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9902a 36 mo. survival Provenge - 31.6 months, Placebo - 21.2 months. You should now these numbers Crou as you made a boat load on those calls.
As far as the 9901 TTP p-value adjustments, from AC stat briefing docs:
Study D9901 was unblinded in JUN 2002. At that time, the p-value for time to disease progression in the ITT population was P = 0.088 (log-rank test) when comparing the two arms. The p-value changed to P = 0.085 due to a correction by the independent radiology facility reviewing the scans. A complete clinical audit was performed comparing source documentation at the clinical study centers to the clinical database. Based upon this intensive review of the unblinded data, additional corrections and/or adjustments to the data were warranted, and the p-value changed to P = 0.061 for time to disease progression. A radiographic error was subsequently discovered by the third party CRO responsible for confirmation of objective disease progression, resulting in a p-value change to P = 0.052 for time to disease progression.
"Chimp-in-Chief" I love it, Wall you are too funny. BTW - My favorite picture from the rally is "Replace Dr. Pazdur!".
Handy approved drug list:
http://bio.org/speeches/pubs/er/approveddrugs.asp
Handy approved drug list:
http://bio.org/speeches/pubs/er/approveddrugs.asp
Wow. What a post. I am dying to get back in, but can't figure out how to play it.
Just another IV conspiracy theory – Dr. Small abandoning Provenge in favor of GVAX and his MIA on 3/29. Ocyan pointed to this recent article refuting this conspiracy theory where reportedly the article states that Provenge will be on the market if 9902B confirms 9901. I only quickly scan IV these days, as sometimes it feels like I’m reading the same 5 posts a thousand times a day.
Thanks to Ocyan - evidently Dr Small is still publishing articles about provenge.
http://www.expertopin.com/doi/abs/10.1517/14712598.7.8.1275?journalCode=ebt
I read it on Yahoo HealthDay News. I did not know au2man owned Yahoo.
Dew has discussed this effect in the past:
Study Questions Dead-End Cancer Clinical Trials By E.J. Mundell
HealthDay Reporter
Mon Sep 10, 7:01 PM ET
MONDAY, Sept. 10 (HealthDay News) -- Little more than one in eight phase II cancer clinical trials with encouraging results go forward to the larger, phase III stage that's needed to bring a new therapy to patients, a new study finds.
In many cases, the researchers conducting the phase II effort knew beforehand that, due to financial or other constraints, a phase III trial was unlikely.
According to experts, that raises the troubling question of why the phase II study was done at all.
"If all of this effort in supporting phase II trials doesn't go anywhere, it means that the patients included -- and the efforts of their doctors -- could have been spent in finishing potentially practice-changing phase III studies," said the study's lead author, Ian Tannock, professor of medical oncology at Princess Margaret Hospital and the University of Toronto, Canada.
The bench-to-bedside evolution of any new cancer treatment occurs in three stages once a drug clears animal testing. First, a small phase I trial assesses the therapy's safety and calibrates the best dose. Next, a phase II trial (usually less than 100 patients) looks at how effective the therapy might be against a particular type of tumor.
If those results are positive, the drug should next go on to a much larger -- and expensive -- randomized trial comparing the new agent against the current standard of care. Positive results from phase III trials are required for U.S. Food and Drug Administration approval of most new agents.
Given the scarcity of both money and willing volunteers for cancer research, "a phase II trial shouldn't even be started unless there is an intention -- if the phase II results look promising -- to take it forward," said Tannock, who presented the study findings in June at the American Society of Clinical Oncology annual meeting.
And yet, for years, he and his colleagues had noticed a troubling trend: An overabundance of phase II trials presented at ASCO and other meetings that claimed promising results but then went nowhere.
In their study, the Canadian researchers reviewed the post-presentation histories of 200 phase II trials with "encouraging results" for breast, lung, gastrointestinal, genitourinary, and gynecological cancers. One hundred of the trials were presented at ASCO's 1995 and 1996 annual meetings, while the other 100 were presented at the society's 2006 conference.
They found that just 13 percent of the trials did, in fact, go on to a phase III study, despite results that had shown a positive response of the therapy against the targeted tumor.
Many of the trials reached a dead end, because the researchers couldn't get financial backing or enough patients for a phase III look at the treatment.
However, the study also found that "many of these limitations are known [to the researchers] when planning the phase II study, implying that many phase II trials are not planned as precursors of phase III trials."
So, why the wasted time, money, and effort for research that the investigators suspect will go nowhere? Tannock believes that, in many cases, the researchers' career goals may have come first.
"There's a lot of young oncologists out there, and they are encouraged to publish," he explained. "Their promotion at academic centers is dependent on publication. So, many of them may be encouraged to put together a protocol in which they take new drugs and treat a small number of patients with a certain disease in a phase II trial."
