Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Bavituximab vs: Avastin, results to date -------
Bavituximab info:
http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=319343
Avastin info:
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
(and THAT'S from the earlier phase II "rosey" Avastin trial results, as discussed last Sunday in the NYT in my previous post...)
---------
j
Avastin Efficacy Chart from NY Times ---------
This is info from the
New England Journal of Medicine, ASCO, & FDA.
----------
j
THE SUNDAY NYT AVASTIN ARTICLE ----------
The Evidence Gap
Costly Cancer Drug Offers Hope, but Also a Dilemma
By GINA KOLATA and ANDREW POLLACK
Published: July 6, 2008
It took only an instant for 58-year-old Gailanne Reeh to go from the picture of health to death’s door. By chance, her doctor noticed a lump under her arm during a routine exam. It turned out to be advanced breast cancer.
Soon she was having tests to reveal the extent of the cancer and hearing the grim results.
The surgeon, she recalled, “looked at me and said: ‘This is not a conversation I like to have. But I can’t do anything for you. You can’t be cured. You can’t be treated. All we can do is manage your cancer.’ ” On scans to detect tumors, the doctor told Ms. Reeh, “you light up like a Christmas tree.”
And so, like many others in that situation, Ms. Reeh, the vivacious owner of a staffing agency in Boston, was given bevacizumab, also known as Avastin, a drug that signifies both the hopes and dilemmas of modern medicine.
Looked at one way, Avastin, made by Genentech, is a wonder drug. Approved for patients with advanced lung, colon or breast cancer, it cuts off tumors’ blood supply, an idea that has tantalized science for decades. And despite its price, which can reach $100,000 a year, Avastin has become one of the most popular cancer drugs in the world, with sales last year of about $3.5 billion, $2.3 billion of that in the United States.
But there is another side to Avastin. Studies show the drug prolongs life by only a few months, if that. And some newer studies suggest the drug might be less effective against cancer than the Food and Drug Administration had understood when the agency approved its uses.
While many patients and their doctors say the drug can improve the quality of life — like a sense of well-being and an ability to carry out daily tasks without exhaustion or pain — such effects can be hard to document. Meanwhile, many patients with cancers other than those of the colon, lung or breast are taking the drug, even in cases where there is no compelling evidence that it can help.
Avastin also has serious, if infrequent, side effects, some of which can be lethal. And because it is almost always used with standard chemotherapy — it did not work as well when researchers tried it alone — patients on Avastin do not escape chemotherapy’s side effects.
“I still use Avastin routinely, but it’s sobering,” Dr. Leonard Saltz, a colon cancer specialist at Memorial Sloan-Kettering Cancer Center in New York, said of the new data. “It’s not a slam dunk and, in fact, the incremental benefit may be more modest than we want to admit.”
If Avastin were inexpensive or if it cured cancer or even held it at bay, as the drug Gleevec does for blood cancer, few might care. But like a half-dozen or so new biotechnology drugs with a similar combination — alluring promise, high price and only arguable benefits — Avastin raises troubling questions:
What does it mean to say an expensive drug works? Is slowing the growth of tumors enough if life is not significantly prolonged or improved? How much evidence must there be before billions of dollars are spent on a drug? Who decides? When, if ever, should cost come into the equation?
For a patient like Ms. Reeh, fighting for her life, the cost is not the main concern. If her insurer did not pay, she said, she would go into debt, find a way to raise the money.
But some in the pharmaceutical industry worry that such prices will raise concerns about whether the drugs are worth it, leading to a backlash like price controls or restrictions on use.
Roy Vagelos, a former chief executive of Merck who is considered an elder statesman of the industry, said in a recent speech that he was troubled by a drug, which he would not name but which was a clear reference to Avastin, that costs $50,000 a year and adds four months of life. “There is a shocking disparity between value and price,” he said, “and it’s not sustainable.”
Some patient advocates are also troubled by very expensive treatments like Avastin coming into routine use on what they see as little more than a hope and an expensive prayer.
“It’s absolutely critical that we start having a public discussion,” said Barbara Brenner, executive director of Breast Cancer Action, an advocacy group. “I think of Avastin as a model that is showing us where the problem is.”
The Rising Cost
The problem is largely one of cost.
Cancer drugs constitute the second biggest category of drugs in the United States behind cholesterol-lowering medicines, and accounted for $17.8 billion of total prescription drug sales of $286.5 billion in 2007, according to IMS Health, a health care information company. Spending on drugs for cancer grew 14 percent last year, faster than for all but three other diseases.
About 100,000 Americans take Avastin, according to Genentech’s data. The drug is being formally tested in as many as 450 clinical trials for about 30 types of cancer. And Genentech, its partner Roche and the National Cancer Institute are now starting studies that will include more than 26,000 people with lung, colon or breast cancer at earlier stages of the disease than were studied initially. If Avastin is approved for those earlier-stage patient groups, it could have a major impact in delaying the return of their cancer, but hundreds of thousands of additional people could end up taking it, possibly for years.
And that, insurers and patient advocates say, could impose a considerable financial burden.
The drug’s price, as charged by Genentech, can be $4,000 to more than $9,000 a month, depending on a patient’s weight and the type of cancer. Avastin’s cost to patients and insurers can be much higher, though, because doctors and hospitals buy the drug and then sell it to patients or their insurers, often marking up the price. So the $2.3 billion that Genentech recorded in sales of Avastin represents only part of what Americans spent on the drug last year.
And while doctors typically want the best for their patients, there also are other factors that may push them to prescribe Avastin.
“Think about where the interests are aligned,” said Dr. Deborah Schrag, a colon cancer specialist at the Dana-Farber Cancer Institute in Boston. “Patients who seek out cancer care are often quite willing to try all kinds of things. Doctors want to help them and may be financially incentivized. And it is often quite hard for insurance companies to intervene.”
Medicare requires that the doctor or hospital buying Avastin be paid an amount equal to Genentech’s average selling price plus a markup of 5 to 6 percent. Of that amount, Medicare pays 80 percent and the patient pays 20 percent. Doctors and hospitals typically do not make much money on Avastin for Medicare patients, and can even lose money if they buy the drug at a price that is higher than average. But patients can end up paying thousands of dollars a month. Some have supplemental insurance to take care of it; others do not.
But private insurers sometimes pay several times as much as Medicare pays for Avastin. Doctors and hospitals have at times charged as much as $35,000 a month for the drug, said Dr. Peter Dumich, who reviews claims for cancer patients for AWAC, a company that helps employers contain health care costs. The insurers have little choice, Dr. Dumich says, when their contracts say they must pay a portion, like 80 percent of the charge, whatever the charge actually is. “Providers have them over a barrel,” he said.
And, like Medicare, private insurers may in turn require patients to pay a percentage of what can be hefty bills.
That has happened to Jim Lemieux, a colon cancer patient at Dana-Farber. His private insurance requires that he pay 25 percent of the cost of his treatment, which includes Avastin. His insurer, he said, is charged $6,000 a month for the drug, making his share $1,500.
Mr. Lemieux, who was a sales manager at a car dealership, says he cannot bear to look at his medical bills. They include bills for hospitalizations and surgery and co-payments for standard chemotherapy, as well as Avastin.
To try to make ends meet, he and his wife just sold their house and are moving into their son’s basement. Even so, he says, he expects he will have to file for bankruptcy.
“You figure you’ve got insurance,” Mr. Lemieux said. “I paid 30 years and never got sick. I should have just paid the money to myself.”
But he is not planning to give up Avastin.
“I’m trying to stay alive,” Mr. Lemieux said. “I decided I’m not going to die from Stage 4 colon cancer.”
A Promising Dream
When Napoleone Ferrara was hired by Genentech in 1988, he was assigned to work on a drug to ease labor during childbirth. But he could not get cow pituitary glands out of his mind.
Dr. Ferrara had noticed in his previous academic job that when he mixed extracts from the glands with cells from blood vessels, the vessel cells started to grow rapidly. Something made by those glands, he reasoned, could spur vessel growth. He found that substance in 1989 and called it vascular endothelial growth factor, or VEGF (pronounced VEJ-eff). He even isolated its gene. And that led to a new idea for a cancer drug.
It drew from a hypothesis for a sort of universal cancer treatment, advanced by the late Dr. Judah Folkman of Harvard. Dr. Folkman had argued, starting in 1971, that tumors must grow their own blood vessels to bring them nourishment and oxygen. If you could choke off those vessels, Dr. Folkman said, you could halt cancers.
Dr. Ferrara and his colleagues realized that if they could block VEGF, cancer cells might not be able to grow blood vessels. So Genentech developed a monoclonal antibody, a type of protein, that would bind to VEGF and disable it. In 1997, the company began testing its antibody, which became Avastin, in cancer patients.
There were some setbacks. Avastin failed in its first big clinical trial, against very advanced breast cancer. Genentech’s stock dropped 10 percent in one day, and some analysts questioned whether the company’s investment would ever pay off.
Meanwhile, the company was well into a trial of Avastin for colorectal cancer. Patients got chemotherapy plus either Avastin or a placebo. The Avastin patients lived more than four months longer, a median of 20.3 months, compared with 15.6 months for the other group. “We were excited,” Dr. Schrag said. “Four months is big.”
In February 2004, 15 years after Dr. Ferrara’s initial discovery, the Food and Drug Administration approved Avastin for patients with advanced colon cancer. A blockbuster was born.
But now there is a question mark over that evidence. That first exciting result compared Avastin with a type of chemotherapy that has since been widely replaced by a more effective regimen.
In a later, larger study comparing Avastin with current chemotherapy, Avastin slowed the growth of tumors but did not extend life by an amount considered statistically significant.
Dr. Schrag said she would continue to give the drug to her colon cancer patients. But when she talks to patients about Avastin now, she said, she will add a few more caveats.
She believes that some patients are helped — that they may feel better and, she hopes, may even, in some cases, live longer. She says a few of her Avastin patients lived several years and some are still alive. Of course, she acknowledges, there is no proof that Avastin was responsible, but it is stories like those that give her, and patients, hope.
“All patients want to be the tail end of the survival curve,” Dr. Schrag said.
When Avastin was approved for colon cancer, Genentech decided to charge $2,200 for an average dose, taken every two weeks. That was a reflection of the research and development it had put into the drug as well as continuing research, said Walter Moore, the company’s director of government relations.
Genentech, which has never before revealed what it spent to develop Avastin, now says that it and its partner Roche have spent more than $2.25 billion starting with Dr. Ferrara’s original work. The figure includes research, clinical trials and filing for regulatory approval and is well beyond what was spent by the federal government, which conducted important clinical trials of Avastin. Through May 2006, the government had spent $44.6 million on Avastin trials and related laboratory work, according to figures obtained from the National Cancer Institute by Consumer Watchdog, an advocacy group.
While it is impossible to compare directly the company’s investment to the costs of developing other cancer drugs, the amount Genentech says it spent is “on the high side” of the industry average, said Henry Grabowski, a professor of economics at Duke University who has analyzed drug development costs.
Genentech says it and Roche — which owns a majority of Genentech and markets Avastin outside the United States — will spend an additional $1 billion testing Avastin as a treatment for early-stage cancers.
The price also reflected Genentech’s perceived value of the drug compared with other cancer treatments. The price was half that of Erbitux, a colon cancer drug from ImClone Systems and Bristol-Myers Squibb that was approved the same month as Avastin and had not been shown to prolong life.
But Avastin is typically used for a longer time and by more patients than Erbitux. And the Avastin dose for lung and breast cancer is twice that for colon cancer, doubling the price.
Eric Schmidt, an analyst at Cowen and Company, said pharmaceutical companies typically based drug prices on what the market could bear.
“It’s high because Genentech can price it high,” he said, noting that Avastin’s price was in line with that of some other cancer drugs. Despite the company’s research and development costs, Mr. Schmidt said, Genentech is one of the most profitable of pharmaceutical and biotechnology companies.
Other countries have different views about whether Avastin is worth its price. An institute that advises the British government on which drugs to pay for recommended against it, saying that the drug was not cost effective based on its cost per year of life extended.
In the United States, Genentech argues that it puts patients first, with free drugs for those who have no way to pay for them and donations to charities that can help with payments. It also capped the price for a year’s supply of Avastin at $55,000 (not counting markups by doctors and hospitals) for patients with incomes of less than $100,000 a year.
But progress against cancer has a price, the company says. “The quest is to eliminate the disease,” Arthur D. Levinson, Genentech’s chief executive, said at an annual investor meeting. “And, yes, there is going to be a cost to that.”
Of Dubious Benefit
After colon cancer, the next target was lung cancer.
Dr. Bruce Johnson of Dana-Farber knew the difficulties well. He had been at the National Cancer Institute, where he reviewed 25 years’ worth of clinical trials, 30 studies that started with high hopes and ended with little progress. He used to give talks quoting a World War I general: “Ground gain minimal. Casualties huge. Conclusion — press on.”
Avastin, in that context, looked like something of a triumph. Patients who took it along with standard chemotherapy survived for a median of 12.3 months, compared with 10.3 months for those getting only chemotherapy. The results were announced in 2005. “Finally,” Dr. Johnson said, “something worked.”
But as with colon cancer, a newer study adding Avastin to a different chemotherapy regimen has raised questions about its effectiveness against lung cancer. The study’s Avastin patients lived no longer than those who got the chemotherapy plus placebo. Although the drug did slow the median time until progression of tumors, the difference was less than a month.
The third approval for Avastin, for advanced breast cancer, came in February of this year. The clinical trial found it significantly slowed the progression of cancer but did not significantly extend life. The F.D.A. went against its own panel of outside experts, who had voted 5 to 4 against approval.
The agency’s action has not sat well. Senator Charles E. Grassley, Republican of Iowa, asked the Government Accountability Office to look into the F.D.A.’s approval of Avastin and some other drugs that “appear to have little to no effect in protecting lives and increasing health.”
Dr. Lee Newcomer, an oncologist and executive at the insurer United HealthCare, said patients were not well served, and neither were insurers, nor the public, which ultimately foots the bill. If a drug just stops tumor progression, without the woman’s living longer or feeling better, without her noticing anything different, Dr. Newcomer said, “you’re treating an X-ray.”
Patient advocacy groups were split.
“Even when these drugs ‘work,’ what kind of impact are you talking about?” said Fran Visco, president of the National Breast Cancer Coalition, which opposed approval. “But we market them and give them to everybody.”
Yet other doctors and advocates for patients say that when tumors grow, patients can notice new or worsening symptoms. And they certainly experience greater anxiety.
Dr. Kathy Albain, a breast cancer specialist at Loyola University Medical Center in Maywood, Ill., polled colleagues and patients and found overwhelming support for approving drugs based on delaying tumor progression. It would be ideal to show that a drug also prolongs life, but that may not be realistic, she said. The reason is that when a woman’s cancer progresses, doctors change the drugs they use, hoping to slow the cancer. That dilutes any impact of the first drug — in this case Avastin.
