Gone for good.
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Image from the paper.
Figure 4B, panel (ii), shows the increased localization of bavituximab in tumor vessels, indicating
that PS becomes exposed (>90%) on tumor endothelium in response to 10 Gy radiation (green).
In contrast, about 20% PS exposure and bavituximab localization was observed on the unirradiated tumor
tissue [Fig. 4C, panel (ii)]. No bavituximab localization was noted in normal rat lung exposed to 10 Gy
radiation [Fig. 4A, panel (ii)]. To confirm tumor vasculature labeling by bavituximab, vascular
endothelium was stained with a mouse anti-rat CD31 antibody [red, Fig. 4A–C, panel (i)]. Nuclei were stained
with DAPI [blue, Fig. 4A–C, panel (iii)]. Figure 4B, panel (iv), shows that the merged image of the tumor vessel is yellow.
Paper by Thorpe and others on pre-clinical work about the grant subject
FREE: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917257/pdf/nihms220242.pdf
An Orthotopic Lung Tumor Model for Image-Guided Microirradiation in Rats
Author(s) :Debabrata Saha, Linda Watkins, Yi Yin, Philip Thorpe, Michael D. Story, Kwang Song,
Pavithra Raghavan, Robert Timmerman, Benjamin Chen, John D. Minna, and Timothy D. Solberg
Source: Radiation Research, 174(1):62-71. 2010
Abstract
The purpose of this study was to develop a rat orthotopic lung
tumor model with a solitary intrapulmonary nodule to study the
effects of high-dose radiation. A549-Luc non-small cell lung
cancer (NSCLC) cells were implanted into nude rats in the
intercostal space between ribs 5 and 6 of the right lung.
Bioluminescence and microcomputed tomography (CT) imaging
were performed after implantation to confirm the presence of a
solitary tumor and to monitor tumor growth. A device using
image guidance for localization was developed to facilitate highprecision
irradiation in small animals. A pilot irradiation study
was performed, and response was assessed by bioluminescence
imaging and immunohistochemistry. Radiation response was
confirmed through serial bioluminescence imaging, and the
strength of the bioluminescence signal was observed to be
inversely proportional to dose. Response was also observed by
the monoclonal antibody bavituximab, which binds to exposed
lipid phosphatidylserine (PS) on tumor vessels. The ability to (1)
reproducibly generate solitary tumor nodules in the rat lung, (2)
identify and monitor tumor growth by bioluminescence imaging
and CT imaging, (3) accurately target these tumors using high
doses of radiation, and (4) demonstrate and quantify radiation
response using bioluminescence imaging provides significant
opportunity to probe the biological mechanisms of high-dose
irradiation in preclinical settings.
Here is Thorpe's CPRIT grant description. Awarded 8/2/2012
http://www.cprit.state.tx.us/files/funded-grants/RP120670-P4.pdf
There is actually a whole bunch here for many parts of one big project and they all have the same description.
RP120670 Exploiting the Radiobiology of Stereotactic Ablative Radiotherapy for Lung Cancer
Timmerman, Robert D
The University of Texas
Southwestern Medical Center at Dallas
$4,119,113.80
RP120670-AC Administrative Core RES Timmerman, Robert D The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $310,602*
RP120670-C1 C1: Biostatistical RES Ahn, Jung-Mo The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $269,129*
RP120670-C2 C2: Clinical Trials RES Timmerman, Robert D The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $0*
RP120670-C3 C3: Image Guided Irradiation of Small Animals RES Solberg, Timothy The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $887,912*
RP120670-P1 P1: Modulation of Normal Tissue Response RES Story, Michael D The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $0*
RP120670-P2 P2: Targeting Hypoxic Lung Cancers through blockade of the Epidermal Growth Factor Receptor RES Nirodi, Chaitanya The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $0*
RP120670-P3 P3: Effects of Hypoxia RES Mason, Ralph P The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $1,298,237*
RP120670-P4 P4: Radiation-Guided Vascular Targeting of Lung Cancer RES Thorpe, Philip E The University of Texas Southwestern Medical Center at Dallas Dallas Lung and Bronchus 08/02/2012 $1,353,233*
*Subject to contract negotiations
Thanks, that shows it beautifully that bavi reduces TGF-beta. The latest paper on tumor associated neutrophils (TAN)
is from the lab at UPenn that did the study using bavi.