Because the teams that conduct phase II trials are smaller, a young researcher is more likely to be listed as the prestigious "lead researcher." This gains researchers more recognition than if their name is buried among the much-longer list of authors that typically accompanies phase III studies, Tannock explained.
Most phase III trials are headed by seasoned leaders in the field. "It is clearly impossible for a young investigator to run a large phase III study," Tannock noted. "And they just don't get the academic kudos for entering patients into a potentially practice-changing phase III study that they do from running a 20-patient phase II study."
Tannock believes that most young researchers do not "consciously" seek to begin a dead-end phase II trial, "but I think the system encourages it." He believes the same paradigm may exist in other areas of medical research, such as heart disease or other illnesses.
Another expert agreed that the preponderance of phase II trials is troublesome.
Dr. Bruce Hillner, a professor of medicine at Virginia Commonwealth University, has researched the issue on a global scale. In a study published in 2003 in the Journal of Clinical Oncology, Hillner found that phase II trials are much more common in the United States than Europe, where more resources are poured into practice-changing phase III trials.
"One of the pressures may be the 'publish-or-perish' that's disproportionately felt by American junior faculty," he said. "The other is the depth of financial entanglements with the pharmaceutical industry."
In some cases, Hillner said, drug companies use promising results from small phase II trials to encourage doctors to use an already FDA-approved drug 'off-label' for another purpose. In this way, he said, the company boosts drug sales while sparing itself the expense of the multimillion-dollar phase III trial that's required for new agency approvals.
Hillner also believes that, in many cases, phase II trials simply aren't presented well enough to garner the wider interest that's needed to take them to the next level.
In many cases, he said, researchers simply label their results "encouraging" or "positive," but never compare them to outcomes seen with currently available drugs or treatments.
"They compare it to a straw man, just saying 'this looks great,' " Hillner said. "This failure to define a benchmark is a major reason why many of these reports are just short-term fireworks."
Another expert agreed.
"While a phase II study might be 'positive,' it may not be as positive as something that's already been tested in a similar patient population," said Dr. Richard Schilsky, ASCO's president-elect and associate dean of clinical research at the University of Chicago.
He called the overabundance of dead-end phase II trials "a tough academic and cultural issue," and agreed that much of the problem is caused by the "publish-or-perish" phenomenon.
"As an academic community, we have to develop a better reward system for people who play important roles in developing these large, multi-center [phase III] trials," Schilsky said. Such a move would give young researchers a way of gaining peer recognition besides heading a phase II trial.
The message for the public is also clear, the experts said.
"The public should also be very cautious about 'exciting' results from phase II trials," Tannock said. "The literature is replete with things that looked very good in phase II but did not prove to be any better than standard treatment in phase III. You have to be careful."
http://news.yahoo.com/s/hsn/20070910/hl_hsn/studyquestionsdeadendcancerclinicaltrials
It looks like the filing yesterday may have had to do with the cv note offering:
http://www1.investorvillage.com/smbd.asp?mb=971&mn=155060&pt=msg&mid=2975012
Not that I have seen Wall. BNP has quite a few entities including these, but I could not find any DNDN holdings:
http://www.sec.gov/Archives/edgar/data/1007281/000100728107000003/0001007281-07-000003.txt
http://www.sec.gov/Archives/edgar/data/1166588/000116658807000003/0001166588-07-000003.txt
Also nothing on Nasdaq inst. holdings.
I just noticed that the article I posted below is nearly 5 years old, but I think its still relevant today. A lot of times it takes the market a while to recognize technology values.
FYI - Interesting brief article:
http://sanfrancisco.bizjournals.com/sanfrancisco/stories/2002/10/28/story3.html
Did you see my last post.
;)
Thanks
The pendulum has certainly swung the other way from 7 or 8 years ago during the bubble days when garbage P1 companies traded at $1billion – plus market caps. One reason for the swing to the other extreme today was the excesses of the past, but certainly another is the more burdensome FDA that has been approving fewer and fewer drugs in recent years. If however, a company can conquer these increasing barriers to entry, as I hope RPRX does with a good partner, the rewards at the other side should be greater.
Agree with you on the compelling risk-reward on RPRX, especially at 1/5 the current market cap of DNDN. Disagree with the rest. I hope that both companies bring successful products to market and I am a shareholder in both at the time. My comments on Pazdur's behavior are based as a disinterested observer of some of his tactics in the past in company's I had no position in. Seems to me he attended the J Edgar Hoover school of public administration. We will just have to see how things play out over time. Enough of this debate for now. Always welcome your thoughts.
Steve
"after NDA submission/review turn around and state that something else is needed". Isn't that what happened to Provenge, oh I forgot they got an overwhelming positive AC vote as well.
