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"It Works" is a relative term. The handful of patients with remarkable success describe themselves as "cured" (even though that's not the case: they still have the tumors, but they're under control).
In a single patient, this is nearly perfect success. But "approval" requires "safe" (which we seem to have) and "effective" (which means a trial result presented in official format on paper that fills a small truck). The idea is to know pretty well about how many people will be expected to respond in a controlled experiment. Then the FDA has a committee to look at it, and finally a Federal Drug prevention Agency team will rule on the work of the committee. Erbitux was delayed a year or two because the FDA didn't like the way the data was presented (ask Martha Stewart).
I already feel pretty sure Panzem works, but nobody is asking me. The FDA still has a ways to go before they're likely to be convinced, so nobody's even bothered to tell them much, so far.
As an insider once confided to me, the critical skill in this business is in getting a clinical trial design that will incisively demonstrate effectiveness against a disease. That's what we gotta do, and still haven't done yet. PI is about figuring out how to shoot, PII is about aiming, and PIII is about firing for effect.
Cialis, a medication nobody really needs (there are other choices), was approved on a PIII with 483 patients. A really strong PII can be enough for approval.
We could get great results in 2005, or we could be still screwing around with new, improved versions for several years. But the smart people here are encouraged, and so am I.
To believe ENMD wasn't or isn't at the cutting edge is to believe the following from the article posted by Docaaron this morning:
"But the drugs failed in human trials, proving scientific adages about the difference between curing cancer in mice and people. Drug company stocks, which had soared after the Times' story, plummeted."
What we all know is that the cancer establishment rejected early ES results because ES didn't significantly reduce the size of tumors in the trials, and therefore "failed" in the trials by the standards of their arrogant ignorance. In retrospect, the trials were designed to fail with their inflexible subtherapeutic dosing protocols and ridiculous rules that kicked people out to die, people who by all accounts had zero alternatives. In other words, all those smart cancer researchers couldn't accept the simple idea that something working slowly without toxicity has significant value (or that taking another few years to discover the obvious is a big problem).
Say what you want about management, but a short attack stripped capital from the company at a time when large quantities of cash were needed.
In retrospect, both the shorts and the cancer researchers were right, and now they both have what they wanted: The shorts have the money that should have been spent by ENMD on ES research, and the cancer researchers have had another 5 years of grants to help them realize that there's something to antiangiogenics after all. Even better, we have Avastin with its hemoragic deaths and Erbitux with its anaphalactic shock, so we can be pretty sure that these agents actually work. (If you put a nontoxic drug a patient and nothing much seems to happen in the first 30 days, it must be that it doesn't do anything, right?)
What was conclusively proved in the ES trials was that ES (perhaps as complicated to apply as insulin) has promise, is very expensive, and is nontoxic. And the side conclusion: The cancer establishment isn't remotely interested in doing anything to assist in either of those first 2 issues (how about a trial protocol that would allow a doctor to adjust a dose on a per-patient basis until its understood a little better, or an FDA that would allow a little broader experimentation with a nontoxic drug with promise against a fatal disease).
Too bad 2.5 million more Americans are dead from cancer in the last 5 years, too.
Investors: Put your money where your mouth is. If you think the company has promise, buy a share (they're affordable). If not, sell. Nobody who is still here told you anything they didn't believe to be true. Nobody here made a dime from your losses.
Thalidomide analogs (like Revlimid)...
The conversation's about the deal between and CELG and ENMD, not CH (which also was years earlier).
ENMD had an active program for Thalidomide analogs at the time Thalidomide-for-cancer was sold to Celgene in the first place (Thalidomide analogs were specifically excluded from that deal). Those who enjoy "what-if" games can speculate over the potential outcomes of these: What if ENMD had put its resources behind Thalidomide (and not selling it out to CELG, who was in the leprosy business at that time), placed ES and AS on the back burner until the NCI came salavating over human trials, or got the pharmacokinetics right for PZ before going into the clinic in the first place?
But in all honesty, if I'd run the company at the time, I'd have wanted to swing at the ball pretty darned hard on every pitch. And anybody would still like to believe that the FDA wouldn't turn down a non-toxic cancer med...
But enough second guessing: Today's game is Panzem. I own season tickets (maybe a whole row or two in the section), I like the lineup, and I just cant wait to see the team in action.
I'd be real surprised if there's any CELG==>ENMD royalty involved. There was no question that ENMD had a case for the same molecule, and no question that sole ownership by CELG was the key objective in what must have been a high stress negotiation.
The ENMD view then was that Revlimid was an interesting avenue, but that Thalomide analogs will never be as interesting as ES, AS, and 2ME2 analogs. I think that's probably still true at ENMD.