Tumor-associated neutrophils: friend or foe?
Zvi G.Fridlender 1,2, and Steven M.Albelda 2
1Institute of Pulmonary Medicine, Department of Medicine,
Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel and
2Thoracic Oncology Research Laboratory, Department of Medicine,
University of Pennsylvania, Philadelphia, PA.
Carcinogenesis vol.33 no.5 pp.949–955, 2012.
http://carcin.oxfordjournals.org/content/33/5/949.abstract
Summary
It is becoming increasingly clear that TAN play a major role in cancer
biology. TAN are a distinct population of neutrophils, which in their
basic unmanipulated state are induced by the tumor microenvironment
(by TGF-b and probably other factors) to elicit pro-tumor
responses (N2 TAN). However, recent evidence shows that these cells
can be altered to assume antitumor roles (N1 TAN). Neutrophils are
thus an important underappreciated cell population in cancer biology,
and their functions need to be better characterized. A more complete
understanding of the way these cells support or fight cancer will be
important to develop strategies to direct the immune system against
tumors.
No. It is not clear that Bavi directly switches the neutrophils like it does with macrophages.
Thorpe specifically stated that in the case of macrophages Bavi was directly, by binding
to the macrophages, causing the switch from M2 to M1. In the paper I cited the neutrophils
do seem to be switched but it may be that the tumor microenvironment has been changed so
that neutrophils that arrive at the tumor are switched by the environment and not
directly by Bavi, but Bavi is the reason the change has occurred in the microenvironment.
In another paper, which first showed this switching from N2 to N1, the blockade of TGF-beta
was what was doing it, and Bavi by blocking PS causes a reduction in TGF-beta. I think this
was probably happening all along but nobody looked specifically at the neutrophils before.
So it is another part of Bavi's MOA.
Fire Fox, yes that is my thinking too. But if someone asks King maybe he would say "less than 9 months", or something.
The Wedbush website doesn't even have a location or the date listed.
Life Sciences: Management Access Conference
Date: August 2012 (Exact dates TBD)
Location: TBD
http://www.wedbush.com/services/cmg/equities-division/mgmt-access-events
MANAGEMENT ACCESS CONFERENCES & EVENTS
Wedbush Securities' Management Access Conferences bring together our institutional clients with leading global companies from a wide-array of sectors. Investors gain access to management teams from prominent public and best-of-breed private companies through intimate small group meetings and corporate presentations. This conference format provides our clients with significant insight and opportunities, while demonstrating our strong commitment to providing premier research and execution services.
These events are for institutional clients of Wedbush Securities and by invitation only
I would like someone to ask if the control arm MOS for the first-line NSCLC trial
has been triggered, and how many months is it.
It still only requires 50% + 1 of the patients to die to trigger the MOS call. For King
to be so confident I would think it would have to be way more than one CR, you might
expect one CR from the control arm. More than that, I expect at the time of the
conference call, 7/16/2012, there must have been a substantial number of patients
still alive and in good condition, say 65%, which would be 52/80 of the treatment arms.
Just a guess.
Except that there is no competing drug to Bavi. At least nothing that works the same way, nothing.
RRdog,
I am in total agreement. I especially like this sentence.
In all of the bearish articles that accompany bearish stock action, I see very little understanding or mention of the fundamental science.
Here is a recent and good overview of the anti-HCV drugs in development
FREE: http://f1000.com/reports/b/4/5/
New Antiviral Agents for Hepatitis C
....
Nucleoside/nucleotide analogue inhibitors of HCV RNA-dependent RNA polymerase
PSI-7977 Pharmasset/Gilead III
Mericitabine Roche/Genentech II
IDX-184 Idenix II
PSI-938 Pharmasset/Gilead II
INX-189 Inhibitex Ib
....
It was only in January that BMS bought out Inhibitex for $2.5 billion!
Does this put the whole class of nucleotide polymerase inhibitors in doubt?