I hope you are right that any FDA roadblocks to approval have been pushed aside for RPRX. It is my 2nd largest stock holding. I hope that RPRX gets acquired next year for $80 bucks/sh. This way I will have more to invest in DNDN for Round 2. I enjoy biotech investing because of the challenge of it - trying to figure out the mosaic with a lot of missing pieces, coupled with the huge potential profits for investors if you are right and have the staying power to see things through. I enjoy watching science progress. I also find it fulfilling in playing a very very small role in bringing products to market that reduce human suffering. I still think that some of the FDAs top brass, especially Pazdur, are "double-talking scumbags". I have most certainly become more jaded in recent months having witnessed the FDA's modus operandi in more detail over the period of March 29 to May 9, 2007. :)
My comments were based more on establishing safety, not efficacy. IMO 75 patient trials are not going to be enough to comfort the FDA for a large patient population. The FDA can agree to these pivotal trials now and hold the NDA up on any grounds they want in the future. The FDA seems to enjoy running little biotechs in circles, wasting valuable development time and dollars. They are rarely held accountable for holding up drugs (especially for non life threatening diseases). If RPRX can get Proellex approved on such trials, great. Uterine fibroids or endos is not a 25,000 patient population for a terminal disease. We are talking about millions of women potentially being prescribed this drug. I don't see the FDA not asking for more safety data. In my view, these trials would be run by a large partner which RPRX needs to bring these drugs to market. When you absolutely need a partner the terms of the deal are not as attractive as they would be otherwise. How large were the patient databases for Lupron or Androgel? The FDA will not want to be put in a position 5 years from now explaining to the US female population why their uteruses are exploding ;) (just kidding). They are too busy allowing in substandard food and toys for mass US consumption from China, while denying promising treatments to terminal patients.
Again, I own RPRX and think Proellex and Androxal are promising products that very easily justify RPRX's current $140 market cap. I also believe that the FDA is run by a bunch of double talking scumbags.
I currently own RPRX and do not own DNDN. I don't know about the "massive employee turnover" at DNDN as they have roughly 180 employees. Burris was a disaster, but Simonetti left on good terms to be a CEO of another biotech. With an advised $50 million annual burn rate, they have over 2 years of cash.
NDAs do average a 1/2 million pages. Where did I say RPRX having a low cash burn rate is "a hinderance". All I am saying is is likely that more than 7 people will be required to get 2 drugs to market, and I could easily envision larger trials being required before approval.
9001 with 33% 3 year survivors vs 11% placebo and a p value of .01 had very stong results (not a "strong signal") and 9902a had 33% 3 year survivors vs 21% placebo with imblances against the treatment arm , and both trials had a 75% crossover rate so these results were essentially early provenge versus later provenge. Yet Nerf bashes Provenge saying that DNDN will never get anything to market. I do not wish to debate DNDN here. I feel that RPRX has a lot of promise or I would not own the stock. But, the FDA could care less how long it takes to bring something to market (except for AIDS drugs) and usually takes the cautious path, so my question relating to the FDA potentially not requiring additional studies before Proellex or Androxal should not be so quickly dismissed. The FDA could easily ask for more data than what is discussed here as the potential patient populations are huge.
For some examples of NDA page length, please see below:
http://www.drugs.com/nda/indiplon_041221.html
http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=8440756&dopt=A...
My view is that the FDA will likely not allow marketing of RPRX products to potentially millions of people based solely on the trial results of a few hundred patients. They are risk adverse and can place roadblocks anywhere they chose. A partner will likely be required to run large studies that they may require, as well as prepare the 1/2 million page NDAs. With 7 employees that would be around 100,000 pages per employee, so help obviously will be required. RPRX has promising products, but there is plenty of heavy lifting yet to do be done by RPRX or RPRX and its partner, before they market products. I own RPRX because of these promising products, their potential appeal to big pharma/biotech and its cheap market cap. Your knock of DNDN is completely unwarranted ("nary a prayer to get anything approved, ever..") DNDN has, in my opinion, a much clearer pathway to approval. If 9902B hits its survival endpoint (which 9901 did with 1/4 the patients), Provenge will likely be approved, despite the competing economic interests of the chemotherapy community.
"assuming executing a successful NDA for all three study designs." This the crux of the matter. My view is that the FDA will likely not allow marketing of RPRX products to potentially millions of people based solely on the trial results of a few hundred patients. They are risk adverse and can place roadblocks anywhere they chose. A partner will likely be required to run large studies that they may require, as well as prepare the 1/2 million page NDAs. With 7 employees that would be around 100,000 pages per employee, so help obviously will be required. RPRX has promosing products, but there is plenty of heavy lifting yet to do be done by RPRX or RPRX and its partner, before they market products. I own RPRX because of these promising products and their potential appeal to big pharma/biotech. Your knock of DNDN on BV is completely unwarranted ("nary a prayer to get anything approved, ever..") DNDN has, in my opinion, a much clearer pathway to approval. If 9902B hits its survival endpoint (which 9901 did with 1/4 the patients), Provenge will likely be approved, despite the competing economic interests of the chemotherapy community.