Kay Wissmann, director for government relations at the Breast Cancer Network of Strength, a patient advocacy group, said women should have a choice to use Avastin.
“We’ve got some good evidence about this particular drug,” she said, “so maybe we should let the people with metastatic disease have the option of using it.”
Unapproved Uses
Then there are patients who cannot wait for evidence that a drug works for their cancer.
One patient’s husband had no medical training. But he determined through his own literature search that his wife’s form of brain cancer produced a lot of VEGF, the very substance Avastin neutralized. So the couple wanted to try Avastin, even though it had never been tested for brain cancer. It was 2004, when the only Avastin approval was for colon cancer.
They asked the woman’s doctor, Dr. Virginia Stark-Vance, to give them the drug.
Dr. Stark-Vance, a solo practitioner in Dallas and Fort Worth, was reluctant, worried that Avastin could cause bleeding in the brain. That had happened in one of the earliest clinical trials, when a 29-year-old woman whose liver cancer had spread to her brain collapsed from a hemorrhage while riding her bicycle.
Finally, Dr. Stark-Vance agreed on the condition that the woman be hospitalized to receive Avastin, in case there was a brain hemorrhage. Had there been one, Dr. Stark-Vance “could have lost her license,” said Dr. Henry Friedman, a brain cancer specialist at Duke.
Like many others taking Avastin, this woman plunged into the unknown, without the assurance of a clinical trial studying whether the drug worked for her type of cancer.
Doctors are free to prescribe Avastin, or any other drug on the market, for unapproved uses, at their discretion. As much as 75 percent of cancer drug use is of this “off label” variety, according to an estimate by the National Comprehensive Cancer Network, a group of big cancer centers. And some doctors say that with patients dying, they simply cannot wait for airtight evidence.
“Of course we want everything to be evidence-based,” said Dr. Yashar Hirshaut, an oncologist in Manhattan. “I also like the American flag and apple pie.”
But, he explained, “You say, ‘This person is dying right here and I need something that will help, and there’s a logical construct that I can see how it will help.’ ”
One of his patients, Alice Lichter, has had gastric cancer since 2006. Dr. Hirshaut is throwing the whole arsenal at it, giving her gemcitabine, a drug used for pancreatic cancer, plus virtually every drug approved for colon cancer: Avastin, Erbitux, Eloxatin, irinotecan, 5-FU and leucovorin. Most are not approved for gastric cancer.
Once every two to four weeks, Ms. Lichter, 72, flies from her home in Miami and checks into Lenox Hill Hospital in Manhattan, where she undergoes four days of intravenous infusions.
“I call Lenox Hill my second home,” she said.
‘You Name It, It Got Tried’
Ms. Lichter, whose cancer appears to have receded, said she never questioned Dr. Hirshaut’s judgment. And she has no idea how much her drugs cost because Medicare is paying for them and her supplemental insurance covers her co-payment. Insurers say they are often forced by state laws to pay for cancer drugs not approved by the Food and Drug Administration, and Medicare must pay if the drug’s use is listed in a compendium, a reference compiled by cancer specialists, whose standards are looser than the F.D.A.’s.
Such requirements are one reason about 12 percent of United HealthCare’s Avastin patients have cancers other than colon, breast and lung. “Brain, stomach, pancreas, primary cancers of the liver, bladder, small bowel, larynx, prostate — you name it, it got tried,” Dr. Newcomer said.
But the anecdotes and evidence from small trials that may seem to justify off-label use sometimes turn out to be misleading. That happened with pancreatic cancer. After patients and doctors decided Avastin had to be helping, cancer researchers themselves conducted a large study. So did Roche. Avastin, both studies concluded, did not prolong life for people with cancer of the pancreas.
For brain cancer, doctors are encouraged, although they do not really know for sure whether Avastin helps. The brain tumor in Dr. Stark-Vance’s patient shrank so much after two infusions of Avastin that the radiologist who performed the brain scans called Dr. Stark-Vance in wonderment.
Dr. Stark-Vance began treating more patients. Some insurers paid for the drug. Others, including Medicare and Medicaid, did not. But Dr. Stark-Vance said Genentech agreed to provide the drug free for her patients who could not otherwise pay.
As word spread, Dr. Friedman at Duke and Genentech organized studies of a type generally considered less than definitive. There was no control group that took another drug or got a placebo. Everyone got Avastin. Otherwise, no one would enroll in the study, doctors argued.
Then the investigators compared the results with what they thought would have happened without Avastin. The patients lived a median of about nine months, about three months longer than the researchers estimate would have been expected.
But such comparisons have led scientists seriously astray in the past because the people being treated with a new drug often are very different from previous patients who did not take it and because overall medical care steadily improves. Nonetheless, Genentech has said it planned to apply this year to the F.D.A. for approval for Avastin to treat glioblastoma, the deadliest form of brain cancer.
Dr. Stark-Vance said her initial Avastin brain cancer patient broke her hip and had to be taken off the drug because it interfered with wound healing. She eventually died.
But by now, even without an F.D.A. approval, “the whole country” is using Avastin for glioblastoma, Dr. Friedman said.
Better Than Nothing?
Gailanne Reeh remembers what life was like within a few months of those initial scans, when her cancer began causing terrible symptoms.
Her abdomen grew so full of fluid that it was hard to bend to tie her shoes. Bowel movements were difficult, and even lying down was uncomfortable with that huge mass in her abdomen.
She says she was chilled by what she recalls her doctor saying: “There was so much growing so fast in my abdomen and so much in my bowel, it was not a matter of maybe I would get a bowel obstruction. It was when I would get a bowel obstruction,” Ms. Reeh said. “And when I got it, there would be nothing anyone could do. I would die.”
To try to stave off such a horrible outcome, her oncologist, Dr. Eric Winer of Dana-Farber, offered to enroll her in a clinical trial comparing Avastin with another new biotech drug. Ms. Reeh was assigned to the group that got Avastin in combination with the chemotherapy drug paclitaxel, also known as Taxol.
The study closed after six months, but Ms. Reeh continued with her drug regimen, and her insurer is paying. After six months of treatment the fluid in her abdomen was down to just a trace, her tumors were stable or smaller and she felt like her former self again.
“I’m really, really excited,” she said.
Was it the Avastin?
Dr. Winer said he did not know, since Taxol can also shrink tumors. It is impossible to draw conclusions from individual patients, he said. Still, he said, “I think it is quite likely that the combination of Taxol and Avastin improved her odds of having a better quality of life.”
Dr. Winer says that when he is not sitting in front of a patient, he thinks about whether drugs like Avastin are worth it to society. But when facing a seriously ill patient, who, based on clinical trial results, might benefit — even if only a little — from Avastin along with chemotherapy, he has to think about his patient’s needs.
“I can’t say, ‘Let’s not use Avastin; it’s a very expensive drug and I am worried about the cost to society,’ ” Dr. Winer said.
And so, Dr. Winer said, the answer you get when you ask whether drugs like Avastin are worth it very much depends on whom you ask.
“A person who hasn’t been affected by cancer will say, ‘Gee, why should we pay for an expensive treatment that doesn’t extend life when we have other needs?’ ” Dr. Winer said.
A person like Ms. Reeh will have a different response. She does not want to give up Avastin.
Last month, she reluctantly stopped taking her drugs for a while because Taxol was injuring the nerves in her feet. But later this month she hopes to resume taking both drugs, or at least Avastin.
Ms. Reeh says she knows her cancer may very well kill her eventually. But what is it worth to feel better again?
“It’s really about living and not waiting to die,” she said.
And what if 5 percent of Avastin patients live a lot longer than they would have without the drug?
“I might be in that 5 percent,” she said.
http://www.nytimes.com/2008/07/06/health/06avastin.html?pagewanted=1&ei=5087&em&en=6759085dd1342680&ex=1215489600
-------------
j
Army-funded Bavi work at Dept. of Defense
Breast Cancer Research Program Meeting
(the Bavi/74As work,
and the Bavi + PRIMA-1 work)
http://cdmrp.army.mil/bcrp/era/eoh2008/proceedingsbook.pdf
June 25-28, 2008
Baltimore
P8-10: BREAST TUMOR DETECTION AND TREATMENT USING
BAVITUXIMAB LABELED WITH ARSENIC RADIONUCLIDES
Ralph P. Mason,1 Marc Jennewein,1 Xiankai Sun,1 Guiyang Hao,1 Marcus Jahn,2
Matthew A. Lewis,1 Dawen Zhao,1 Linda Watkins,1 Sean O’Kelly,3 Padmakar V.
Kulkarni,1 Alex Hermanne Alex Hermanne,4 Frank Rösch,2 and Philip E.
Thorpe1
1University of Texas Southwestern Medical Center at Dallas, 2Institute of Nuclear
Chemistry, Johannes Gutenberg-University of Mainz, Germany, 3University of Texas
at Austin, and 4University of Brussels, Belgium
Background and Objectives:
This project aims to generate a novel approach for
detection and therapy of advanced disseminated breast cancer based on fundamentally
novel concepts. The first critical component exploits the discovery of a novel naked
antibody, 3G4, which targets phosphatidylserine (PS) expressed on tumor vasculature.
In collaboration with Peregrine Pharmaceuticals, this agent has been chimerized and is
currently in clinical trials as bavituximab. Normally, PS exclusively resides on the
cytosolic leaflet of the plasma membrane. However, in tumors PS becomes externalized
on the vascular endothelium and upon some tumor cells. Bavituximab not only
targets tumors, but also induces vascular damage and tumor regression with minimal
accompanying toxicity. The second key component is the application of diverse arsenic
radionuclides suitable for imaging based on positron emission tomography (PET;
72As T1/2 26 h, 74As- T1/2 17.8 days) and radio immunotherapy (RIT; 77As (T1/2 38.8 h,
Ē β- 226 keV)). New isolation methods provide arsenic radionuclides in useful yields
and labeling antibodies derivatized with N-succinimidyl-S-acetylthioacetate (SATA)
generates viable products of high specific radiochemical and biological activity. Aims
include i) optimizing bavituximab labeling with arsenic radionuclides for imaging,
biodistribution, and radio immunotherapy; ii) detecting diverse primary breast tumors
and evaluation of metastatic spread using radio arsenic labeled bavituximab.
Results:
Initial studies show a labeling time of 30 min generated [74As]bavituximab
with a labeling yield >99.9%. Radio-HPLC confirmed the absence of any aggregates
or free 74As. Incubation of [74As]bavituximab in undiluted fetal bovine serum up to 72
hr confirmed in vitro stability of [74As]bavituximab with no aggregation or breakdown
products. Immunoreactivity comparing
ELISA of [77As]bavituximab, unlabeled
unmodified bavituximab and
[77As]rituximab as a negative control
demonstrated that SATA modification
and radioarsenic labeling caused no
reduction of immunoreactivity.
Conclusions:
Since phosphatidylserine expression appears to be a universal characteristic
of stressed vasculature in tumors, we hypothesize that studies in rodents will
be directly translatable to the clinic. The radionuclides of arsenic were selected
because their long half-lives are consistent with the long biological half lives of antibodies
in vivo and because their chemistry permits stable attachment to antibodies.
We believe that radio arsenic-labeled antibodies will be useful for the imaging, detection,
and therapy of cancer.
This work was supported by the U.S. Army Medical Research and Materiel Command
under W81XWH-06-1-0475 and National Cancer Institute (U24 CA126608).
-------------------------------------------------
P18-4: A NOVEL AND EFFECTIVE COMBINATION TARGETING
THERAPY FOR ADVANCED HUMAN BREAST TUMORS
Yayun Liang,1 Cynthia Besch-Williford,1 Indira Benakanakere,1 Sandra L.
Brandt,1 Philip E. Thorpe,2 and Salman M. Hyder1
1University of Missouri, Columbia and 2University of Texas Southwestern Medical
Center at Dallas
Mutations in tumor suppressor p53 facilitate tumor cell survival and resistance to
chemotherapeutic drugs. Consequently, restoring p53 function within tumors is a promising
strategy for targeted cancer therapy. Furthermore, vascular targeting agents
for treatment of cancer are designed to cause selective shutdown of tumor blood vessels
and offer yet another opportunity to reduce tumor load. Anionic phospholipids
(AP), exposed on the surface of tumor endothelial cells, serve as an excellent marker
for vascular disruption. Thus, treatment strategies that incorporate both of these pathways
may result in improved and more potent responses. The aim of this study was to
determine whether combination therapy targeting mtp53 and tumor blood vessels
could be an effective therapeutic strategy for suppression of advanced breast cancer.
We therefore tested therapeutic effects of PRIMA-1, which re-activates mtp53 and induces
tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor
vasculature by binding to AP on tumor endothelial cells, causing selective shutdown
of tumor blood vessels. Two advanced breast tumor models that express mtp53 and
are also Her-2/neu positive (BT-474) or negative (HCC-1428) were used to evaluate
this combination therapy. Fluorescence staining and tumor blood vessel perfusion
assays were performed to determine therapeutic mechanisms of action. Our results
showed that (1) combination treatment with PRIMA-1 and 2aG4 suppressed BT-474
tumor growth additively, leading to complete arrest of tumor progression during treatment;
(2) some BT-474 tumors were completely eradicated when PRIMA-1 or 2aG4
was used alone, and combination treatment led to synergistic loss of tumors in nude
mice; and (3) an increased antitumor effect was observed with PRIMA-1 plus 2aG4
treatment in HCC-1428 tumor model, and HCC-1428 tumors did not progress with
2aG4 or PRIMA-1 treatment and regressed slightly when combination treatment was
tested; however, combination therapy did not lead to complete remission of HCC-
1428 tumors; (4) the incidence of lymph node metastasis in nude mice bearing BT-
474 breast tumors was reduced by combined treatment using PRIMA-1 plus 2aG4;
and (5) no toxic effects were observed in any treatment groups. While seeking mechanistic
explanations for antitumor effects we found that (1) PRIMA-1 induced exposure
of AP in vitro in endothelial (HUVEC) cells, in BT-474, and extensively in HCC-
1428 tumor cells and (2) PRIMA-1 plus 2aG4 treatment severely disrupted the ability
of tumor blood vessels to perfuse in BT-474 and HCC-1428 tumors.
These results
indicate that PRIMA-1 plus 2aG4 combination therapy has a complementary and potent
antitumor activity and could define a new strategy for suppression of advanced
breast cancers.
This work was supported by the U.S. Army Medical Research and Materiel Command
under W81XWH-06-1-0646; National Institutes of Health (CA-86916); and Susan G.
Komen for the Cure (PDF 0600723).
-----------
j
BeanStalk,
re: "1) 100% of metastatic patients had their cancer metastasis arrested after 8 weeks."
The trial is in, and I quote, "Patients With Locally Advanced or Metastatic Breast Cancer".
