Discovery. Prior to that, Dr. Varney held positions of increasing responsibilities over his six-year tenure at SIBIA Neuroscience, Inc., including his most recent position as Director of Neuropharmacology. Upon the acquisition of SIBIA by Merck, Inc in 1999, he was appointed a Director of Merck’s San Diego facility. Prior to SIBIA, he held research positions at Servier in France and Merck Sharp & Dohme in the U.K. Dr. Varney received his B.Sc. in Biochemistry with honors from Surrey University, U.K. and completed his Ph.D. and postdoctoral training at Oxford University, U.K.
Dr. Varney’s career has focused on drug discovery programs for treating schizophrenia, depression, cognitive disorders, anxiety, epilepsy and insomnia. He has been successful in developing drug candidates in several of these disease areas, and has filed numerous patent applications relating to new chemical entities and methods of use. Dr. Varney has published extensively in peer-reviewed journals, and is the Editor-in-Chief of the journal “CNS & Neurological Disorders-Drug Targets.” <<<
Renovis had a major collapse last year, so no wonder Dr. Street is bailing out. Perhaps Neuro has some insights into what happened. Prior to Renovis, it looks like Street spent 20 years at Merck in the UK.
Losing Dr. Rogers is a major blow, since he's the chemistry guru behind Ampakines. If a Nobel prize should ever be given for Ampakine science, it would go to the two Garys - Lynch and Rogers.
Dr. Rogers actually posted once over on the Yahoo board. He apparently did some sports car racing back in the early 1960s, and he made a racing analogy to describe the differences between Cortex's compounds and other company's AMPA upmodulators. Cortex won't be the same without Dr. Rogers.
MarketFest, OT - Similar debt situations have occurred many times in the past. During the late Roman Empire, in order to cover the ever growing government expenditures, they similarly increased the money supply by debasing the coinage (reducing and then removing the gold/silver content), leading to horrendous inflation. The invention of paper money made the debasing process easier, and after World War I, the German govermnent just cranked up the printing presses to cover their massive war related obligations. In less than 4 years they completely destroyed the currency, eventually producing trillion mark notes (printed on one side to save ink). Anyone stuck holding paper money quickly lost everything, as did people who owned bonds of any kind. A similar process happens after most protracted wars, though not often as dramatically as in the above example.
Hyperinflation has occurred all over the world at various times. The winners are those who have exchanged their depreciating currency for tangible items like land, real estate, commodities, gold, paintings, diamonds, etc. Common stocks have been a good inflation hedge over time, though in the short term the economic problems associated with a debt crisis/inflation can wreak havoc on the economy and corporate profits.
As a general rule, in times of high inflation, borrowers are winners and lenders are losers. Those who borrow to buy tangible assets not only see the value of that asset increase (relative to the falling currency), but also get to pay back their debt with the depreciated currency. Those who lend on the other hand, via owning bonds, CDs, savings accounts, etc, watch as the value of their life savings evaporates.
You don't have to have hyperinflation to wreak havoc. Just look at the loss of purchasing power of the US dollar in the last 30-40 years. The same house built in 1965 for $30,000, measured in dollar terms now costs $300,000. Likewise cars, college tuition, postage stamps, most everything. The relentless loss of purchasing power is what inevitably happens when you have a "fiat" paper currency.
Neuro, I wonder what prompted him to leave Lilly after all those (20) years?
Looks like Dr. Schoepp is a glutamate guy :o) Hopefully he'll cast off the Lilly imposed handcuffs and consider doing a deal with Cortex -
>>> He is recognized for having made major contributions in the investigation of the excitatory amino acid neurotransmitter glutamate in disease pathophysiology, pharmacology and therapeutics. He led early and current efforts to discover agents that act at the receptor level to activate, antagonize, or allosterically modulate excitatory amino acid neuronal transmission. With his colleagues at Lilly, Dr. Schoepp discovered many novel compounds that entered clinical development for the management of pain, migraine, epilepsy, anxiety, schizophrenia and neurodegenerative diseases. Most recently, his research has been focused on discovery of receptor agonists, antagonists and modulators in studying the role of glutamate regulation in psychiatric illnesses. <<<
Jerry, OT - Concerning the overall market, I'm getting some bad vibes. A few more down days globablly and the Dow could break through 12000, and then it's look out below. There could then conceivably be some panic/capitulation selling if the market can't stage a sustained rebound soon.
One of the problems with running huge deficits over long periods is that the Fed eventually gets boxed in with interest rate policy. If they lower rates, then the dollar weakens further and foreigners could start moving their money back out of the US. It is foreigners who are primariliy funding our massive deficits every year. Anyone who remembers the 1970s saw a period when the Fed couldn't lower rates in spite of a slowing economy due to high inflation/weakening dollar, so growth stayed slow and inflation high, and we had a long period of "stagflation". The underlying cause was sustained massive deficit spending by the government (exacerbated by the oil shock/embargo). Then, as now, we were emerging from a costly and protracted war, coupled with essentially out of control domestic spending. A similar phenomenon occurred after World War II in England, ending in the sterling crisis.
The crux of the problem lies with a system where government can borrow and spend fiat currency endlessly from a central bank. For a while it's a happy little triad, with citizens getting their myriad of government programs, defense contractors getting theirs, Congress buying votes by promising still more programs, and the central bank "creating" the funds to make the whole party possible. It's not like the whole house of cards will collapse next week, but give it time..
Jerry, OT - I remember Bill Walton mainly from the championship year in Boston with Bird, McCale, Parrish, etc. That was a phenomenal team. Walton was a real animal on the court, physical and intimidating, one of the greatest I've seen. He never said much publicly when he was playing due to a stuttering problem, so in the 70's everyone thought he was some kind of Neanderthal or something. Once he cured the stuttering, people were amazed at how intelligent he was.
Concerning Roger Waters, I saw him interviewed on the Dark Side of the Moon retrospective video. They all seem a lot more settled now, but he was apparently very difficult in the old days. Amazingly, with the exception of Syd Barrett, they were apparently not huge drug users. I've never seen him or Pink Floyd in concert, only on video, but I did get to see a Floyd cover band once, called The Machine, which was great. In the 70's I always thought they were just too weird, but I did listen to The Wall for a while, during one of my bleaker periods. I thought Meddle was interesting, and the Pompeii video is one of the strangest videos I've ever seen. "One of these days.." I actually got to visit Pompeii several years ago and saw some of the sites depicted in the video.
Thanks Neuro. Not having to count non-responders does wonders statistically :o) Thanks for the heads up.
That reminds me of Biomarin's current Phenoptin trial, with the exception that in that trial the elimination of non-responders was an integral part of the trial protocol. A great way to guarantee good results if you can get away with it -- just prescreen all patients for drug activity prior to enrollment, and then enroll only those who respond :o)
PDLI (3-07) - Third Point Urges PDL BioPharma to Cut Costs
Monday March 5, 11:05 am ET
(Note, this is the same outfit that is putting pressure on Acorda to put itself up for sale) -
>>> NEW YORK, March 5 /PRNewswire/ -- Third Point LLC today announced that it has filed a Schedule 13D with the Securities and Exchange Commission expressing disappointment and concern over PDL BioPharma Inc.'s (Nasdaq: PDLI - News) high rate of spending and significant underperformance relative to industry peers. In a letter sent to PDLI's Chief Executive Officer and Board of Directors, Third Point urges that the Company cut costs and not pursue additional acquisitions. A copy of the letter appears below:
March 5, 2007
Mr. Mark McDade
Chief Executive Officer
PDL BioPharma, Inc.
34801 Campus Drive
Fremont, California 94555
CC: Max Link, Ph.D.
Samuel Broder, M.D.
Karen A. Dawes
L. Patrick Gage, Ph.D.
Bradford S. Goodwin
Laurence Jay Korn, Ph.D.
Jon S. Saxe, Esq.
Dear Mr. McDade and PDLI Directors:
Funds advised by Third Point LLC ("Third Point") hold 8,000,000 shares of the common stock of PDL BioPharma, Inc. ("PDLI" or the "Company"), as well as options to purchase an additional 600,000 shares, collectively representing 7.5% of the common shares outstanding. We believe that the significant value inherent in the Company's product line, royalty revenues and R&D pipeline has been obscured by excessive overhead and apparently undisciplined research spending. We at Third Point have had substantial experience working strategically with healthcare companies to enhance value(1) and we would welcome the opportunity to share our views and work constructively with you to help put the Company on the right track. We believe that, with our timely input, the Company should be able to reverse its significant underperformance.
I am certain that you and the Board share our consternation that since January 1, 2004, the Company's share price has remained flat versus a 50% increase in the biotech index (BTK). This is particularly troubling given that the Company has received approximately $400M of royalty revenues over this time period, largely attributable to several of biotech's fastest-growing products, including Genentech's Avastin and Herceptin. By comparison, Genentech shares have doubled over this time period.
The past three years should have been a golden era for PDLI's shareholders: Genentech's successful development of both Avastin and Herceptin, from which PDLI earns royalties based on its antibody humanization patents, enabled royalty revenues to grow from $52.7M in FY'03 to $184M in FY'06. To review the facts, in February 2004 Avastin was approved for first- line metastatic colorectal cancer. Subsequently, in March and April 2005 respectively, Avastin was shown to extend survival in first-line non-small cell lung cancer and to improve progression-free survival in first-line metastatic breast cancer. Then, on April 25, 2005, Genetench announced that Herceptin had demonstrated an improvement in disease-free survival in the adjuvant setting for early-stage breast cancer patients. Unfortunately, instead of channeling this royalty stream into earnings generation and expeditious product development, you made what we consider to be an ill- conceived purchase of ESP Pharma for $500M to gain access to products Cardene IV, Retavase and Busulfex.
I am sure that both you and the Board share our disappointment that, contrary to your guidance, these products have generated little net cash flow since this purchase. Moreover, Cardene, which represents close to 60% of the combined $165M revenue stream from the three products, will go generic in 2009. With the benefit of hindsight, it is apparent that your purchase of ESP Pharma has squandered $500M of your shareholder's money. It is easy to see how some in the biotech industry have accused you, in this instance, of engaging in a classic case of biotech empire building. Based on the failure of this acquisition and the significant discount to fair value at which the Company's shares trade, we urge you not to pursue any such further acquisitions. Additionally, given your disappointing efforts with ESP Pharma's products, we believe that you should NOT partner Ularitide in exchange for yet another specialty pharmaceutical product. Instead, to enhance shareholder value you should accept an upfront cash payment. Indeed, we believe that you should sell your ESP Pharma assets to a specialty pharmaceutical company and focus PDLI on its core strength of biotechnology product development. We welcome the opportunity to discuss with you and the Board these initiatives in person.
Compounding our concerns, PDLI shareholders have had little to show to date for the roughly $400M spent on research and development between 2004 and 2006. There has been only one new investigational new drug ("IND") application since 2004. While we believe that the pipeline prospects will become apparent to investors in 2007, we find it hard to comprehend -- either historically or prospectively -- the enormity of that level of spending. We remain extremely concerned that this apparently "run-away spending" will continue, especially since a significant portion of PDLI's royalty stream ends in 2014. Pipeline development and cash flow generation are not mutually exclusive. Cash flow generation and retention, or monetization, should be as high a priority as pipeline development. We encourage the Company to reduce its spending to essential product development and research which can be justified by satisfactory rate of return expectations.
Underlying our approach is our strongly held belief that PDLI's shares are significantly undervalued due to the market's worry that the Company is squandering valuable cash flow on undisciplined R&D spending as well as its concern that the Company will make another acquisition. We estimate that between now and the end of 2014, PDLI will generate close to $2.2B in revenues from its royalty stream. Discounting this back at the current cost of capital, we calculate that this revenue stream is worth $1.8B today, just slightly below PDLI's current market capitalization. In addition to these royalties, specialty pharmaceutical revenues should approximate $200M in 2007 and the Company has other valuable assets: an exciting, albeit slowly- progressing, product pipeline; undisclosed royalties that extend beyond 2014; approximately $430M in net operating loss carry-forwards; real estate and other assets that can be monetized; and a valuable antibody technology platform that should continue to generate new compounds over time.
We believe that, with our assistance, the Company could significantly close the value gap by taking several simple steps. We would like to work with management in developing a plan to streamline the cost structure and asset base at PDLI as soon as practicable. To that end, we would be willing to sign an appropriate NDA or other documents to work through this budgeting process and to share our views with management and the Board.
