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‘Dark Pool’ Trading Causes Headaches on Wall Street
Most of us don't have access to these 'dark pools'. Although it is perhaps a bit off-topic, I am wondering if anyone has any general trading strategies to avoid moving stock prices around that they are willing to share with the board.
In the past few years, the size of trading blocks has gotten a lot smaller. If you look on level 2 for a thinly traded stock (say 100-300K shares/day -- typical for a $100-500M market cap company), almost all bids and asks are 100-200 shares ... which is ridiculously small!
I'm told that funds have computer systems which automatically break up their trades into such bite-sized chunks ... but what should the rest of us do?
If you want to trade ~10-100+K shares of a thinly-traded stock, it is a frustrating exercise which wastes a lot of time or a lot of money - or both. Either you spend all day breaking your trade up into lots of tiny little pieces and pay a ton in commissions ... or you just let fly with ~5K orders and watch in pain as the bid and ask RUSH away from you ... and idiots toss their 100 and 200 shares orders just ahead of you -- confident that you will 'protect' them should the market direction change.
Of course the more money you have and the more money you want to trade, the worse the problem. So as a result of the decrease in the average order size and the fact that I am trading much larger amounts than a few years ago ... this issue has become much more serious for me.
Does anyone have a strategy to deal with this problem??
I imagine someone will suggest simply staying away from $100-500M market cap companies. And maybe that is the only answer.
micro
ONXX
With the first full quarter of liver cancer sales under its belt ... I am displeased with the Nexavar revenue ramp.
$151.9M in the 9th quarter of sales, of which $51M was in the U.S.
Compare to Avastin ...
http://www.gene.com/gene/ir/financials/historical/avastin.html
In the 9th quarter of sales, Avastin had $398M in sales just in the U.S!
It isn't clear to me if the ultimate liver cancer opportunity is much smaller than I thought or if the ramp is going to simply take longer than I thought. Apparently it is tricky to market a drug for liver cancer, because oncologists are the johnny-come-latelies to the medical team taking care of liver cancer patients. These patients are also getting treated by hepatologists, surgeons, radiologists - and those guys aren't used to prescribing oral cancer therapies. So more education is required to fully tap the liver cancer market.
Or maybe that's just what Onyx is saying because they don't want to admit that they are already saturating the liver cancer market in the U.S., Germany and France ...
;o)
micro
>>HGSI is “still talking” with NVS about starting a q4w Albuferon study, according to today’s CC. Doesn’t sound as though this is a high priority.<<
As soon as the 1200 mcg q2w arm of the Phase 3 trial was stopped due to AEs, q4w dosing went out the window IMO. Because previous studies showed that in order to keep the trough from being so low as to allow an HCV rebound, at least 1800 mcg q4w is needed.
This also follows from common sense. 1800 mcg q4w is the same amount of drug as 900 mcg q2w, and less than that is clearly too low a dose.
If they can't dose at 1200 mcg, how can they dose at 1800 mcg?? One would expect that the 1800 mcg C_max would generate a lot more pulminary problems than 1200 mcg, regardless of the dosing interval.
So the fact that HGS continued to talk about q4w dosing after the pulmonary issue hit confused me.
Maybe eventually the talk will die down and it will be quiet ...
micro
>>But suppose it were the fact that for some minority of patients, say, 10%, a particular drug actually cures the patient and they live a relatively normal life span? Should we run around saying that the drug adds a few months of life because that is its effect on median survival. Now, I am not saying that this is the case for any drug, just asking whether it might be so and if any studies have indicated it is so for any particular oncology drug.<<
High dose IL-2 in metastatic RCC comes to mind. The cure rate is a bit less than 10%, maybe closer to 5%, but it's certainly not 0. Because of all the new fancy targeted therapies that work in RCC (Sutent, Nexavar, Torisel, Avastin ...), it seems that oncologists are using high dose IL-2 less and less because it hardly moves the median survival and there are serious side effects.
But what about the mean survival??
I think if I had metastatic RCC I'd try high dose IL-2 first. If you have any chance of getting off the Kaplan-Meier curve rather than riding it down ... why not try? The cure rate with the targeted therapies is essentially 0.
micro
>>The devil is in the details, and it looks like ASCO may finally have closed the loopholes.
The question is: How many other medical conferences will follow suit?<<
? I thought ASCO was the exception to the rule (until this year), and the rule was that conferences made abstracts available to everybody at the same time.
micro
>>Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity. It may also lead to lower activity, if the drug is normally changed to the active form in vivo. Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and other compounds. Deuteration increases effectiveness of long-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdown by target microorganisms. A few deuterated antibiotics have been prepared, and their antimicrobial activity was found to be little changed.<<
Lowbrow interpretation: So it's another knob that one can turn and see what happens.
micro
>>I don’t know the first thing about deuterium or heavy water except that I think I don’t want it in the drinking supply <<
Ditto. Talk about water retention weight gain ...
But seriously - probably the only effect of replacing H by D in drugs is to jack up the COGS like crazy.