Its ultimately going to be about working without side effects, and if CELG can make a billion in the meantime, better them than BMY.
Keepingapromise,
ENMD shares have a long history of unusual trading events, probably due to a whole lot of shorts and speculators. So it wouldn't surprise me if one could identify reliable daily/weekly/monthly patterns. In the good old days, for example, we were all waiting for news from the first people on Endostatin in theoretically therapeutic doses while something like 25% of the publicly available shares were shorted.
These days, we're enjoying a much lower profile. This takes pressure off of the researchers and patients, and allows the company to invest its energy on trials and drug development instead of PR and the energy spent placating the drug prevention team at the FDA.
The "somebody knows something" concept that people often associate with stock price variations have never meant anything useful for us here, and the "smart money" hasn't historically been all that smart, IMO. ENMD is a great place to strap a few bucks to the rocket, and see what happens.
And, this board is a great place to learn some incredible things real early in the process.
Speaking of recommending ENMD to our friends, here's somebody seeing the upside too (source: Yahoo):
6-Apr-05 BURNS, JAMES S
Chief Executive Officer 15,000 Purchase at $2.35 - $2.4 per share. $36,0002
10-Jan-05 BURNS, JAMES
Chief Executive Officer 14,500 Purchase at $3.63 - $3.68 per share. $53,0002
10-Jan-05 BURNS, JAMES
Chief Executive Officer 500 Purchase at $3.68 per share. $1,840
24-Sep-04 BURNS, JAMES
Chief Executive Officer 10,000 Purchase at $1.66 - $1.7 per share. $17,0002
keepingapromise...
You raise interesting questions.
I've been a stockholder ever since my son came home from a symposium at the National Institute of Health in November of 1997, having seen a Dr. Folkman presentation which received a standing ovation, and told us at the dinner table that he thought he'd heard a man speak who would one day win the Nobel prize.
Since then, we've had our good days and bad days.
Yes, I would (and have) encourage friends to invest in ENMD, and Yes, most of them are still friends.
Here's some advice, since you asked:
1) Don't invest money you can't afford to lose, as this is a long process and we never can be certain that we know for sure all that we think we know for sure. (for example: somebody knows if we're seeing any positive patient responses in the PIb trial for NCD Panzem, but it's not us)
2) The process of cancer drug approval is a slower one than any compassionate, intelligent human being can justify, or should accept. Don't count on quick bucks, just buy the shares to hold, don't play options, and hang on.
3) The market doesn't know or care squat about the science.
4) The current situation looks pretty darned good to me. I don't see a lot of downside from here. The research was giving us great encouragement vs. Avastin and Erbitux 5-7 years ago in preclinical studies. But Panzem has never hurt anybody, let alone kill any trial participants with anaphalactic shock or massive lung bleed outs. It's logical that Panzem, a natural human body substance, should work better with fewer side effects than those single mode of action anti-angiogenic predecessors. But I'm an optimist, so don't count on any of my advice.
Trial results...
Patients often talk about their stories, and we have had an unbelievable record of getting a line on their anecdotal successes, sometimes from more than one source. Over the years with ENMD, we've had a line on most of the success stories here, long before anything official.
The SEC can't tell a patient how to feel or what to say. They can only tell people with inside information that they can't trade on it.
Trial results are held close to the vest by the company for several reasons:
- Patient confidentiality
- The trial "story" is supposed to be told by the trial's research team (apparently we're supposed to believe they're the discoverers of something important) (I guess it's a balanced system: they get the public credit and the company gets the money for the drug)
- SEC rules about disclosure force a tendency to speak conservatively
- The FDA (Federal Death Agency) takes a very, very dim view of corporate grandstanding about trials still in process
- There's a tendency for the SEC and the FDA to blame leaks on the company. ENMD has been meticulous so far about not releasing trial data before its' time.
Hope this helps.
moberylane,
I feel your pain. Lets just say I had a lot of money once in a chunk of shares I still have now. Once I had more invested in ENMD than was prudent, but it was OK because I had a balanced portfolio (Ford, Oracle, MCI, Sun Microsystems, etc.) (etc performed best, I think). But now I have more ENMD shares than I did then, because I still believe in the upside.
Like the good old days, We're again seeing something that the rest of the world isn't seeing. Either George and Doc Aaron are crazy, or the rest of the world is. Personally, I like George and Aaron (and many others), and after all these years, it's become clear that good friends are important if you're going to persist in being crazy by the world's standards.
Hang on, hang in, because there are still good things to come. How fortunate we are to have a second set of rainbows coming from the same pot!
Haod and irrational exuberance...
As an outsider, I can't tell you exactly what happened or where things went awry in the good old days, but I infer the following from the facts we have:
- Endostatin dosing probably requires per-patient tweaking like insulin, versus iterating through the endless per-trial tweaking of the foolish, self-satisfied people in the medical research business.