Our preliminary analysis shows that PDLI should, with some cost-cutting, be able to earn $1.00 per share in 2008 and to increase that to $1.50 per share in 2009. To be clear, we believe that PDLI can produce these results while it also does the following: conducts PIII trials for Nuvion, develops Daclizumab with BIIB for multiple sclerosis, develops M200 with BIIB for numerous cancers, partners Ularitide, partners Daclizumab for asthma, develops HuLuc63 for multiple myeloma and advances the early stage pipeline.
We understand that certain exasperated shareholders (those who haven't sold their shares) have suggested that PDLI either undergo a change of management or sell the Company to the highest bidder. We do not recommend such a course at this time so long as you and the Board agree to take immediate and decisive action and implement the sort of plan discussed above.
We at Third Point can only imagine the frustration that you and the Board must feel given the 40% plunge in PDLI stock price over the past 12 months and the series of operational disappointments that led to this decline. In light of this, we understand the sense of vulnerability that led you to recently implement the shareholder-unfriendly poison pill. We believe that a better course than "circling the wagons" would be to cease money losing initiatives and wasteful practices so that the underlying cash generating ability and value of the Company can be fully developed and made visible to shareholders. We look forward to meeting with you to discuss how we can be of assistance.
Sincerely,
Daniel S. Loeb
Chief Executive Officer
1 Third Point was a founding investor and is represented on the board of
Ception Therapeutics. We led a proxy contest and ultimately were
granted three seats on the board of Ligand Pharmaceuticals, where we
worked diligently with the board over the past year to sell divisions
and replace management. This past November, two directors nominated by
Third Point were added to the board of Nabi Biopharmaceuticals, leading
to positive changes at that company as well.
About Third Point LLC
Third Point LLC, founded by Daniel S. Loeb in 1995, is a registered investment adviser based in New York with over $4 billion of assets under management. <<<
Gilead, HIV landscape (3-07) - New HIV Drugs Grab the Spotlight
>>> By Adam Feuerstein
Senior Writer
3/5/2007 10:37 AM EST
URL: http://www.thestreet.com/newsanalysis/biotech/10342241.html
The curtain has closed on the big HIV research meeting in Los Angeles, with new "integrase inhibitor" drugs from Gilead Sciences (GILD) and Merck (MRK) garnering much of the spotlight.
These new drugs represent a promising novel class of therapies for HIV patients, especially for those with a virus that has mutated and become resistant to currently marketed HIV drugs.
Unlike existing HIV drugs, the new drugs from Gilead and Merck work by blocking integrase, an enzyme that helps the HIV virus merge its genetic material with that of a patient's host cell.
On the surface, the efficacy of Merck's drug, raltegravir, looked better than Gilead Sciences' drug, known as GS9137. This may account for some of the weakness seen last week in Gilead shares (in addition to the big downturn in the overall market.)
Gilead closed Friday at $70.44, losing 4.3% for the week. Merck closed Friday up 20 cents to $44.19.
But for important reasons that I'll detail below, it's difficult to make head-to-head comparisons between the two drugs. In fact, both drugs showed strong efficacy with clean safety profiles. Merck expects to seek FDA approval for raltegravir in the second quarter; while Gilead will start phase III studies of GS9137 by the middle of the year.
I put together a chart of the major data highlights from both drugs, which was presented at the annual meeting of the Conference on Retrovirus and Opportunistic Infections last week.
From an efficacy standpoint, the most stringent measure is the percent of patients achieving viral load less than 50 copies. It's at this point that HIV patients are deemed to have undetectable virus in their systems.
A glance at the chart shows that 61% and 62% of raltegravir patients achieved undetectable status compared with 44% and 36% in the controls arms of the two phase III studies.
Merck
Gilead Sciences
Raltegravir Benchmark 1 control Raltegravir Benchmark 2 control GS9137 phase IIB 125 mg control
baseline HIV RNA (log) 4.6 4.5 4.7 4.7 4.7 4.54
baseline CD4 cell count 156 153 146 163 157 158
Efficacy
Time (weeks) 16 16 16 16 16 16
Mean viral load reduction 1.7 1.2
% less than 400 copies 77% 41% 77% 43%
% less than 50 copies 61% 44% 62% 36% 40% 30%
increase CD4 cells 83 31 86 40 61 28
In Gilead's study, 40% of GS9137 patients on the highest dose had undetectable virus compared with 30% of control patients.
What the chart doesn't tell you, however, is that patients in Merck's study had less-advanced disease and were less heavily pretreated with other HIV drugs than those enrolled in Gilead's study. For instance, 25% of HIV patients enrolled in the raltegravir studies had virus that was resistant to all currently marketed drugs. For the Gilead study, 48% of patients taking GS9137 were resistant to all drugs.
Furthermore, the Merck studies allowed potent protease inhibitors drugs to be included in the background regimen that all patients received in addition to raltegravir. But in the Gilead study, protease inhibitors were only allowed in the control arm at first, which put GS9137 patients at a clinical disadvantage. It was only partway through the trial that GS9137 patients were allowed to start taking protease inhibitors as well.
That's not to take anything away from Merck's drug, because it showed impressive efficacy, but the phase III studies were somewhat optimized to get the best results. The Gilead study, however, set up a more difficult challenge for GS9137. Viewed through that lens, the drug's efficacy still came through strongly.
Once approved, integrase inhibitors will likely be used in treatment-experienced HIV patients, although the drugs' clean safety profile could lead some doctors to use them off-label in newly diagnosed patients. Merck's raltegravir has a good 18-month lead on Gilead's drug, but once approved, raltegravir will likely be most used in combination with Gilead's top-selling HIV treatment backbone, Truvada.
Current HIV drugs most at risk for being shunted aside by the use of integrase inhibitors include the NNRTI class of drugs, such as GlaxoSmithKline's (GSK) Sustiva, and some older protease inhibitors, including Abbott Labs' (ABT) Kaletra.
Fuzeon, marketed by Roche and Trimeris (TRMS) , also faces considerable headwind from new HIV drugs because Fuzeon must be given by injection and causes significant, painful side effects. <<<
OT - Jerry, I re-watched the Rolling Stone "20 Year Anniversary" video over the weekend (was made in the 1980s, hosted by Dennis Hopper). If you haven't seen it, they have an interview with Jerry Garcia throughout the video, along with many other rock personalities. I had never previously heard him speak, and he seemed like such a great guy, very intelligent and articulate. And funny too - great sense of humor. It's a shame he's no longer with us.
Myriad (3-07) Presents Additional Flurizan(TM) Phase 2 Study Data Demonstrating Benefit in Alzheimer's Patients
Monday March 5, 6:30 am ET
>>> 42% of Patients on Flurizan(TM) Had Improved or Not Declined After 24 Months
SALT LAKE CITY, UT--(MARKET WIRE)--Mar 5, 2007 -- Myriad Genetics, Inc. (NasdaqGS:MYGN - News) (www.myriad.com) announced today that it presented additional results of its completed Phase 2 follow-on study of Flurizan(TM) in patients with mild Alzheimer's disease at the annual meeting of the American Association for Geriatric Psychiatry (AAGP), held March 1-4, 2007 in New Orleans. The data indicate that Flurizan may be capable, not only of slowing the decline of Alzheimer's disease, but of halting the disease in its tracks. In this study, many patients with Alzheimer's disease got no worse over two full years, and in some cases, patients treated with Flurizan appear to have improved.
At 24 months, study participants in the Phase 2 trial with mild Alzheimer's disease taking 800 mg twice daily Flurizan experienced a 67% improvement in their level of cognitive decline compared with placebo, as measured by the Mini Mental State Exam (MMSE) score. This difference was highly significant statistically (p=0.001). Additionally, based upon the MMSE score, three times the percentage of patients on Flurizan demonstrated improvement in cognition or zero decline, compared to patients on placebo: Forty-two percent of patients on 800 mg twice daily Flurizan experienced improvement or zero decline, compared with 14% of patients taking placebo. MMSE is the primary test used by most clinicians to help diagnose, assess and monitor progression of patients with Alzheimer's disease. It was also the principal criterion for selecting patients to enroll in the Phase 2 study, and is a secondary endpoint in the two ongoing Phase 3 trials of Flurizan.
Overall, 42% of patients on Flurizan showed improvement or no decline in one or more of the three primary endpoints of cognition, global function and activities of daily living, compared to 10% of patients on placebo. On the test that measures cognition, ADAS-cog, 25% of study participants taking 800 mg BID of Flurizan showed cognitive improvement or experienced zero decline in cognition after 24 months, compared with none on placebo. With the CDR-sb test, a measure of overall function in Alzheimer's patients, 29% of study participants on Flurizan experienced an improved or zero decline score, compared with none of those on placebo.
Robert C. Green, M.D., MPH, Co-Director, Alzheimer's Disease Clinical & Research Program, Professor of Neurology, Genetics and Epidemiology at the Boston University School of Medicine, and a lead investigator on the Phase 3 trial of Flurizan, commented, "This analysis of patient response to Flurizan in the Phase 2 trial suggests that the drug may, in many patients, actually halt disease progression over a 24-month time frame. Since Flurizan appears to slow the biological progression of the disease, this is an exciting and novel finding, and if replicated in the ongoing Phase 3 trials will be extraordinarily important."
To recap the efficacy results of the Phase 2 study at month 24 presented earlier, mild patients taking 800 mg of Flurizan twice daily had an effect size of 72%, with a statistically significant value of p=0.0005, as measured by their global function on the CDR-sb test. In activities of daily living, the patients showed a statistically significant 67% effect size (p=0.015). Cognition improvement showed an effect size of 52% at 24 months on the ADAS-cog scale. These data suggest that there is a substantial benefit from Flurizan.
The additional data presented at the AAGP meeting and announced today add detail to these effect sizes by demonstrating that, not only did the population as a whole respond to the treatment, but a meaningful portion of the patients who responded to the treatment did so by experiencing either zero decline after two years or a reversal of their decline to actual improvement, something that is very rare in Alzheimer's disease. Comparisons to placebo at 24 months refer to the placebo group as originally randomized.
The vast majority of patients in this Phase 2 study, approximately 94% at the time of enrollment, were receiving stable doses of acetylcholinesterase inhibitors, which are FDA-approved drugs for symptomatic treatment of Alzheimer's disease. Thus, the benefits of Flurizan observed in these patients were over and above the current standard of care.
"The 24 month Phase 2 responder analysis provides further evidence of efficacy against mild Alzheimer's disease that is consistent with our understanding of Flurizan's mechanism of action as a SALA," said Adrian Hobden, Ph.D., President of Myriad Pharmaceuticals, Inc. "The results support our belief that Flurizan is modifying the course of the underlying disease process."
About Flurizan
Myriad has two Phase 3 trials of Flurizan ongoing in patients with mild Alzheimer's disease. In each study, participants are taking 800 mg of Flurizan or placebo twice daily, and the last participant enrolled will have taken the study drug for 18 months. Flurizan is the first in a new class of drug candidates known as Selective Amyloid beta-42 Lowering Agents (SALAs). Flurizan lowered levels of Abeta42 in cellular assays and animal models. Abeta42 is the primary constituent of senile plaque that accumulates in the brain of patients with Alzheimer's disease. It is thought to be the key initiator of Alzheimer's disease, since Abeta42 has the greatest tendency to aggregate, cause neuronal damage and initiate amyloid deposits in the brain. Most genetic mutations that cause early-onset Alzheimer's disease appear to do so by increasing production of Abeta42. Myriad believes that Flurizan is the most advanced drug candidate that modifies the production of Abeta42 to be evaluated in a clinical trial for the treatment of Alzheimer's disease.
About Myriad
Myriad Genetics, Inc. is a biopharmaceutical company focused on the development and marketing of novel healthcare products. The Company develops and markets molecular diagnostic products, and is developing and intends to market therapeutic products. Myriad's news and other information are available on the Company's Web site at www.myriad.com. Flurizan is a trademark of Myriad Genetics, Inc. in the United States and other countries.
<<<
Neuro, Any thoughts on the Flurizan/AD results? I like Myriad primarily for their diagnostics business, but success with Flurizan would make this a monster stock. Thanks for any input -
>>> Myriad Presents Additional Flurizan(TM) Phase 2 Study Data Demonstrating Benefit in Alzheimer's Patients
Monday March 5, 6:30 am ET
42% of Patients on Flurizan(TM) Had Improved or Not Declined After 24 Months
SALT LAKE CITY, UT--(MARKET WIRE)--Mar 5, 2007 -- Myriad Genetics, Inc. (NasdaqGS:MYGN - News) (www.myriad.com) announced today that it presented additional results of its completed Phase 2 follow-on study of Flurizan(TM) in patients with mild Alzheimer's disease at the annual meeting of the American Association for Geriatric Psychiatry (AAGP), held March 1-4, 2007 in New Orleans. The data indicate that Flurizan may be capable, not only of slowing the decline of Alzheimer's disease, but of halting the disease in its tracks. In this study, many patients with Alzheimer's disease got no worse over two full years, and in some cases, patients treated with Flurizan appear to have improved.