Of course that's irrelevant since they aren't likely to be approved ...
micro
ASCO Virtual Meeting
I'd like to again recommend ASCO Virtual Meeting for those who like to follow that meeting but (like me) are too lazy to attend. Instead of waiting 6 months to view almost all the oral presentations, you get them online within 24 hours.
http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Virtual+Meeting
Cost for non-ASCO members: $195. I've already subscribed.
Should anybody feels like piggybacking on my subscription - email me at microcapfun@yahoo.com.
micro
1Q08 Worldwide Ifn-Alpha Sales
Dew: Do you happen to know the relative cost of Pegasys, Peg-Intron and Intron-A?
micro
HCV: Most Likely to Succeed
Much appreciated as always, Dew.
micro
Is the Drought Over for Pharming?
Science 25 April 2008:
Vol. 320. no. 5875, pp. 473 - 475
DOI: 10.1126/science.320.5875.473
News
Is the Drought Over for Pharming?
Jocelyn Kaiser
Despite technological, economic, and social issues, companies are plowing ahead, making drugs and other compounds in plants
In the bag. These cultured carrot cells are engineered to make a human drug.
CREDIT: PROTALIX
Many a child has been told "carrots are good for you." That advice could soon take on new meaning for people with Gaucher disease, an inherited metabolic disorder that leads to liver and bone problems. Patients must now be injected every 2 weeks with a manufactured enzyme that costs on average $200,000 a year, making it one of the most expensive drugs ever. If ongoing clinical trials go well, the 5000 Gaucher patients on the therapy could soon have a second option--a cheaper version of the enzyme that stays in the bloodstream longer and can be injected less often.
If the U.S. Food and Drug Administration (FDA) approves recombinant glucocerebrosidase, it will be good news not only for medicine but also for a community far removed from the clinic: plant scientists. Protalix Biotherapeutics in Karmiel, Israel, produces this new version of the protein in giant plastic bags, not in steel vats of mammalian cells like most biologics are. The bags are filled with transgenic carrot cells that are cultured and then processed to extract the drug. "If Protalix gets regulatory approval, that would [make it] the first plant-made pharmaceutical," says plant scientist Charles Arntzen of Arizona State University in Tempe. "For people who work in this field, it will be a very exciting step forward."
Arntzen is chasing an elusive dream: using whole plants as factories to make drugs. Nearly 20 years ago, when researchers first showed that a tobacco plant could be engineered to crank out an antibody, they envisioned harvesting cheap supplies of therapeutic proteins, antibodies, and vaccines from vast fields of crops. For this approach, researchers isolate the target gene and usually insert it into a bacterium called Agrobacterium that readily infects the plants and passes on the gene. The gene becomes part of the plant and is passed from one generation to the next, producing foreign protein much as if it were one of the plant's own genes.
However, technological hurdles and a lack of interest from drug companies have hamstrung "pharming," as have worries that pharma crops will escape from their experimental plots and taint the food supply. As a result, many companies have abandoned this research or gone under. And no plant-made drugs for humans have made it to the pharmacy.
But academic scientists and some companies have persisted, improving yields of plant-made drugs and developing innovative ways to keep pharming inside the lab, or the greenhouse. Several plant-made pharmaceuticals (PMPs) are now in patient trials (see chart). Moreover, the European Union, the Bill and Melinda Gates Foundation, and the U.S. Department of Defense are fertilizing the field with new funding. "We're actually not doing too bad," says Julian Ma, an immunologist at St. George's University of London in the U.K. "It's just that everyone is in a hurry."
Fields of dreams
The excitement over plant-made pharmaceuticals began with a 1989 paper in Nature showing that monoclonal antibodies could be produced in tobacco. The paper "really captured the imagination," says Ma. Monoclonal antibodies were being used to treat a growing number of diseases, from arthritis to cancer, but were expensive to make in mammalian cells. So-called plantibodies appeared to offer a cheaper production method--a kilogram might cost $100 rather than $3 million--and might be simpler to process because they would be free of animal pathogens.
Temporary transgenic. Fluorescing protein shows tobacco leaf's pharming potential.
CREDIT: BAYER AG
Other discoveries followed. In 1995, for instance, Arntzen's group reported in Science that potatoes engineered to make a cholera protein worked as a vaccine when the spuds were fed to mice. Such "edible vaccines" could offer developing countries cheap oral vaccines that didn't require refrigeration, Arntzen suggested (Science, 5 May 1995, p. 658).
A company called Large Scale Biology Corp. in Vacaville, California, came up with a shortcut. It didn't bother to create a new tobacco strain when it wanted to produce an antigen for a lymphoma vaccine. It simply sprayed tobacco plants with a tobacco mosaic virus carrying the appropriate gene. The leaves produced useful amounts of the vaccine protein within 14 days. The drug worked in mice, suggesting that vaccines tailored to lymphoma patients' tumors could be made in plants in just weeks. And because the plants carried the foreign gene only until they shed their leaves, they were potentially more acceptable than permanently modified crops.
Steps along the way. No plant-made human drug has made it through final clinical trials, but several "pharmed" proteins are close to or on the market as supplements, a vaccine reagent, and a medical device.