January 07, 2012 09:13 PM Eastern Daylight Time
Bristol-Myers Squibb to Acquire Inhibitex
Strategic Acquisition Supports Long-Term Growth Potential of the Company
Builds on Company’s Strong Legacy and Commitment in Virology
Enhances Company’s Broad HCV Portfolio with Addition of INX-189, a potent NS5B Nucleotide
NEW YORK & PRINCETON, N.J. & ATLANTA--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) and Inhibitex, Inc. (Nasdaq:INHX) announced today that the companies have signed a definitive agreement under which Bristol-Myers Squibb will acquire Inhibitex for $26.00 per share in cash pursuant to a cash tender offer and second step merger. The transaction, with an aggregate purchase price of approximately $2.5 billion, has been approved by the boards of directors of both companies. The board of directors of Inhibitex has agreed to recommend that Inhibitex’s shareholders tender their shares in the tender offer. In addition, shareholders with beneficial ownership of approximately 17% of Inhibitex’s common stock have entered into agreements with Bristol-Myers Squibb to support the transaction and to tender their shares in the tender offer.
Inhibitex is a clinical-stage biopharmaceutical company dedicated to the development of innovative products that can treat or prevent serious infections, whose primary focus is on the development of nucleotide/nucleoside analogs for the treatment of hepatitis C virus (HCV). Its lead HCV asset is INX-189, an oral nucleotide polymerase (NS5B) inhibitor in Phase II development that has exhibited potent antiviral activity, a high barrier to resistance and pan-genotypic coverage. Nucleotides/nucleosides are emerging as an important class of antivirals that may play a critical role as the backbone of future direct-acting antiviral-only combination approaches to HCV treatment.
“The acquisition of Inhibitex builds on Bristol-Myers Squibb’s long history of discovering, developing and delivering innovative new medicines in virology and enriches our portfolio of investigational medicines for hepatitis C,” said Lamberto Andreotti, chief executive officer, Bristol-Myers Squibb. “There is significant unmet medical need in hepatitis C. This acquisition represents an important investment in the long-term growth of the company.”
“This transaction puts INX-189 and the Company’s other infectious disease assets in the hands of an organization that can more optimally develop them and which believes as strongly as we do in INX-189’s potential in the treatment of chronic HCV,” said Russell Plumb, President and Chief Executive Officer of Inhibitex. “Bristol-Myers Squibb’s expertise in antiviral drug development, and its existing complementary portfolio, will assure that the potential of INX-189 is realized as part of future oral combination therapies for millions of patients in need around the world.”
......
Lets hope that by the end of the year we get ORR, PFS for both control and treatment arms, and
control MOS < 6 months, but MOS for treatment arm not yet reached.
One of the advantages that bavituximab with chemo has is that it doesn't add much to toxicity, unlike these new drugs.
Nature Reviews Clinical Oncology 31 July 2012
TARGETED THERAPIES
The toxic reality of new drugs
Targeted anticancer therapy was originally envisaged to be the optimal method of targeting cancer without having the usual toxic effects associated with systemic therapy. Part of the original aim has been realized, but unfortunately theses novel anticancer therapies are not without their drawbacks. Now, a meta-analysis of new anticancer therapies has shown that they are more toxic than their traditional counterparts.
This meta-analysis was initiated by Eitan Amir and his colleagues based on previous work assessing toxicity in patients with breast cancer. As Amir describes, “we noted that aromatase inhibitors were associated with a higher frequency of certain serious toxicities than tamoxifen and, therefore, decided to extend the hypothesis that new drugs are more toxic than old drugs to a general cancer population.” To test their hypothesis, the researchers identified 38 randomized clinical trials that each assessed a novel anticancer drug that was approved for the treatment of solid tumours by the FDA between 2000 and 2010. The meta-analysis of these clinical trials had three safety and tolerability end points: treatment-related death, treatment discontinuation related to toxicity, and grade 3 or 4 adverse events.
The assessment of these 38 trials was complicated by the fact that only 13 of the clinical trials reported the proportion of patients with at least one grade 3 or 4 adverse event. Six of the included studies did not report details of treatment discontinuation and, surprisingly, three of the trials did not report data on deaths related to toxicity. Taking these data alone, it seems that the systematic approach to the collection and reporting of toxicity that has been advocated by the FDA, had not been implemented at the time of these trials and is of crucial importance in the future.
The study showed that for all of the safety and toxicity end points assessed, the new drugs performed significantly worse than the old drugs. Amir summarized the more significant findings as: “despite improvements in cancer outcomes and occasionally overall survival, many new drugs are associated with increased toxicity across the board. It should be noted that as this study used data from clinical trials, it is anticipated that the use of drugs in clinical practice where patients are less selected for good performance status and few comorbidities may lead to an even less favourable balance between efficacy and toxicity.”