At 24 months, study participants in the Phase 2 trial with mild Alzheimer's disease taking 800 mg twice daily Flurizan experienced a 67% improvement in their level of cognitive decline compared with placebo, as measured by the Mini Mental State Exam (MMSE) score. This difference was highly significant statistically (p=0.001). Additionally, based upon the MMSE score, three times the percentage of patients on Flurizan demonstrated improvement in cognition or zero decline, compared to patients on placebo: Forty-two percent of patients on 800 mg twice daily Flurizan experienced improvement or zero decline, compared with 14% of patients taking placebo. MMSE is the primary test used by most clinicians to help diagnose, assess and monitor progression of patients with Alzheimer's disease. It was also the principal criterion for selecting patients to enroll in the Phase 2 study, and is a secondary endpoint in the two ongoing Phase 3 trials of Flurizan.
Overall, 42% of patients on Flurizan showed improvement or no decline in one or more of the three primary endpoints of cognition, global function and activities of daily living, compared to 10% of patients on placebo. On the test that measures cognition, ADAS-cog, 25% of study participants taking 800 mg BID of Flurizan showed cognitive improvement or experienced zero decline in cognition after 24 months, compared with none on placebo. With the CDR-sb test, a measure of overall function in Alzheimer's patients, 29% of study participants on Flurizan experienced an improved or zero decline score, compared with none of those on placebo.
Robert C. Green, M.D., MPH, Co-Director, Alzheimer's Disease Clinical & Research Program, Professor of Neurology, Genetics and Epidemiology at the Boston University School of Medicine, and a lead investigator on the Phase 3 trial of Flurizan, commented, "This analysis of patient response to Flurizan in the Phase 2 trial suggests that the drug may, in many patients, actually halt disease progression over a 24-month time frame. Since Flurizan appears to slow the biological progression of the disease, this is an exciting and novel finding, and if replicated in the ongoing Phase 3 trials will be extraordinarily important."
To recap the efficacy results of the Phase 2 study at month 24 presented earlier, mild patients taking 800 mg of Flurizan twice daily had an effect size of 72%, with a statistically significant value of p=0.0005, as measured by their global function on the CDR-sb test. In activities of daily living, the patients showed a statistically significant 67% effect size (p=0.015). Cognition improvement showed an effect size of 52% at 24 months on the ADAS-cog scale. These data suggest that there is a substantial benefit from Flurizan.
The additional data presented at the AAGP meeting and announced today add detail to these effect sizes by demonstrating that, not only did the population as a whole respond to the treatment, but a meaningful portion of the patients who responded to the treatment did so by experiencing either zero decline after two years or a reversal of their decline to actual improvement, something that is very rare in Alzheimer's disease. Comparisons to placebo at 24 months refer to the placebo group as originally randomized.
The vast majority of patients in this Phase 2 study, approximately 94% at the time of enrollment, were receiving stable doses of acetylcholinesterase inhibitors, which are FDA-approved drugs for symptomatic treatment of Alzheimer's disease. Thus, the benefits of Flurizan observed in these patients were over and above the current standard of care.
"The 24 month Phase 2 responder analysis provides further evidence of efficacy against mild Alzheimer's disease that is consistent with our understanding of Flurizan's mechanism of action as a SALA," said Adrian Hobden, Ph.D., President of Myriad Pharmaceuticals, Inc. "The results support our belief that Flurizan is modifying the course of the underlying disease process."
About Flurizan
Myriad has two Phase 3 trials of Flurizan ongoing in patients with mild Alzheimer's disease. In each study, participants are taking 800 mg of Flurizan or placebo twice daily, and the last participant enrolled will have taken the study drug for 18 months. Flurizan is the first in a new class of drug candidates known as Selective Amyloid beta-42 Lowering Agents (SALAs). Flurizan lowered levels of Abeta42 in cellular assays and animal models. Abeta42 is the primary constituent of senile plaque that accumulates in the brain of patients with Alzheimer's disease. It is thought to be the key initiator of Alzheimer's disease, since Abeta42 has the greatest tendency to aggregate, cause neuronal damage and initiate amyloid deposits in the brain. Most genetic mutations that cause early-onset Alzheimer's disease appear to do so by increasing production of Abeta42. Myriad believes that Flurizan is the most advanced drug candidate that modifies the production of Abeta42 to be evaluated in a clinical trial for the treatment of Alzheimer's disease.
About Myriad
Myriad Genetics, Inc. is a biopharmaceutical company focused on the development and marketing of novel healthcare products. The Company develops and markets molecular diagnostic products, and is developing and intends to market therapeutic products. Myriad's news and other information are available on the Company's Web site at www.myriad.com. Flurizan is a trademark of Myriad Genetics, Inc. in the United States and other countries. <<<
Dew, I'd be interested in hearing Neuro's take on that. If the acetylcholine system goes through a similar change as the glutamate system does as Alzheimer's progresses (low neurotransmitter levels in early stage AD, and then high levels in the later stages as cellular destruction increases), then replacing the cholinesterase enzyme would make sense in later stage AD to reduce the abnormally high level of acetylcholine. In early stage AD on the other hand, the opposite would be the case, with an ACHase enzyme inhibitor like Aricept helping to increase the low acetylcholine level.
This would loosely correspond to the glutamatergic system, where an Ampakine would theoretically provide benefit in early stage AD by increasing the low glutamatergic activity, while a glutamate/NMDA antagonist like Namenda does the opposite in later stage AD, reducing the effects of excess glutamate.
Haysaw, Modafinil isn't a regular stimulant like amphetamines or methylphenidate, but it looks like it does have some cardiovascular effects, and can also interact strongly with MAO inhibitors -
Contraindications (from Wikipedia) -
>>> patients with left ventricular hypertrophy, or
patients that have previously experienced mitral valve prolapse. It should be used with extreme caution in patients that are currently using monoamine oxidase inhibitors.. <<<
They also note that hypertensive patients need to get their blood pressure under control prior to taking modafinil.
So a low impact Ampakine like CX-717 should have a distinct advantage due to its complete absence of cardio side effects -- no effect on heart rate or blood pressure.
Aiming, The only gambling stock I follow (sort of) is Penn National Gaming (PENN). They were on the Forbes "America's Best Managed Companies" list several months ago. Heebner's other pick also looks interesting (Deere), with a nice long term chart.
>>> America's Best -Managed Companies
The Best Of The Best
Matthew Miller 01.29.07
Hotels, Restaurants & Leisure
Penn National Gaming
The glitz and glamour of gambling might be in Las Vegas or Monte Carlo, but the real scratch is made on the slots--no matter where they are. Just ask the bosses at Penn National Gaming, which operates 21,000 slot machines at 16 casinos, racetracks and off-site betting centers in Pennsylvania, Maine, Colorado, Louisiana and Mississippi. Penn National's stock was up 12% in the first 11 months of 2006 and up a staggering 984% since the middle of 2000. Sales have grown four times what they were in 2001, from $520 million then to roughly $2.2 billion in 2006.
That swelling stack of chips comes from tapping regional markets and local gamblers, and adding slot machines to existing horse racing facilities. "Our bread-and-butter customers are middle-income American gamblers with average incomes between $40,000 and $90,000 a year," says J. William Clifford, Penn National's chief financial officer. "And they are almost always within a 90-minute drive of our casinos. We haven't focused on destination gambling; we are not trying to get people to travel across the country."
At least not yet. Look for the company to enter Las Vegas soon. "We'd like to buy several properties at once, probably on the Strip," says Clifford. The company was reportedly bidding for Harrah's Entertainment, the largest gambling company in the world by sales ($7.1 billion in 2005), but lost out to a private equity group last month. <<<
Ken Heebner's World View (3-07) -
>>> by Fred W. Frailey
The manager of CGM Focus fund discusses what's happening with the economy and specific stocks he likes now.
Ken Heebner has made tons of money for shareholders by astutely attuning CGM Focus fund to powerful economic trends and riding those trends like a cowboy atop a Brahman bull. Before 2000, lots of people forecast a bursting of the tech bubble, but Heebner put Focus's money on the line by shorting the high flyers in a bet that their prices would plummet, as they did. Then he invested heavily in homebuilding stocks just as their businesses took off. By 2004, Heebner steered Focus into energy and metals stocks -- yet another home run.
Moves like these propelled Focus into the top 10% of diversified domestic stock funds in four of the past seven calendar years (it finished in the top half or better the other three years). From the end of 1999 through February 27, CGM Focus (symbol CGMFX) returned a remarkable 25% annualized, thumping Standard & Poor's 500-stock index by an average of 24 percentage points per year. Heebner also runs CGM Capital Development (LOMCX), which is closed to new investors; CGM Mutual (LOMMX), a balanced fund; and CGM Realty (CGMRX).
As we sit down with Heebner this week in his office 45 floors above Boston Harbor, the question on our minds is where his instincts for broad economic trends are sending Focus fund these days. He doesn't disappoint us.
"The subprime mortgage disaster is much bigger than anyone can imagine," Heebner begins. Subprime mortgages are those made to borrowers who would otherwise not be given credit, and are largely unsecured in the event of default. Officially they come to almost $1 trillion, but Heebner is convinced that the amount of mortgage money in the hands of wobbly borrowers is even greater. He forecasts massive foreclosures -- a 30% default rate on subprimes -- as homeowners walk away and mail back their keys to lenders. As Heebner puts it: "It takes time for housing prices to go down to the point that people are under water. But when that happens, who is going to sit there in a $700,000 house that's now worth $500,000 and keep making the mortgage payment?"
But this is good news, Heebner explains, because the investment implications are counterintuitive. The effect of massive defaults will be to crimp consumer spending, and that will slow economic growth a bit and assure a longer life for today's bull market by causing the Federal Reserve Board to refrain from raising interest rates.
"I wish I could find a way to double my money" on the subprime debacle, says Heebner. "What I'd like to do is short the hedge funds, which I know own this stuff. They're buying mortgage-backed securities with an 8% yield and leveraging 10-to-1 or 20-to-1. They're going to be gone. But the mortgage holders we can short are small, and there aren't a lot of opportunities."
Heebner's biggest play these days -- 25% of assets at the end of 2006 -- is in investment banks: Lehman Brothers (LEH), Merrill Lynch (MER), Bear Stearns (BSC), Morgan Stanley (MS) and Goldman Sachs (GS). Explains Heebner: "They are in three new businesses. One is feeding the private-equity companies. I've seen a study that shows that between 2000 and 2006, the fees the investment banks got from private-equity companies equaled 10% of the assets of the private-equity companies. They are in the hedge fund business, too. Goldman has one. Finally, they sponsor these hedge funds by providing them with seed capital, providing brokerage services and making very profitable arrangements in terms of trading. As long as global liquidity remains robust, they will enjoy new avenues of profit."
How do you invest in the prosperity of farmers? Why, by owning John Deere. Deere & Co. (DE) is a 5% position in CGM Focus. The effect of the ethanol boom -- refineries are springing up across the Midwest -- is that corn prices are at record levels and staying there. "As we harvest corn and sugar to make hydrocarbons, we create a permanent demand for these crops," says Heebner. "That means that grain prices, which historically have only gone up when the weather was bad, are going to plateau. The agricultural sector is now endowed with a secular jump in its level of profitability. I was aware of this, but when Deere had its conference call recently and laid out the incremental demand for corn that ethanol was causing, the stock jumped $10. I don't think that most people who buy and sell stocks had been looking at corn prices." Farmers will have money to burn, and it's a good bet they'll buy lots more Deere farm equipment. (Read more about Deere & Co. as a global agricultural play.)
Heebner's investing style is hard to stuff inside a Morningstar style box. He calls himself a contrarian who looks for companies that will surprise people on the up side. One company with these characteristics is Las Vegas Sands (LVS), the casino operator. Run by Sheldon Adelson, the company has spread out from Las Vegas. There are deals now for casinos in Singapore, Macau and (get this) the former Bethlehem Steel plant in its namesake city of Pennsylvania. It's the Macau development that excites Heebner, who says it's not on the Wall Street radar yet. Macau is the former island colony that Portugal ceded to China in 1999. Chinese are renowned for their love of gambling, and Macau is China's Las Vegas -- except, as Heebner points out, Las Vegas took 40 years to develop as a gambling mecca and Macau is taking four. "If you want a direct play on the growth of Asian wealth," says Heebner, "this stock is it."