CREDIT: (GRAPHICS)N. KEVITIYAGALA/SCIENCE (SOURCE) INDIVIDUAL COMPANIES AND MOLECULARFARMING.COM
Scores of biotech companies sprang up to commercialize these discoveries, and some big agbiotech companies got involved as well. By the mid-1990s, more than 180 companies and organizations were working on pharming, according to the Biotechnology Industry Organization.
The companies soon ran into technological snags, however. Biotechnologists couldn't always get plants to express enough protein and had trouble purifying the protein product. Efforts to make edible vaccines stalled after researchers realized that the amount of antigen fluctuated widely from plant to plant. Arntzen thinks that oral vaccines made from dried plant material could work for developing countries, but a vaccine without a strictly controlled dose "would never be approved" in the United States, he says.
Another reality check: lukewarm interest from the big drug companies. They didn't much care that plant-made drugs would be cheaper to make because production is a small chunk of the cost of drug development; the big-ticket item is clinical trials. The companies were also leery of the regulatory hurdles, because both the drug and the new production process would have to clear FDA. "Most pharmaceutical companies aren't willing to take a chance on a drug produced in plants," says Roger Beachy, president of the Donald Danforth Plant Science Center in St. Louis, Missouri.
Also, like other genetically modified crops (see pp. 468, 472), pharma plants can be a public relations nightmare. In 2002, leftover corn plants engineered by ProdiGene Inc. to make a pig vaccine sprouted in a soybean field in Nebraska. For this and an Iowa mishap, the U.S. Department of Agriculture (USDA) fined the company $250,000 and made it pay $3 million to buy and destroy tainted soybeans. The incident stoked opposition from farmers and activists worried about "drugs in your cornflakes."
Other companies underestimated the public's concerns. A company called Ventria Bioscience that wanted to conduct field trials of rice containing two breast-milk proteins useful in combating diarrhea drew the ire of rice growers in California, then Missouri. It wound up in Kansas, where no other rice is grown.
USDA tightened its rules for field trials of pharma plants in 2003 to prevent mistakes like the ProdiGene episode. But skeptics were not assuaged. Bill Freese of the Center for Food Safety in Washington, D.C., says enforcement is "horrendous." As a result, "we don't think [drugs] should be in any food crops, indoors or outdoors," he adds. Many ecologists and some plant scientists are also leery of using food crops for pharma. "It's too dangerous," says Kenneth Palmer, former director of the vaccine program at Large Scale Biology.
Flower power. This transgenic safflower makes seeds containing insulin.
CREDITS: SEMBIOSYS
These concerns drove many companies away from using food crops such as corn for pharmaceuticals. A few big companies, such as Monsanto, dropped PMP research altogether. Stung by bad press and lack of interest from drug companies, many leading plant pharma companies have folded, including ProdiGene and Large Scale Biology. As Palmer puts it, "the field imploded."
Close to the clinic
Despite the setbacks, a handful of companies in the United States and Europe haven't given up. A few have plowed ahead with food crops, grown outdoors, for their pharma products; others have focused on other plants or on unconventional growing schemes.
Meristem Therapeutics in Clermont-Ferrand, France, plans to start final clinical trials for a corn-grown gastric lipase for cystic fibrosis patients by the end of the year. And the Canadian company SemBioSys Genetics Inc. uses transgenic safflower--"much less of a lightning rod than some other crops," says CEO Andrew Baum--to produce insulin, which should be in clinical trials this year. Companies such as Protalix and Biolex Therapeutics sidestep the growing of crops altogether: the former with its carrot-cell culture to make a Gaucher disease enzyme, and the latter by producing interferon using duckweed, tiny clonal plants grown as a layer in clear plastic bags. "We are careful not to be associated with whole-plant transgenic technology," says Protalix CEO David Aviezer.
New technologies are attracting attention. To boost expression, the German biotech Icon Genetics relies on bacteria to get transgeneladen viruses into tobacco plants. The company dips the plants into a solution of Agrobacterium that carries the DNA for a deconstructed tobacco mosaic virus, which in turn contains the gene for the desired drug. The bacterial bath, followed by a few seconds in a vacuum, gets far more of the virus into plant-leaf tissue than conventional spraying.
In a 2006 paper in the Proceedings of the National Academy of Sciences (PNAS), they reported that this method, combined with other techniques, increases the amount of antibody by up to 100-fold, reducing the size of the crop needed and making it feasible to grow plants commercially indoors. Compared with making a transgenic plant, which takes a year or two to develop, this "magnifection" can go from gene to grams of protein in a couple of weeks. "It's incredibly promising technology," says Ma, who, like other academic researchers, is trying out magnifection.
With help from the drug giant Bayer, which bought the company in 2006, Icon Genetics will open a clinical-grade manufacturing plant in June. It expects to begin trials with a cancer vaccine tailored to individual patients in 2009, says CEO Yuri Gleba.
Bayer's move is a healthy sign of regrowth for the pharming field, Ma and others say. And other new sources of support are helping too. Last month, Pharma-Planta, a €12 million, 5-year, European Union-funded project co-coordinated by Ma, described in PNAS an anti-HIV microbicide grown in corn or tobacco that could be ready for testing next year. The Defense Department and other U.S. government agencies have provided the Fraunhofer USA Center for Molecular Biotechnology in Newark, Delaware, nearly $14 million to use a technique like magnifection to make vaccines. It has tested anthrax and plague vaccines in nonhuman primates and a pandemic flu vaccine in ferrets. "[We] can do things much faster than any other technology," says Executive Director Vidadi Yusibov, slashing in half the 6 months it now takes to make flu vaccine the traditional way, in chicken eggs. The organization also has $8 million from the Gates Foundation for plant-based vaccines for malaria, sleeping sickness, and flu.