YES, your statement is correct.
To clarify: NO patient has had a new lesion appear, and NO patient has had a (already-existing when trial commenced) "non-target" lesion show progressive disease.
re: "2) 50% of patients are stable( no further tumor growth) after 8 weeks."
YES. 50% of patients are stable, defined as between 30% reduction and 20% growth in target lesion.
But- Peregrine has gone beyond that, to tell us that NO patient has experienced ANY tumor growth, meaning that ALL patients so far, 14 in number, 100% of patients treated to date, are experiencing between 0% and 99% tumor reductions. Further, we know that seven of them (50%) are between 0% and 29% 'target lesion' reductions, and seven of them (50%) are between 30% and 100% target lesion reductions. (Yes, there could be patients with 100% target lesion reduction classified as "partial response" if their target lesion completely disappeared but 'non-target' lesions still remain "stable" or have not completely disappeared).
re: "3) 50% of patients showed >30% shrinkage of tumor mass after 8 weeks."
YES.
re "4) 100% of the patients are progression free after 4 months."
To be clear:
ALL patients ARE progression-free.
and 100% of the patients who are out 4 months ARE progression-free.
but not all patients are out 4 months.
ALL patients have passed 2 months, and have been progression-free at 2 months.
SOME patients are out 4 months, and all of THEM are still progression-free.
ALL patients are currently progression-free, but obviously were treated staggered over time.
Some are farther into the trial than others, but ALL were progression-free at whatever point in time they were at as of July 2.
Some were past 4 months, some weren't.
re: "5) Stage 1 objective was met at 8 week point only after the first scan, therefore, moving to stage 2 with additional enrollment of 31 patients."
YES.
re:"Did I miss anything?"
Well, I'm not sure if you realize this or not, but with Docetaxel alone, the "MEDIAN TIME TO RESPONSE" is about 2 months.....
Meaning - with Docetaxel alone, only HALF the patients that are going to respond, have responded at 8 weeks :)
keep watching :)
j
doccg,
re: "When you say Bavi patients are progression free in the chart
is this using the Recist Criteria ?"
Yes. All the measurements are being done using RECIST criteria.
j
It will be getting very interesting very shortly. This is why a lot of pharma deals happen during phase II...
Maybe now people see the difference between phase I (safety) trials, and phase II proof of concept trials.
In the phase 1 Bavituximab trials, it was shown to be very safe, and we also saw "promising signs of efficacy".
But now in phase II, we start going apples/apples with the best, in some very strictly defined parameters.
and- "so far so good", against the best treatment regimen there is, in the most common cancer in women, with similar implications for ALL cancers...
j
All overlays together -------------
j
"median progression-free survival" ---------------
Avastin "median PFS was 7.5 months"
As our responders and stables pass the 7.5 month mark, if more than 50% of them are still not progressing, it bodes very well for Bavi.
As of NOW, 100% of Bavi patients out past four months who were stable or responders, are STILL stable or responders. On the chart above, you can see where some of the Avastin stable/responder patients had already dropped off at this point in time.
j
"median duration of response" -------------------
Avastin "median duration of response was 6.0 months"
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
There were 14 out of 27 responders in the Avastin trial.
Out of those 14, HALF of them had started progressing BEFORE 6 months out.
Bavi currently has 100% of responders who are at 4 months STILL not progressing.
Unless they suddenly start dropping like flies, thing are looking good.
Bavi responders will be crossing the 6 month point soon. If more than 50% of them, (or up to 100% of them :) pass that point in time without progression, it will be a strong indicator that Bavi will blow through Avastin/Docetaxel median duration of response.
j
"median duration of stable disease" -----------
early indicators.......
"Avastin median duration of stable disease in the nine patients was 5.3 months."
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
translated:
Nine patients in the Avastin trial were classified stable.
The middle patient lasted 5.3 months before tumor progression.
Four patients lasted less time.
Four patients lasted more time.
Now here's that Avastin/Docetaxel median duration of stable disease, illustrated on our chart -
As of now, 100% of the Bavi patients with stable disease that have made it PAST THE 4 MONTH POINT ARE STILL STABLE.
If 100% of 'Bavi stables' to date out four months are still stable, how likely is it that a slew of newer 'Bavi stables' will start coming up short (progressing) at four months?
Not very likely...
So what does that tell us? Anything?
To me, it tells me that, unless all of a sudden bavi patients start droppin like flies, bavi is going to blow through the avastin median duration of stable disease.
If 100% of Bavi stables to date are still stable after four months, (which is indicative of future Bavi stables), I don't expect half of them to suddenly drop off over the course of the next 4 weeks, which would bring us to the point in time when half of the Avastin stables had already started progressing, and you can bet that the Avastin stables that started progressing before the 5.3 months median didn't all drop off right at 5 months... In our admittedly small sample, I'd bet Bavi is already ahead of where Avastin was.
j
interesting comparisons ----------------
(A FEW CHARTS coming up...)
The original chart can be found here, in the paper discussing the phase II Avastin/Docetaxel breast cancer trial, which the current Bavi trial is hoping to beat-
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
Here is the Avastin PFS chart with the latest Bavi info overlay
It's obviously early but promising info to date.
Sure, it looks good.
But how early is it?.............
How much can we see in this?.........
I've posted the "benchmarks" Bavi hopes to beat, here they are again -
* "median duration of response was 6.0 months"
* "median PFS was 7.5 months"
* "median duration of stable disease in the nine patients was 5.3 months"
Now remember your high school math -
MEDIAN: The middle value in a set of numbers arranged in increasing order. If there is an even number of values, then median is the average of the middle two values. For example: The median of the set {10, 12, 14, 19, 20} is 14. The median of the set {2, 3, 4, 6, 8, 9} is 5, which is the average of 4 and 6.
charts to follow........
j
Also -
as per RECIST:
"to be assigned a status of SD or PR, patients cannot have the appearance of any new lesions."
ALL PATIENTS in the Bavi trial are either PR or SD, (currently 50/50. Zero patients with PD).
NO PATIENTS in the Bavi trial have had any new lesions appear.
(Metastatic disease is what kills ya).
see Bavi's results in mice reducing breast cancer lung metastases, with this very combo - Bavi/Docetaxel -
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=30171990
read why IMO Bavi should perform better in humans than in mice.
To data, it HAS performed better in humans, IMO this is why-
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=30172392
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=30172509
j
Beanstalk,
re: "it looks like data from 07/02 PR is from 8 week scans only so it was not a progressive update beyond the 1st scan after the initial dose."
Actually it was.
The July 2 PR gave us more than just an 8 week report on each patient.
remember -
July 2:
"100% of Evaluable Patients to Date Continue to Show Objective Tumor Response or Stable Disease"
"100% of Evaluable Patients to Date
Continue to Show Objective Tumor Response or Stable Disease"
In the July 2 PR, since they mention the number of responders and stables was based on patients' 8-week scans, we learned that in the three new patient (8 week) scans, two out of those three were partial responses, and one was stable disease, for a total of seven responses, seven stable, in the 14 patients.
But the other quote, "100% of Evaluable Patients to Date Continue to Show Objective Tumor Response or Stable Disease", tells us that the five earlier classified as responders have been confirmed via additional scans, and any early stable patients are still stable.
King: "with patients now out over four months since the start of the study, none have shown tumor growth or disease progression. "
but-
What I would like to learn now is info on any change in tumor reductions, from scan to scan, in the responders and the stables.
Have the responders continued to see their tumors shrink?
Have the stables gotten closer to the 30% point in tumor reduction to be classified as responders?
Have they stayed the same?
Personally, I expect the bavi 'vaccination effect' to kick in also...
j
further clarification -
Upon another read of the July 2 PR, I realize that the additional two responders were at 8 week scans, not any of the June 2nd stable group.
the quote - "seven achieving partial tumor responses and seven having stable disease at week eight according to RECIST criteria."
I'd recommend everyone read the RECIST criteria I posted previously,
http://ctep.cancer.gov/forms/TherasseRECISTJNCI.pdf
as well as THE TRIAL that is the most comparable to ours,
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
(but remember there were a lot of patients who had had no prior chemo in that trial. But it is basically what the Bavi trial was designed to compare to, for good reason).
Remember the important benchmarks for Bavi.
In the Avastin/Docetaxel trial,
* "median duration of response was 6.0 months"
That's for those who responded. Meaning half of the patients who responded got progressive disease before 6 months, and half got it after. As the Bavi responders cross that point, (and some are already out 5 months), it bodes well...
* "median PFS was 7.5 months"
that's the combo of responders and the stables, (disregarding the patients who never responded, which the Peregrine trial has so far seen ZERO :)
It's the mid point between when half of the responders and stables had already started progressing, and half hadn't.
Meaning, as the Bavi patients cross that important point in time respective to when they each started, if more than 50% of them are passing that point in time without progressive disease, it bodes well for an improvement in PFS over SOC.
Also, the illustration of PFS falling off over time in the Avastin Docetaxel trial is an excellent thing to watch. There were already patients falling off at 2 months, three months, four months. In comparison, NO PATIENTS have dropped off in the Bavi trial yet, and some are out 4 to 5 months...
* "median duration of stable disease in the nine patients was 5.3 months"
That's the median duration of stable disease in the nine patients who never achieved a partial response, but did manage to be classified as stable. Half of them got PD before 5.3 months, half after. As the Bavi patients cross that point, if more than 50%....
Also, if you're curious, you can look into one more parameter- other studies' "median time to response" for other interesting indicators - indicators that lend insight into why King was excited about 50% responders at 8 weeks!....
j
PS Suppresses Immune Response
exposed PS - 5 must read papers
to understand the potential of therapeutic anti-PS
j
---------------------------------------------------------------------
REQUIRED READING #1 of 5 (abridged) ------
Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo
http://www.jimmunol.org/cgi/content/full/174/3/1393
Peter R. Hoffmann2,*, Jennifer A. Kench*, Andrea Vondracek{dagger}, Ellen Kruk*, David L. Daleke{ddagger}, Michael Jordan{dagger}, Philippa Marrack{dagger}, Peter M. Henson* and Valerie A. Fadok*,{dagger}
The Journal of Immunology, 2005
.
Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo
Introduction
The rapid engulfment of apoptotic cells by professional and nonprofessional phagocytes prevents the release of potentially toxic or immunogenic intracellular contents from the dying cells (1, 2, 3, 4). Much attention has recently focused on the effects of apoptotic cells on phagocytes engulfing them. Interactions between macrophages and apoptotic cells result in the secretion of anti-inflammatory mediators such as TGF-{beta}, IL-10, and PGE2, as well as inhibition of the production of proinflammatory mediators (5, 6, 7, 8, 9, 10, 11). Similar results have been found with nonleukocytic phagocytes including fibroblasts and epithelial cells (Ref.12 ; J. Monks and V. A. Fadok, unpublished observations). In addition, apoptotic cells have been shown in some cases to inhibit dendritic cell maturation and Ag presentation (13, 14, 15).
Apoptotic cells have also been shown to affect inflammation and adaptive immune responses in vivo, although the results are conflicting. For example, apoptotic cells have been shown to be poor adjuvants compared with their necrotic counterparts in the generation of delayed-type hypersensitivity (15). Other evidence suggests that the uptake of apoptotic cells is not an immunologically null event, but is capable of modulating immune responses to self-Ags through induction of T cell-tolerance (16). The tolerizing effects of apoptotic cells have been further demonstrated in studies in which injection of apoptotic cells inhibited rejection of bone marrow allografts (17). By contrast, it has been suggested that apoptotic tumor cells can stimulate antitumor responses in vitro and possibly in vivo (18, 19, 20, 21).
Surprisingly, little is known regarding the mechanisms by which apoptotic cells inhibit inflammation and adaptive immune responses. Exposure of the anionic phospholipid phosphatidylserine (PS)3 in the outer leaflet of the plasma membrane is one of the most striking and consistent changes on the surface of apoptotic cells (22, 23, 24, 25, 26, 27, 28, 29). It has been known for some time that PS can inhibit macrophage production of proinflammatory cytokines and NO, and that it can block macrophage killing of intracellular parasites (30, 31, 32, 33, 34, 35, 36). Data derived from experiments in vitro and in vivo suggest that PS exposure is crucial for the release of TGF-{beta} by phagocytes that accompanies apoptotic cell recognition and uptake (11, 37, 38). Furthermore, PS-containing liposomes can mimic the response to apoptotic cells by generating TGF-{beta} release (11, 38). Blocking PS on apoptotic cells with annexin V (a Ca2+-dependent, PS-binding protein) has been shown to eliminate the inhibitory effects of the apoptotic cells on the humoral responses (39).
We hypothesized that PS exposed on apoptotic cells was a key factor in inhibiting the inflammatory response required for survival of Ag-specific T lymphocytes and subsequent activation of the adaptive immune response (40, 41). If this is true, PS should inhibit immune responses in vivo. Using three different immunogens and several different assays to measure immune responses, we determined that PS stereo-specifically inhibited responses of Ag-specific CD4+ T and B cells in vivo, and that these effects could be mimicked using an activating Ab directed against the PS receptor. Furthermore, these inhibitory effects could be reversed, at least in part, with anti-TGF-{beta} Ab, implicating TGF-{beta} as an important mediator of the inhibitory response to PS. PS-containing liposomes did not appear to block maturation of bone marrow-derived dendritic cells in response to bacterial endotoxin, TNF-{alpha}, or other stimuli as determined by alternation in expression of surface markers or by ability to present Ag to CD4+ lymphocytes. PS-containing liposomes also failed to block the Ag-induced migration of dendritic cells into regional lymph nodes in vivo. Taken together, these findings suggest that PS inhibits the immune response by inhibiting inflammation in tissue.
-------------------------------------------------------------------------
REQUIRED READING #2 of 5 (abridged) ------
Phosphatidylserine Regulates the Maturation of Human Dendritic Cells
http://www.jimmunol.org/cgi/content/full/173/5/2985
The Journal of Immunology, 2004
Xiao Chen*, Kara Doffek*, Sonia L. Sugg{dagger} and Joel Shilyansky2,*
* Division of Pediatric Surgery and {dagger} Division of Endocrine Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226
Phosphatidylserine Regulates the Maturation of Human Dendritic Cells
Phosphatidylserine (PS), which is exposed on the surface of apoptotic cells, has been implicated in immune regulation. However, the effects of PS on the maturation and function of dendritic cells (DCs), which play a central role in both immune activation and regulation, have not been described. Large unilamellar liposomes containing PS or phosphatidylcholine were used to model the plasma membrane phospholipid composition of apoptotic and live cells, respectively. PS liposomes inhibited the up-regulation of HLA-ABC, HLA-DR, CD80, CD86, CD40, and CD83, as well as the production of IL-12p70 by human DCs in response to LPS. PS did not affect DC viability directly but predisposed DCs to apoptosis in response to LPS. DCs exposed to PS had diminished capacity to stimulate allogeneic T cell proliferation and to activate IFN-{gamma}-producing CD4+ T cells. Exogenous IL-12 restored IFN-{gamma} production by CD4+ T cells. Furthermore, activated CTLs proliferated poorly to cognate Ag presented by DCs exposed to PS. Our findings suggest that PS exposure provides a sufficient signal to inhibit DC maturation and to modulate adaptive immune responses.