In Macau, LVS is already filling a swamp on which it is building eight casinos, along with shopping malls, condos and hotels. And the company is believed to be near an agreement with the government to develop nearby Hengqin with golf courses, convention spaces and hotels (but no casinos). The impact of all this on the earnings of Las Vegas Sands, says Heebner, will be electrifying. He cites a Goldman Sachs estimate that earnings will jump from $1.70 a share this year to $5.60 in 2008 and $6.85 in 2009.
We ask Heebner what would make him reconsider all of these investments. "Well," he replies, "if oil broke down to $30, that would derail the whole thing because the ethanol plants would close down. I don't see that happening. Also peace in Iraq, because Iraq has the second-largest oil production capacity. Investment banks would be hurt by a big decline in the stock market, and that could be brought about by higher inflation and higher interest rates. All these trends would be interrupted by a big decline in the stock market."
Significantly, when asked, he says he doesn't think Tuesday's 3.3% fall in the Dow Jones industrial average is such a decline -- more of a blip. Ken Heebner's world view remains intact. <<<
Modafinil Info, from Wikipedia. A low impact Ampakine like CX-717 would appear to have a better systemic side effect profile, especially cardiovascular -
>>> Modafinil
Systematic (IUPAC) name
2-benzhydrylsulfinylethanamide
Identifiers
CAS number 68693-11-8
ATC code N06BA07
PubChem 4236
DrugBank APRD00534
Chemical data
Formula C15H15NO2S
Mol. mass 273.351 g/mol
Pharmacokinetic data
Bioavailability ?
Protein binding 60%
Metabolism Hepatic, including CYP3A4 and other pathways
Half life 8-18 hours
Excretion Urine (as metabolites)
Therapeutic considerations
Pregnancy cat. C
Legal status Schedule IV (USA)
Routes Oral
Modafinil is a eugeroic drug generally prescribed to treat narcolepsy, made by the pharmaceutical company Cephalon Inc. It is not a typical stimulant and is often described as a "wakefulness promoting agent." The drug is sometimes prescribed off-label for ADD/ADHD. In mass-media advertisements and websites, Cephalon markets the drug for improving 'alertness' and reducing 'excessive daytime sleepiness.'
Contents [hide]
1 Commercial Trade Names
2 Indications
3 Off-label use
3.1 ADHD (off label indication)
4 Contraindications and warnings
5 Side-effects
6 Research
7 Military use
8 Pharmacology
9 Pharmacokinetics
10 History
10.1 Formulation patent
10.2 Particle size patent
11 Price
12 Legal status
13 See also
14 References
15 External links
[edit] Commercial Trade Names
Provigil (US, UK, Italy)
Vigil (Germany)
Modalert, Provake (India)
Modiodal (France, Mexico, Turkey, Greece, Sweden)
Modavigil (Australia)
Alertec (Canada), and possibly Vigicer
Resoty, Mentix (Chile)
[edit] Indications
The patient insert for Modafinil states that it is meant for the treatment of narcolepsy, obstructive sleep apnea/hypopnea and shift work sleep disorder. In some countries, it is also approved for idiopathic hypersomnia (excessive daytime sleepiness).
A single dose of 200 mg taken shortly after waking is the usual initial dosage, which may be increased up to 400 mg per day if necessary. Some patients will need to divide their total dose over two or more smaller doses in order to maintain effectiveness throughout the day and/or to reduce the incidence of side-effects. In patients with cirrhosis of the liver or severely compromised renal function, these figures should be halved.
[edit] Off-label use
Modafinil is widely used off-label to suppress the need for sleep. It is also used off-label in combatting general fatigue unrelated to lack of sleep, in treating ADHD, and as an adjunct to antidepressants (particularly in individuals with significant residual fatigue).
In suppressing the need for sleep, it is generally administered up to three times daily in doses of 100-200 mg. Users without prior experience with stimulants generally respond well to lower doses.
Cephalon hopes to soon release the longer-lasting Nuvigil (R-modafinil) as a "truly once-a-day" wakefulness medication. In 2006, the FDA sent Cephalon an "approvable letter" for Nuvigil, pending agreement on the final product labeling.
Yet another off-label use for modafinil is as a nootropic, or a "smart drug." As a nootropic, it is taken by healthy non-sleep-deprived users in doses of 100-200 mg once a day. It is believed to have cognitive enhancing[1] and neuroprotective[2] effects.
Modafinil has received some publicity in the past when several athletes were discovered allegedly using it as a doping agent. It is not clear how widespread this practice is. Since there are no studies pertaining to this sort of use, it is unknown whether modafinil can have any positive impact on an athlete's performance.
Modafinil is sometimes used to treat intense 'neurological fatigue' experienced by the vast majority of Multiple Sclerosis sufferers. In some cases, patients are recommended to follow the standard usage pattern for the drug. In other cases, patients are instructed to take 100 to 200 mg early in the morning on days when they feel they will be extremely fatigued. In 2000, the manufacturer, Cephalon, conducted a study of modafinil in people with MS to evaluate it as a potential treatment for MS-related fatigue. Seventy-two people with different forms of MS took two different doses of modafinil and inactive placebo over nine weeks, and self-evaluated their fatigue levels using standard fatigue and sleepiness scales. Participants reported feeling least fatigued while taking a lower dose of modafinil, and there was a statistically significant difference in fatigue scores for the lower dose versus placebo. The higher dose of modafinil was not reported to be effective.[3]
[edit] ADHD (off label indication)
As of Febuary 2007, there are at least seven English-language articles on randomized clinical trials in humans in the Medline database addressing the use of modafinil for the treatment of attention deficit/hyperactivity disorder (ADHD). Some studies have shown the use of modafinil in the treatment of ADHD is associated with significant improvements in primary outcome measures. Cognitive function in ADHD patients may also improve following modafinil treatment, in some studies. Studies for ADHD report insomnia and headache were the most common adverse effects, seen in approximately 20% of treated individuals. These studies were not adequate to demonstrate that the beneficial effects of modafinil are maintained with chronic administration. Additional large, long-term studies using flexible titration methods to establish safety and efficacy and head-to-head comparisons between modafinil and stimulants are needed to determine the role of modafinil in the treatment of ADHD.[4]
[edit] Contraindications and warnings
Modafinil should not be used by
patients with hypersensitivity to the drug or other constituents of the tablets, or
patients that have previously experienced cardiovascular problems while using other stimulants, or
patients with left ventricular hypertrophy, or
patients that have previously experienced mitral valve prolapse.
It should be used with extreme caution in patients that are currently using monoamine oxidase inhibitors such as Parnate (tranylcypromine), Nardil (phenelzine), Emsam (deprenyl), or Marplan (isocarboxazid), as well as patients that have used such drugs in the past 2 weeks. Such combinations have not been tested, and these drugs are expected to significantly potentiate the drug response (factor of 4 or more), creating the potential for hazardous and potentially fatal side-effects.
Patients with severe anxiety should be carefully supervised, as modafinil may exacerbate their condition. It may be necessary to coadminister an anxiolytic. High blood pressure should be stabilized before initiating treatment with modafinil or any other stimulant.
The patient should inform the prescribing physician of any other drugs they are currently taking, as modafinil may interact with a great number of drugs.
Modafinil should not be used while pregnant or breastfeeding, and may reduce the effectiveness of contraceptives.
Alcohol and similar depressants should be avoided if at all possible while taking Modafinil.
[edit] Side-effects
The most common side-effects observed with modafinil, as compared to placebo, when prescribed in the recommended doses for the approved indications, are as follows:
Common
Headache (34% vs 23%)
Nausea (11% vs 3%)
Uncommon
Nervousness (7% vs 3%)
Insomnia (5% vs 1%)
Anxiety (5% vs 1%)
Anorexia (4% vs 1%)
Dry mouth (4% vs 2%)
Rare
Chest pain (3% vs 1%)
Hypertension (3% vs 1%)
Tachycardia (2% vs 1%)
Vasodilation (2% vs 0%)
Dizziness (5% vs 4%)
Paresthesia (2% vs 0%)
Somnolence (2% vs 1%)
Pharyngitis (4% vs 2%)
Additionally, gastrointestinal distress, which may be alleviated by taking the drug after a meal, aggressiveness and skin irritation have been reported, but are rare.
Most side-effects subside after a few weeks without reducing the dose. Only headaches and anxiety have been shown to be proportional to dose, and these may benefit from a temporary reduction.
A single case of premature ventricular contractions appeared causally linked to administration of modafinil (Oskooilar 2005).
Modafinil may have an adverse effect on hormonal contraceptives, lasting for a month after cessation of dosage.[5]
Modafinil toxicity levels vary widely among species. In mice and rats, the median lethal dose LD50 of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. In clinical trials on humans, taking up to 1200 mg/day for 7 to 21 days or one-time doses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea. As of 2004, FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil).[6] Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine.
[edit] Research
In January 2005, researchers at the University of Pennsylvania published the results of a small study, which found that modafinil may help recovering cocaine addicts fight their addiction. Similar published case reports suggest that modafinil might also be useful in the treatment of amphetamine addiction.
Clinical trials have suggested that modafinil may be effective for treatment of Attention-deficit hyperactivity disorder (ADHD). However, in March 2006, the FDA advisory committee voted 12-to-1 against approval, citing concerns about a number of reported cases of skin rash reactions in a 1,000 patient trial, including one which was thought to be likely a Stevens-Johnson syndrome.[7][8] Final rejection occurred in August of 2006, although subsequent follow-up indicated that the skin rash reaction was not Stevens-Johnson syndrome.[citation needed] Cephalon then decided to discontinue development of the Sparlon product for use in pediatric cases, though there is potential for use in treating Adult ADHD.
A few studies have indicated that modafinil may have an appetite reducing effect on some people, leading to weight loss. During 9-week double-blind clinical trials of 320 mg/day and 425 mg/day doses of modafinil in children suffering from ADHD, patients receiving modafinil lost an average of 1.7 kg compared to those receiving placebo.[9] This appetite reducing effect appears to be similar to that of amphetamines, but, unlike amphetamine, the dose of modafinil that is efficacious in decreasing food intake does not significantly increase heart rate.[10] Conversely, a U.S. patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.
[edit] Military use
Militaries of several countries are known to have expressed interest in Modafinil as an alternative for Amphetamine - the medicine traditionally employed in sleep-deprivation situations. The concensus seems to be that Modafinil is generally well received, but it is not quite as efficient as amphetamines.
The French government indicated that the Foreign Legion used modafinil during certain covert operations. The UK's Ministry of Defence has admitted conducting ongoing research into Modafinil.[11] In the United States military, Modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.[12]One study on helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert and maintain their accuracy at pre-deprivation levels for 40 hours without sleep.[13]However, significant levels of nausea and vertigo were observed. Another study of fighter pilots showed that 300 mg modafinil given in three divided 100 mg doses sustained the flight control accuracy of sleep-deprived F-117 pilots to within about 27 percent of baseline levels for 37 hours, without any considerable side effects.[14] In an 88-hour sleep loss study of simulated military grounds operations, 400 mg/day doses were mildly helpful at maintaining alertness and performance of subjects compared to placebo, and it was concluded that the dosing regimen was too low to obviate the majority of performance decrements brought about from complete sleep loss.[15]
It's unclear what the long-term effects on the brain would be from this sort of sleep deprivation.
[edit] Pharmacology
The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine and, more potently, norepinephrine. While the co-administration of a dopamine antagonist is known to decrease the stimulant effect of amphetamine, it does not negate the wakefulness-promoting actions of modafinil. Modafinil activates glutamatergic circuits while inhibiting GABAergic neurotransmission. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects.
The central stimulating effect of modafinil shows dose and time-related features. The effect tends to be enhanced by chlorination but reduced by methylation. Modafinil blocks the reuptake of norepinephrine by the noradrenergic terminals on sleep-promoting neurons from the ventrolateral preoptic nucleus (VLPO). Such a mechanism could be at least partially responsible for the wake-promoting effect of modafinil.
Modafinil has a binding coefficient (Ki) of about 4,000 nmol/L for the dopamine reuptake transporter, and in excess of 10,000 nmol/L for the norepinephrine reuptake transporter.
A newly proposed mechanism of action involves brain peptides called orexins, also known as hypocretins. Orexin neurons are found in the hypothalamus but project to many different parts of the brain, including several areas that regulate wakefulness. Activation of these neurons increases dopamine and norepinephrine in these areas. There are two receptors for hypocretins, namely hcrt1 and hcrt2. Animal studies have shown that animals with defective orexin systems show signs and symptoms similar to narcolepsy. Modafinil seems to activate these orexin neurons thus promoting wakefulness. However, a study of genetically modified dogs lacking orexin receptors showed that modafinil still promoted wakefulness in these animals, suggesting that orexin activation is not required for the effects of modafinil.