- Everybody had a chance to do something different in Q1 of 2000, including you, me, and John Holaday.
- ENMD's hopes for ES were cut short by a cash crisis caused in large part by a relentless short attack that stripped capital from the company.
- The company produced promising but inconclusive (in FDA terms) results without side effects. The government side of the partnership was nowhere to be seen at the critical moment, proving themselves to be the gutless cowards that the naysayers had always proclaimed them to be.
- Haod's forecast has been consistent. If you keep saying the same thing over and over and over and over and over and over, you'll likely remain right until things change. And then you'll be wrong. According to Haod, there's no way for ENMD to do any of this successfuly (just opinion). And for the record, the good Dr. Hoad is very sincere, but hardly courageous.
- There are people on this board looking for somebody to blame for their portfolio performance. For those so inclined, we all have great sympathy for you, but please go find a mirror and step up to your personal responsibilities while you remember that you cheerfully decided to invest all by yourself, based on the facts available to you at the time. Nobody here with a real interest in the science ever posted anything on the boards with deceptive intent, nor is it likely that any of us who are still around achieved any profit from your losses.
Cialis was approved on a study of less than 500 patients. Maybe those guys also paid a lot of money to NIH scientists that we don't know about, but a pIII on 500 patients by itself isn't "too much" money. And don't forget that the "safety" high ground seems to already be looking pretty strong for Panzem.
Cox-2 and Vioxx et al have serious issues that were detected early enough to create more expansive study requirements (maybe not expansive enough), but the studies were certainly good enough to impress Dr. Haod at the time. Fortunately, Dr. Haod produces better tomatoes than drug stock forecasts, and all here should find that encouraging. Regardless, Dr. Haod and I stubbornly hang on to our shares, and we look forward to the first publication of Panzem NCD results with great interest.
As an ENMD luminary once told me, the critical step for Entremed is to define a study in humans that slam dunks the efficacy question in a low toxicity protocol. Everything else will be easy after that.
From your keyboard to God's ears:
"...it will be crystal clear that Panzem NCD causes regression of tumors in patients with advanced cancer without any severe adverse side effects."
I started to say that I am much more patient than your timeline. But then I remembered: There are about 50,000 patients dying to find out before we get there.
But it IS being done for the company, as well as the rest of us, because the company has IP rights that include participation in the success of ES.
Since going to PIII, we haven't heard much about ES in China. Given that there was so much published before and so little lately, I don't hold great hope for smashing ES success as a single agent in the current trial.
Celgene's exercise of warrants at this particular time is definitely significant IMO. There's no particular external reason to act. Following so soon on the microtubule announcement, there's a plan in this somewhere.
Most likely, it's to have and hold the voting rights for the shares.
One thing for sure: the downside in ENMD shares is less today than it has ever been. The upside story is still unclear, until we see a little more of PZ's story, some new IND's, and Celgene's intentions.
Green Tea megadoses...
Another "U" shaped curve.
A riddle:
What has no significant side effects, a few remarkable human successes against the annual killer of six million people, and a shamefully inadequate story from a self serving government/medical bureaucracy posing as people on the side of patients?
Cialis was approved on a study of 483 patients. A good sized cancer center loses that many in a month.
Pasteur learned to prevent rabies with a patient who had no choice but to take a risk. We can't cure cancer because doctors won't let other doctors try things on people who are otherwise without options (patients have a right to make decisions, not doctors).
Who (other than those making billions from chemo-toxins) can be happy about the state of Endostatin research?
Those with nothing to offer six million dying people this year, please step out of the way of those who are trying to make a contribution. No wonder people resort to quackery!
The subdued response is grounded in seven years of experience, in my case. Yes, the results are encouraging, and yes, I think they are significant. But the market is fickle and populated by a lot of short sighted fast buck artists, so I also think we'll see downs again before we go up to stay. We might see the clinical results we'd all love to see this spring. Or maybe next year. Or maybe we'll find a new hurdle to get over before we really know the answer.
My strategy: buy and hold, add some shares on the dips, and never over react to today's news.
Re: Resveratrol, I have a few technical questions.
I get the essence of this: Resveratrols control cancers by inhibiting cell growth and causing cancer cell deaths to occur, and that "Gee, maybe we can work on making a pill out of 3,4,5-trimethoxy-4'-bromo-cis-stilbene (BCS), after we finish the rest of the Cabernet."
The most important question I have is "How much Cabernet (or Pinot Noir) is necessary to achieve 33.0 microM of serum resveratrol, and at that concentration, would one be alert enough to be aware of any other questions?"
You heard it here first:
"It may be difficult to explore the area under the curve, while you're exploring the area under the table."