Given Scher's COI and Moorin's relationship to Scher, you have to wonder:
Novacea Announces Resignation of Two Board Members
Thursday August 30, 4:50 pm ET
SOUTH SAN FRANCISCO, CA--(MARKET WIRE)--Aug 30, 2007 -- Novacea, Inc. (NasdaqGM:NOVC - News) today reported that two of its founding venture investors, James Blair, Ph.D., of Domain Associates and Jay Moorin of ProQuest Investments, will resign as members of the board of directors in September 2007. Dr. Blair and Mr. Moorin have been members of the Novacea board since 2001.
http://biz.yahoo.com/iw/070830/0296919.html
OT - Fair enough. Fear and euphoria were my emotions as well. I was actually rich for a few days. I chose to unload only a small number of shares pre CR as I thought the share price was only 1/2 the way to where it was going over the next 2 years when it was at $25, as I thought Provenge would sell very well and approval of some sort was likely. I was not anticipating that Pazdur would hijack the whole process from another division of the FDA. As far as the upcoming interim, I don't think we will ever know the interim p value if the trial continues, as such data is very rarely, if ever, released for a Data Monitoring Comm. interim look. To everyone else, sorry for hijacking the RPRX board, but other peoples biotech experiences are always worth noting, especially since in the end FDA can do whatever the F___ it wants without explanation and without accountablilty to anyone. I do feel that both RPRX drugs have a lot of potential, but plenty of things can still go wrong. I added to my position near the open this morning, could not resist with a $135 million market cap, and 2 potentially huge drugs targeting underserved markets.
Can you post a link as to what "CMF" is. I now generally what money flow is, but would like to see it for JAV. Thanks
OT: Crou
Which was it for your DNDN options going into the AC? I held exclusively stock acquired over years and felt cheated ("Pazdurized") by the whole thing. It was a huge portion of my portfolio. Who new the FDA would for the first time reverse an overwhelming positive AC vote for a life threatening disease. You made out like a bandit, Wall did well, and I made 35%, yet our call was basically the same. I will probably at sometime be in heavy again, but can't figure out the best way to play the interim, as I feel the odds of clinincal success are much higher at the final, but we don't even know what p value will be required at the interim something around .015 or something only supportive.
Steve
This may part of the reason for the weakness:
Indevus Pharmaceuticals
Last: 7.08-0.02-0.28%
10:20am 08/28/2007
IDEV7.08, -0.02, -0.3%) said that it has submitted its application with the FDA to market the testosterone treatment Nebido for the treatment of male patients with the hormonal condition hypogonadism. Indevus said the Nebido only has to be administered by needle every 12 weeks, as opposed to current treatment which often must be injected every two to three weeks. Nebido is already on the market overseas. Indevus acquired the U.S. rights to Nebido in July 2005 from German drugmaker Bayer AG. Indevus estimates the U.S. testosterone market to be worth over $550 million.
Thanks, that is what I thought. What prompted my question - didn't mgt. release interim results for 9901 or was that just ongoing follow-up as survival data matured? FWIW, I think, that if a trial is stopped for futility by the DMSB, it is typically only done if the placebo group is doing better than the treatment group or if there is no evidence of treatment effect at all.
"b. The efficacy of the treatments being tested as pre-specified in the interim monitoring plan of the protocol and independently make recommendations to researchers to continue, to amend or to terminate a clinical trial based on the interim analysis for efficacy (e.g., terminate a clinical trial because the analyses indicate the study is having a negative effect, the intervention is not adequately implemented or there is no evidence of a treatment effect after the prescribed level of power is reached)."
http://www.nida.nih.gov/Funding/GuideDSMB.html
Wall, should the trial continue at the interim, do you think DNDN will provide interim results regarding p-value, HR, median surival, % surviving, etc., or will the data monitoring committee keep the data blinded and we get a PR only stating words to the effect: "no safety issues have surfaced and the trial will continue until its conclusion", and nothing else as I have seen in many other trials? Thanks
Wall, any plans to get back in or strategies for playing the interim that you wish to divulge? The steady price erosion that I expected post 5/9 has not materialized. I think the huge short interest has kept the stock price propped up and David may have missed that point in his price predictions post CR. I am reluctant to get back in prior to the interim given the late separating curves and immature data at the interim, but I would hate to miss out at this point after scraping every spare penny together for years and putting it into DNDN, then 40 days of anxious euphoria sitting on a seven figure portfolio, followed by the Pazdur shafting. I realize there are risks in any trial meeting its endpoints and I wish that Gold would not have bet the whole co. on the results of IMPACT, but I am still a big time believer in Provenge.