As visions of endless fields of pharma crops have faded, so have unrealistic expectations for pharming. Scientists say they now realize that they need to be smarter about the marketability of the drugs they develop in plants. They think the best bets--Protalix aside--may be high-volume biologics, such as microbicides, monoclonal antibodies, and vaccines, particularly for use in developing countries. Getting these first low-hanging fruits through clinical trials and FDA approval should allay concerns about safety and environmental risks. Says Palmer, now at the University of Louisville in Kentucky, "Once two or three products [win approval], the field should really take off."
micro
Feuerstein
>>Come on, Adam—do your freaking homework!<<
A serious question. Name a biotech 'journalist' who is better than Feuerstein.
Can't be one of the posters on this board, though. That's too easy ...
micro
>>I hate these 10b5-1 plans and wish the SEC would ban them.<<
I'd be happy if they simply had to be published in publicly available SEC filings. (They aren't, are they?)
At times one can do reverse engineering from sales to see how a plan is set up, e.g. if 10K sales occur once every week except when the stock price is below xxx for the entire week. But it would be nice to know the exact set-up of each plan at the time it is set up. Minimum prices for sales would be of special interest to me.
micro
Bayer/Onyx/Nexavar
>>Bayer, in its "Q1 2008 Analyst and Investor Briefing," announced sales of Nexavar for the quarter ended March 31, 2008 of €101M ($153M).<<
More like $150.5M, which is even more of a disappointment, given that it includes a currency exchange boost, and a small amount of sales from Japan where Onyx only gets a single digit royalty.
So my belief in a super-rapid sales ramp for Nexavar in liver cancer appears to have been unfounded. (Wipe that egg off your face, micro!) Nevertheless, we are probably looking at a ~$20M/quarter ramp for years to come.
That's a $320M/year ramp for those too lazy to do the arithmetic. So $1B in sales won't come until next year, but it will come, and probably $2B and $3B will come eventually too. I see no reason at this point why Nexavar won't eventually be in the same league as Avastin and Rituxan.
micro
HEADINGS FOR POSTS
ghmm: A reminder ... please. With all the posts, please don't force readers to follow the thread back in time in order to figure out what you are talking about and whether it is of interest to them.
Thanks very much in advance.
micro
>>Editor Out as Murdoch Speeds Change at WSJ<<
There is hope in the world yet. Maybe by 2100 they will accept the fact that global warming isn't a left-wing conspiracy ...
micro
>>
>Not true. You know me, pgs.<
I couldn't pick you out of a crowd!
>I am now at nearly 100% and my family is *way* above 50%.<
When you were working, were you making the household median, or were you well above it?
(I suspect you're going to affirm my conclusions)
<<
Golly gee, I resent that! I still work at least as many hours as before. And I still read research articles and attend conferences. Only difference is that most days I work in my PJs at home, sipping beer while reading not just research articles, but also SEC filings, PRs and the Biotech Values message board posts, rather than lecturing to bored students and writing research papers that 10 people not counting my mother might read.
;o)
Oh, yeah. The answer to your question is "well above it". Why?
micro
>>Please lighten up, and don't take things that are
said in jest with such fervor and call me things
or others, like political hatchet jobs that should
be expunged from the board when so much worse stuff
gets posted and sticks.<<
Sorry, Precious. I still feel your post was way out of line and it certainly wasn't humerous.
And I really don't care if you blame Hilary for your losing money in GSK. Don't vote for her as I didn't, but don't post crap like this on a Biotech Values board either:
>>Great article Dew, and is cryogenics and time/space
continuum teleportation, where we can bring President Reagan back and avoid these "mutant" candidates from ever taking the world's highest office?
Over 300 million people in America and this is the best
we have to offer up as candidates??
Scary, and sad state of affairs imho, and between the
Obama who will shun Israel, invite terrorists like Iran,
Venezuela, and others here for visits, to Ms Hillary,
the Hun, we are looking at a future that is scary as
a parent....sad.<<
Surprised Dew lets such things stand, even though I realize he is enamored with the WSF editorial page.
micro
>>GSK Acquires SIRT at 85% Premium to Market<<
Sirna acquired for $1.1B, SIRT for $720M. I suggest that Big Pharma is no longer only interested in companies which have (at least) established P2b proof-of-principle results in man. They are also interested in landgrabbing IP and expertise in wide-open new areas which *might* result in multi-billion dollar cash flow streams 10-20 years from now.
So what follows the pattern of Sirna and Sirtris?
How about Geron for embryonic stem cells??
micro
>>Dew-what is your take on the MLNM deal. I know that there is some discontent on some of the message boards for MLNM not entertaining other offers.<<
MLNM got more than they deserved. They have one drug on the market that they bought, and a pipeline that has failed to produce anything worthwhile since the time of Jesus.