**************************************************
"G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5-trimethoxy-4'-bromo-cis-stilbene, in human lung cancer cells.
Lee EJ, Min HY, Joo Park H, Chung HJ, Kim S, Nam Han Y, Lee SK.
College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-ku, Seoul 120-750, Republic of Korea.
Stilbenoids, including resveratrol (3,5,4'-trihydroxy-trans-stilbene) which is a naturally occurring phytoalexin abundant in grapes and several plants, have been shown to be active in inhibiting proliferation and inducing apoptosis in human cancer cell lines. Using resveratrol as the prototype, we have synthesized various analogs and evaluated their growth inhibitory effects in cultured human cancer cells. In the present study, we show that one of the stilbenoids, 3,4,5-trimethoxy-4'-bromo-cis-stilbene (BCS), was more effective than its corresponding trans-isomer and resveratrol on the inhibition of cancer cell growth. Prompted by the strong growth inhibitory activity of BCS (IC50; 0.03 microM) compared to its trans-isomer (IC50; 6.36 microM) and resveratrol (IC50; 33.0 microM) in cultured human lung cancer cells (A549), we investigated its mechanism of action. BCS induced arrest at the G2/M phase cell cycle in the early time and subsequently increased in the sub-G1 phase DNA contents in a time-dependent manner, indicating induction of apoptosis. Morphological observation with round-up shape and DNA fragmentation was also revealed the apoptotic phenomena. BCS treatment elevated the expression levels of the pro-apoptotic protein p53, the cyclin-dependent kinase inhibitor p21, and the release of cytochrome c in the cytosol. The down-regulation of checkpoint protein cyclin B1 by BCS was well correlated with the cell cycle arrest at G2/M. These data suggest the potential of BCS to serve as a cancer chemotherapeutic or chemopreventive agent by virtue of arresting the cell cycle and induction of apoptosis of human lung cancer cells."
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_....
Good luck and God bless,
George
Wmboot thought whatever he said at the time was accurate, but the truth turned out different when the FDA "partnership" turned out to be no more than the same bunch of gutless self satisfied bureaucrats that cynics always knew them to really be. Haod at the time didn't believe it anyhow, so no harm, no foul.
Haod is entitled to gloat a little (Chicken Little, actually). The funny thing about Hoad, though, is that even Hoad hopes he's wrong.
The pharmacokinetics were a "miss" in the previous trials. If they have it right, we'll know real soon if there are results in man that live up to preclinical hopes.
Comparisons among preclinical studies for PZ compared to the preclinical studies for avastin, Novartis' struggles with shark cartilege extracts, Imclone's Erbitux, etc. give us nothing to fear on safety or efficacy grounds. Yes, it's always possible that something way behind comes in with the grand slam home run we once hoped we'd see in Endostatin.
But the odds aren't good for that. Remember that we've spent the last several years talking about cancer patients living and feeling great who logically should be dead, with agents that have a safety profile that could allow these drugs to be approved for minor maladies, yet blocked by the FDA's drug prevention program. Somehow we just can't get the message across that a couple of Tsunami's worth of Americans died of cancer in 2004 (563,700 per the American Cancer Society) because of the lousy state of cancer care, the outrageously slow drug development process, and an intractable, murderous FDA bureaucracy.
New trials
My conjecture would be that they will test initially to quickly make sure they have the bioavailability issue nailed. Then, when they do, they'll begin rolling forward in trials that look more like pII's (and PIII's when the efficacy question looks good enough).
EntreMed Commences Clinical Trials of Panzem(R) NCD in Patients With Advanced Cancer
ROCKVILLE, Md., Jan. 5 /PRNewswire-FirstCall/ -- EntreMed, Inc.
(Nasdaq: ENMD), a clinical-stage pharmaceutical company developing novel
therapeutics for the treatment of cancer and inflammation, announced today
that it has commenced Phase 1b clinical trials to evaluate the pharmacokinetic
properties and safety of Panzem(R) NCD, its next generation formulation of its
lead product candidate, Panzem(R) (2-methoxyestradiol or 2ME2). Advanced
cancer patients whose disease has failed to respond to existing therapies or
where no approved therapy is available are expected to be enrolled in the
studies. The purpose of the dose escalation studies will be to evaluate the
pharmacokinetics and safety of Panzem(R) NCD. George Wilding, M.D., Director,
University of Wisconsin Comprehensive Cancer Center, and Christopher J.
Sweeney, M.D., Co-Director, Experimental and Developmental Therapeutics
Program, Indiana University Cancer Center, are the Principal Investigators of
the studies.