INTRODUCTION
Dendritic cells (DCs),3 which are the most potent professional APCs of the immune system, play an important role in the initiation of adaptive immunity (1). DCs acquire, process, and present Ags derived from pathogenic organisms to activate naive T cells, which mount a specific anti-pathogen immune response. DCs also continuously acquire self-Ags from cells that undergo apoptosis as part of normal cell turnover. However, pathological autoimmune conditions occur rarely, suggesting that the ability of DCs to stimulate self-reactive T cells is tightly controlled. The mechanisms permitting DCs to activate vigorous immune responses to most pathogens and to maintain tolerance to tissue-derived "self" Ags are not fully understood (1, 2). There has been a growing body of evidence suggesting that phagocytosis of apoptotic cells under steady state conditions leads to impaired DC maturation and may induce tolerance (3, 4).
snip
.......Recent studies demonstrate that PS-dependent recognition and ingestion of apoptotic cells by macrophages triggers the release of anti-inflammatory cytokines and inhibits the production of proinflammatory cytokines (20, 21, 22). These studies offer a link between the recognition of apoptotic cells and the physiological consequences of their phagocytosis. Whereas the role of PS in the interaction of apoptotic cells with macrophages and the immunological consequence of PS ligation have been broadly delineated, the role of PS in regulating the phagocytosis of apoptotic cells by DCs and the immunological implication of such interactions are not known. Because of the close lineage relationship between macrophages and myeloid DCs, we hypothesized that PS might play a role in the inhibition of myeloid DC maturation. To test this hypothesis, we prepared large unilamellar liposomes containing PS as a simplified model of cell membrane alterations associated with apoptosis. We examined the effect of PS containing liposomes on DC maturation and immunostimulatory capacity. Our results suggest that PS inhibits the ability of DCs to undergo maturation, secrete IL-12, activate T cells, and stimulate IFN-{gamma}-producing CD4+ T cells.....
snip
DISCUSSION
An emerging paradigm suggests that under steady state conditions, apoptotic cells modulate DC function, inducing immune tolerance to self-Ags and preventing autoimmunity (3, 4, 9). Early apoptosis is characterized by loss of membrane asymmetry and exposure of PS on the cell surface (13). PS recently has been shown to play a central role in the recognition of apoptotic cells by macrophages and may be a signal to secrete anti-inflammatory cytokines (17, 20). However, the effects of PS on the maturation and function of human monocyte-derived DCs, whose lineage is closely related to macrophages, have not been well described. We found that PS, which is recognized specifically by DCs, triggers phagocytosis and plays a key role in modulating DC maturation and function....
....Our findings, for the first time, demonstrate that PS is specifically recognized via PSR expressed on the surface of DCs and triggers phagocytosis....
...Previous reports have suggested that iDCs can induce immune unresponsiveness in vitro and in vivo, possibly due to reduced Ag presentation and T cell costimulation (38, 39, 40, 41). Inhibition of DC maturation by exposure to PS is a potential mechanism for inducing immune unresponsiveness or tolerance. We found that DCs exposed to PS had impaired ability to activate allogeneic T cells (Fig. 5, A and B) and to stimulate IFN-{gamma} production (Fig. 6, A and C). Increasing the ratio of DCs to responders restored the proliferation of allogeneic T cells; however, IFN-{gamma} production by allogeneic CD4+ T cells was still impaired. Increased susceptibility to apoptosis by DCs exposed to PS after LPS treatment could not explain the inability to stimulate IFN-{gamma}-producing T cells in vitro, because IL-4-producing T cells were still induced. Furthermore, exogenous IL-12, which does not affect DC viability, restored IFN-{gamma} production by T cells. The findings suggest that PS did not simply inhibit the ability to activate T cells, but selectively modulated the ability to induce IFN-{gamma}-producing T cells.
....Taken together, these findings suggest that DCs exposed to PS would fail to initiate and may extinguish cellular immune responses.....
...Our findings suggest that PS exposure directly inhibits DC maturation and modulates their ability to activate T cell responses. PS is specifically recognized by DCs and triggers phagocytosis via the PSR. Our findings suggest that PS modulates the adaptive immune response at three different levels: 1) PS inhibits survival, Ag presentation, and costimulation by DCs, leading to ineffective T cell proliferation; 2) PS inhibits IL-12p70 secretion by DCs, diminishing the ability to stimulate IFN-{gamma}-producing T cells characteristic of Th1 responses; and 3) DCs exposed to PS have reduced ability to stimulate the proliferation of activated CD8+ T cells, even in the presence of abundant Ags. PS may synergize with additional signals, such as CD200, IL-10, and TGF-{beta}, expressed by apoptotic, inflammatory, or stromal cells (20, 22, 50, 51, 56, 65, 66). Further understanding of the mechanisms by which PS modulates DC function may lead to the development of effective immunotherapies for autoimmune diseases and for cancer.
----------------------------------------------------------------
REQUIRED READING #3 of 5 (abridged) ------
Apoptotic cells, through transforming growth factor-beta, coordinately induce
anti-inflammatory and suppress pro-inflammatory eicosanoid and NO
synthesis in murine macrophages.
Celio G. Freire-de-Lima∗†‡2, Yi Qun Xiao†‡, Shyra J. Gardai†, Donna L. Bratton†, William P.
Schiemann† and Peter M. Henson†
*Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro,
RJ 21944-970, Brazil
†Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research
Center, 1400 Jackson Street, Denver, Colorado 80206
Running title: TGF-beta modulates inflammatory eicosanoids
http://www.jbc.org/cgi/reprint/M605146200v1
--------------
In the studies reported here, we showed that the
TGF-beta induction by apoptotic cells was
dependent on exposed PS
...............
These results strongly
suggest that the apoptotic cell inhibition of
pro-inflammatory mediator production is
pleiotropic and significantly dependent on the
stimulation of TGF-beta production.
...............
The
implication is that recognition of PS drives the
production of TGF-beta and the downstream antiinflammatory
responses reported herein.
..............
The induction of TGF-beta itself
could be attributed to exposed
phosphatidylserine on the apoptotic cells,
which therefore, appears to drive the
balanced inflammatory mediator responses.
..............
Apoptotic cells are rapidly engulfed by
adjacent tissue cells or macrophages before
they can release pro-inflammatory/proimmunogenic
intracellular contents. In
addition, recognition of the apoptotic cells is
actively anti-inflammatory and antiimmunogenic
with generation of antiinflammatory
mediators such as
transforming growth factor-beta (TGF-beta) and
anti-inflammatory eicosanoids. Here, we have
investigated the role played by the induction
of TGF-beta in the coordinate expression of antiinflammatory
eicosanoids or PPARγ and in
the suppression of pro-inflammatory lipid
mediators and nitric oxide (NO).
................
As a
cell becomes apoptotic, it is generally removed
in situ by near-neighbor cells or macrophages in
a quiet, almost invisible fashion; that is, the
process does not induce a local tissue reaction.
In fact, recognition and removal of apoptotic
cells is normally both anti-inflammatory and
anti-immunogenic (6-9).
...............
The interaction and recognition are triggered by
surface changes on the apoptotic cells.
.................
there is considerable evidence to implicate PS as
the main stimulus for the anti-inflammatory or
anti-immunogenic effects (6-8,14-16).
...............
A major anti-inflammatory mediator induced in
response to apoptotic cells, mAb217 or PS
liposomes is TGF-beta (6,8,16). Blockade of TGF-
beta has been shown to reverse the suppressive
effects of apoptotic cells or PS in vivo on either
inflammation or adaptive immunity (7,8).
................
A key issue, therefore, is whether apoptotic cellinduced
TGF-beta, acting in an autocrine/paracrine
fashion, mediates the alterations in eicosanoid
generation. By use of a dominant negative TGF-
beta receptor construct we have been able to show
that apoptotic cells stimulate via their induction
of active TGF-beta, a co-ordinate production of
generally anti-inflammatory, and simultaneous
inhibition of generally pro-inflammatory,
eicosanoids.
................
Results
Apoptotic cells or antibody to PSRS on murine
macrophages stimulate production of TGF- beta
and concomitant blockade of LPS-induced
TNF alpha, NO and iNOS.
.................
Discussion
Apoptotic cells are known to induce an antiinflammatory
and anti-immunogenic response,
in part mediated by their induction of active
TGF-beta in responding cells. Here we show that
the effect of the apoptotic cells is to drive a
complex coordinated inhibition of potentially
inflammatory mediators along with induction of
potentially anti-inflammatory molecules in
macrophages that are orchestrated by the TGF-beta
production.
.................
The observations required the demonstration of
TGF-beta production in response to the apoptotic
cells – shown earlier by numerous investigators
and confirmed herein. A number of ligands have
been demonstrated on apoptotic cells that can
interact with a number of “receptors” on
responding cells, in this case macrophages.
Additionally there are a large group of “bridge”
molecules (see ref. 39) that can link the
apoptotic cell ligands to the receptors. We have
suggested that two important ligands are
phosphatidylserine (PS) and calreticulin. The
latter, as well as the collectin family of bridge
molecules (40) has been suggested to interact
with LRP as a receptor and, in isolation, seems
to induce a more pro-inflammatory response
(5,13). On the other hand, PS and its receptors
and possibly some or all of its bridge molecules
appear to induce the anti-inflammatory effects
and, in most cases, to act in a dominant fashion
in the normal response to apoptotic cells.
Necrotic cells are usually thought to be proinflammatory
(see for example 9,15) and may
have reversed this PS-driven dominance. Other
studies that have suggested that apoptotic cells
can in some circumstances act in a proinflammatory
fashion may also reflect variations
in balance between pro-inflammatory (e.g. LRP)
versus anti-inflammatory (e.g. PS driven)
responses.
................
The results indicate a complex effect of
apoptotic cells acting through release of TGF-beta
to upregulate generally anti-inflammatory
mediators and inhibit the production of proinflammatory
molecules.
--------------------------------------------------------------
REQUIRED READING #4 of 5 (abridged) ------
The influence on the immunomodulatory effects of dying and
dead cells of Annexin V
The Journal of Leukocyte Biology, Jan, 2007
http://www.jleukbio.org/cgi/rapidpdf/jlb.0306166v1
-----------
Abstract: Apoptotic and necrotic cells expose
phosphatidylserine (PS). This membrane modifi-
cation ensures a swift recognition and uptake by
phagocytes of the dying and dead cells. Annexin
V (AxV) preferentially binds to anionic phospholipids
and thereby, modulates the clearance process.
First, we analyzed the influence of AxV on
the immunogenicity of apoptotic cells. The addition
to apoptotic cells of AxV prior to their injection
into mice increased their immunogenicity
significantly. Next, we studied the influence of
endogenous AxV on the allogeneic reaction
against apoptotic and necrotic cells. To preserve
heat-labile, short-lived “danger signals,” we induced
necrosis by mechanical stress. Wild-type
mice showed a strong, allogeneic delayed-type
hypersensitivity (DTH) reaction. In contrast,
AxV-deficient animals showed almost no allogeneic
DTH reaction, indicating that endogenous
AxV increases the immune response against dead
cells. Furthermore, AxV-deficient macrophages
had a higher immunosuppressive potential in
vitro. Next, we analyzed the influence of AxV on
chronic macrophage infection with HIV-1,
known to expose PS on its surface. The infectivity
in human macrophages of HIV-1 was reduced
significantly in the presence of AxV. Finally, we
show that AxV also blocked the in vitro uptake by
macrophages of primary necrotic cells. Similar
to apoptotic cells, necrotic cells generated by
heat treatment displayed an anti-inflammatory
activity. In contrast, mechanical stress-induced
necrotic cells led to a decreased secretion of
IL-10, indicating a more inflammatory potential.
From the experiments presented above, we
conclude that AxV influences the clearance of
several PS-exposing particles such as viruses,
dying, and dead cells. J. Leukoc. Biol. 81:
000–000; 2007.
In healthy situations, cells dying by apoptosis maintain their
membrane integrity until they get cleared. Cell shrinkage leads
to formation of apoptotic bodies containing organelles. Nevertheless,
the dead corpse still has an important message: “No
inflammation, please!”
We were asking the question of whether an interference with
the anti-inflammatory clearance by macrophages of apoptotic
cells, mainly mediated by PS recognition, consecutively restores
the immunogenicity of apoptotic cells in vivo. For this
purpose, mice were immunized with apoptotic cells in the
presence or absence of the PS-binding protein AxV. Using
AxV-deficient mice [21], we further analyzed the physiological
function of AxV in the induction of an immune response
against apoptotic and necrotic cells. PS is also expressed on
monocytes as part of their differentiation program [22]. Many
viruses including HIV cause extensive apoptosis, and infected
monocytes/macrophages therefore express elevated levels of
PS, which consecutively, can also be found in the outer membrane
of the enveloped retrovirus [23]. Using an in vitro culture
system, we examined whether, like the swift uptake of apoptotic
cells, the AxV can also block the silent entry of HIV-1 into
human macrophages. To better understand the mechanism how
PS exposing AxV-binding particles modulates the immune
response, we examined the cytokine secretion of activated
human macrophages and peritoneal macrophages from AxVdeficient
mice after contact with dying and dead cells.
DISCUSSION
Apoptosis is defined as programmed cell death or cellular
suicide, whereas necrosis arises as a result of a violent external
stimulus. A hallmark of apoptotic cells, in contrast to necrotic
ones, is that they maintain their membrane integrity over time.
Thus, the release of intracellular components, which could
damage the surrounding tissue, induce inflammation, or elicit
immune responses, is avoided [26]. To ensure immediate recognition
and uptake by phagocytes, apoptotic cells undergo
early membrane modifications. One such event is the exposure
of PS in the outer leaflet of the plasma membrane associated
with a loss of phospholipid asymmetry. Phagocytes interact
with PS on apoptotic cells mainly through secreted bridging
adaptor proteins, also called opsonins. The latter are important
for a high-capacity clearance of apoptotic cells [27].
The recognition of exposed PS triggers the release of immunosuppressive
cytokines [14, 15, 28], which quench inflammation
and prevent the maturation of antigen-presenting dendritic
cells (DC). Apoptotic cells per se do influence the production
of soluble pattern recognition receptors such as pertussis toxin
3 by maturing DC [29]. Furthermore, the opsonization of apoptotic
cells by soluble factors influences their antigen presentation
by DC and thereby, modulates their immunogenicity
[30]. Recently, it was discussed that alterations of the plasma
membrane phospholipid distribution have important influences,
not only for cell clearance but also for the execution of
apoptosis [31].