It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine and norepinephrine reuptake, as well as orexin activation.
It has been shown in rats that modafinil increases histamine release in the brain, and this may be a possible mechanism of action in humans.[16]
[edit] Pharmacokinetics
Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP2B6 and CYP3A4, as well as inhibiting CYP2C9 and CYP2C19 in vitro. It may also induce P-glycoprotein, which may affect drugs transported by Pgp, such as digoxin.
Cmax occurs approximately 2–3 hours after administration. Food will slow absorption, but does not affect the total AUC. Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine.
[edit] History
Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, also including adrafinil, by scientists working with the French pharmaceutical company Lafon. Adrafinil was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil and has similar activity but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil. It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who leased the rights from Lafon. Cephalon eventually purchased Lafon in 2001. In 2005, a petition by a private individual was filed with the FDA requesting over-the-counter sale of modafinil.[17]
[edit] Formulation patent
A U.S. Patent 4,927,855 was granted to Lafon for modafinil in 1990. The FDA granted modafinil orphan drug status in 1993. The formulation patent expired on 30 March 2006.
[edit] Particle size patent
Cephalon filed for U.S. Patent 5,618,845 , covering pharmaceutical compositions of modafinil, in 1994. That patent, granted in 1997, was reissued in 2002 as RE 37,516, which provides Cephalon with patent protection for certain preparations of the drug in the United States until 2014, which is now apparently extended to April 6, 2015 after Cephalon received a six-month patent extension from the FDA.[18] However, a settlement in which Cephalon apparently paid out US$ 200 million to four generic drug manufacturers[19] may mean that generic forms of the drug will become available in April 2012 (October 2011 prior to the six month extension).
Some competing pharmaceutical manufacturers have applied to the FDA to market a generic form of modafinil in 2006. At least one withdrew their application after early opposition by Cephalon based on their new patent on particle sizes. There is some question as to whether a particle size patent is sufficient protection against the manufacture of generics. Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent, and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art.
[edit] Price
Brand-name Provigil is very expensive. Currently it retails in the United States for $7-8 per one 200 mg pill.[20] Modiodal and Alertec are somewhat cheaper. Modalert, the version of Modafinil produced by an Indian company Sun Pharma, is the most affordable and can be found as cheaply as $1 per one 200 mg pill; however, it is sometimes claimed not to be as effective as Provigil. As of January 2007, no generic versions of Provigil exist yet; prices can be expected to go down considerably if Cephalon's monopoly in the U.S. market is successfully challenged.
Not all U.S. health insurance companies cover Modafinil/Provigil, and those that do may require proof of severity of one's condition before paying for the drug. As a result, many Americans in need of this medication turn towards online pharmacies or try to bring Modafinil from neighboring countries (Canada and Mexico). One is advised to examine the following section before attempting to buy Modafinil.
[edit] Legal status
Currently, use of modafinil is controversial in the sporting world, with high profile cases attracting press coverage as prominent United States athletes have tested positive for the substance. Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offence. However, the World Anti-Doping Agency (WADA) maintains it is related to already banned substances, so the decisions stand. The agency added modafinil to the list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.
Modafinil is currently classified as a non-narcotic Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer ( and, therefore, to buy from most online pharmacies ), with or without a prescription.[21] It is also illegal to possess without a valid prescription. However, one may legally buy Modafinil in United States or bring up to 50 dosage units (i.e. pills) in person from a foreign country, provided that he or she has a prescription for it, and the drug is properly declared at the border crossing.[22]
The following countries do not classify Modafinil as a controlled substance:
Canada (not listed in the Controlled Drugs and Substances Act)
Mexico[23]
United Kingdom (not listed in the Misuse of Drugs Act and is available by prescription without legal restrictions)
[edit] See also
Adrafinil
Ampakines
Armodafinil
Human factors
Human reliability
Hypopnea syndrome
Narcolepsy
Seasonal affective disorder (SAD)
Shift work sleep disorder (SWSD)
Sleep apnea
Sleep disorder
Adderall
Nootropics
[edit] References
^ Cognitive enhancing effects of modafinil in healthy volunteers
^ Antiparkinsonian and neuroprotective effects of modafinil in the mptp-treated common marmoset
^ http://www.nationalmssociety.org/Meds-modafinil.asp
^ Use of modafinil for the treatment of attention deficit/hyperactivity disorder. The Annals of Pharmacotherapy October 2006, retrieved December 7,2006.
^ NIH MedicinePlus Drug Information
^ FDA Approved Labeling Text for Provigil
^ FDA Psychopharmacologic Drugs Advisory Committee minutes from March 23, 2006
^ Briefing document (2006) (PDF format)
^ Efficacy and Safety of Modafinil Film-Coated Tablets in Children and Adolescents
^ Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity
^ BBC report on MoD research into Modafinil
^ Modafinil and Management of Aircrew Fatigue - United States Air Force memo
^ The Effects of Modafinil on Aviator Performance During 40 Hours of Continuous Wakefulness
^ The efficacy of Modafinil for sustaining alertness and simulator flight performance in F-117 pilots during 37 hours of continuous wakefulness
^ http://stinet.dtic.mil/cgi-bin/GetTRDoc?AD=ADA454558&Location=U2&doc=GetTRDoc.pdf
^ Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A (2003). "Modafinil increases histamine release in the anterior hypothalamus of rats.". Neurosci Lett 339 (2): 143-6. PMID 12614915.
^ FDA
^ "bizjournals.com"
^ E. Pringle (2006)
^ Provigil pricing
^ DEA and online pharmacies
^ USC 201 Section 1301.26 Exemptions from import or export requirements for personal medical use
^ http://www.cofepris.gob.mx/pyp/estpsic/es.htm <<<
Blade, Yes, the Sleep Related indications are not exactly chopped liver. I wonder though how receptive the FDA is going to be to letting another cognition drug through the Narcolepsy back door route to approval? Cephalon got modafinil onto the market that way, and then expanded the label all over the place. Finally they were going for expansion into ADHD and the FDA put its foot down.
From what I could gather (Neuro will correct this if it's wrong), Sparlon/Provigil had good data that clearly supported label expansion into ADHD. The FDA simply found an excuse to shoot it down (the one case of skin rash). I'm not sure how much of that decision was due to the heat the FDA was under with ADHD drugs generally, or perhaps they were also trying to get back at Baldino for past transgressions, or some combination of reasons. Even considering the numerous FDA approved legitimate label expansions for Modafinil/Provigil, it is increasingly being used/abused off label by school kids and as a cognitive lifestyle drug by adults. So the FDA may not be receptive to allowing still another lifestyle type cognitive drug loose in the US. That's why my jets have cooled considerably on the Narcolepsy orphan approach to approval, even though a low impact Ampakine would likely be ideal for those indications.
The other reason to downplay the Narcolepsy/EDS/Sleep Related indications as an alternative to the non-Ampakine in-license strategy is that the ultimate BP partner isn't going to want such a wide market, with large off label potential, out of their control. To carve it out could make the BP deal terms considerably less favorable than they'd otherwise be. Anyway, with Stoll so intent on the non-Ampakine in-license route, my guess is that in the end he'll include EDS/Sleep in the BP deal. He'll probably try to hold it out as a lever to get a better terms, but in the end I could see him including it, especially if its carve out is a serious sticking point for a really big name BP partner.
Bladerunner, Plus neuropathic pain isn't an orphan indication, so it might have been beyond what Cortex could easily manage in-house.
While Dr. Stoll seems firmly set on the non-Ampakine in-license approach, Cortex's alternative strategy would be to continue on exclusively with Ampakines. The chief limitations here involve the availability of indications and compounds -
1) Indications - Since the biggies are either already outlicensed (Schizo, Depression), or will soon be outlicensed (ADHD, Neurodegenerative/AD/MCI/Parkinson's), that only leaves some relative crumbs as potential carveout indications, things like - a) EDS/Narcolepsy/Sleep Related, b) Memory Loss Post-ECT, c) Memory Loss Post-CABG, d) Fragile-X/Autism, e) Huntington's, ALS.
2) Compounds - A low impact like CX-701 or CX-1501 will be available before too long (Phase 2 for CX-701 could start in Q1-08, according to Dr. Stoll's timetable at Roth). So the compound lag time that was such an issue a year ago is no longer so big an issue. Of course the high impacts will still take quite some time to perfect in humans, so there is still a big lag time for those.
So the alternative to the non-Ampakine in-licensing would be to advance CX-701 for either EDS/Sleep Related, or post-ECT, or post-CABG. Another alternative is to keep CX-717 in-house for another year and do a larger Phase 2b ADHD trial prior to outlicensing, with hopes of getting a considerably bigger ADHD pharma deal. Of course this entire discussion is likely moot since Dr. Stoll seems clearly intent on the non-Ampakine strategy.
Thanks Neuro. Yes, it looks like they tried Bicifadine for both acute and chronic pain, but eventually abandoned those and went to neuropathic pain instead. Your Porsche analogy sounds about right. I followed Pain Therapeutics for a while and saw some of the difficulties encountered with pain trials - placebo effects, high dropout rates, use of rescue meds, etc. Man, I hope Coleman knows what the heck he's doing. I just hope they hold off on the in-licensing deal until the Summer -- just give me a good clean FDA dosing decision in May and then I can go back to watching from the sidelines :o)
Well, out of posts again til midnight..
Here's the press release that announced the Bicifadine deal -
>>> XTL Biopharmaceuticals Announces the In-Licensing of Bicifadine - A Late-Stage Clinical Compound for the Treatment of Neuropathic Pain
Tuesday January 16, 3:22 am ET
NEW YORK, January 16 /PRNewswire-FirstCall/ -- XTL Biopharmaceuticals Ltd. (NASDAQ: XTLB, LSE: XTL, TASE: XTL) announced today that, through a wholly-owned subsidiary, it has signed an agreement with DOV Pharmaceutical, Inc. (PS: DOVP.PK) to in-license the worldwide rights for Bicifadine, a serotonin and norepinephrine reuptake inhibitor (SNRI).
XTL intends to develop Bicifadine for the treatment of neuropathic pain - a chronic condition resulting from damage to peripheral nerves. With 15 million people suffering from neuropathic pain in the United States alone, and limited treatment options available, neuropathic pain represents a significant unmet medical need. According to Datamonitor, the market for neuropathic pain drugs is expected to grow from $1.8 billion in 2005 to $5.5 billion by 2015.
Bicifadine is a serotonin and norepinephrine reuptake inhibitor (SNRI). Other members of the SNRI class include Cymbalta® (approved for depression and neuropathic pain), and Effexor® (approved only for depression). Both Cymbalta® and Effexor® have been shown to be efficacious in neuropathic pain. Activity on norepinephrine reuptake is thought to be necessary for anti-depressants to be effective in neuropathic pain.
Compared to the currently approved SNRI's, Bicifadine has a unique ratio of serotonin versus norepinephrine reuptake inhibition, which is weighted toward norepinephrine reuptake inhibition, providing a strong scientific rationale for using Bicifadine for the treatment neuropathic pain indications.
Bicifadine has been tested extensively in over 15 clinical trials involving over 3,000 patients, and has been shown to be safe and generally well tolerated. Bicifadine was evaluated in various pain indications, including two large, randomized clinical trials (n=750 and n=540) in patients suffering from acute (non-neuropathic) pain, where Bicifadine demonstrated statistically significant efficacy.
Dr. Christine Sang, Director of Translational Pain Research at the Brigham and Women's Hospital, Harvard Medical School, commented, "Neuropathic pain continues to be an area of growing unmet medical need, and I believe that Bicifadine represents an exciting potential treatment option. Clinical data clearly support the role of SNRI's for the treatment of neuropathic pain. Based on its mechanism of action that includes a unique ratio of serotonin versus norepinephrine reuptake inhibition, the demonstrated effect of other SNRI's in this disease area, and the activity it has demonstrated in acute pain studies, I have a high degree of confidence that Bicifadine could be successfully developed as a treatment for neuropathic pain."
Ron Bentsur, XTL's Chief Executive Officer, commented, "This is a very important event for XTL, as this in-license transforms us immediately into a late-stage development company. It is rare to come across an opportunity such as Bicifadine, a drug candidate that addresses a multi-billion dollar market, in a class with a proven mechanism of action, and with an established safety profile and clear evidence of activity in the treatment of pain." Mr. Bentsur added, "By re-directing the development of Bicifadine away from the novel indications in acute and chronic pain toward a proven area of efficacy of SNRI's in the treatment of neuropathic pain, we believe we can be the second approved SNRI for neuropathic pain, offering a differentiated efficacy and possibly safety profile based on the drug's emphasis on norepinephrine reuptake inhibition. We are excited to bring Bicifadine on board as our lead compound."