2ME2 is an orally active small molecule that attacks tumor cells through
multiple mechanisms of action and blocks the development of new blood vessels
that feed tumor cells. Panzem(R) Nanocrystal Colloidal Dispersion (Panzem(R)
NCD), an oral liquid formulation, has been shown in pre-clinical studies to
significantly increase the drug's bioavailability, which is expected to result
in enhanced drug levels of 2ME2 in patients.
"Given the results from previous clinical studies with Panzem(R), we are
excited to begin studies with Panzem(R) NCD," stated Dr. Wilding. Dr. Wilding
continued, "We believe that the reformulated drug candidate should yield
greater bioavailability, as demonstrated in pre-clinical models, which will
hopefully improve the clinical outcome for patients."
Dr. Sweeney also commented on the study, "We are looking forward to
participating again in the Panzem(R) clinical program and resuming trials in
our patients along with Dr. Wilding at the University of Wisconsin. The goals
of these trials are to evaluate pharmacokinetics and safety in cancer patients
and, with these results, move into more focused efficacy trials."
"EntreMed is fortunate to be working with exceptional investigators and
cancer centers that have previously conducted clinical studies with 2ME2 and
recognize its potential," said Carolyn F. Sidor, M.D., EntreMed's Vice
President and Chief Medical Officer. "Valuable safety, pharmacokinetic and
dosing information will be obtained from this study, which will enable us to
move aggressively into the next stages of clinical testing focusing on
specific tumor types and combinations with approved treatments. One of the key
attributes of next generation cancer treatments will be drug candidates like
Panzem(R) that affect multiple cellular pathways thereby limiting drug
resistance. Panzem(R) is known to have direct anti-tumor activity in addition
to anti-angiogenic activity while maintaining a strong safety profile," Dr.
Sidor concluded.
In previous Phase II studies in more than 165 cancer patients, Panzem(R)
capsules showed evidence of clinical efficacy, including one partial response
and several patients with stable disease. The drug was well tolerated with
few side effects. Panzem(R) capsules were also tested clinically in
combination with Taxotere in advanced breast cancer patients resulting in an
objective response rate of 20 percent with no added toxicities.
For more information on this study, visit the Clinical Trials section of
EntreMed's web site at http://www.entremed.com.
About EntreMed
EntreMed, Inc. (Nasdaq: ENMD) is a clinical-stage pharmaceutical company
developing therapeutic candidates primarily for the treatment of cancer and
inflammation. Panzem(R) (2-Methoxyestradiol or 2ME2), the Company's lead drug
candidate, is currently in clinical trials for cancer, as well as in
preclinical development for indications outside of oncology. EntreMed's goal
is to develop and commercialize new compounds based on the Company's expertise
in angiogenesis, cell cycle regulation and inflammation -- processes vital to
the treatment of cancer and other diseases. The Company's expertise has also
led to the discovery of new molecules, including analogs of 2ME2, peptides of
tissue factor pathway inhibitor (TFPI), and inhibitors of fibroblast growth
factor-2 (FGF-2) and proteinase activated receptor-2 (PAR-2). EntreMed is
developing these potential drug candidates for either in-house advancement or
external partnering. Additional information about EntreMed is available on
the Company's website at http://www.entremed.com and in various filings with
the Securities and Exchange Commission. Panzem(R) NCD is in clinical trials
and has not been approved by the Food and Drug Administration.
Forward Looking Statements
This release contains, and other statements that EntreMed may make may
contain, forward-looking statements within the meaning of the Private
Securities Litigation Reform Act with respect to the outlook for expectations
for future financial or business performance, strategies, expectations and
goals. Forward-looking statements are typically identified by words or phrases
such as "believe," "feel," "expect," "anticipate," "intend," "outlook,"
"estimate," "target," "assume," "goal," "objective," "plan," "remain," "seek,"
"trend," and variations of such words and similar expressions, or future or
conditional verbs such as "will," "would," "should," "could," "might," "can,"
"may," or similar expressions. Forward-looking statements are subject to
numerous assumptions, risks and uncertainties, which change over time.
Forward-looking statements speak only as of the date they are made, and
EntreMed assumes no duty to update forward-looking statements. Actual results
could differ materially from those currently anticipated due to a number of
factors, including those set forth in EntreMed's Securities and Exchange
Commission filings under "Risk Factors," including risks relating to
EntreMed's need for additional capital and the uncertainty of additional
funding; the early-stage products under development; uncertainties relating to
clinical trials (including the risk that clinical results will not be the same
as those obtained in preclinical studies); our success in the further clinical
development of Panzem(R); dependence on third parties; future capital needs;
and risks relating to the commercialization, if any, of the Company's proposed
products (such as marketing, safety, regulatory, patent, product liability,
supply, competition and other risks).
CONTACT: Ginny Dunn, Associate Director, Corporate Communications &
Investor Relations, of EntreMed, Inc., +1-240-864-2643.