Testosterone: The Benefits and The Dangers of Testosterone Replacement Therapy
Radio show on the topic by an MD.
http://www.healthradio.net/component/option,com_mtree/task,viewlink/link_id,3858/Itemid,/
Interesting Article courtesy of Demotek and the Science News:
Taking a Jab at Cancer
Combined with drugs, vaccines against tumors may finally be working
Patrick Barry
Imagine a patient getting a vaccine injection in the doctor's office—but not to ward off a virus or a bacterium that causes smallpox, measles, or any other infectious disease. This vaccine is for cancer, specifically for a tumor already growing within the patient's body. The treatment, perhaps in combination with others, is intended to train the patient's immune system to recognize and kill malignant cells.
THE CURE WITHIN. This multilobed killer T cell, part of the immune system, is destroying a cancer cell. But tumors can undermine such attacks.
G. Kaplan/Univ. of Medicine and Dentistry of New Jersey
It's a strategy that scientists have been working on for more than 15 years, but rallying the immune system to fight cancer has proved more difficult than most people expected. Designing a cancer vaccine requires a deep understanding of the immune system's intricacies—knowledge that has come about only in the past few years. In addition, cancer cells can flip chemical switches to subvert attacks by the immune system, adding a layer of difficulty to vaccine design.
To date, no cancer vaccine has been approved by the U.S. Food and Drug Administration. The vaccine against cervical cancer that's been in the headlines is a conventional preventive vaccine that targets the virus that causes cervical cancer.
The only therapeutic cancer vaccine that's come close to approval is a prostate cancer treatment called sipuleucel-T. In March, an FDA advisory panel gave sipuleucel-T the thumbs-up, but the agency decided to delay approval pending the completion of a large trial in men with prostate cancer.
"The reality is that [the field] has been and continues to be waiting for a clear clinical success," says Drew Pardoll, professor of oncology at Johns Hopkins University in Baltimore.
Recent research has not only revealed the switches that tumor cells flip to defuse an attack from the immune system, but has also yielded possible drugs to counteract this ploy. Paired with vaccines, several of these new drugs appear to be able to unleash the potential of the vaccines to spur the immune system to attack cancer cells.
Many researchers say that these "combinatorial" therapies could be the way forward for cancer-vaccine research. "We can beat this disease with the immune system with the right kinds of combinatorial approaches," Pardoll says.
Subterfuge and betrayal
In their housecleaning role, roving sentries of the immune system identify and destroy badly damaged cells in the body. But cancer cells, which by definition are damaged cells that grow and proliferate unchecked, are surprisingly crafty adversaries.
The immune system has control mechanisms to prevent immune cells from attacking the body's healthy cells. As part of this control system, killer T cells, the immune system's attack dogs, require multiple signals before they'll swing into action.
First, they need immune cells called dendritic cells to chew up a sample of the target and present a piece to the killer T cell as an example of what to look for. Dendritic cells play a key role in activating an immune response—whether against a foreign microbe or a damaged body cell—so many of the most promising new cancer vaccines use dendritic cells to train the immune system to recognize tumor cells. Sipuleucel-T is one such product.
But to activate killer T cells, or killer Ts, so-called helper T cells must release chemical cues. Regulatory T cells (T-regs), yet another kind of cell, function as the brakes of the immune system by producing compounds that keep killer Ts in check.
Tumors manipulate these elaborate control mechanisms to fool the immune system into treating cancer cells like friends instead of foes, a phenomenon called tolerance. "This is the central mission of the field—to selectively break tolerance to these tumors," Pardoll says.
For example, cancer cells emit a protein called vascular endothelial growth factor (VEGF), which triggers the creation of new blood vessels to feed the fast-growing tumor. Conveniently for the tumor, VEGF also stifles the maturation of dendritic cells. Keeping dendritic cells stuck in an immature state prevents them from performing their critical role of training and activating killer Ts. What's more, these immature dendritic cells actually stimulate T-regs, which suppress the immune response even further. Dendritic-cell development is also hindered by other tumor compounds, including the immune-signaling molecules interleukin 6 and 10, a substance called transforming growth factor—beta, and the inflammation-related enzyme cyclooxygenase-2.
Cancer cells can also release chemical signals that recruit T-regs and draw them into the tumor. "We know that these T-regs are sitting in the cancer and actually deactivating the [killer] T cells," says Elizabeth M. Jaffee of the Sidney Kimmel Cancer Center at Johns Hopkins.
Ironically, it's often the immune system itself that pushes cancer cells to such nefarious lengths. Scientists have confirmed in recent years that a person's immune system has an innate ability to detect and kill some precancerous cells.