AxV is a natural-occurring, specific ligand for PS and may
consequently interfere in vivo with the immunosuppressive
effects of apoptotic cells. We showed that the immunogenicity
of apoptotic cells could be restored by the addition of AxV.
During apoptotic as well as necrotic cell death, autoantigens
are cleaved or otherwise modified, and these modifications may
render cryptic epitopes immune-dominant (reviewed in ref.
[32]). When interfering with the clearance of dying cells, DC
may acquire modified autoantigens such as apoptotic nuclei
and chromatin, and consequently, autoreactive T cells can be
activated. This may also lead to chronic autoimmunity, as is the
case in SLE [24]. It was also shown that an impaired clearance
of dying tumor cells can lead to tumor rejection. AxV decreased
apoptotic cell uptake by peritoneal macrophages and
concomitantly increased their uptake by CD8/11c DC [33].
When AxV binds to apoptotic cells, it “crystallizes” as an
extended two-dimensional network. It has an autocrine function
and activates away from cell entry. This results in the
internalization of the PS-expressing membrane patches from
the surfaces of apoptotic macrophages [35]. We have shown
previously that AxV shows positive cooperativity for PS binding
on membranes of apoptotic and necrotic but not of viable
cells. We suggested that phagocytes can differentiate between
dying and viable cells by means of PS clustering and consecutively,
by the lateral mobility of the cellular membranes [36].
PS-mediated phagocytosis of apoptotic cells suppresses inflammatory
signals such as TNF-, IFN- , and NO and also triggers
the production of TGF-, an anti-inflammatory cytokine
[15]. We have previously shown that necrotic cells, like apoptotic
ones, can also engage CD36 and a surface receptor
recognized by mAb 217G8E9. They thereby mediate antiinflammatory
signals [12]. Here, we show that necrotic cells
induced by heat treatment promote the release of anti-inflammatory
cytokines by LPS-activated macrophages, as is the case
for apoptotic cells. Heat-induced necrosis destroys heat-labile
and short-lived danger signals. The uptake of the necrotic cells
then becomes anti-inflammatory. In contrast, mechanical
stress-induced necrotic cells led to a decreased secretion of the
anti-inflammatory cytokine IL-10 and consecutively, displayed
a more immunostimulatory phenotype. We conclude that the
proinflammatory properties of necrotic cells depend on the
inductor of necrosis. Furthermore, we added AxV to this experimental
setting and found a significant, further up-regulation
of IL-10 secretion in the case of heat-necrotized cells but
not in the case of stress-induced necrotic cells (not shown),
further confirming the higher proinflammatory potency of mechanical
stress-induced necrotic cells when compared with
heat-induced necrosis.
The primary force of the immune system is the need to detect
and protect against danger [37]. One mode of action of danger
signals is to stimulate the maturation and activation of DC
necessary for the initiation of primary and secondary immune
responses. Endogenous danger signals, released by tissues
undergoing stress, damage, or abnormal death, and also exogenous
danger signals, elaborated by pathogens, can contribute
to this stimulation. Some endogenous danger signals, which
have been discovered recently are heat-shock proteins, nucleotides,
reactive oxygen intermediates, extracellular matrix
breakdown products, neuromediators, cytokines such as the
IFNs [38], as well as uric acid [39], ATP [40, 41], and HMGB1
[16, 42], which as well as its best-characterized receptor for
advanced glycation end products, is important for the maturation
of human plasmacytoid DC [43] and also controls T cell
activation [44]. Furthermore, the release of intracellular factors
from necrotic tumor cells can promote reactive angiogenesis,
stromal proliferation, and local immune suppression [45]. Future
work has to be focused strongly on all such “alarmins”
[46], which signal the body: “Attention, tissue damage has
occurred!”
Many viral infections (such as HIV) lead to the release of
several proinflammatory cytokines and to extensive apoptosis.
The latter may contribute to the impaired immune response
accompanying such infections [50, 51]. Recently, it has been
shown that PS can be detected at the surface of HIV-1 and that
AxV can be used to enrich these virus particles. Furthermore,
the infection by HIV-1 strains of monocytes can be compromised
upon the addition of AxV during the infection process
[23]. Here, we demonstrated that clinically relevant, chronic
infections of HMDM with HIV-1 isolates can be inhibited by a
single application of AxV. In addition, Ma et al. [52] showed
that Annexin II is necessary for HIV-1 uptake into human
macrophages. This HIV-1 PS interaction with Annexin II could
be disrupted by a secretory leukocyte protease inhibitor [52].
Taken together, AxV efficiently blocks the silent entry of
HIV into macrophages as well as the swift clearance of apoptotic
and necrotic cells. The disturbed, PS-dependent clearance
by macrophages of apoptotic cells leads to the accumulation
of the latter and to the occurrence of late apoptotic cells,
which have lost their membrane integrities. The proinflammatory
cytokine profile of the late clearance and endogenous
danger signals released from cells, which have lost their membrane
integrity, build a proinflammatory microenvironment. DC
may then pick up antigens derived from the dying cells in a
proinflammatory milieu and present the cell-derived antigens
together with costimulation (Fig. 5). We showed that AxV
increased the immunogenicity of apoptotic cells significantly.
In addition, immunization with mechanical stress-induced necrotic
cells was used to mimic the above-mentioned scenario.
Only in the presence of endogenous AxV (WT animals) was a
specific immune response against the dead cells to be observed.
Furthermore, endogenous AxV led to a decreased
secretion of IL-10 in peritoneal macrophages in response to
mechanical stress-induced necrotic cells. Examinations of the
in vitro mechanisms underlying the observed effects revealed
that mechanical stress-induced necrotic cells led to an inflammatory
modulation of macrophages in contrast to apoptotic
cells and heat-induced necrotic ones. In conclusion, apoptotic
and necrotic cells strongly influence the immune response.
AxV is an important modulator of this interaction. It inhibits
certain viral infections and increases the immune response
against tumor cells and more general, that against dying and
dead cells.
-----------------------------------------------------------------
REQUIRED READING #5 of 5 (abridged) ------
Cancer Cell Immune Escape and Tumor Progression by Exploitation
of Anti-Inflammatory and Pro-Inflammatory Responses
Cancer Biology & Therapy 4:9, 924-933, September 2005
http://www.landesbioscience.com/journals/cbt/article/kim4-9.pdf
-----------
Apoptotic cells can be eliminated by phagocytosis, which is mediated by antigen-
presenting cells (APCs), such as macrophages and dendritic cells (DCs), through
phosphatidylserine (PS) on apoptotic cells and phosphatidylserine receptor (PSR) on
APCs. The phagocytosis of apoptotic cells by macrophages is strictly regulated by not
only the inflammatory reaction, but also by an increase in anti-inflammatory factors such
as IL-10, TGF-b, and prostaglandin E2 (PGE2), leading to an anti-inflammatory situation,
whereby apoptosis contributes to a noninflammatory response. However, because PS and
PSR are expressed in cancer cells, shed soluble phosphatidylserine (sPS) can interact with
the PS receptor on macrophages, which promotes an anti-inflammatory response to
macrophages that may lead to immune escape. The sPS derived from cancer cells also
reacts with the PSR on the cancer cells to produce IL-10, TGF-b, and PGE2, which can
cause suppression of anti-tumor immunity through the anti-inflammatory response to
macrophages, which produces tumor-associated macrophages. Furthermore, sPS and
TGF-b inhibit the maturation of immature DCs, resulting in a functional inhibition of DCs.
The potential roles of PS and PSR in cancer cells and macrophages in immune escape
mediated by sPS and anti-inflammatory factors are discussed, which may explain their
dual regulation of anti- and pro-inflammatory responses during tumor progression.
-----------------
the PS/PSR-mediated
anti-inflammatory response can be induced by soluble phosphatidylserine (sPS) derived
from cancer cells. The sPS can interact with either APCs or PSR on cancer cells, resulting
in the production of IL-10, TGF-b and PGE2, whereby the function of APCs is inhibited.16,17
Thus, the production of anti-inflammatory cytokines mediated by sPS/PSR on APCs and
cancer cells may promote immunosuppression, which impairs macrophage cytotoxicity
and DC function. The impairment
prevents an immune response in the
tumor microenvironment and facilitates
tumor progression and metastasis.18,19
-------------
The shift
to an anti-inflammatory response to immune cells mediated by
TAM in response to sPS from cancer cells may result in the inhibition
of maturation of DCs and their migration to a primary lymphoid organ
for activation of T-cells.
----------------
The
production of soluble factors such as IL-10 and TGF-b helps cancer
cells to avoid immune recognition through inhibition of development
and activity of immune cells.
-----------------
Given that the immunosuppressive mediators such as IL-10,
TGF-b, and PGE2 play an important role in promoting immune
escape in the microenvironment of cancer cells, the release of these
cytokines take place from TAMs as well as from cancer cells.42
-----------------
vascular endothelial cells in tumors
externalize PS to their luminal surface, whereas PS is absent from the
external surface of vascular endothelial cells in normal tissues.19 (Thorpe/Ran, j.)
-------------
the sequential immune response by TAM
and DCs can be abrogated by sPS derived from cancer cells. The
enforced anti-inflammatory response by sPS-not only by interaction
with the PSR on TAM but also with the PSR on immature DCs to
inhibit their maturation-may cause immune escape and tumor
proliferation. Furthermore, the sPS derived from cancer cells binds
to these cells’ own PSR, resulting in the production of IL-10,
TGF-b, and PGE2 in the tumor microenvironment and facilitation
of tumor proliferation.
---------------
During the anti-inflammatory response, the TGF-b derived from
TAM prevents the maturation of antigen-presenting DCs, thereby
inhibiting the activation of natural killer cells and CTLs.86 In addition,
the TGF-b promotes the proliferation of stromal cells such as fibroblasts
and macrophages and induces them to secrete angiogenic and
cell survival factors that stimulate tumor proliferation through
NF-kB, which is activated by Akt.52 These stromal cells also produce
Th2 cytokines, such as IL-4 and IL-10, as well as PGE2 as a
result of TGF-b secretion.
-----------------
Thus, the production of
IL-10, TGF-b, and PGE2 from TAM mediated by sPS or hydroxide
plays a critical role in immune escape.
-----------
j
Defense Industry Daily -
"Work will be performed in locations across the USA, as well as the United Kingdom..."
http://www.defenseindustrydaily.com/dtra-researching-hemorrhagic-fever-antiviral-compounds-02646/
j
Clinical / Regulatory / Litigation Calendar
[Please keep entries up to date! See updating procedure at the end of this post.]
NOTE: ANYONE MAY UPDATE THIS FILE
Edits: PPHM
AMGN – Data from phase III HALT trial in prostate cancer: 2H08.
AMLN – LAR NDA submission: mid 2009 if bioequivalence study needed; earlier if not needed.
BMY Apixaban – phase-3 ADVANCE-1 trial (VTE prevention following in orthopedic surgery): data at ASH Dec08; phase-2 in ACS: data at European Society of Cardiology Sep08.
CEGE - 1H08: additional P2 GVAX prostate data; CG0070 P1 data (AUA- May); additional GVAX-prostate+MDX-0010
- 2H08: GVAX pancreas, leukemia P2 data
- 1H09: GVAX prostate VITAL-2 P3 enrollment completion and interim analysis
- 2H09: GVAX prostate VITAL-1 P3 Final Analysis
CYT.TO - Initiated pivotal A-fib trial Oct/06. Complete enrollment 2nd/half 07. Results 2nd half 08.
DDSS – Tramadol NDA: “escalation” of FDA appeal announced 4/1/08. Ph III Trazodone results 2nd qtr/08.
DNA – Avastin adjuvant CRC interim look Q2 08 (every six months).
DNDN – Provenge 9902b study: interim analysis 2H08; final analysis (304 deaths) 2H09.
ELN – AAB-001 phase-3: Interim data 2H09 (est.), final data 2H10 (est.). (First patient dosed 12/21/07.)
ELN – ELND005 for AD phase-2: Interim data mid 2009 (est.), final data 1H10 (est.) (First patient dosed 12/21/07.)
GILD – Viread in HBV: FDA PDUFA date 8/11/08. (Approved in EU Apr08.)
GILD – GS9190 polymerase inhibitor for HCV: new phase-1 trial to test QT-prolongation announced 10/18/2007; further details pending.
GTCB – ATryn in US: BLA submission Jul 2008; FDA action: early 2009, assuming priority review.
GTCB – ATryn phase-2 DIC trial by Leo Pharma in Europe/Canada: enrollment complete end 2008, data 1H09.
GTCB – Merrimack MM-093: results of phase-2 extension trial in RA: Aug 2008; results of pilot study in uveitis: 2008.
HGSI – Phase-3 Albuferon: report data from genotype-2/3 phase-3 trial: end 2008; report data from genotype-1 phase-3 trial: spring 2009; submit BLA fall 2009.
IDIX – IDX899 phase-1/2 seven-day monotherapy data: ESCMID June 15-21, 2008. (800mg cohort was reported 2/6/08.)
IDIX – IDX899 phase-2 six-week head-to-head vs Sustiva (IDX899+Truvada vs Sustiva+Truvada): start enrollment 3Q08; report data at CROI Feb 2009.
IDIX – IDX184 nucleotide polymerase inhibitor for HCV: file IND/CTA mid 2008; report first data in patients by year-end 2008.
IDIX – First protease inhibitor for HCV: file IND/CTA in 1H09. (A second PI for HCV to follow soon thereafter.)
ISA.TO-European psoriasis P3 results 2008. Phase II/III Uveitis results 2008.
ITMN – ITMN-191 Final MAD monotherapy data at AASLD in Oct08 (data from first four cohorts announced at EASL 4/1/08). Data from 14-day triple- combination study: late 2008 (probably not in time for AASLD; trial started 5/29/08).
ITMN - Pirfenidone - CAPACITY Trials enrollment completed May 2007. Top-line results January 2009 (72 week treatment period).
LBPFF – see DDSS
MAXY – Maxy-Seven FVIIa analogue: phase-1 trial in UK to start 2H08. (Go-ahead to start received 6/11/08.)
Merrimack: see GTCB
MNT PureTox botulinum toxin: report data from first phase-3 trial calendar 4Q08; submit BLA calendar 4Q10 (after completion of two other phase-3 trials).
MNTA – Lovenox ANDA resubmission: 3Q08. (Prior FDA response received 4/28/08.)
MNTA – M118: report phase-2 data in stable angina at unspecified medical conference in 2H08.
MNTA – M118: start phase-2b in ACS in 2H08.
MNTA – Submit Copaxone ANDA: 2H08.
MS.TO - Complete enrollment in pivotal Secondary Progressive MS trial this year, interim results mid 2008, trial results in 2009.