I think Takeda overpaid and MLNM knew darn well nobody else was stupid enough to pay more.
micro
HGS - TRAIL
>>I was wondering if it is a possibility for HGSI to strike a deal with either AMGN or DNA to consolidate IP, compare clinical data, and to select the best antibody(s). Otherwise, why would HGSI agree to such a deal?<<
The way they are going, HGS is expected to run out of non-restricted cash early in 2010 - and still have a debt overhang of >$750M coming due in 2011 and 2012.
By repartnering ETR1 and ETR2 HGS can get upfront cash, milestones and help with P2 expenses as well as P3. With GSK they were getting none of that except help with P3 expenses.
From the cc, this seems to be the main reason they un-did the partnership with GSK.
The payment HGS must make to get back all rights to ETR1 and ETR2 from GSK is less royalties from Syncria - but these are unlikely to materialize before 2011 or 2012 (if ever) whereas the cash flow benefit to HGS could start sometime this year.
micro
>>Any one who does taxes professionally or who has had significant capital losses knows that they are recoverable in very limited fashion ($3,000 per year)<<
False. Capital losses can be netted against capitals gains in subsequent years - up to any amount and any number of years, I believe.
micro
capital gains
Nice article. At a glance it appears to blow Mr. Charles Gibson (and the WSJ Editorial page) out of the water.
micro
>>Nobody I know makes even 5% of their yearly take-home salary from capital gains.<<
Not true. You know me, pgs.
I am now at nearly 100% and my family is *way* above 50%.
Got to do a little averaging to get there, though. So far this year I'm below 0% ...
micro
Capital gains.
Like many here, I'd personally love for the capital gains rate to stay the same or go down. On average the great majority of my revenue comes from the markets (made 107% in the market last year and lost 8% this year to date, with only 40% of the investments tax protected). Nevertheless, Obama made two valid points.
1. It isn't fair when someone who makes billions of dollars has a lower tax rate than their secretary simply because their income comes from capital gains rather than salary.
2. It isn't necessarily the case that increasing the capital gains rate from 15% to (say) 20% would reduce the IRS inflow. "Well, that might happen, or it might not.", said Obama. Whereas Gibson (who probably reads the WSJ Editorial page) acted like three (claimed) data points make a proof. They don't.
0% capital gains tax generates no revenue for the government and 100% capital gains tax probably generates no revenue for the government. The optimum point is somewhere in between, but there is no reason to believe it is 15% or below. Most data I've seen suggests it is above 15%.
http://en.wikipedia.org/wiki/Image:Neo-Laffer_curve.svg
http://www.washingtonmonthly.com/blogphotos/Blog_WSJ_Corporate_Laffer_Curve.gif
Maybe each of the U.S. corporate tax rate, the personal income tax rate and the short-term capital gains rate are too high and the long-term capital gains rate is too low, if the goal is to maximum revenue to the government. Maybe.
micro
>>Great article Dew, and is cryogenics and time/space
continuum teleportation, where we can bring President Reagan back and avoid these "mutant" candidates from ever taking the world's highest office?
Over 300 million people in America and this is the best
we have to offer up as candidates??
Scary, and sad state of affairs imho, and between the
Obama who will shun Israel, invite terrorists like Iran,
Venezuela, and others here for visits, to Ms Hillary,
the Hun, we are looking at a future that is scary as
a parent....sad.<<
I'd like to see blatant political hatchet jobs like this expunged from the board, Dew. More generally, unless a political post has something to do with biotech or investing, I suggest it has no place here.
Sorry Precious.
micro
>>Hepatitis C New Drug Pipeline<<
I guess it shouldn't be surprising that only 3 out of ~70 are in Phase 3 ... but it still is.
micro
CEGE
Never mind.
Always bad to get into an argument that people have already finished, buried and forgotten about a week before you showed up ...
micro
>>You don't mount an antibody response to a cell line. You mount antibody responses to antigens.<<
Isn't an antibody response to a cell line defined as an antibody response to any of the surface antigens found on that cell line?
>>They might have created a response to an antigen that has been identified as present within one of their two cell lines (which would contradict their last data). If that's what they did, they ought to say so and for which antigen.<<
Apparently the targeted GVAX antigens vary from patient to patient.
As we all know, a lot of cancer vaccines have failed despite producing B and T cell immune responses. So hard to get excited about anything other than clinical endpoints (TTP, PFS, OS).
micro
>>It looked to me like AVXT's study had strong results for the entire study population. It looks like they have a good chance for approval.<<
So that's why their market cap is $12M.
Seriously - I looked into them a few years ago and decided they looked worse than Introgen. I doubt anything has changed since then.
micro
>>The housing crisis is not the only reason our economy is in trouble. Our economy is in trouble because the government went on a spending spree, thanks in part to a totally foolish and needless Iraq war, and cut taxes at the same time, thus causing a massive deficit and weakening the dollar.<<
I agree the Iraq war and deficit hurt the economy and helped weaken the dollar. But there have been many cases where the deficit was larger as a percentage of GNP w/o immediately sending the economy into a recession. In fact usually a war helps the economy short term and the shit doesn't hit the fan until after it stops.