SOURCE EntreMed, Inc.
When the company issues shares and gives them away to their friends, that's dilution. I suppose you could get the same effect in cases where the company raises capital and then squanders the proceeds. When the company issues shares and obtains appropriate value which then becomes invested in the company, that's not dilutive in the present situation.
Yes, our future opportunities are diluted with these latecomers. But in this case, there's not one of us that didn't have a recent opportunity to buy more of that upside with a deal as good or better. And, as Syndi pointed out, the market has historically been very kind to the company in the 30-90 days following a PP.
If the company doesn't eventually come up with a revenue stream, that's a problem caused not by dilution, but rather by issues like research, product development, and drug approvals. Nobody says they don't need the money. A PZ partnership for oncology indications at this time would cost the shareholders a whole lot more in the long run (and probably has never been considered). So there's probably not a better way to come up with $15 million or so right now, and we know darned well that waiting too long to raise cash invites disaster.
There's been a lot of pain in the last 5 years, hasn't there? Look at the bright side: we still have our shares, and then some.
Here's to a better 2005!
"Dilution" happens when you cut the value of a share. If the company obtains fair market value for a new share issued, the remaining shareholders have not been diluted because the value has beed added to the company. Therefore, the only people who have any right to feel injured by a PP are those who feel the price was too low.
But that's not any of our complainers posting here. There were zillions of chances to buy more at those prices in the last few months. The whiners still holding onto their same old 200 shares obviously felt that it wasn't a "buy" to them then, or they'd be happily counting short term profits now.
A 2 week study on 14 patients, with the answer you were hoping for, is a good time to publish. If only a cancer drug with a few remarkable cases among patients with zero options, and with no downside effects, would strike so positive a note with us.
The problem for Pfizer is that Celebrex may not be safe enough.
Ya gotta wonder what went on in the trial that raised the issue, when the heart disease problem hasn't come up elsewhere.
Pfizer Celebrex Trial Stopped After Heart Attacks
http://story.news.yahoo.com/news?tmpl=story&cid=568&e=1&u=/nm/20041217/bs_nm/health_pfiz...
NEW YORK (Reuters) - Pfizer Inc. on Friday said patients taking its blockbuster arthritis drug Celebrex in a long-term cancer-prevention trial had more than twice the number of fatal or non-fatal heart attacks as those taking a placebo.
The New York-based drugmaker said patients in the trial, sponsored by the National Cancer Institute (news - web sites), are no longer being given the drug, one of Pfizer's biggest selling medicines, because of the unfavorable findings.
It said Celebrex was not shown to increase heart risk in a second trial to see if the drug could prevent cancer of the colon.
There's a few false presumptions in the post:
Blocked by lobbyists? Nah. Blocked by entrenched thinking at the FDA, yes. I haven't seen evidence that anybody on Capitol Hill ever understood any part of the problem, pro or con.
And Dr. Folkman never, ever worked for Entremed. Nor did he ever deal with the FDA (though his lab probably gets grant money all the time from the NCI). Nor was he ever a shareholder. Nor has he ever resigned anything without either actually doing it first, or at least giving it his best for a lot of years, as far as I remember. (The poster has Dr. John Holaday, founder of Entremed, cross linked with Dr. Folkman of Harvard University, both of whom still believe in the potential of Endostatin as far as I know).
Entremed's biggest problem has been money. The short attack destroyed the company's ability to raise the capital necessary to fund the trial process.
As for the 500,000 people dying from cancer every year in the US (about 1/7 of the world's total), the problem is indeed that our government can't figure out how to get the job done (but it isn't about the taxes or even the far bigger dollar amounts associated with annual government cancer care). The cancer establishment continues to bungle the "War on Cancer." Research has become the business of doing lengthy studies of insignificant things in great detail. Successes are therefore small and any big thing that might mean real progress is never actually studied, so that a real breakthrough could never happen quickly (and if it did, they'd still want to study it for ten years to see how it worked before they'd let people actually use it).
The news media are all over the FDA for their approvals that haven't worked out, which puts the FDA in the business of preventing drugs, not approving them. The FDA just can't get their minds around the idea of a slow acting harmless cancer medication that also seems to help arthritis and macular degeneration, instead preferring things that smash a tumor quickly so long as it smashes the tumor more than it smashes the patient (if the tumor grows back it will be part of some other study).
For example, The famous Folkman studies of Angiostatin and Endostatin together were done in mice in 1997, but have never actually been tried in humans (in these seven years, 3.5 million Americans have died of cancer). Endostatin was administered in the trials to patients with a cancer death sentence under mostly subtherapeutic dosages and under rigid conditions that bounced out patients who didn't respond quickly enough. The resulting small successes were triumphantly called "unimpressive" by a medical establishment with no clue about how to keep these patients alive.