NBIX - NBI-56418 Topline data, 6-month phase 2b endometriosis trial 2Q08
NRMX, NRM.TO – European ph-3 Alzhemed trial complete 2008 (N Amer ph-3 failed, as reported 8/26/07).
OXGN - H1 2008 File IND for Zybrestat topical in ophthalmology
OXGN - H1 2008 Results from oxi4503 phase I
OXGN - H1 2008 Final Zybrestat + Avstin phase Ib data
Pharming – Rhucin submission to FDA possibly in 2008; positive phase-3 data reported 6/16/08.
PPHM- Bavituximab (cancer): PII MBC Bavi/Docetaxel 1st stage successful. Trial moves to 2nd stage July 08
PPHM- Bavituximab (cancer): first patient dosed in PII NSC lung cancer trial w/carboplatin/paclitaxel June 08
PPHM- Bavituximab (cancer): approval received to conduct PII MBC trial w/carboplatin/paclitaxel Jan 08
PPHM- Bavituximab (cancer): phase I monotherapy trial, estimated completion Sept 08
PPHM- Bavituximab (viral): phase I trial: HCV / HIV coinfected patients: estimated completion Sept 08
PPHM- Cotara: phase II glioblastoma multiforme trial - next interim update 2H 08
PPHM- Cotara: glioblastoma multiforme US trial - data presented at ASCO 08, estimated completion Sept 08
RDEA – RDEA806 in HIV: start phase-2b combination study 2Q08; report phase-2a mono data at unspecified conference in 2008.
RPRX– Proellex
*Initiate Fibroids Pivotal PIII trials (?)
*Initiate Anemia Pivotal PIII trials (?) (IND approved 2/22/08)
SGP – Boceprevir ph-2 trial in treatment-naïve HCV: full SVR data late 2008 or early 2009. (SVR12 data for the active arm only was presented at EASL in Apr2008.)
SRDX - Novocell phase-1/2 trial in type-1 diabetes: top-line data due in 2008 (enrollment complete 8/30/06).
VRTX – PROVE-3 trial in treatment-experienced HCV: SVR data 4Q08, presumably at AASLD. (EoT and some SVR12 data were reported on 6/9/08.)
VRTX – Interim data from BID-dosing phase-2 Telaprevir trial conducted by Tibotec: 2H08.
ZGEN – IFN-Lambda in HCV: report interim ph1 monotherapy data at AASLD in Oct 2008.
ZGEN – IL21 w Nexavar in RCC: interim ph2 data at EORTC in Oct 2008.
ZGEN – IL21 in melanoma: interim ph2 data at ZGEN’s R&D Day Dec 2008.
--
Procedure For Updating Clinical-Trials List
When adding or modifying entries, please follow these steps:
1. Copy the complete text from the old list. You can find a pointer to this list in the iBox at the top of the main message-board screen.
2. Make your additions or modifications, inserting any new items in alphabetical order.
3. Post the updated text in a new message in reply to the message with the old list.
mojo,
great chart, thanks.
j
jake,
you can't compare Herceptin. It's not for evceryone, only HER2...
THE benchmark is Avastin + Docetaxel.
j
Avastin + Docetaxel benchmarks for Bavi --------
the paper:
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
the important bits -
* "The overall response rate was 52%, (32-71%.)"
(That's saying that 52% of patients had a partial response.
The smallest response was 31%, the largest was 71%.
No comlete responses).
* "median duration of response was 6.0 months"
* "median PFS was 7.5 months"
* "median duration of stable disease in the nine patients was 5.3 months"
That's the median duration of stable disease in the nine patients who never achieved a partial response, but did manage to be classified as stable.
--------
j
Avastin + Docetaxel PFS -------------
Below is the graph illustrating progression free survival from the phase II Avastin/Docetaxel breast cancer trial.
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
in contrast:
According to the PPHM PR this morning, some of the patients in the Bavituximab/Docetaxel have been out four to five months, and NONE of them have had any tumor growth. Neither have the more recenty treated patients - There's been NO GROWTH in ANY of the patients. But most impressive are the patients at 4+ months.
That's a very important parameter with great results so far, with indications for an improvement in PFS over Avastin.
j
jess,
Off the top of my head -
Bavituximab
humanized Bavituximab
fully human bavituximab, (PGN365)
a half-dozen or so other anti-PS mabs mentioned in Thorpe's patents, (9D2, etc.)
anti-PS conjugated to IL-2
anti-PS conjugated to IFN
bavituximab conjugated to 74As
- and probably a few I'm forgetting.
j
jake,
http://clincancerres.aacrjournals.org/cgi/reprint/12/10/3124
Right now, (with only 8-week first-scan data) Bavituximab has already equalled the percentage of objective responses in the Avastin/Docetaxel phase II breast cancer trial.
(Over the course of the Avastin Docetaxel trial, they had 14 out of 27 responses. Bavi/Docetaxel has so far, afeter only 8 weeks, generated 7 out of 14).
Also, an important thing to remember when comparing the two trials is that, as similar as they are in terms of design, be aware of the important fact that in the Avastin study, 78% of the patients had no prior chemotherapy for metastatic breast cancer.
ALSO---------------
WITH REGARD TO THE MORE IMPORTANT PARAMETER OF PROGRESSION-FREE SURVIVAL:
Patients in the Avastin/Docetaxel trial began progressing again.
IMO, where Bavi will really shine brightest are in the most important parameters - PFS & overall survival, becasue, as is being reported today, Bavi should KEEP working in patients, based on how it does what it does...
See the all-important "stair-step" PFS graph in the Avastin trial.
Each drop is when one of the 14 individual responders sarted progressing again...
WE HAVE HAD SOME PATIENTS OUT FOUR TO FIVE MONTHS NOW, AND NOBODY HAS HAD ANY TUMOR GROWTH. ZERO.
j
now SEVEN objective responses.
and seven stable.
NO progressive disease.
j
Bavituximab BREAST CANCER NEWS
Peregrine Pharmaceuticals Reports Positive Early Results in Phase II Study of Bavituximab in Breast Cancer
Wednesday July 2, 9:30 am ET
- Pre-Specified Primary Efficacy Endpoint Met in Stage 1 of Two-Stage Study -
- 100% of Evaluable Patients to Date Continue to Show Objective Tumor Response or Stable Disease -
TUSTIN, Calif., July 2 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM - News) today reported that its lead product candidate bavituximab achieved the pre-specified Stage 1 primary endpoint in its ongoing Phase II clinical trial in patients with metastatic breast cancer. The trial is an open-label, Simon two-stage design to evaluate the safety and efficacy of a combination of bavituximab and docetaxel in metastatic breast cancer patients. Fourteen of the 15 patients enrolled in Stage 1 were deemed evaluable for tumor response, with seven achieving partial tumor responses and seven having stable disease at week eight according to RECIST criteria. All 14 of the evaluable patients remain in the study and are continuing to receive treatment, along with continuing assessments of tumor response. With the Stage 1 primary endpoint of six or more objective tumor responses achieved, the design of the clinical trial now allows for an additional 31 study patients to be enrolled.
"We are very pleased with the early positive results from this Phase II breast cancer study," said Steven W. King, president and CEO of Peregrine. "We are particularly encouraged by the fact that at an early time point of eight weeks, half of the patients had achieved objective tumor responses. Equally encouraging is that with patients now out over four months since the start of the study, none have shown tumor growth or disease progression. As these patients continue on treatment, we will continue assessing them for signs of anti-tumor activity. We look forward to sharing more data from this study as patient treatment and follow-up progress."
The primary objective of the multi-center Phase II clinical trial is to assess overall tumor response rate. Secondary objectives include measuring time to tumor progression, duration of response, overall patient survival and safety parameters. All tumor responses in the trial are being evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Patients may continue to receive bavituximab as solo therapy after completion of chemotherapy as long as the cancer does not progress and side effects are acceptable. The trial is being conducted in the Republic of Georgia according to International Conference on Harmonization (ICH) and Good Clinical Practices (GCP) guidelines.
According to the RECIST criteria, patients are categorized as having "stable disease" ("SD") if they have less than a 20% increase to a 30% reduction in the sum of the target lesions, and they are categorized as having a "partial response" ("PR") if they experience greater than a 30% reduction in the sum of target lesions. In addition, to be assigned a status of SD or PR, patients cannot have the appearance of any new lesions.
According to the World Health Organization, breast cancer is the most commonly diagnosed cancer in women, and is second only to lung cancer as a leading cause of female cancer deaths. The National Cancer Institute estimates that approximately 182,460 U.S. women will be diagnosed with breast cancer in 2008 and 40,480 women will die of the disease in the U.S. alone.
Bavituximab is a monoclonal antibody that binds to the cellular membrane component phosphatidylserine (PS) that is usually located inside cells, but which becomes exposed on the outside of the cells that line the blood vessels of tumors, creating a specific target for anti-cancer treatments. By binding to PS, bavituximab is believed to help mobilize the body's immune system to destroy the tumor and the tumor blood vessels. Bavituximab currently is in two Phase II combination therapy trials for the treatment of metastatic breast cancer and for the treatment of non-small cell lung cancer (NSCLC). A second Phase II combination therapy study in breast cancer patients is expected to begin soon. Data presented at the 2008 ASCO annual meeting showed that half of evaluable patients in a Phase Ib trial of bavituximab plus chemotherapy achieved an objective tumor response or stable disease after eight weeks of dosing, that the safety profile of bavituximab and chemotherapy appeared consistent with chemotherapy alone and that the pharmacokinetic properties of bavituximab were not affected by co-administration with conventional chemotherapies. A Phase I bavituximab monotherapy trial in advanced solid cancers is continuing.
-------
j
Charlie,
No. Actually, the recent publications have discussed how viruses rely on the PS stuck on their exteriors to infect cells. It's quite a big insight.
These discoveries have been coming fast and furious. The basic discovery that PS was exposed on HIV was just made recently, (Henderson & Schlegel at Penn. just a couple years ago). Perhaps most interesting are the other recent discoveries that have shown how PS alters the functions of immune cells, (Henson, Fadok, Hoffman, Shilyansky, etc.). Most recently, it's looking like the PS-altered immune function (which has been used by viruses, cancer, and protozoan critters to help them survive and thrive in the body). is now being seen as occuring on a "vesicular" level as opposed to a cellular level. Microparticles that bleb off of infected or dying cells are beeing seen as playing a big role in shutting down any counter-attack by the immune system, (Haynes, Pisetsky, Distler, Rivoltini, Whiteside, etc.)
Peregrine is commenting on how these studies point toward agents that block PS as being very promising.
Peregrines abundance of pre-clinical data, now combined with CLINICAL data using anti-PS against multiple cancers and viruses strongly backs it up.
As for other publications 'naming Peregrine', I agree, it will be nice. You may be surprised how focussed the scientists that have been making the recent important PS-related discoveries are. For instance, Mercer & Helenius, who wrote the recent paper in Science about PS being essential for viral entry into cells, had no idea that there was an anti-PS mab in clinical trials. (They are now aware). That's usually the case.
Understand that all the publications I refer to above are delving into the function(s) of PS - How it is used by viruses, cancers, and how it shuts down immune responses.
It is only very very recently that a few scientists have taken the next step, and have started discussing DELIBERATELY TARGETING PS itself.
(which is contrary to traditional immunological common-sense).
The most recent cancer example came from Glenn Dranoff of Harvard.
The most recent viral example came from Bart Haynes of Duke.
- yet Peregrine has an anti-PS mab in phase II cancer trials.
I think the first publication that mentions Peregrine's mabs in relation to antival therapeutics will come out of Duke University, under Bart Haynes, discussing work funded by the Gates Foundation.
j
steve,
No. They're talking about a mab whose target is part of the virus itself. Peregrine's anti-PS targets a lipid from your own cells which gets stuck to the outside of the virus when it pops out of one of your cells.
j
"This substantial five-year contract award is especially timely in view of recent scientific publications highlighting the broad anti-viral potential of our anti-PS agents such as bavituximab," said Steven W. King, president and CEO of Peregrine.
'What's he referring to', you ask?........
The tide has turned in the past couple months, as science has recognized that PS is responsible for entry of viruses into cells, and also that PS tricks the immune sysytem into not putting up a fight.
In April, a paper was published in the journal Science, by Mercer and Helenius:
:Vaccinia Virus Uses Macropinocytosis and Apoptotic Mimicry to Enter Host Cells
Jason Mercer and Ari Helenius
http://www.ncbi.nlm.nih.gov/pubmed/18436786?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
It describes how PS is responsible for viral entry into cells.
It discusses how PS stops the immune system from mounting a fight.
It even has MOVIES of virus entering a cell, and the cell having eruptions of PS blebs on it's surface...
--------------------------------
In the same issue of Science, other authors discussed how important the Mercer/Helenius findings were:
They also speculated that HIV may use the identical method of infection, and that,
"The role of phosphatidylserine
in the entry of HIV and other
viruses will surely be explored in greater
detail now.
"
A One-Sided Signal
Gregory D. Fairn and Sergio Grinstein
Changes in the distribution of a lipid within the
plasma membrane affect normal cell function
and virus infection.
As reported by Mercer and Helenius, loss
of phosphatidylserine asymmetry in the
plasma membrane is also important for some
viral infections. Like other viruses with a
lipid bilayer coating, vaccinia virus acquires
its membrane envelope as it buds off of the
infected host cell. Because the infected cells
undergo apoptosis, and thus experience
scrambling of plasma membrane lipids, the
budding virus also acquires an envelope that
exposes phosphatidylserine on its external
surface (see the figure). The authors found
that, although not required for the virus to
bind to the surface of the host cell, the presence
of exofacial phosphatidylserine is
required for viral entry. The nature of
the internalization pathway is particularly
intriguing because like other poxviruses,
vaccinia virus is large (³200 nm in diameter),
exceeding the size accommodated by
endocytosis, the engulfment process that
uses specialized minute invaginations to
internalize only a small area of the cell surface.
Using a series of pharmacological
agents, the authors showed that vaccinia
enters cells by a process akin to macropinocytosis
a less specific internalization
process that is more generally involved in the
uptake of surrounding fluids. The sensitivity
of vaccinia entry into cells to inhibitors of
tyrosine kinases suggests the involvement
of a transmembrane receptor for phosphatidylserine,
as well as the existence of
separate binding determinants on the receptor
for the virus and for phosphatidylserine.
This is consistent with a “tether and tickle”
mechanism in which a separate attachment
site is required for phosphatidylserine receptors
to effectively bind and internalize apoptotic
cells (8). The involvement of phosphatidylserine
may not be limited to infection
by vaccinia viruses. Papuamide B, a natural
compound with anti-HIV properties,
also binds to phosphatidylserine (9). It is
therefore conceivable that HIV similarly
requires phosphatidylserine for infection and
that papuamide B interferes by occluding the
lipid on the viral surface. The role of phosphatidylserine
in the entry of HIV and other
viruses will surely be explored in greater
detail now.