>>It's a recession when your neighbor loses his job; it's a depression when you lose yours.
Harry S Truman, in Observer, April 13, 1958
33rd president of US (1884 - 1972) <<
micro
>>Antigenics' personalized cancer vaccine was proven to extend life an extra year and a half.<<
Retrospective data mining never proves anything other than if you sift through a sufficient number of subgroups you can get almost any result you want.
micro
>>It is not clear to me, and possibly to Soros, that this Bernake intervention will solve the problem rather than simply postpone the inevitable...<<
In my mind the real concern is that housing prices will go down another 25% and instead of a couple million families walking away from their underwater mortgages, it will be 10 times as many. (Obviously I am picking these numbers out of my a__.) The banks holding the mortgages, whether sliced and diced or not, will fail. And then we suffer through another ~10 year depression like the one 70-80 years ago.
If, on the other hand, government actions that may make free-market adherents grit their teeth manage to keep most of those 25 million families in their homes, we might see an economic recovery later this year.
>>Looking forward, I really can not see the markets recovering decisively any time soon because we are in a recession as well as heading towards inflation...<<
Let's treat the more immediate needs of the patient right now. The slowing economy may well take care of the budding inflation. If any case, it is a given that interest rates will go back up after the economy recovers.
micro
Is it too late to comment on the CEGE - Takeda deal?
I studied the contract, listened to the cc ... It looks like a very good deal to me - and I hate to say that, having been a CEGE critic for some time. U.S. royalties are tiered. Incremental royalties start out at 20%, then go up to 30% (at some unknown sales level), then 40%, then 50% (!!), then down to 40%, and finally they level out at 30%. See Section 8.4 of this:
http://www.sec.gov/Archives/edgar/data/865231/000119312508071298/dex101.htm
My guess is that average royalties will be ~35%.
My rule of thumb is that royalties for therapeutics in the 20-25% range correspond to retaining about half the value of the therapeutic. (Any arguments with that?) So CEGE appears to be retaining ~3/4 of the value of GVAX prostate in the U.S., and they don't have to do any of the sales and marketing ... though they have the right to co-develop w/o any impact to the royalty structure if they so choose.
Ex-U.S. royalties are not tiered and vary from country to country between 12% and 20%. Probably CEGE is retaining ~1/3 of the value of GVAX prostate ex-U.S.
There is also $50M upfront, and registration and manufacturing milestones of up to $270M. CEGE is responsible for manufacturing but gets reimbursed in full. My feeling is that if GVAX prostate gets approval in the U.S., Europe and Japan and CEGE doesn't run into manufacturing problems, they may get the entire $270M in milestones.
It's not like they have to reach $1 trillion in sales to get the last few $M.
Takeda is taking over all Vital-1/2 costs except for CEGE FTEs, and if GVAX prostate is approved, they will pay for all additional GVAX prostate development costs - in addition to all commercial and regulatory costs (except for CEGE FTEs).
So including Vital-1/2 expenses, Takeda is probably putting up a total of >$100M before they even find out if GVAX prostate works at all. (There was never a randomized Phase 2 study of GVAX prostate!) And CEGE gets to reduce their cash burn significantly - or keep the same cash burn and take another GVAX indication (presumably pancreatic or leukemia) forward into Phase 3.
Plus CEGE is free to partner each GVAX indication separately. If GVAX works for prostate cancer, it may work for any other type of cancer as long as the cell lines are well chosen.
I think this is a great deal for CEGE. I can't find any problems with it - and I looked pretty hard.
But as Feuerstein points out, Vital-1 and Vital-2 may well still fail. (Personally I think the odds are slightly over 50% that they will both fail.) GVAX prostate + MDX-010 looks very good in the first few patients, but that will require a lot more development work since it is now only in Phase I. According to the contract, it appears that in the event Vital-1 and Vital-2 fail and more development work is required, CEGE has to help pay for that up to some maximum level. Whether they would be financially able to do so is questionable. Even after this deal the stock price is only ~$3/share and cash is about the same as debt. (Most of the debt is convertible at $9.10/share in 2011.)
In summary - yeah CEGE is still going to be in a lot of trouble if Vital-1 and Vital-2 both fail, but they look a lot better than they did before the Takeda deal was announced.
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Cordaptive Causes Less Flushing, More Side effects Than Niaspan
Incyte's HM74a agonist program sounds interesting. I think they are interested in elevating HDL cholesterol in addition to the diabetes application discussed below.