However, sooner or later, one of these precancerous cells will mutate such that it begins producing some of the signaling molecules that protect it against attack. In the same way that the overuse of antibiotics drives the evolution of drug-resistant "superbugs," the immune system applies an evolutionary pressure on precancerous cells that pushes them to develop defenses against it. The cell in which that pivotal defensive mutation occurs is then free to proliferate wildly and to develop into full-blown cancer.
"We've come to look at the development of cancer in a person as an evolutionary struggle between rapidly mutating cells and the immune system," says Louis M. Weiner of the Fox Chase Cancer Center in Philadelphia.
Decloaking tumor cells
The latest strategy in cancer vaccines combines them with drugs that subvert these sophisticated defenses of tumors. By disabling the stop signals that cancer cells send to a person's immune system, these combination therapies should enable vaccines to do their jobs and spur immune cells into action against tumors. Experiments in mice and early trials in cancer patients are beginning to show that scientists might finally be on the right track.
WEB OF DECEIT. Tumor cells send out chemical signals such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), and cyclooxygenase-2 (COX2) that reduce the immune system's attack on the cancer. Activation steps (arrows) and inhibition (lines with bars) boost regulatory T cells, curb killer T cells, and stifle the maturation of dendritic cells. Immature dendritic cells and stimulated regulatory Ts further subdue the antitumor response of the killer Ts.
E. Roell
"There are [experimental] vaccines now that are going into patients that are so much more potent at breaking tolerance than has ever been seen in the vaccines from the previous era," Pardoll says.
One promising strategy involves combining vaccines with drugs that block the action of a protein called cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). This substance sits on the surface of T cells, and when activated, suppresses killer Ts' tumor-fighting activity. Blocking CTLA-4 can release this brake on the immune system.
A small trial in patients in the Netherlands combined a CTLA-4 blocker called ipilimumab with an experimental cancer vaccine called GVAX. At the 2007 conference of the American Society of Clinical Oncology in Chicago, Winald Gerritsen of the Free University Medical Center in Amsterdam and his colleagues announced that the combination treatment reduced blood concentrations of prostate-specific antigen, a protein produced in excess by abnormal prostate cells, in 5 of 6 prostate cancer patients.
Tests of the patients' immune system activity showed that their killer Ts and dendritic cells had become activated, indicating that the drug had released the checks on these cells so that the vaccine could rally them to action. With so few people in the trial, the results are only provisional, but "you have to sit up and take notice," Pardoll says.
"If you saw results like this in larger trials, it would be almost unprecedented," says Jeffrey Schlom, chief of the Laboratory of Tumor Immunology and Biology at the National Cancer Institute in Bethesda, Md.
Studies of similar combination therapies in mice have produced even more dramatic results. A team led by James P. Allison of the Memorial Sloan-Kettering Cancer Center in New York City treated mice with skin cancer using a similar therapy of GVAX with a CTLA-4 blocker. The treatment eliminated tumors in more than 90 percent of the mice, the team reported in the July 2006 Journal of Clinical Investigation. The balance between the numbers of killer T cells and T-regs within the tumor clearly shifted in favor of killer Ts, showing that the combo therapy weakened the cancer's defenses and released the brakes on the immune system.
Unfortunately, releasing these brakes can also have adverse effects. In the Netherlands study, for example, most of the patients developed significant loss of kidney and thyroid function as well as flulike symptoms, all presumably due to the patients' immune systems attacking healthy cells in their bodies.
Another strategy involves pairing a vaccine with a compound that inhibits T-regs. Suppressing T-regs removes the brake on killer Ts, allowing them to mount an attack against the tumor. One particularly effective T-reg suppressor is the chemotherapy drug cyclophosphamide. François Martin and his colleagues at the French National Institute of Hygiene in Dijon showed in 2004 that giving rats with colon cancer cyclophosphamide along with a cancer vaccine enabled their immune systems to destroy the tumors, while the vaccine alone could not.
"Finding ways to reduce T-regs is one of the most promising things going on in the field," says Jarrod Holmes of the Cancer Vaccine Development Lab in Bethesda, Md.
VEGF also provides a ripe target for drugs. Drugs that block VEGF allow dendritic cells to mature, thus improving the effectiveness of cancer vaccines, as Leisha A. Emens of the Johns Hopkins University School of Medicine and her colleagues report in the July 1 Clinical Cancer Research. The researchers found that a cancer vaccine for breast cancer shrank tumors in mice more quickly when given with a VEGF inhibitor called DC101. Suppressing T-regs by adding cyclophosphamide to the mix made the cancer-fighting effect of the combination even stronger.
Round peg, square hole
Although researchers in the field are optimistic, these combination vaccines are moving through the drug-development pipeline toward larger trials very slowly.