In accordance with the terms of the license agreement, XTL will make an up-front payment of $7.5 million in cash. In addition, XTL will make milestone payments of up to $126.5 million, in cash and/or XTL ordinary shares over the life of the license, of which up to $115 million will be due upon or post approval of the product. XTL is also obligated to pay royalties on net sales of the product to DOV. In addition, the Company has committed to pay a transaction advisory fee in the form of stock appreciation rights in the amount equivalent to 3% of the Company's current fully diluted ordinary shares, vesting after one year of the close of the transaction, and 7% of the Company's current fully diluted ordinary shares, vesting following successful Phase 3 clinical trial results or the acquisition of XTL. Payment of the stock appreciation rights by XTL can be satisfied, at XTL's discretion, in cash and/or by issuance of the Company's ordinary shares.
ABOUT BICIFADINE
Bicifadine is a serotonin and norepinephrine reuptake inhibitor (SNRI) being developed by XTL for the treatment of neuropathic pain. Bicifadine was licensed by XTL from DOV Pharmaceutical, which originally licensed it from Wyeth Pharmaceuticals.
Four Phase 1 clinical trials and 14 Phase 2 clinical trials involving more than 1,000 patients were conducted by Wyeth or DOV with an IR (immediate release) formulation of Bicifadine. In five exploratory double-blind, placebo-controlled Phase 2 clinical trials of the IR formulation conducted by Wyeth, Bicifadine demonstrated a statistically significant reduction in pain versus placebo, in some cases with an outcome suggesting it might be comparable to or better than positive controls such as codeine. In addition to these trials with the IR formulation, eight Phase 1 clinical trials using the SR (sustained release) formulation have been conducted, a formulation that permits less frequent daily dosing, improves tolerability and for which patents have been filed. It is intended that the SR formulation will be used in future clinical development and for commercial use
In two additional and larger (n=750 and n=540) single-dose, double-blind, placebo-controlled clinical trials with Bicifadine in the treatment of moderate to severe post-surgical acute dental pain, Bicifadine produced a highly statistically significant, dose-related reduction in pain compared to placebo, and which was comparable to a positive control arm (codeine or Tramadol). Both trials demonstrated Bicifadine to be safe and generally well-tolerated without producing any serious adverse events.
In a Phase 3 double-blind, placebo-controlled, clinical trial (n=325) with Bicifadine in the treatment of moderate to severe acute pain following bunionectomy surgery, statistically significant increases in analgesia were measured as early as 30 minutes after administration and these effects were sustained for the balance of the eight-hour measurement period. In this study, Bicifadine was safe and generally well-tolerated. The complete assessment of the analgesic action of Bicifadine under repeat dosing conditions could not be fully elucidated due to the high level of "rescue" analgesic medication used in both the placebo and active drug groups.
Due to the highly competitive nature of the market for acute pain drugs, and the FDA requirement to complete two repeat-dosing clinical trials in two different acute pain indications, no further studies in acute pain are planned.
Bicifadine has been further evaluated in three Phase 3 trials in Chronic Lower Back Pain (CLBP). The primary efficacy endpoint in these trials was the change in pain severity rating score between baseline and the end of dosing. In these trials, Bicifadine was safe and generally well tolerated, but did not show a statistically significant effect relative to placebo on the primary endpoint of the study at any of the doses tested.
XTL believes that the failure of Bicifadine in the CLBP trials was a result of the inherent heterogeneity of the studied patient population (i.e. the varying causes of CLBP pain), uncontrolled physical activities in what is largely an activity-dependent pain indication, and a high placebo response.
XTL believes that by re-directing the development of Bicifadine away from the novel indications in acute and chronic pain toward a proven area of efficacy of SNRI's in the treatment of neuropathic pain, Bicifadine could be successfully developed to be the second approved SNRI for neuropathic pain, offering a differentiated efficacy and possibly safety profile based on the drug's emphasis on norepinephrine reuptake inhibition.
ABOUT XTL BIOPHARMACEUTICALS LTD.
XTL Biopharmaceuticals Ltd. ("XTL") is engaged in the acquisition, development and commercialization of therapeutics for the treatment of neuropathic pain and hepatitis C. XTL is developing Bicifadine, a serotonin and norepinephrine reuptake inhibitor, for the treatment of neuropathic pain. In addition, XTL is developing XTL-2125 - a small molecule, non-nucleoside inhibitor of the hepatitis C virus polymerase. XTL-2125 is currently in a Phase 1 clinical trial in patients with chronic hepatitis C. XTL is also developing XTL-6865 - a combination of two monoclonal antibodies against the hepatitis C virus - presently in Phase 1 clinical trials in patients with chronic hepatitis C. XTL's hepatitis C pipeline also includes several families of pre-clinical hepatitis C small molecule inhibitors. XTL also has an active in-licensing and acquisition program designed to identify and acquire additional drug candidates. XTL is publicly traded on the NASDAQ, London, and Tel-Aviv Stock Exchanges (NASDAQ: XTLB; LSE: XTL; TASE: XTL). <<<
Thanks Neuro. Concerning Bicifadine, I was just wondering what it was about that program that you didn't particularly like, or was it more the terms of the deal, etc? It looks like DOV had done a ton of work on Bicifadine, with multi Phase 3s (1600 patients), in post surgical pain and chronic lower back pain, plus safety data on 3000 patients. Looking at the deal with XTL, I see the terms were for $7.5 mil in upfronts, with the total deal potentially reaching approx $130 mil, including milestones, etc, with royalties in the low double digits.
At Roth, Dr. Stoll indicated that they had been pretty close to doing this deal, but that it would have probably been too much financially for Cortex to handle. Just wondering if you could briefly give us your general take on Bicifadine itself, it's merits / chances for approval, etc. Thanks!
Neuro, I wanted to ask you if you could remember offhand any other neuro-based drug trials where they encountered postmortem-only tox related events? Thanks.
Generics (3-07) industry set for more consolidation
>>> By Carolyn Pritchard, MarketWatch
Last Update: 7:17 PM ET Mar 2, 2007
PHOENIX (MarketWatch) -- The generic drugmaking industry is poised for further consolidation due to increased competition and difficulty in attaining growth, a leading investment banker told the industry's annual gathering in Phoenix Friday.
Over the past year, transactions totaling roughly $20 billion took place among generic drugmakers, according to Tommy Erdei, director of health-care banking at UBS Warburg. They included Watson Pharmaceuticals Inc.'s (WPIWatson Pharmaceuticals) $1.9 billion acquisition of Andrx Corp., Barr Pharmaceuticals Inc.'s (BRLBarr Laboratories) $2.5 billion purchase of Pliva d.d. and Teva Pharmaceutical Ltd.'s (TEVAteva pharmaceutical) $7.4 billion purchase of Ivax Corp.
"The abundance of transactions we're seeing is due to a lack of growth, or difficulty of attaining growth," Erdei told the audience at the Generic Pharmaceutical Association's annual meeting.
The generic industry went through a period of robust growth, he said, but gross margins have dropped significantly over the past two to three years as the number of companies filing abbreviated new drug applications with the Food and Drug Administration has increased.
The increased competition is prompting more vertical integration in the industry as well, Erdei added, such as when Mylan Laboratories Inc. (MYLMylan Laboratories) last summer agreed to buy almost three-quarters of the outstanding shares of Matrix Laboratories Ltd. in a $736 million deal to gain controlling interest of the Indian drug-ingredients maker.
Acquiring drug-ingredients makers, also known as APIs, afford a generic drugmaker, among other things, enhanced product development and a shorter reaction time to pricing pressures, which could lower its cost structure.
But Erdei said that Barr's acquisition of Croatia's Pliva is the sign of consolidation to come, geographically speaking. Central Europe will continue to be a ripe spot for acquisition targets, Erdei told MarketWatch, as it still remains a source of independent companies and low-cost manufacturing facilities. <<<
Aiming, In trying to figure out the share price movements between now and the FDA decision (I'm figuring mid-May), some of the factors/variables I'm considering include -
1) Non-Ampakine in-license announcement prior to FDA decision.
2) General market conditions. For example, say the recent China related volatility turns into a more serious market crash that takes down everything.
3) Wildcard events. These would include things like the Organon Schizo (monotherapy) results, news on the Euro patent challenge, Stoll deciding to do another mini-PIPE on the eve of the FDA decision, Org-24448 running into difficulties, a meteorite hitting Cortex headquarters, etc.
Trying to consider what these factors might mean timing wise -
#3 (wildcards) - not much sense worrying about these.
#2 (overall market meltdown) - you never know, it's not out of the realm of possibility. I figure I'll just buy gradually every week over the next 10-12 week period just in case.
#1 (Non-Ampakine in-license) - this occuring is a distinct possibility. I'd rather not see it happen until later, but at Roth, Dr. Stoll's estimate was for the first in-license to be completed "during Q2". There are several ways the market could conceivably take this announcement, the most obvious being that it could appear that Stoll is hedging the CX-717 FDA decision. However, followers of the stock know that Stoll has been talking about this in-licensing idea for 1 1/2 years or so, so it shouldn't be much of a surprise, though perhaps some newcomers/momentum crowd won't realize that. The more important factor determining market reaction should be the program itself, but of course there won't be many investors who can really evaluate the merits of the particular program. I'm actually warming up to the idea, though not necessarily the timing.
Anyway, I figure I'll just buy gradually over the next few months, and if for some reason there is a decline back to $1.40-1.50 then I'll increase my buying. In the next 2 months I don't see much downside beyond that level, unless there's a general market meltdown or something of that nature. The general market is becoming less risk tolerant lately, but sentiment can change considerably either way in 2 months. I'm getting nervous (as usual), though still have to wait a few more weeks to get my buying funds in place.
Jerry, Now that I look at Dew's long/watch list, I don't see RPRX on it, so perhaps someone else over on his thread is following them. I would definitely run the company by Dew though prior to getting in heavy.
Jerry, I don't follow RPRX, but Dew has an info page on them over on the I-Hub Biotech Values thread (as a "Read Me First" link). Dew follows them, so there's likely to be a ton of info assembled there.
Chart-wise, the stock doubled a couple months ago, and it looks like it's rolling over (my less than expert take on the chart pattern, fwiw :o)
Gilead (3-07) - competition, >>> A Dynamic Duo of AIDS Drugs
Merck and Pfizer have developed promising treatments for drug-resistant patients, but investors seemed to have missed the news
by Arlene Weintraub
On Feb. 27, as the Dow Jones industrial average was plunging to its biggest loss in six years, two Dow components announced surprisingly good news. At a medical conference in Los Angeles, Merck (MRK) and Pfizer (PFE) each presented data showing that their experimental drugs to treat HIV and AIDS were successful in pivotal clinical trials. Both drugs could win Food & Drug Administration this year, offering two new treatment options for the more than 1 million Americans who suffer from the disease. "This is a very special moment," says Dr. Jacob Lalezari, assistant clinical professor of medicine at the University of California, San Francisco and the lead trial investigator for the Pfizer program.
Yet Wall Street has been curiously mum on how the two drugs might contribute to the turnaround efforts under way at Merck and Pfizer. No analysts have adjusted their earnings models to account for the potential drug introductions. Shares of both companies dropped slightly the day the data was announced.
Investors may be taking a wait-and-see stance, because the market potential of the two drugs is still uncertain. They work differently: Pfizer's drug, Maraviroc, blocks a protein on the surface of cells in the immune system, thereby closing one of the doors HIV uses to infect those cells. Merck's drug, Isentress, inhibits a specific enzyme, which, in turn, prevents the virus' DNA from infiltrating cells and replicating.
Cautious Approach
Both were initially tested in patients who had become resistant to one or more available treatments—and that would likely be the audience for the drugs when they are first released. The companies are loath to estimate just how many patients make up the drug-resistant group, but analysts have put the number somewhere between 40,000 and 65,000. Once physicians gain experience with the new drugs and further studies are done, they may prove useful in larger patient groups, or even in combination. But, says Stephen Felstead, Pfizer's vice-president of research and development: "It's hard to estimate how it will play out."
That may be why the numbers being thrown around are somewhat cautious. An FDA advisory panel is scheduled to discuss the drug on Apr. 24, and if it's approved, it could be launched as early as this summer. Tim Anderson, an analyst for Prudential Financial (PRU), estimates sales for Maraviroc will be $120 million in 2008 and rise to $591 million in 2010. A good drug to be sure, but clearly not enough of a blockbuster to offset the expected loss of revenues when the patent for Pfizer's $12-billion-a-year cholesterol drug Lipitor expires in 2011.