In their article, the authors state that these toxicities are “the price we pay for progress.” However, they also point out that many of the safety studies of new drugs are carried out at the phase I or II stage, with a small patient population. It seems that it is now time to ensure that phase III registration trials report on the risks as well as the benefits of a therapy, and that the follow up is sufficient after registration to protect patients.
Rebecca Kirk
Original article Niraula, S. et al. The price we pay for progress: a meta-analysis of harms and newly approved anticancer drugs. J. Clin. Oncol. doi:10.1200/JCO.2011.40.3824
I would not do that because Bavi will do more than Avastin or Herceptin and does not
have the toxicity they do, in addition the cost of using both Bavi and Avastin or Herceptin
might be prohibitive. Better to stick to chemo/radiation with Bavi.
Some of the investigator sponsored trials (IST) are run purely by doctors from academic medicine.
As someone working in academic medicine I can tell you that if it is up to the investigators their
results would most likely be presented at a scientific conference and not in a PR from Peregrine.
The PIs get money for travel to meetings in their grants and like to put presentations at meetings
on their CVs. Here is a list of some oncology meetings for the rest of the year.
http://www.asco.org/ASCOv2/Meetings/Calendar+of+Events
http://www.aacr.org/home/scientists/meetings--workshops/meetings--workshops-calendar.aspx
PI for Bavi CRPC trial moves from UCI to MUSC.
http://www.clinicaltrials.gov/ct2/show/NCT01335204?term=Bavituximab+OR+Peregrine&recr=Open&rank=1
May 1, 2012, Charleston, SC – Michael B. Lilly, MD, a noted translational cancer researcher and urologic oncologist, has joined the Hollings Cancer Center at the Medical University of South Carolina to co-lead the cancer center’s translational research program. Dr. Lilly will also see patients with advanced prostate cancer at Hollings and the Ralph H. Johnson VA Medical Center.
Lilly is a recognized expert in the field of targeted therapeutics. Specifically, he has focused on stress response pathways that are triggered in cancer cells and which contribute to resistance to cancer therapy. Many stresses (including the stresses generated by cancer treatment) lead cells to activate defense pathways that allow them to survive the stress.
“We are so fortunate to have a physician-scientist of Dr. Lilly’s caliber join the MUSC faculty,” said Hollings Cancer Center Director Andrew S. Kraft, MD. “He joins Hollings at an exciting time, and I can’t think of anyone better to help foster collaborations between laboratory scientists and clinicians.”
Lilly holds significant funding from the US Department of Defense and the biotech industry. His lab will establish Hollings as the headquarters of a nationwide consortium to carry out a clinical trial in men with castration-resistant prostate cancer previously treated with chemotherapy. His team, in collaboration with UCLA, will work to identify additional ways of improving outcomes for those patients.
....
Dr. Lilly, a professor of Medicine, was recruited from the University of California, Irvine, where he most recently served as vice chief for Clinical Programs in the Division of Hematology/Oncology. He also served as co-leader for the Translational Oncology Program and the Prostate Translational Working Group. Prior to his tenure at the University of California, Irvine, Lilly spent eight years at the Loma Linda University School of Medicine where his leadership roles included director at the Center for Molecular Biology and Gene Therapy.
In the PR in which Peregrine announced the trial was this at the bottom.
"This trial is being conducted by the Chao Family Comprehensive Cancer Center at the University of California, Irvine, through a nationwide consortium of investigators."
So I assume the trial is now being run from the MUSC.
This is pointless. There really is nothing to say until some new data is released. See you then.
Putting the pressure on the BPs they are talking to?
Making it easier to get that loan?
Because they are happy?
Why not?
Where did that date come from?
The foreign trial issue is a red herring because the data will be looked at geographically
and if there was any big difference in results between domestic and foreign it will stand out
and flag the results. The FDA would notice that and so you wouldn't use any foreign data
if it was dubious. This is not something that only small biotechs do, all of the big pharmas
run foreign trials. Part of the reason it that foreign trials are cheaper, and part is that they
are easier to recruit.
I don't know, you tell me why. I have said I think it will happen sooner rather than later.
Because of what I said, too many people have heard about mice being cured, and so
aren't buying it yet. Unless you delve deeply into the science, and few people can, or do,
then you won't have reason to believe it. I think it is as simple as that. Once the survival
data for the human 2nd-line NSCLC is public it will all change in my opinion.