---------------------------
Here is a beautiful illustration form the Fairn & Grinstein comments in Science.
-------------------------------
The Mercer/Helenius paper in Science spawned several articles about the work. The role of exposed PS was simply and beutifully described in layman's terms in the following articles:
Have a look at these hits, googling the title: "A Step Forward In Virology"
http://www.google.com/search?hl=en&q=%22+A+Step+Forward+In+Virology%22&btnG=Search
As for the article-
It's beautiful how the author simplified the process of apoptotic phagocytosis for the reader:
- (the fact that exposed PS is a sign of a dying host cell,
- and that exposed PS signals immune cells not to mount a fight etc.)
- by caling PS "cell waste",
and an "official waste tag"! :)
That's just brilliant IMO.
Well done.
This same article is also spreading under the title, "Trojan Horse Of Viruses Revealed"
http://www.google.com/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&q=%22Trojan+Horse+Of+Viruses+Revealed%22&btnG=Google+Search
That's an excellent title for an article about the paper.
Also, another layman's article summarizing the paper has spread, here is a link googling: "Dirty Rotten Poxviruses"
http://www.google.com/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&q=%22Dirty+Rotten+Poxviruses%22&btnG=Google+Search
In "Dirty Rotten Poxviruses" the author writes,
"poxviruses have engineered a way to sneak into cells through the garbage chute."
and - "the virus disguises itself as junk"
Again, great writing!
It can't be said much more simply than that.
She also writes,
"the team wondered if the virus was playing dead. They found that the virus's surface was studded with phosphatidylserine, a lipid that also flags dead cells as garbage. Removing lipids from the virus's surface stopped infection, and recoating the virus with phosphatidylserine restarted it. The results suggest that the virus is "more clever than originally thought" because it exploits a garbage-collection process found in almost all cells, says Mercer.
"phosphatidylserine, a lipid that also flags dead cells as garbage."
perfect!
------------------------------------
The next month, the journal Nature picked up the new insights into PS facilitated viral infection and immune shut-off.
NATURE REVIEWS: Molecular Cell Biology, June 2008
Virus plays dead
http://www.nature.com/nrm/journal/v9/n6/full/nrm2420.html
Research Highlight
Nature Reviews Molecular Cell Biology 9, 422 (June 2008) | doi:10.1038/nrm2420
Cellular microbiology: Virus plays dead
Arianne Heinrichs
Vaccinia virus is a large, complex, enveloped DNA virus that belongs to the Poxviridae family of viruses, which includes variola, the causative agent of smallpox. The infectious mature virus (MV) form of vaccinia has been shown to bind to actin-containing finger-like protrusions (filopodia) of the host cell and enter the cell in a pH-dependent manner. In a new study published in Science, Jason Mercer and Ari Helenius report that the MV form of vaccinia virus enters host cells using macropinocytosisand apoptotic mimicry.
The authors prepared fluorescent MV particles and used live imaging to follow the entry of individual particles into host cells that expressed fluorescent actin. Virus particles that bound to filopodia moved towards the cell body in an actin-dependent manner. Once they reached the cell body, membrane blebs formed at the site of contact with virus, followed by the formation of further blebs along the entire cell body. The blebs eventually retracted, which coincided with virus entry. Inhibiting membrane blebbing caused a large reduction in infection, which suggests that blebbing is required for infection.
The Ser/Thr kinase p21-activated kinase-1 (PAK1) is essential for MV infection; indeed, knockdown of PAK1 reduced infection significantly. MV infection is accompanied by phosphorylation of residue Thr423 of PAK1, which is known to be essential for macropinocytosis. PAK1 knockdown studies also showed that PAK1 is required for events that occur prior to viral fusion, including blebbing. Perturbance of several other factors, including the PAK1 activator GTPase Rac1 and Na+/H+ exchangers, inhibited both blebbing and infection. This further confirmed that these processes are linked. Sensitivity to Na+/H+ exchangers is also characteristic of macropinocytosis. Indeed, MVs co-internalized with fluid-phase cargo, but not clathrin-dependent cargo, in a macropinocytosis-type endocytic process.
Apoptotic bodies are macropinocytosed by phagocytes and other cell types, and uptake of apoptotic debris is triggered by the presence of exposed phosphatidylserine (PS) on the plasma membrane. The MV membrane is known to be enriched in PS, which is required for infection. The authors showed that PS is exposed on the MV surface and that virus particles extracted with a detergent that removes all lipids fail to induce blebbing and infection. Reconstitution of the extracted virus particles with PS restored infection. Because MVs are comparable in size to apoptotic bodies and the uptake mechanisms are the same, Mercer and Helenius concluded that viral PS might be analogous to cellular PS and triggers the uptake of virus particles by mimicking apoptotic bodies. Consistent with this, late-stage vaccinia-infected cells were shown to undergo apoptosis.
The clever use of apoptotic mimicry and subsequent entry by macropinocytosis allows large particles such as vaccinia virus to infect many different potential host cells. And by posing as apoptotic bodies, MVs may also avoid immune detection.
----------------
IT'S HAPPENING! :)
j
It's a good thing Peregrine's manufacturing plant happens to be the first US contract manufacturer authorized by Crucell to crank out mabs ( at over 27 grams/liter!) with the PER.C6 cell line...
Avid will be brewing a lot of bavi and humanized anti-PS, and contrary to the bavi that they've been using in all the clinical trials, IMO this bavi will be generating revenues.
j
Here are charts with all DTRA awards for March, April, and May 2008 -
These charts list every DTRA award over $100,000 for the past three months.
take a look at these amounts,
and consider the amount of Peregrine's award for its broad spectrum antiviral mab today :)
VERY impressive. The planned govt. antiviral work with Peregrine's mabs must be a BIG project...
j
MAY 2008
APRIL 2008
MARCH 2008
wxcbs,
last year they announced that 'they were in negotiations' for the award, which came back to bite them because then unfortunately congress cut the defense budget...)
Today's news is announcing the award. This time they stayed quiet until they GOT the deal.
---------------
last year's headline-
Peregrine Enters Contract Negotiations With U.S. DTRA for Hemorrhagic Fevers
- U.S. Department of Defense Agency Has Selected Peregrine for a Multi-Year Award That Could Total $44.5 Million Pending Successful Contract Negotiations -
----------------
TODAY'S HEADLINE -
Peregrine Pharmaceuticals Awarded DTRA Contract Worth up to $44.4 Million to Develop Bavituximab for Viral Hemorrhagic Fevers
- Five-Year Defense Threat Reduction Agency Contract Will Support Development of Bavituximab and Fully Human Equivalent as Potential Broad-Spectrum Anti-Viral Agents -
------
big difference :)
j
PPHM & DEPT OF DEFENSE, 44 MILLION $$ DEAL
Peregrine Pharmaceuticals Awarded DTRA Contract Worth up to $44.4 Million to Develop Bavituximab for Viral Hemorrhagic Fevers
Tuesday July 1, 7:50 am ET
- Five-Year Defense Threat Reduction Agency Contract Will Support Development of Bavituximab and Fully Human Equivalent as Potential Broad-Spectrum Anti-Viral Agents -
TUSTIN, Calif., July 1 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (Nasdaq: PPHM - News), a clinical stage biopharmaceutical company developing monoclonal antibodies for the treatment of cancer and hepatitis C virus (HCV) infection, today announced it has entered into a five-year contract worth up to $44.4 million to test and develop bavituximab and an equivalent fully human antibody as potential broad-spectrum treatments for viral hemorrhagic fever infections. The initial contract was awarded through the Transformational Medical Technologies Initiative (TMTI) of the U.S. Department of Defense's Defense Threat Reduction Agency (DTRA).
Bavituximab is Peregrine's lead anti-phosphatidylserine (anti-PS) monoclonal antibody and is currently in clinical trials for the treatment of HCV infections and cancer. In preclinical animal models, bavituximab has demonstrated encouraging anti-viral activity as a potential treatment for viral hemorrhagic fevers. Peregrine's fully human anti-PS antibody, which will also be assessed under this contract, is currently in preclinical development.
Under the terms of the contact, DTRA funds are available to cover testing and development efforts totaling up to $22.3 million over a 24-month base period, with $5 million appropriated immediately for the current federal fiscal year ending September 30, 2008. The remainder of the $22.3 million in funding is expected to be appropriated over the remainder of the two-year base period ending June 29, 2010. The contract can be extended beyond the base period to cover up to $44.4 million in funding over the five-year contract period. Work and funding under this contract are expected to begin immediately.
"This substantial five-year contract award is especially timely in view of recent scientific publications highlighting the broad anti-viral potential of our anti-PS agents such as bavituximab," said Steven W. King, president and CEO of Peregrine. "We are pleased that DTRA has recognized bavituximab's safety profile to date and its promising anti-viral activity, which have been demonstrated in proof of concept models of hemorrhagic fever infection and in two successful clinical trials in patients with chronic HCV infection."
Mr. King continued, "We welcome the opportunity to contribute to the anti-bioterrorism mission of the Defense Threat Reduction Agency, and we also believe that some of the work performed under this contract can be leveraged to support common development tasks applicable to our ongoing bavituximab clinical programs for the treatment of HCV and cancer. The non-dilutive capital provided by this government contract will enable us to further assess the potential of bavituximab to combat the threat of viral hemorrhagic fevers and to help advance the overall bavituximab clinical program."
The DTRA biodefense contract award has the potential to create long-term value for Peregrine, including generating future potential revenues from government stockpiling to combat bioterrorism threats. In the near-term, funding from this initiative will also allow Peregrine to use data and experience obtained from the development and scale-up of bavituximab to support its ongoing clinical development programs.
"We look forward to a close partnership with the DTRA during the performance of this program," said Ronald T. Aimes, Ph.D., associate director of research & development at Peregrine and principal investigator on the contract. "This is an exciting opportunity for Peregrine to contribute to the country's defenses while also achieving important synergies with our development programs for bavituximab and our earlier stage anti-PS technologies."
---------
j
e,
You seem to be reading something in my post that wasn't there.
I'm encouraged that the CAVD (Gates Foundation $) is funding HIV work with Peregrine's anti-PS. If the work is successful, it's logical to think it will be continued and expanded.
By reading the latest CHAVI update, it is evident how much Haynes and team are stressing the importance of needing to deal with apoptotic microvesicles, which have taken center stage in the CHAVI/Gates CAVD HIV vaccine work.
You'll remember I pointed it out when the update came out...
I implied that anti-PS, while not specifically mentioned in the CHAVI update, was obviously what they were planning on using to deal with the PS-exposing microvesicles.
Sure enough, just last week an international Haynes patent application went public on the WIPO database, which finally specifically discusses using anti-PS to deal with the PS-exposing microvesicles.
There is only one reason Haynes would put forth such an idea-
because he's done preliminary work with promising results.
The preliminary work was done with Peregrine's anti-PS, funded by both CHAVI and the Gates Foundation.
If you want to discuss hypotheticals like rich people buying into the PPHM anti-PS tech, I'd recommend waiting until after some good concrete data comes out of Duke with all the work they've done with Peregrine's mabs. If the data is good, it will be pointing to a true "immunological breakthrough", and hey, who knows, but let's not put the cart before the horse.
j
Clinical / Regulatory / Litigation Calendar
[Please keep entries up to date! See updating procedure at the end of this post.]
NOTE: ANYONE MAY UPDATE THIS FILE
Edits: PPHM
AMGN – Data from phase III HALT trial in prostate cancer: 2H08.
AMLN – LAR NDA submission: mid 2009 if bioequivalence study needed; earlier if not needed.
BMY Apixaban – phase-3 ADVANCE-1 trial (VTE prevention following in orthopedic surgery): data at ASH Dec08; phase-2 in ACS: data at European Society of Cardiology Sep08.
CEGE - 1H08: additional P2 GVAX prostate data; CG0070 P1 data (AUA- May); additional GVAX-prostate+MDX-0010
- 2H08: GVAX pancreas, leukemia P2 data
- 1H09: GVAX prostate VITAL-2 P3 enrollment completion and interim analysis
- 2H09: GVAX prostate VITAL-1 P3 Final Analysis
CYT.TO - Initiated pivotal A-fib trial Oct/06. Complete enrollment 2nd/half 07. Results 2nd half 08.
DDSS – Tramadol NDA: “escalation” of FDA appeal announced 4/1/08. Ph III Trazodone results 2nd qtr/08.
DNA – Avastin adjuvant CRC interim look Q2 08 (every six months).
DNDN – Provenge 9902b study: interim analysis 2H08; final analysis (304 deaths) 2H09.
ELN – AAB-001 phase-3: Interim data 2H09 (est.), final data 2H10 (est.). (First patient dosed 12/21/07.)
ELN – ELND005 for AD phase-2: Interim data mid 2009 (est.), final data 1H10 (est.) (First patient dosed 12/21/07.)
GILD – Viread in HBV: FDA PDUFA date 8/11/08. (Approved in EU Apr08.)
GILD – GS9190 polymerase inhibitor for HCV: new phase-1 trial to test QT-prolongation announced 10/18/2007; further details pending.
GTCB – ATryn in US: BLA submission Jul 2008; FDA action: early 2009, assuming priority review.
GTCB – ATryn phase-2 DIC trial by Leo Pharma in Europe/Canada: enrollment complete end 2008, data 1H09.
GTCB – Merrimack MM-093: results of phase-2 extension trial in RA: Aug 2008; results of pilot study in uveitis: 2008.
HGSI – Phase-3 Albuferon: report data from genotype-2/3 phase-3 trial: end 2008; report data from genotype-1 phase-3 trial: spring 2009; submit BLA fall 2009.
IDIX – IDX899 phase-1/2 seven-day monotherapy data: ESCMID June 15-21, 2008. (800mg cohort was reported 2/6/08.)
IDIX – IDX899 phase-2 six-week head-to-head vs Sustiva (IDX899+Truvada vs Sustiva+Truvada): start enrollment 3Q08; report data at CROI Feb 2009.
IDIX – IDX184 nucleotide polymerase inhibitor for HCV: file IND/CTA mid 2008; report first data in patients by year-end 2008.
IDIX – First protease inhibitor for HCV: file IND/CTA in 1H09. (A second PI for HCV to follow soon thereafter.)
ISA.TO-European psoriasis P3 results 2008. Phase II/III Uveitis results 2008.
ITMN – ITMN-191 Final MAD monotherapy data at AASLD in Oct08 (data from first four cohorts announced at EASL 4/1/08). Data from 14-day triple- combination study: late 2008 (probably not in time for AASLD; trial started 5/29/08).
ITMN - Pirfenidone - CAPACITY Trials enrollment completed May 2007. Top-line results January 2009 (72 week treatment period).
LBPFF – see DDSS
MAXY – Maxy-Seven FVIIa analogue: phase-1 trial in UK to start 2H08. (Go-ahead to start received 6/11/08.)