Investors may need to see a few more Maravirocs—completely novel drugs that address unmet medical needs and have strong data to back them up—before they pile back into Pfizer's stock. The New York company's shares dropped 10% in early December, after the company had to stop developing a new cholesterol remedy because of unexpected deaths in its clinical trials, and the stock has not quite recovered.
The Gilead Example
For Merck, the need for a huge HIV success is not quite as urgent as it is for Pfizer (see BusinessWeek.com, 3/6/06, "Pfizer's Latest Growing Pains"). True, Merck is still fighting lawsuits stemming from its arthritis drug Vioxx, which it pulled from the market after reports of cardiovascular side effects. But it has launched several promising new drugs over the past year, including its diabetes treatment Januvia, as well as Gardasil, its vaccine to prevent human papillomavirus, one of the leading causes of cervical cancer. Strong pickup on those and other products led the company to estimate it will earn between 63¢ and 67¢ a share this quarter—outpacing analysts' average estimate of 60¢. And on Feb. 28, the FDA delayed approving Novartis' (NVS) competitor to Januvia, which may brighten the outlook for Merck's drug this year. An HIV success would be icing on the cake. The company plans to file for approval for Isentress in the second quarter of this year.
Still, the potential for both companies to be richly rewarded for their work in HIV can't be underestimated. Consider the recent performance of Foster City (Calif.)-based Gilead Sciences (GILD), which last year introduced a new HIV drug, Atripla, that combines three existing treatments into one. On Feb. 2, Gilead announced that demand for the drug helped fuel record annual revenues of $3 billion, up 49% from 2005, and profits that jumped 51%, to $1.2 billion, before acquisition charges and other expenses. Gilead's stock rose 11%, to $71 a share, on the announcement (see BusinessWeek.com, 2/19/07, "How Gilead Primed the Pipeline").
While the outlook for Merck and Pfizer investors may be uncertain, one thing is clear: It couldn't be a better time for HIV patients. In addition to these potential new products, the coming years could see new drug launches from other companies working in HIV, including Gilead and Johnson & Johnson (JNJ). "We're seeing definite steps forward for our treatment of HIV," says Dr. Roy Steigbigel, professor of medicine and microbiology at Stony Brook University and one of the lead trial investigators for Merck. <<<
Amedisys (3-07) Acquires a Home Care and Hospice Business
Friday March 2, 9:03 am ET
- Acquisition Furthers Amedisys' Presence in Texas -
>>> BATON ROUGE, La., March 2 /PRNewswire-FirstCall/ -- Amedisys, Inc. (Nasdaq: AMED or the "Company"), one of America's leading home health nursing companies, today announced the acquisition of a home care and hospice business providing services in the greater San Antonio, Texas area. The transaction was effective as of March 1, 2007, and is expected to contribute approximately $5.4 million in total annualized revenues.
"We are excited to further expand our home care services in Texas with this acquisition," said William F. Borne, Chief Executive Officer of Amedisys, Inc. "The acquisition of OptimaCare Home Health, Inc. will be our sixteenth home health location in Texas, and MissionPlus Healthcare LLC will mark our first hospice location in the state."
"This purchase is representative of our disciplined acquisition strategy to increase our geographic coverage," continued Mr. Borne. "We continuously assess many similar opportunities in order to identify those that most appropriately fit our profile and acquisition criteria."
The acquisition is not expected to add materially to Amedisys' earnings in 2007. Terms of the acquisition purchase agreement were not disclosed.
Amedisys, Inc. is headquartered in Baton Rouge, Louisiana. Its common stock trades on the Nasdaq Global Select Market under the symbol "AMED". <<<
Idenix (3-07) Pharmaceuticals Reports Fourth Quarter and Year End Financial Results
Friday March 2, 7:30 am ET
CAMBRIDGE, Mass., March 2 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX - News), a biopharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of human viral and other infectious diseases, today reported unaudited financial results for the fourth quarter and year ended December 31, 2006. At December 31, 2006, Idenix's cash, cash equivalents and marketable securities totaled $186.4 million.
For the fourth quarter ended December 31, 2006, Idenix reported total revenues of $15.3 million, compared with total revenues of $18.1 million in the fourth quarter of 2005. Total revenues consist of reimbursement by Novartis of Idenix expenses incurred in connection with the development of Idenix's product and product candidates, TYZEKA® (telbivudine) and valtorcitabine for the treatment of hepatitis B virus (HBV) and valopicitabine (NM283) for the treatment of hepatitis C virus (HCV); the amortization of the up-front fees received by Idenix in connection with Novartis' license of TYZEKA, valtorcitabine and valopicitabine; and product sales of TYZEKA in the United States. Idenix reported a net loss of $23.6 million, or a loss of $0.42 per diluted share, for the fourth quarter ended December 31, 2006, compared to a net loss of $14.4 million, or a loss of $0.27 per diluted share, for the fourth quarter ended December 31, 2005.
For the year ended December 31, 2006, Idenix reported total revenues of $67.4 million, compared with total revenues of $64.7 million for the year ended December 31, 2005. Idenix reported total operating expenses of $153.1 million for the year ended December 31, 2006, compared with total operating expenses of $120.2 million for the year ended December 31, 2005. The company reported a net loss of $75.1 million, or a loss of $1.34 per diluted share, for the year ended December 31, 2006, compared with a net loss of $50.8 million, or a loss of $1.03 per diluted share, for the year ended December 31, 2005.
Business Highlights
"In 2006, Idenix continued to evolve from a research and development organization to a company with comprehensive antiviral discovery programs, significant development expertise and commercialization capabilities, culminating with the U.S. approval and launch of our first product, TYZEKA, for the treatment of chronic hepatitis B," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "As we advance our hepatitis C product candidate, valopicitabine, in clinical development, we are also actively working to expand our pipeline with complementary HCV drug candidates and novel anti-HIV agents. We are committed to providing better treatment options for patients with viral diseases, building on the foundation that we established in 2006."
Major developments realized over the past twelve months are detailed below.
- In 2006, TYZEKA (telbivudine) was approved by the U.S. Food and Drug
Administration (FDA) as a new treatment for patients with chronic
hepatitis B. TYZEKA has been shown to effectively suppress replication
of the hepatitis B virus.(1) Telbivudine, called SEBIVO®
(telbivudine) outside the U.S., received regulatory approval in China
and was recommended for approval in the European Union by the European
Medicines Agency's (EMEA) Committee for Medicinal Products for Human
Use (CHMP) in the first quarter of 2007. To date, TYZEKA/SEBIVO has
been approved in more than 10 countries and is under review with
additional regulatory authorities worldwide.
- We continued to make progress in our hepatitis C program, determining
the best valopicitabine dosing regimen to advance in clinical
development in treatment-naive and treatment-experienced patients and
initiating a new phase I/II trial to assess the use of valopicitabine
in combination with ribavirin. We also worked to expand our HCV program
through organic discovery and collaborative research and development;
our comprehensive HCV discovery efforts are focused on discovering
next-generation drug candidates in each of the major classes of small
molecules.
- Our HIV discovery program generated the filing of exploratory
Investigational New Drug (IND) applications for two non-nucleoside
reverse transcriptase inhibitor (NNRTI) compounds. The initial micro-
dosing (phase 0) study is now complete and we have selected the drug
candidate that will be moved into full clinical testing based on its
overall profile.
2007 Financial Guidance
The company expects to end 2007 with between $100 million and $110 million of cash, cash equivalents and marketable securities. Included within this guidance are $20 million in regulatory approval milestone payments related to TYZEKA/SEBIVO that the company anticipates receiving from Novartis Pharma AG.
Conference Call Information
Idenix will hold a conference call today at 8:00 a.m. ET. To access the call please dial (800) 774-5358 U.S./Canada or (706) 758-9475 International and enter passcode 9228831 or to listen to a live webcast of the call, go to "Calendar of Events" in the Idenix Investor Center at www.idenix.com. Please log in approximately 10 minutes before the call to ensure a timely connection. An archived webcast will be available on the Idenix website for two weeks after the call. A replay of the call will also be available from 12:00 p.m. ET on March 2, 2007 until 12:00 p.m. ET on March 16, 2007. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 9228831.
About Idenix
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of human viral and other infectious diseases. Idenix's current focus is on the treatment of infections caused by hepatitis B virus, hepatitis C virus and HIV. For further information about Idenix, please refer to http://www.idenix.com.
About TYZEKA
TYZEKA 600mg tablets are indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on virologic, serologic, biochemical and histologic responses after one year of treatment in nucleoside-treatment-naive adult patients with HBeAg-positive and HBeAg- negative chronic hepatitis B with compensated liver disease.
Important Safety Information About TYZEKA (telbivudine)
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues alone or
in combination with antiretrovirals.
- Severe acute exacerbations of hepatitis B have been reported in
patients who have discontinued anti-hepatitis B therapy, including
telbivudine. Hepatic function should be monitored closely with both
clinical and laboratory follow-up for at least several months in
patients who discontinue anti-hepatitis B therapy. If appropriate,
resumption of anti-hepatitis B therapy may be warranted.
- Cases of myopathy have been reported with telbivudine use several weeks
to months after starting therapy. Myopathy has also been reported with
some other drugs in this class. Physicians considering concomitant
treatment with these or other agents associated with myopathy should
weigh carefully the potential benefits and risks and should monitor and
advise patients to report any signs or symptoms of unexplained muscle
pain, tenderness or weakness, particularly during periods of upward
dosage titration. Telbivudine therapy should be interrupted if myopathy
is suspected, and discontinued if myopathy is diagnosed.
- Because telbivudine is eliminated primarily by renal excretion, co-
administration of telbivudine with drugs that affect renal function may
alter plasma concentrations of telbivudine and/or the coadministered
drug. Dose interval adjustment is recommended in patients with
creatinine clearance <50mL/min.
- The safety and efficacy of telbivudine in liver transplant recipients
are unknown. If telbivudine treatment is determined to be necessary for
a liver transplant recipient who has received or is receiving an
immunosuppressant that may affect renal function, such as cyclosporine
or tacrolimus, renal function should be monitored both before and
during treatment with telbivudine.
- Patients should be advised that treatment with telbivudine has not been
shown to reduce the risk of transmission of HBV to others through
sexual contact or blood contamination.
- Safety and effectiveness of telbivudine in pediatric patients under the
age of 16 years have not been established.
- Frequently occurring adverse events (>5%) in clinical studies were
upper respiratory tract infection (14%), fatigue and malaise (12%),
abdominal pain (12%), nasopharyngitis (11%), headache (11%), blood CPK
increased (9%), cough (7%), nausea and vomiting (7%), influenza and
influenza-like symptoms (7%), post-procedural pain (7%), diarrhea and
loose stools (7%), and pharyngolaryngeal pain (5%).
- Creatine kinase (CK) elevations were more frequent among subjects on
telbivudine treatment. Grade 3/4 CK elevations occurred in 9% of
telbivudine-treated patients and 3% of lamivudine-treated patients.
- The optimal duration of treatment with TYZEKA has not been established.
The relationship of initial treatment response to outcomes such as
hepatocellular carcinoma and decompensated cirrhosis are unknown.
Forward-looking Statements
This press release contains "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward- looking statements can be identified by the use of forward-looking terminology such as "progress," "advance," "expand," "promising," "better treatment option," "continues to evolve" or similar expressions and implied statements with respect to Idenix clinical development programs or commercialization activities in HIV, hepatitis B or C, or any potential pipeline candidates and expectations with respect to cash balances at the end of 2007. Such forward- looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantees that Idenix will successfully commercialize TYZEKA or SEBIVO (telbivudine), advance any clinic product candidate or other component of our potential pipeline in the clinic or in the regulatory process. In particular, management's expectations could be affected by unsuccessful efforts to commercialize TYZEKA or SEBIVO; unexpected regulatory actions or delays; uncertainties relating to results of clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the company's ability to obtain additional funding required to conduct its research, development and commercialization activities; the company's dependence on its collaboration with Novartis Pharma AG; the ability of the company to attract and retain qualified personnel; competition in general; and the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its other product candidates and its discoveries. These and other risks which may impact management's expectations are described in greater detail under the caption "Risk Factors" in the company's quarterly report on Form 10-Q for the quarter ended September 30, 2006 and filed with the Securities and Exchange Commission and other filings that the company makes with the Securities and Exchange Commission.