Because drugs are normally tested and approved one at a time, the industry is organized around single-drug development. This structural bias against multiagent therapies has hampered the development of these new vaccines, researchers say. Vaccines that are farthest along in the approval process, such as the prostate cancer treatment sipuleucel-T, generally aren't combination therapies.
"I'm not saying that it's anyone's fault," Jaffee says, "but unfortunately, the way our process for drug development is, it's very slow if you want to get approval for more than one agent."
Normally, each component of the treatment must make it through human trials on its own. And to pass the trials, a drug must be more than just safe; it must also be effective. Often, contend Jaffee and others, the components of a combination vaccine are effective at killing tumors only when used together, making it difficult to get a component approved on its own.
Scientists are afraid of trying combined vaccine-drug therapies until each component is FDA approved, Schlom says. A scientist who combines an unapproved drug with an experimental vaccine puts both compounds at risk of never reaching the market and the clinic. If early trials of the combo show toxic effects in people, it may be impossible to justify further trials of the compounds, even though the cause of the toxic effects—be it the drug, the vaccine, or the synergy of the two—may be unknown.
With these policy challenges, as well as formidable research obstacles, to overcome, the field certainly has a long way to go. But recent progress hints at the unique payoff that's possible with cancer vaccines. "The future is very, very bright," Pardoll says.
Genta Announces Launch of Genasense(R) Named-Patient/Compassionate Use Program
PR Newswire Europe (inc. UK Disclose) - Aug. 13, 2007
BERKELEY HEIGHTS, N.J., Aug. 13 /PRNewswire-FirstCall/ -- Genta Incorporated today announced the launch and initial sales of its lead oncology product, Genasense(R) (oblimersen sodium), on a named patient/compassionate use basis outside the United States. "Named-patient" distribution refers to the distribution or sale of a product to a specific healthcare professional for the treatment of an individual patient. In most countries, this program provides for full cost recovery of providing late- stage investigational drugs that are either pending regulatory approval or are in late-stage clinical trials that are intended to lead to formal regulatory approval. Until now, the Company had been supplying Genasense at no charge. The proceeds from this program, which are recorded as gross revenue for accounting purposes, will appear as of the third quarter 2007.
"With the launch of the named-patient/compassionate use program, Genta reaffirms its commitment to make Genasense available to patients in need while we are conducting additional registration-quality clinical trials," said Dr. Raymond P. Warrell, Jr., Genta's Chairman and Chief Executive Officer. "With published results earlier this year of our randomized trials in melanoma and chronic lymphocytic leukemia, the Company has received a number of requests for Genasense to treat specific patients. We are pleased to make this program available to patients outside the U.S. We expect that proceeds from this new program will be used to offset costs associated with our confirmatory randomized trial in patients with advanced melanoma."
About Genta
Genta Incorporated is a biopharmaceutical company with a diversified product portfolio that is focused on delivering innovative products for the treatment of patients with cancer. The Company's research platform is anchored by two major programs that center on oligonucleotides (RNA- and DNA- based medicines) and small molecules. Genasense(R) (oblimersen sodium) Injection is the Company's lead compound from its oligonucleotide program. The leading drug in Genta's small molecule program is Ganite(R) (gallium nitrate injection), which the Company is exclusively marketing in the U.S. for treatment of symptomatic patients with cancer related hypercalcemia that is resistant to hydration. Genta is partnered with IDIS (http://www.idispharma.com/) on a program whereby both Ganite(R) and Genasense(R) are available on a "named- patient" basis in countries outside the United States. For more information about Genta, please visit our website at: http://www.genta.com/.
Safe Harbor
This press release may contain forward-looking statements with respect to business conducted by Genta Incorporated. By their nature, forward-looking statements and forecasts involve risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. Forward- looking statements include, without limitation, statements about:
-- the Company's ability to obtain necessary regulatory approval for
Genasense(R) from the U.S. Food and Drug Administration ("FDA") or
European Medicines Agency ("EMEA"); -- the safety and efficacy of the Company's products or product
candidates; -- the Company's assessment of its clinical trials; -- the commencement and completion of clinical trials; -- the Company's ability to develop, manufacture, license and sell its
products or product candidates; -- the Company's ability to enter into and successfully execute license
and collaborative agreements, if any; -- the adequacy of the Company's capital resources and cash flow
projections, and the Company's ability to obtain sufficient financing
to maintain the Company's planned operations; -- the adequacy of the Company's patents and proprietary rights; -- the impact of litigation that has been brought against the Company and
its officers and directors and any proposed settlement of such
litigation; and -- the other risks described under Certain Risks and Uncertainties Related
to the Company's Business, as contained in the Company's Annual Report
on Form 10-K and Quarterly Report on Form 10-Q.
The Company does not undertake to update any forward-looking statements. There are a number of factors that could cause actual results and developments to differ materially. For a discussion of those risks and uncertainties, please see the Company's Annual Report on Form 10-K for 2006 and its most recent quarterly report on Form 10-Q.