And so the Endostatin opportunity was squandered (but we're still hoping the Chinese are able to get it right).
The bottom line: Cancer research is way too important to be managed and directed by cancer researchers!
SLAPP happy...
I'm sorry to hear that you (or anyone else) have been the victim of a SLAPP abuse. Some here might have sought some sort of relief in your case, on occasion, but apparently none of us here were ever that friendly with any lawyers. A SLAPP is also much more expensive than simply another post in this forum, if only because you'd have to pay a lawyer to do it for you (as I recall, most posts about haod suggested that 200 shares really couldn't possibly be a big enough part of anybody's life to warrant all his energy, so hoad must have some obscure but nefarious purpose).
Since then, of course, we posters on this board have learned that our postings haven't mattered much one way or the other (the truth has so often changed faster than anybody's wildest imagination, and made honesty, lies and liars irrelevant). (these days, nobody here has any money for lawyers anyhow)
It would seem to me that would-be SLAPPers, being a**h*les with a goal of harrassment by the biggest a**h*le lawyers available, would be SLAPPing whomever/wherever without much regard for "opinion" disclaimers.
However, my opinion has always been that one should seek legal counsel on legal matters from appropriate professionals. The people in this illustration are skilled professionals. Your mileage may vary. Don't try this at home. The material in this package is intended for making concrete, and should not be used as a lubricant, toothpaste, or salad dressing...
CPep,
"...Studies also indicate that resveratrol breaks down within a day after you've uncorked the bottle." (Us News Article) (I guess this means that once we open it, we gotta finish it)
"...which in one sitting would certainly cancel any health benefits from the resveratrol."
The evidence here is all anecdotal, and requires much more study. There will be years and years, exploring methods, dosage, and sources.
In designing the study, we probably don't need to spend a lot of time looking for maximum tolerated dose because we just don't need to go there (it's hard to explore the area under the curve problem when we're exploring the area under the table problem).
We probably should start with a wine tasting report on your recommended vintages (btw, on the list of wet weather wineries, I'm thinking we have those here in Virginia, and I know we'll be able to find some reds that taste like medicine). On a $/µM basis, where do you suppose the best results would be? I bet this study is going to show that I've been paying waaay too much.
Thanks for your posts. You're a great friend to all here!
Now you're talking science. (First I'm gonna finish the Cabernet, and then I'm going to start into the Merlot)
http://www.nutrition.org/cgi/content/full/132/2/298
"Piceatannol, a naturally occurring analog of resveratrol, was previously identified as the active ingredient in herbal preparations in folk medicine and as an inhibitor of p72Syk. We studied the effects of piceatannol on growth, proliferation, differentiation and cell cycle distribution profile of the human colon carcinoma cell line Caco-2. Growth of Caco-2 and HCT-116 cells was analyzed by crystal violet assay, which demonstrated dose- and time-dependent decreases in cell numbers. Treatment of Caco-2 cells with piceatannol reduced proliferation rate. No effect on differentiation was observed. Determination of cell cycle distribution by flow cytometry revealed an accumulation of cells in the S phase. Immunoblotting demonstrated that cyclin-dependent kinases (cdk) 2 and 6, as well as cdc2 were expressed at steady-state levels, whereas cyclin D1, cyclin B1 and cdk 4 were downregulated. The abundance of p27Kip1 was also reduced, whereas the protein level of cyclin E was enhanced. Cyclin A levels were enhanced only at concentrations up to 100 µmol/L. These changes also were observed in studies with HCT-116 cells. On the basis of our findings, piceatannol can be considered to be a promising chemopreventive or anticancer agent. "
The size of Panzem molecules is not the issue. The new formulation is designed to get more of it into the bloodstream, without being broken down in the intestines (small particle size makes absorption quicker). Keeping it in circulation longer is a good idea, however.
Also, we have two targets with Panzem: The blood vessels that feed tumors, and the tumors themselves. In all the dense prose posted here (unless I've missed something), I don't think anybody's ever been worried about getting to either destination (though dosage time over the target, in those 6 hours between doses, has our rapt attention as a possible issue).
Regards to all.
"If finding Georgejj, doc4of6,potsy,cpeptide, billy, reason4,jento,docaaron, rrgyzk, notadoc, syndi, lothar... even Haod3 in one spot doing their thing isn't a fun thing, I don't know what is. (Heaven, would be all the above with eye8 and boot, to boot.) "
(While we're at it, don't forget Mr. Haney, NHL, and dozens of other pretty interesting posters, with a host of notable lurkers)
We've had something close to this on occasion at our pre-annual meeting gatherings. Maybe if the share price recovers to $3 or so, more of us will feel rich enough to make the trip. While sobered by a renewed focus on our day jobs, at least we can still take a mental vacation to the good old days.