>>Incyte will also introduce its HM74a agonist program. HM74a is the receptor to which niacin binds and activates, resulting in a reduction in plasma free fatty acid levels. High free fatty acid levels have been shown to cause insulin resistance and hyperglycemia, and while substantial clinical data support the potential for HM74a agonism to provide therapeutic benefit in type 2 diabetes, the currently available HM74a agonist - niacin - in its various formulations is not used primarily because its short duration of activity does not allow for effective and sustained lowering of free fatty acid levels. In addition, niacin causes cutaneous flushing which is often poorly tolerated. Our lead HM74a agonist, INCB19602, has now completed a single-dose Phase I trial, in which low and well tolerated doses dramatically reduced free fatty acid levels in an effective and sustained fashion and did not cause any cutaneous flushing. Provided the compound successfully completes the ongoing multiple-dose Phase I trial, Incyte plans to initiate a Phase IIa trial in type 2 diabetic patients in the first half of 2008.<<
http://investor.incyte.com/phoenix.zhtml?c=69764&p=IROL-NewsText&t=Regular&id=1093195&
>>For INCB19602, our recently announced lead HM74a agonist that we
intend to develop as a treatment for type 2 diabetes, we completed a
single-dose Phase I trial in healthy volunteers in which low and well
tolerated doses dramatically reduced free fatty acid levels and did
not cause any of the cutaneous flushing that is seen with the
currently available HM74a agonist, niacin <<
http://investor.incyte.com/phoenix.zhtml?c=69764&p=IROL-NewsText&t=Regular&id=1108185&
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Interesting article on correlation between drugs approved near the FDA 'deadline' and drugs which later developed safety issues.
http://money.aol.com/news/articles/qp/ap/_a/late-approval-of-drugs-linked-to-safety/rfid86136386
>>Late approval of drugs linked to safety issues
AP ONLINE
Posted: 2008-03-27 11:35:54
Eds: Via AP.
By KEITH J. WINSTEIN
The Wall Street Journal
Although every unsafe drug is different, most of them have something in common: last-minute approvals by the Food and Drug Administration, according to a new study.
Liver problems led Pfizer Inc. to withdraw its diabetes drug Rezulin from the U.S. market in 2000. Bayer AG pulled cholesterol-lowering Baycol in 2001 because it caused muscle damage in some patients. Vioxx, Merck & Co.'s controversial painkiller, was withdrawn in 2004 because it sometimes caused heart attacks and strokes.
These and other unsafe drugs all received approval shortly before the FDA deadline for deciding on new-drug applications.
Since 1993, the 97 drugs approved near the FDA's deadline had a 14 percent rate of severe safety problems down the road, compared with 3 percent for 216 other drugs. That's according to an analysis in Thursday's issue of the New England Journal of Medicine by Daniel Carpenter, a professor of government at Harvard University. The FDA says some of Dr. Carpenter's data are inaccurate, and disputed his conclusions.
The study is the latest to take aim at the controversial decision deadlines the FDA has set as goals since 1992. In exchange for agreeing to quick approval of drug applications, the FDA gained the legal authority to collect substantial fees from companies with business before the agency. Industry fees now account for about half of the $680 million the FDA will spend on reviewing new drugs this year.
Currently, the agency promises to reach a decision on 90 percent of new drug applications within 10 months after a company submits an application. For so-called priority drugs, the deadline is six months. The schedules have substantially cut the time it takes the FDA to review a new drug - from 33 months on average in 1991 to 19 months in 2001. Several analyses have found that, overall, approving drugs more quickly likely saves lives.
But tighter schedules also led to what the FDA's drug-evaluation director, Janet Woodcock, has called ``a sweatshop environment that's causing high staffing turnover'' among employees who review the voluminous data each company submits on new drugs. Dr. Woodcock's comment appeared in an FDA newsletter posted on its Web site in 2000.
An FDA spokesman said Dr. Woodcock no longer agreed with that sentiment. ``The reason she said that publicly ... is because in 2000 we were lobbying for additional resources,'' said Christopher DiFrancesco, the spokesman. ``She wouldn't say that about the environment today.''
Of the 313 drugs the FDA approved between 1993 and 2004, 97 drugs were ``just-before-deadline'' approvals - meaning they were approved within two months of the deadline, according to Dr. Carpenter's study. But those drugs were more than four times as likely to be withdrawn for safety reasons or require a severe ``black box'' warning on the medicine's label years later, the study found.
Out of 21 withdrawals and black-box warnings for drugs approved since 1993, 14 were for drugs approved within two months of the deadline. This includes Baycol, Vioxx and Rezulin, all of which were approved in the last three days before the deadline and later withdrawn for safety reasons.
In an interview, Dr. Carpenter said it was impossible to say whether the agency was rushed to make a decision in any particular case and made a sloppy decision as a result. ``You can't point to any single case and say, well, an extra two months would have made the difference,'' he said. But he questioned whether setting deadlines tied to industry funding was the best way to speed up drug approvals. ``Congress would be much better off relying less upon these deadlines and relying more on a big increase in full-time employees,'' he said.
The FDA said its own database of drug-approval times didn't match Dr. Carpenter's data and said it suspected his database contained errors. ``We just are unable to replicate the numbers,'' said Clark Nardinelli, an FDA economist. The agency said it is sending a detailed letter disputing the results to the New England Journal of Medicine.
No law requires the FDA to meet the deadlines, but Congress has linked its periodic reauthorization of the agency's authority to collect fees to its performance at meeting the deadlines. The FDA disputes the notion that its judgment is impaired by looming deadlines. ``FDA won't approve a drug if we are not ready,'' Dr. Woodcock said in a statement, adding that the deadlines are ``guidelines'' that the agency has the freedom to miss if necessary.
And the agency may be moving toward more flexibility. Earlier this year, John Jenkins, an FDA official who directs new-drug reviews, ``authorized our managers to miss'' a deadline ``if that needs to happen,'' said the FDA's Mr. DiFrancesco.