All forward-looking statements reflect the company's expectations only as of the date of this release and should not be relied upon as reflecting the company's views, expectations or beliefs at any date subsequent to the date of this release. Idenix anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
()1 Lai, C. Hepatology. 2005 Oct (42.S1):78A
Idenix Pharmaceuticals' Contacts:
Media: Teri Dahlman (617) 995-9905
Investors: Amy Sullivan (617) 995-9838
IDENIX PHARMACEUTICALS, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(IN THOUSANDS, EXCEPT PER SHARE DATA)
(UNAUDITED)
Three Months Ended Years Ended
December 31, December 31,
2006 2005 2006 2005
Revenues:
License fees and
collaborative research
and development
- related party $14,826 $18,103 $66,724 $64,418
Product sales 424 - 424 -
Government research grants 58 - 229 300
Total revenues 15,308 18,103 67,377 64,718
Operating expenses (1):
Cost of sales 62 - 62 -
Research and development 23,067 23,449 96,080 86,590
Selling, general and
administrative 18,227 10,858 56,954 33,657
Total operating
expenses 41,356 34,307 153,096 120,247
Loss from operations (26,048) (16,204) (85,719) (55,529)
Investment and other
income, net 2,270 1,703 9,487 4,038
Loss before income taxes (23,778) (14,501) (76,232) (51,491)
Income tax benefit 197 121 1,145 714
Net loss $(23,581) $(14,380) $(75,087) $(50,777)
Basic and diluted net
loss per share: ($0.42) ($0.27) ($1.34) ($1.03)
Shares used in calculation
of basic and diluted
net loss per share: 56,078 53,241 56,005 49,395
(1) Stock-based compensation
expenses included in
operating expenses
amounted to approximately:
Research and
development $646 $(22) $2,892 $722
Selling, general
and administrative 1,218 104 5,745 666
IDENIX PHARMACEUTICALS, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
(IN THOUSANDS)
(UNAUDITED)
December 31, December 31,
2006 2005
ASSETS
Cash and cash equivalents $ 57,211 $ 83,733
Marketable securities 69,932 95,579
Receivables from related party 12,035 13,723
Other current assets 8,427 6,550
Total current assets 147,605 199,585
Property and equipment, net 17,448 11,051
Marketable securities, non-current 59,208 62,855
Other assets 4,204 4,166
Total assets $ 228,465 $ 277,657
LIABILITIES AND STOCKHOLDERS' EQUITY
Accounts payable and accrued expenses $ 23,429 $ 22,350
Deferred revenue, related party 13,490 9,695
Other current liabilities 527 471
Total current liabilities 37,446 32,516
Long-term obligations 8,523 9,165
Deferred revenue, related party, net of
current position 40,471 29,089
Total liabilities 86,440 70,770
Stockholders' equity 142,025 206,887
Total liabilities and stockholders' equity $228,465 $277,657
Idenix (3-07) - SEBIVO(R) (Telbivudine) Approved in China as New Treatment Option for Patients with Chronic Hepatitis B
Friday March 2, 7:00 am ET
-- Chronic hepatitis B affects an estimated 100 million people in China(1)
-- SEBIVO(R) recently received positive opinion by the European Medicines Agency, and is already approved and available in the United States under the brand name TYZEKA(R)(telbivudine)
>>> CAMBRIDGE, Mass., March 2 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX - News) announced today that SEBIVO® (telbivudine) has received approval from the Chinese State Food and Drug Administration (SFDA) as a once-a-day treatment, taken orally with or without food, for the treatment of chronic hepatitis B (CHB). CHB remains a significant global health care concern, particularly in China where it affects more than 100 million people(1-3) - representing about one-third of those infected worldwide.(2) SEBIVO is expected to be available in China in April.
"The Chinese approval of telbivudine is positive news for the many CHB patients in China," said Dr. Calvin Q. Pan, MD, Director, Clinical Research/Hepatology, Mount Sinai Services at Elmhurst Hospital in New York City. "As a physician who treats many CHB patients in the U.S., it is good to know that the patients in China will also have access to this new treatment option. Now, Chinese patients may also benefit from telbivudine's ability to provide early viral suppression, a primary goal of treatment."
Telbivudine received regulatory approval in the United States from the Food and Drug Administration (FDA) in October 2006 for the treatment of CHB in adult patients with evidence of viral replication and active liver disease. Telbivudine is called TYZEKA in the United States and is called SEBIVO in all other countries. The approval of SEBIVO in China follows earlier approvals in Canada, Australia, Switzerland and several countries in Asia and Latin America. SEBIVO also recently received a positive opinion from the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) recommending approval by the European Commission.
Worldwide regulatory submissions have been based primarily on one-year data from the GLOBE study, the largest worldwide registration trial including hepatitis B e-antigen (HBeAg)-positive and HBeAg-negative patients with CHB, and the first to include patients from China. The study results demonstrated that telbivudine provided potent viral suppression and high rates of PCR- negativity after one year. An additional Chinese phase III trial, involving 332 adult Chinese patients with CHB, corroborated these findings and supplemented the filing in China.
About the GLOBE Study
Data from the worldwide phase III clinical trial, known as the GLOBE study, compared telbivudine to lamivudine, a commonly used antiviral therapy for the treatment of CHB, in 1,367 patients. In the GLOBE study, 60 and 40 percent of HBeAg-positive patients and 88 and 71 percent of HBeAg-negative patients achieved undetectable levels of HBV DNA (PCR-negativity) with telbivudine and lamivudine, respectively, at 52 weeks. Additionally, patients who achieved undetectable HBV DNA levels at 24 weeks were more likely to undergo e-antigen seroconversion, PCR-negativity, normalize ALT, and minimize resistance at one year.
The primary efficacy endpoint of the GLOBE study was therapeutic response at one year, a composite endpoint coupling viral suppression (serum HBV DNA suppression below 100,000 copies/mL) with either improved liver disease markers (ALT normalization) or loss of detectable HBeAg. In HBeAg-positive patients, therapeutic response was 75% (n=345/458) among patients treated with telbivudine and 67% (n=310/463) for those patients treated with lamivudine, while the response for HBeAg-negative patients was 75% (n=167/222) vs. 77% (n=173/224), respectively.
In the GLOBE study, telbivudine was generally well tolerated with most adverse experiences classified as mild or moderate in severity. Frequently occurring adverse events (> 5%) for telbivudine v. lamivudine, respectively, were upper respiratory tract infection (14% v. 13%), fatigue and malaise (12% v. 11%), abdominal pain (12% v. 13%), nasopharyngitis (11% v. 10%), headache (11% v. 14%), blood CPK increased (9% v. 7%), cough (7% v. 6%), nausea and vomiting (7% v. 6%), influenza and influenza-like symptoms (7% v. 8%), post- procedural pain (7% v. 6%), diarrhea and loose stools (7% v. 5%) and pharyngolaryngeal pain (5% v. 4%). Please see Important Safety Information.
Idenix/Novartis collaboration
Idenix and Novartis Pharma AG are co-promoting TYZEKA/SEBIVO, for the treatment of chronic hepatitis B, and co-developing valtorcitabine, a second hepatitis B compound, and valopicitabine, a hepatitis C compound, under a development and commercialization arrangement established in May 2003. Under this agreement, Novartis and Idenix will co-promote TYZEKA/SEBIVO and, if approved, valtorcitabine and valopicitabine in the United States, France, Germany, Italy, Spain and the UK. Novartis has the exclusive right to commercialize TYZEKA/SEBIVO, valtorcitabine and valopicitabine in the rest of the world.
Important Information about Telbivudine
The following information about telbivudine is adapted from the U.S. Food and Drug Administration's approved product label. It is anticipated that similar language related to the product's indication and important safety information will pertain to the product in global labeling.
Telbivudine is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on virologic, serologic, biochemical and histologic responses after one year of treatment in nucleoside-treatment-naïve adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease. Full prescribing information is available at www.tyzeka.com.
Important Safety Information about Telbivudine
-- Lactic acidosis and severe hepatomegaly with steatosis, including fatal
cases, have been reported with the use of nucleoside analogues alone or
in combination with antiretrovirals.
-- Severe acute exacerbations of hepatitis B have been reported in
patients who have discontinued anti-hepatitis B therapy, including
telbivudine. Hepatic function should be monitored closely with both
clinical and laboratory follow-up for at least several months in
patients who discontinue anti-hepatitis B therapy. If appropriate,
resumption of anti-hepatitis B therapy may be warranted.
-- Cases of myopathy have been reported with telbivudine use several weeks
to months after starting therapy. Myopathy has also been reported with
some other drugs in this class. Physicians considering concomitant
treatment with these or other agents associated with myopathy should
weigh carefully the potential benefits and risks and should monitor and
advise patients to report any signs or symptoms of unexplained muscle
pain, tenderness or weakness, particularly during periods of upward
dosage titration. Telbivudine therapy should be interrupted if myopathy
is suspected, and discontinued if myopathy is diagnosed.
-- Because telbivudine is eliminated primarily by renal excretion, co-
administration of telbivudine with drugs that affect renal function may
alter plasma concentrations of telbivudine and/or the co-administered
drug. Dose interval adjustment is recommended in patients with
creatinine clearance < 50mL/min including those with ESRD on
hemodialysis. For patients on hemodialyis, telbivudine should be
administered after hemodialysis.
-- The safety and efficacy of telbivudine in liver transplant recipients
are unknown. If telbivudine treatment is determined to be necessary for
a liver transplant recipient who has received or is receiving an
immunosuppressant that may affect renal function, such as cyclosporine
or tacrolimus, renal function should be monitored both before and
during treatment with telbivudine.
-- Patients should be advised that treatment with telbivudine has not been
shown to reduce the risk of transmission of HBV to others through
sexual contact or blood contamination.
-- Safety and effectiveness of telbivudine in pediatric patients under the
age of 16 years have not been established.
-- Creatine kinase (CK) elevations were more frequent among subjects on
telbivudine treatment. Grade 3/4 CK elevations occurred in 9% of
telbivudine-treated patients and 3% of lamivudine-treated patients.
-- The optimal duration of treatment with telbivudine has not been
established. The relationship of initial treatment response to
outcomes such as hepatocellular carcinoma and decompensated cirrhosis
are unknown.
About Idenix
Idenix Pharmaceuticals, Inc., headquartered in Cambridge, MA, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral and other infectious diseases. Idenix's current focus is on the treatment of infections caused by hepatitis B virus, hepatitis C virus and human immunodeficiency virus (HIV). For further information about Idenix, please refer to http://www.idenix.com. <<<
Sigma-Aldrich (3-07) - Sigma Introduces QuantiGene(R) 2.0 RNA Quantification System
Thursday March 1, 4:00 pm ET
ST. LOUIS, March 1 /PRNewswire-FirstCall/ -- Sigma, a division of Sigma-Aldrich (Nasdaq: SIAL - News), a leading $1.8 billion Life Science and High Technology company, is pleased to introduce the QuantiGene® 2.0 RNA Quantification System (http://sigma.com/quantigene). The technology is comprised of an assay kit and probe set that detect gene expression knockdown, providing a unique approach for RNA quantification.
"QuantiGene® 2.0 contributes to biological drug discovery as an optimal system for high-throughput screening," said Keith Jolliff, Director of Strategic Marketing. "The assay avoids the variation errors commonly seen when extracting and amplifying target sequences, enabling pharmaceutical and academic researchers to maximize efficiency. Sigma is committed to serving the genomics research community with best-in-class technologies."
The QuantiGene® 2.0 RNA Quantification System has been used to quantitate gene expression in a variety of life science applications, including predictive toxicology, microarray validation, and RNAi knockdown. Sigma provides a full range of RNA interference research tools, from gene silencing to validation. The MISSION® RNAi product line offers numerous options for gene knockdown including custom siRNA, siRNA panels and various shRNA formats. Gene knockdown can then be confirmed by QuantiGene 2.0 system's unique approach to RNA detection and quantification.
For information on MISSION RNAi products, please visit our Web site at http://sigma.com/rnai.
About Sigma-Aldrich: Sigma-Aldrich is a leading Life Science and High Technology company. Its biochemical and organic chemical products and kits are used in scientific and genomic research, biotechnology, pharmaceutical development, the diagnosis of disease and as key components in pharmaceutical and other high technology manufacturing. The Company has customers in life science companies, university and government institutions, hospitals, and in industry. Over one million scientists and technologists use its products. Sigma-Aldrich operates in 35 countries and has 7,300 employees providing excellent service worldwide. Sigma-Aldrich is committed to Accelerating Customer Success through Leadership in Life Science, High Technology and Service. For more information about Sigma-Aldrich, please visit its award-winning Web site at sigma-aldrich.com.