Nobody's heard from Boot in years. Maybe he's sworn off of message boards for good (the style in our prose is the poorer for it).
Regards to all!
George, thanks for an interesting article. I'm troubled by it on two points:
1 - Avastin is not a "newer" drug (it's Genentec's old "way ahead" drug), nor is it a "better" drug (it's got a side effect rap sheet that began with fatal ebola-like lung bleeds in the trials; further, there may be long term effects of supressing VEGF). It IS a better financed drug. It galls me to hear government scientists talking about their progress against cancer, when they're so much of the reason we have so little progress against cancer.
2 - "Wall Street" is a broad group, but the people I remember most are the ones who relentlessly shorted this stock to the point where the company had no way to raise the capital necessary to keep Endostatin and Angiostatin going. For their personal opportunity to make a few bucks, these slimeballs denied humanity the chance to find the potential of ES and AS, while ES and AS were hopelessly mired in years of unproductive subtherapeutic study mandated by myopic medical bureucrats.
Formulations and Phases
Back in ancient and wealthier times, I asked one of our Entremed luminaries what the most important issue was in bringing drugs to market. She said without hesitation that the most critical aspect is in choosing the right trials so that they yield results (this person also told me that we'd see Panzem as a drug well before the others, just because its oral formulation and lower cost make trials much easier to do).
The failure to achieve the Entremed vision so far has been a failure to hit sufficient results in the trials. The "new and improved Panzem liquid" is an attempt to get this right. First get bioavailability, and then go for effectiveness.
Most people believe that Endostatin was a big bust because it had disappointing results. I believe that if Dr. Folkman was given the opportunity to design the experiments and adjust dosages on a small number of patients, we would have seen the mouse results in humans years ago. Anybody want to defend kicking dying patients off the Endostatin trials?
Most people believe that the FDA is protecting us from bad acne creams. I believe that the long shadow of the FDA is killing a lot of people every day because of their inability to tell the difference between acne (USA deaths this week = 0) and cancer (USA deaths this week = 10,000).
The system is designed to punish those who swing for the fences. I'll not add my criticism to those who tried (with our full encouragement at the time, by the way).
Chinese contempt for intellectual property rights...
Look at the bright side: the Chinese rights, where Endostatin is in a Phase 3 study without any attempt to license it, have already been sold to a Taiwanese company. If significant results are reported in these trials, it would increase the value of Endostatin in the rest of the world, where at least a minor part of the opportunity still belongs to Entremed. If significant results are never obtained, then licensing is a moot point.
I always figured it was just the dumb companies I worked for that could get themselves tied up without leadership for months and months on end...
I'm thinking there's an announcement due real soon now.
Executive departures...
I agree that NC's sudden and emphatic departure means something very important. It's too bad that we, the owners of the company, have no better clues about what that is or what that means.
Similarly, last year's departure of John Holaday caught us all by surprise. But that case was voluntary, and I have on good authority, done with the best interests of the company in mind. Last I heard, he hasn't sold a share and continues to believe in the long term potential of ES, AS, PZ, and ENMD.
Regards to all!
By: RRGY2K
28 Apr 2004, 08:42 AM EDT
Msg. 49282 of 49282
(This msg. is a reply to 49279 by golfdad970.)
Golfdad, there's triumph in your tone.
So, Congratulations.
Have you read the Fortune article?
I thought not.
Despite nada for side effects and approximately 20 million cancer deaths since Folkman's AS + ES experiment, nobody knows to this day whether AS+ES, in a dose similar to Folkman's mice, would produce a result in a human cancer patient. Congratulations to all who work in the War on Cancer. We've successfully prevented the most important experiment for ES&AS in the name of proper science.
After screwing around for seven years with the subtherapeutic conditions of paper pushing clipboard holders, we still haven't allowed a doctor to apply a drug to his patient with an eye toward a specific patient's disease and condition. In the name of science, we continue to tie up our best therapeutic opportunities in endless bureaucratic testing which misses most of the point of the therapeutic agent.
The miserable failure of cancer treatment is apparently obvious to everyone except to you guys who work in the business. The cancer research establishment and their pals at the FDA have created an unworkable, unproductive, self serving bureaucracy that is in the full time business of preventing advances against cancer and other fatal diseases:
You're not getting the job done. GET OUT OF THE WAY!
Panzem in healthy volunteers
I think we're going to have people whose arthritis will get better. Probably we will have people with improvements in their struggle with obesity. Maybe we'll have people who will never know that their next heart attack got set back a few years.
But all of this will be "anecdotal," and therefore of no interest to real scientists.
Hopefully, we won't encounter substantial side effects.