Sometimes, last-minute approvals seem to tell a story. When Pfizer applied for permission to sell Rezulin in 1996, the drug was the first in a new class of diabetes drugs called thiazolidinediones, or TZDs. So the FDA gave Pfizer's application priority status - meaning the agency had a six-month deadline to reach a decision. It met the deadline, with two days to spare, in January 1997.
But evidence emerged that Rezulin was toxic to the liver. So when GlaxoSmithKline applied in 1999 to sell its own TZD called Avandia, the FDA again awarded it priority status - and met the deadline on the very last day, in May 1999. The next year, with GlaxoSmithKline's seemingly safer drug now available to patients, the FDA asked Pfizer to stop selling Rezulin.
But in rushing approval of Avandia because of Rezulin's liver problems, the FDA didn't recognize Avandia's own increased risk of cardiovascular problems, said Steven Nissen, a cardiologist at the Cleveland Clinic who has been critical of GlaxoSmithKline and the FDA. Last year, after a critical review by Dr. Nissen, the FDA asked GlaxoSmithKline to add a severe warning to Avandia's label.
A GlaxoSmithKline spokeswoman declined to discuss Avandia, but said, ``in our experience the FDA will approve a drug when they feel they have sufficient data to do so.'' She said that was ``usually'' at the deadline.
``It's a tough balancing act,'' Dr. Nissen acknowledged. ``If you have a drug for cancer that can extend survival in a very tough group of patients, by all means, give it priority review,'' he said. But for other drugs, ``I don't know that we need to be in quite such a hurry,'' he said.
Down to the Wire
Researchers at Harvard University found that:
Of the 313 drugs approved from 1993 to 2004, 97 were approved within two months of deadline.
Out of 21 withdrawals and black-box warnings for drugs approved since 1993, 14 were related to drugs approved within two months before the deadline. <<
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>>OT:Bear Stearns Chairman Cayne sells $61.3 mln in stock:
Nothing is illegal when you are above the law.<<
Or so they may think ...
>>March 28, 2008, 12:10 pm
Pfizer Exec Arrested On Child Pornography Charges
Posted by Jacob Goldstein
A Pfizer vice president has been arrested on charges of receiving, possessing and distributing child pornography. Alan Hesketh, 61, was arrested at JFK airport by federal agents Wednesday and is being held without bond, reports the newspaper The Day.
Hesketh, who works on patent issues in the firm’s offices in New London, Conn., is currently on leave from the company, a Pfizer spokesman told the WSJ . The company is “cooperating fully with authorities,” the spokesman added.
A call from the WSJ Law Blog to Hesketh’s lawyer wasn’t immediately returned this morning.
Hesketh is accused of posing as a 28-year-old woman in online chats while trading images of children engaged in sexual acts, according to a court document filed in the case. He signed on as “Suzybibaby” from his home, as well as from an Internet address registered to Pfizer in New York.
If indicted and convicted, he could face a mandatory minimum of five years in prison, a maximum of 20 years for receiving and distributing child pornography and a maximum of 10 years for possessing child porn, the WSJ Law Blog says.<<
http://blogs.wsj.com/health/2008/03/28/pfizer-exec-arrested-on-child-pornography-charges/?mod=WSJBlog
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>>The purpose of the study is to compare between 3x/day and 2x/day telaprevir, but also to confirm that the drug is as effective with Peg-IFN alpha2b (Peg-Intron) as with Peg-IFN alpha2a (Pegasys).
I do not expect any differences between the interferons, and believe the primary goal was dosing, but the fact they did bother testing 2 different interferons may hint that such data will be needed for the kind of label you were thinking of.<<
I didn't - and don't - have much to add, but since Dew thought "this was one of the more interesting threads on this board in a while, but microcapfun seems to have gone missing", I'll say that my feeling is still that Albuferon is (at least potentially) sufficiently different from the pegylated interferons that some trial of telaprevir + Albuferon (maybe randomized, maybe not) will likely be necessary before the FDA will give its blessing to that combination. As supporting evidence, recall that pulmonary problems with Albuferon appear to be more severe than with Pegasys according to Phase 2 and Phase 3 randomized data. IFN may be the active ingredient, but the difference between pegylation and albumin fusion at the gene level could be significant with or w/o telaprevir.
But this is all guesswork and I appreciate hearing from Dew and genisi, both of whom clearly know more about this subject than I do.
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>>Does anyone know if Genta has either set the Guinness Book records for how long or how many times it's tried to get a drug approved?<<
Introgen (Ad-p53) might be a competitor ...
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>>The latter, IMO.
The Avastin label in metastatic colorectal cancer, which includes use with all varieties of infusional-5FU chemotherapy, is a good precedent.<<
Thanks. I was thinking the former, i.e. that it would require a telaprevir/Albuferon trial to obtain FDA approval for that combination.
5FU has many years of experience behind it. I presume that there is very little difference between the different "varieties" of 5FU. It is not so clear that the *new* drug Albuferon would combine with the *new* drug telaprevir the same way that Pegasys combines with telaprevir ... as determined by a Phase 3 clinical trial.
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