Merrimack: see GTCB
MNT PureTox botulinum toxin: report data from first phase-3 trial calendar 4Q08; submit BLA calendar 4Q10 (after completion of two other phase-3 trials).
MNTA – Lovenox ANDA resubmission: 3Q08. (Prior FDA response received 4/28/08.)
MNTA – M118: report phase-2 data in stable angina at unspecified medical conference in 2H08.
MNTA – M118: start phase-2b in ACS in 2H08.
MNTA – Submit Copaxone ANDA: 2H08.
MS.TO - Complete enrollment in pivotal Secondary Progressive MS trial this year, interim results mid 2008, trial results in 2009.
NBIX - NBI-56418 Topline data, 6-month phase 2b endometriosis trial 2Q08
NRMX, NRM.TO – European ph-3 Alzhemed trial complete 2008 (N Amer ph-3 failed, as reported 8/26/07).
OXGN - H1 2008 File IND for Zybrestat topical in ophthalmology
OXGN - H1 2008 Results from oxi4503 phase I
OXGN - H1 2008 Final Zybrestat + Avstin phase Ib data
Pharming – Rhucin submission to FDA possibly in 2008; positive phase-3 data reported 6/16/08.
PPHM- Bavituximab (cancer): first patient dosed in phase II NSC lung cancer trial w/carboplatin/paclitaxel June 08
PPHM- Bavituximab (cancer): first group (15 patients) enrolled in phase II breast cancer trial w/docetaxel April 08
PPHM- Bavituximab (cancer): approval received to conduct phase II breast cancer trial w/carboplatin/paclitaxel Jan 08
PPHM- Bavituximab (cancer): phase I monotherapy trial, estimated completion Sept 08
PPHM- Bavituximab (viral): phase I trial: HCV / HIV coinfected patients: estimated completion Sept 08
PPHM- Cotara: phase II glioblastoma multiforme trial - next interim update 2H 08
PPHM- Cotara: glioblastoma multiforme US trial - data presented at ASCO 08, estimated completion Sept 08
RDEA – RDEA806 in HIV: start phase-2b combination study 2Q08; report phase-2a mono data at unspecified conference in 2008.
RPRX– Proellex
*Initiate Fibroids Pivotal PIII trials (?)
*Initiate Anemia Pivotal PIII trials (?) (IND approved 2/22/08)
SGP – Boceprevir ph-2 trial in treatment-naïve HCV: full SVR data late 2008 or early 2009. (SVR12 data for the active arm only was presented at EASL in Apr2008.)
SRDX - Novocell phase-1/2 trial in type-1 diabetes: top-line data due in 2008 (enrollment complete 8/30/06).
VRTX – PROVE-3 trial in treatment-experienced HCV: SVR data 4Q08, presumably at AASLD. (EoT and some SVR12 data were reported on 6/9/08.)
VRTX – Interim data from BID-dosing phase-2 Telaprevir trial conducted by Tibotec: 2H08.
ZGEN – IFN-Lambda in HCV: report interim ph1 monotherapy data at AASLD in Oct 2008.
ZGEN – IL21 w Nexavar in RCC: interim ph2 data at EORTC in Oct 2008.
ZGEN – IL21 in melanoma: interim ph2 data at ZGEN’s R&D Day Dec 2008.
--
Procedure For Updating Clinical-Trials List
When adding or modifying entries, please follow these steps:
1. Copy the complete text from the old list. You can find a pointer to this list in the iBox at the top of the main message-board screen.
2. Make your additions or modifications, inserting any new items in alphabetical order.
3. Post the updated text in a new message in reply to the message with the old list.
the best part -
Official Title: A Phase II Safety and Efficacy Study of Bavituximab Plus Paclitaxel and Carboplatin in Patients With Previously Untreated Locally Advanced or Metastatic Non-Small Cell Lung Cancer
FINALLY!!!!!!!!
"Previously Untreated"
We saw 50% objective responses with this bavi/carboplatin/paclitaxel combination in the 'death's door' phase 1B (advanced metastatic chemo-resistant) patient group.
I look forward to hearing how this first group does...
j
doccg,
re: "data is worth its weight in gold."
Agreed! :)
some details for you -
As opposed to the current phase II Georgia breast cancer trial, I don't think we'll be hearing any data from the HIV/HCV dose escalation phase I safety trial until it's completely done, and analyzed, and even then - we'll likely have to wait until the appropriate conference, ( just as we did in the previous two HCV trials, to hear the details).
The current HCV/HIV trial is similar to both the HCV 1A and the 1B trials,
which I will remind you of course were started,
and of course were completed,
and of course were reported- in oral sessions at AASLD,
and then of course results were published in the top pertinent journal.
that is the order of things.
By the way, the clinicaltrials.gov page for the current HCV/HIV trial was recently updated.
It now says the trial should be completed in Sept 2008, which IMO means that they're likely currently dosing at a good therapeutic dose, ( 3 mg/kg).
On the other hand, the Georgia breast cancer trial is NOT a safety or a dose escalation trial. They can (and are, as evidenced by the recent PR) issuing interim reports whenever warranted, as defined 'endpoints' come to light...
IMHO, the next important thing we need to hear is that the Georgia trial has cleared the "Simon" hurdle, meaning they will be eligible to move into the next part of the trial, treating the additional 31 patients. I expect they'll also issue updates at other important future milestones, for instance- like when patients pass the point in time that was the median time to progression in the apples/apples Avastin + Docetaxel phase II breast cancer trial. (You see, the current Bavi + Docetaxel trial was wisely designed to be a direct apples/apples comparison to the Avastin + Docetaxel phase II trial, which is the best therapy, 'yet'...)
Whatever the outcome, Bavi will have very clear benchmarks to hopefully exceed.
The upcoming two Indian cancer trials are designed similarly to the Georgian breast cancer trial, although, fortunately, as cjgaddy has discussed, the patients will have even healthier immune systems - an important factor that, due to how Bavi works, should help generate some great 'best ever' data IMO.
As for Duke's work with Peregrine anti-PS mabs, like you, I'm looking forward to reading the paper.
The data should be "worth it's weight in gold"!
Very exciting times,
It's happening,
j
doccg/jess,
Mr. Gates says,
"solving key problems in immunology could provide the kind of breakthroughs needed to prod pharmaceutical companies to invest more in long-neglected problems of the developing world such as tuberculosis or malaria."
I strongly agree with him.
I think immunology is ripe for a breakthrough, and that targeting PS with abs will be seen as a very important breakthrough. (Bart Haynes seems to think so too.)
I happen to think that exposed PS will be seen as an important target, since exposed PS has now been proven to shift immune response away from an antigen-specific response. (Read Bart Haynes most recent paper authored by Nancy Gasper-Smith which cites multiple papers discussing this, or just read my "required reading number 1")...
Exposed PS shifts immune response more towards a homeostasis response, (which is not the way you want to deal with cancer, virus, protozoan pathogens, etc....)
I am not implying anything about Mr Gates involvement beyond of course what is already known about Peregrine's anti-PS mabs involvement in the Gates Foundation's CAVD work.
By reading Bart Haynes recent papers and patent applications, it appears that passive therapy with anti-PS is a promising therapeutifc for HIV, and hence that immunogens that induce anti-PS are a promising component of future HIV vaccines.
I am very encouraged that Mr. Gates is interested in "immunological breakthroughs" enough to specifically mention it! I think he's focussing in the right area.
Whether he personally is aware of Peregrine Pharmaceuticals or not is unknown to me, but what is known is that his foundation, guided by his scientists/administrators, have funded work using Peregrine's anti-PS mabs, to see if the mabs may have a beneficial effect in terms of neutralizing HIV itself, or preventing HIV from destroying T cell reservoirs, or allowing dendritic cells to do their thing better presenting pertinent antigens etc.
Haynes is now saying that inducing anti-PS, or generally interfering with PS/PS-receptor (CD36) signalling, is looking to be an essential component of a successful HIV vaccine.
We'll learn more when the Haynes paper discussing his work with Peregrine's anti-PS mabs is published.
Note: My other posts today all show how exposed PS is used by the pathogens that affect (and kill) millions of people in developing countries. If you familiarize yourself with the diseases that the Gates Foundation is concerned with, you will see these exact diseases as being top priorities, and, as outlined in my posts today, they all use exposed PS to survive and thrive in the body...
exciting times,
it's happening,
j
Leishmania Exploits Exposed PS ------
parasitic infection through "apoptotic mimicry"....
The Journal of Immunology, 2006, 176: 1834-1839
Mimicry of Apoptotic Cells by Exposing Phosphatidylserine Participates in the Establishment of Amastigotes of Leishmania (L) amazonensis in Mammalian Hosts
http://www.jimmunol.org/cgi/content/abstract/176/3/1834
João L. M. Wanderley*,{dagger}, Maria E. C. Moreira*, Aline Benjamin*,{dagger}, Adriana C. Bonomo*,{ddagger} and Marcello A. Barcinski2,*,§
Signaling through exposed phosphatidylserine (PS) is fundamental for the TGFbeta1-dependent, noninflammatory phagocytosis of apoptotic cells. This same mechanism operates in the internalization of amastigotes of Leishmania (L) amazonensis (L(L)a) in a process quoted as apoptotic mimicry. Now we show that the host modulates PS exposure by the amastigotes and, as a consequence, BALB/c mice-derived amastigotes expose significantly more PS than those derived from C57BL/6 mice. Due to this difference in the density of surface PS molecules, the former are significantly more infective than the latter, both in vivo, in F1 (BALB/c x C57BL/6) mice, and in vitro, in thioglycollate-derived macrophages from this same mouse strain. PS exposure increases with progression of the lesion and reaches its maximum value in amastigotes obtained at the time point when the lesion in C57BL/6 mice begins to decrease in size and the lesions in BALB/c mice are still growing in size. Synthesis of active TGFbeta1, induction of IL-10 message, and inhibition of NO synthesis correlate with the amount of surface PS displayed by viable (propidium iodide-negative) infective amastigote. Furthermore, we also show that, similar to what happens with apoptotic cells, amastigotes of L(L)a are internalized by macropinocytosis. This mechanism of internalization is consistent with the large phagolysosomes characteristic of L(L)a infection. The intensity of macrophage macropinocytic activity is dependent on the amount of surface PS displayed by the infecting amastigote.
------------------------
more Leishmania & PS
Braz J Med Biol Res. 2005 Jun;38(6):807-12. Epub 2005 Jun 1.
Apoptotic mimicry: an altruistic behavior in host/Leishmania interplay.
Wanderley JL, Benjamin A, Real F, Bonomo A, Moreira ME, Barcinski MA.
Instituto Nacional de Cancer, 20231-050 Rio de Janeiro, RJ, Brasil.
Apoptosis is the most common phenotype observed when cells die through programmed cell death. The morphologic and biochemical changes that characterize apoptotic cells depend on the activation of a diverse set of genes. Apoptosis is essential for multicellular organisms since their development and homeostasis are dependent on extensive cell renewal. In fact, there is strong evidence for the correlation between the emergence of multicellular organisms and apoptosis during evolution. On the other hand, no obvious advantages can be envisaged for unicellular organisms to carry the complex machinery required for programmed cell death. However, accumulating evidence shows that free-living and parasitic protozoa as well as yeasts display apoptotic markers. This phenomenon has been related to altruistic behavior, when a subpopulation of protozoa or yeasts dies by apoptosis, with clear benefits for the entire population. Recently, phosphatidylserine (PS) exposure and its recognition by a specific receptor (PSR) were implicated in the infectivity of amastigote forms of Leishmania, an obligatory vertebrate intramacrophagic parasite, showing for the first time that unicellular organisms use apoptotic features for the establishment and/or maintenance of infection. Here we focus on PS exposure in the outer leaflet of the plasma membrane--an early hallmark of apoptosis--and how it modulates the inflammatory activity of phagocytic cells. We also discuss the possible mechanisms by which PS exposure can define Leishmania survival inside host cells and the evolutionary implications of apoptosis at the unicellular level.
--------------------------------
Curr Biol. 2001 Nov 27;11(23):1870-3.
Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity.
de Freitas Balanco JM, Moreira ME, Bonomo A, Bozza PT, Amarante-Mendes G, Pirmez C, Barcinski MA.
Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo 05508-900, Brazil.
Programmed cell death by apoptosis of unnecessary or potentially harmful cells is clearly beneficial to multicellular organisms. Proper functioning of such a program demands that the removal of dying cells proceed without an inflammatory reaction. Phosphatidylserine (PS) is one of the ligands displayed by apoptotic cells that participates in their noninflammatory removal when recognized by neighboring phagocytes. PS ligation induces the release of transforming growth factor-beta (TGF-beta), an antiinflammatory cytokine that mediates the suppression of macrophage-mediated inflammation. In Hydra vulgaris, an organism that stands at the base of metazoan evolution, the selective advantage provided by apoptosis lies in the fact that Hydra can survive recycling apoptotic cells by phagocytosis. In unicellular organisms, it has been proposed that altruistic death benefits clonal populations of yeasts and trypanosomatids. Now we show that advantageous features of the apoptotic process can operate without death as the necessary outcome. Leishmania spp are able to evade the killing activity of phagocytes and establish themselves as obligate intracellular parasites. Amastigotes, responsible for disease propagation, similar to apoptotic cells, inhibit macrophage activity by exposing PS. Exposed PS participates in amastigote internalization. Recognition of this moiety by macrophages induces TGF-beta secretion and IL-10 synthesis, inhibits NO production, and increases susceptibility to intracellular leishmanial growth.
-----------------------------
Leishmaniasis
http://www.sbri.org/diseases/leishmaniasis.asp
Impact
Leishmaniasis is a parasitic disease transmitted by the bite of a sandfly that is infected with Leishmania parasites. Currently 350 million people in 88 countries around the world are threatened, and 12 million people are affected by leishmaniasis. Of the 1.5 – 2 million new cases of leishmaniasis estimated to occur annually, most occur in the tropics and subtropics, including the Middle East. In 2002, leishmaniasis reached epidemic levels in Afghanistan, with the World Health Organization calling for more funding and research for the disease. Leishmania/HIV co-infection is emerging as a serious new disease and it is increasingly frequent. It is considered a threat in southwestern Europe, such as Spain, Italy, France, and Portugal.
Symptoms
With the bite of an infected sandfly, Leishmania parasites are passed from one infected animal or human to others. Leishmaniasis is a spectrum of diseases, each distinctly manifested and all with potentially devastating consequences – disfigurement, damage to internal organs, death. Depending on the species of the infecting parasite, the spleen, liver, bone marrow, mucous membranes, and/or skin may be attacked. Leishmania donovani, the most dangerous of these, causes Kala azar, or visceral leishmaniasis, characterized by fever, severe weight loss and anemia. If left untreated, visceral leishmaniasis can lead to death.
--------------------------
j