CONTACT:
For Genta Incorporated
Tara Spiess
TS Communications Group, LLC
(908) 286-3980
info@genta.comGenta Incorporated
CONTACT: Tara Spiess of TS Communications Group, LLC, +1-908-286-3980,
or info@genta.com, for Genta Incorporated
Web site: http://www.genta.com/
http://www.idispharma.com/
http://www.therapeuticsdaily.com/news/article.cfm?contentvalue=1462616&contenttype=sentryarticle...
BioPete - sorry for the last post - you beat me to the bunch.
Hypogondism Market - From Feuerstein's Biotech Mailbag:
"But forget about Sanctura XR. A better reason to own Indevus, according to this hedge fund analyst, is the company's fairly deep pipeline of urology and endocrinology drugs. One highlight is Nebido, a long-acting injectable testosterone that should be a best-in-class treatment for male hypogonadism, a condition where a man's testes fail to produce adequate amounts of testosterone.
Nebido will be filed with the FDA later this quarter and could be on the market in 2008. The drug can be given once every three months, which makes it a much better alternative than current treatments, which are topical gels or two- and four-week injections.
Male hypogonadism is a $500 million market opportunity with room for future growth. If Nebido can capture 30% to 40% of that market, it will have a markedly positive effect on Indevus' market valuation, currently just north of $500 million."
http://www.thestreet.com/_yahoo/newsanalysis/biotech/10373486_4.html
organized short attack - it had the feeling of one - relentless downward pressure without news - I don't think we where anywhere close to being overvalued at $7 (I have been lurking here for months trying to learn) - shorts have all the advantages, but if they are wrong, they get burned big time - sure hope they don't know something we don't know
Just used the hammering to add more. Sure hope we have a couple of approved products within the next few years.
Courtesy of Walldiver and WSJ. This must be an explanation for the wacky JAV stock price behaviour in recent weeks. May the shorts get their just rewards. Wished I had added more than I did a week or two ago.
By KAREN RICHARDSON and JUSTIN LAHART
August 10, 2007; Page C3
On a day when stock prices tumble like they did yesterday, short-sellers -- investors who make big bets on declines -- should be grinning.
But in a twist, some of the day's best-performing shares were ones that these bearish investors love to hate. As a result, even short-sellers took it on the chin.
Shorting involves the sale of borrowed securities by an investor who hopes to make a profit by buying back an equal number of shares later, at a lower price, to replace the borrowed ones.
Yesterday, the Dow Jones Industrial Average fell 387 points, but beleaguered stocks popular among short-sellers -- for instance, those of home builders -- posted double-digit percentage gains. At the same time, long-suffering Vonage Holdings Corp., a telecom stock that has fallen 85% since it went public last year, jumped 10%.
Online retailer Overstock.com Inc., stun-gun maker Taser International Inc. and Krispy Kreme Doughnuts Inc., three popular issues among short-sellers, all closed higher.
The reason? Blame, or thank, so-called quant hedge funds, sophisticated investment vehicles that use complex computer calculations to pick their investments, then use loads of borrowed money to make their bets. Some of these funds have been forced in recent days to not only sell their regular stock holdings -- their "long" positions" -- but also their short positions to raise money as bankers knock on their doors with margin calls on their borrowed money.
When investors are forced to exit short sales, they must buy back shares, which can force prices higher.
"The liquidation of these quant funds is serving to produce not only downside pressure on longs but also upside pressure on shorts," says Douglas Kass, head of Seabreeze Partners Management Inc., a Florida hedge fund heavily involved in shorting.
The result is that some of the worst-performing or most heavily shorted stocks got a boost. Slammed all year by the roiling subprime-mortgage fears, the Dow Jones home builders index edged 0.8% higher. Home builders Beazer Homes USA Inc. and Hovnanian Enterprises Inc. rose more than 10% each.
Some more obscure companies that in previous months or years landed in the cross hairs of short-sellers beat yesterday's market rout. Knot Inc., a New York wedding-planning firm and publisher, vaulted 25% on Nasdaq. Isramco Inc., a Houston firm that explores and produces oil and gas in Israel and the U.S., climbed 21%. InterOil Corp., an oil and gas company that operates out of Papua New Guinea, ended up more than 10%. The company has yet to post an annual profit.
Write to Karen Richardson at karen.richardson@wsj.com and Justin Lahart at justin.lahart@wsj.com
David Miller Article - Pretty Troubling
http://www.minyanville.com/articles/DNDN-prescription-drug-biotech-pharma-ALTH-GPCB/index/a/13558/fr...
P3, I don't find an error dealing with tumor burden imbalances "minor" when it comes to Provenge (esp. for a presentation slide), but I do agree with the rest of what you said.