I have read maybe hundreds of papers over the years about curing cancer in mice.
However, when it gets to human trials it is always depressing. The response to
bavi+docetaxel in the 2nd-line NSCLC is a radical departure from the past. It makes it
hard to believe it is actually happening and that mice models are predictive about this.
I am sure this is how many people feel. I believe it and that is why I am here on this
board and why I first bought shares of Peregrine 7 years ago.
This trial listed as near completion, but still recruiting: Paclitaxel and Bavituximab in Treating Patients
With HER2-Negative Metastatic Breast Cancer
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
http://www.clinicaltrials.gov/ct2/show?term=Bavituximab+OR+Peregrine&recr=Open&rank=4
In case you missed it, this is a good article from The New Yorker.
Mostly about CTLA-4 and the T cell disciples, but a good read.
MEDICAL DISPATCHES
THE T-CELL ARMY
Can the body’s immune response help treat cancer?
by Jerome Groopman
APRIL 23, 2012
http://www.newyorker.com/reporting/2012/04/23/120423fa_fact_groopman?currentPage=1
Yes, I was thinking of it more for research purposes. The oncologists would be interested in the survival times, imaging or not.
From today's online issue of the NCI Cancer Bulletin.
I think Peregrine should move ahead on breast cancer as soon as possible.
http://www.cancer.gov/ncicancerbulletin/072412/page12#c
Also in the Journals: No Overall Survival Benefit from Bevacizumab in Breast Cancer, Meta-Analysis Shows
A meta-analysis has shown that adding bevacizumab (Avastin) to chemotherapy may prolong progression-free survival in women with metastatic breast cancer, but the drug has no significant effect on overall survival or quality of life. The findings were published July 11 in the Cochrane Database of Systematic Reviews.
Researchers analyzed data from seven randomized trials involving more than 4,000 women with metastatic breast cancer. In the trials, treatment-related deaths were lower in women receiving bevacizumab, even though the drug increases the risk of serious adverse events that can lead to death.
“Because of the lack of effect on overall survival and quality of life,” the researchers concluded, “it is…controversial whether bevacizumab is associated with a true patient benefit [despite] the increase in progression-free survival.”
Geo, that is a good idea. I would say image them right when they come off the monotherapy and then
every 3 months or so to follow up. I can see the imaging becoming an integral part of the therapy in the future.
Good question. I don't know. Just give a news conference and say you have cured people with metastatic lung cancer!
From the AACR 2012 meeting poster. No chemo used, but androgen deprivation therapy (castration for mice).
Cure of castration-resistant prostate cancer in TRAMP mice by reactivating tumor immunity
with a phosphatidylserine-targeting antibody
Yi Yin, Xianming Huang, Gustavo Barbero, Dan Ye, Philip E. Thorpe
Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX
Yes, I believe he was talking about the prostate cancer study with the TRAMP mice.
That was in a poster at this year's AACR meeting. I think 50% of the mice died of
old age and not prostate cancer.
The more I think about what is going on the more it blows my mind. All I can think is
that the bavi+docetaxel has reversed the immunosuppression and the immune system is
now holding the cancer in check. The metastasis has been blocked and these patients
are doing fine. I am sure some have been cured. The real test will come if they stop
taking bavi as a monotherapy and they don't relapse, then my guess is that they have
developed immunity. IS that possible? I am hesitant to even mention it.
It might not be bavi, maybe another one of the anti-PS antibodies. Yes, most of the
parasitic diseases, and malaria, and TB, etc, are in third world countries.
This is still far in the future when Peregrine would have money for research on other things.
Things like this would have to be funded by the UN or Bill & Melinda Gates Foundation,
as they do for HIV research. However, there are many other viral diseases and bacterial
that anti-PS could possibly be used for in the wealthier countries.
From the trial webpage. No crossovers to bavi.
http://www.clinicaltrials.gov/ct2/show/NCT01138163?term=bavituximab+OR+Peregrine&rank=5
All patients who complete the Combination Therapy Period (or discontinue for any reason other than disease progression or toxicity) will be eligible to enter the Monotherapy Period. Patients will continue to receive assigned blinded treatment (placebo or 1 or 3 mg/kg bavituximab) weekly until progression or toxicity.
Sunstar, if you do a pubmed search you can find stuff about PS and Leishmaniasis
http://www.ncbi.nlm.nih.gov/pubmed?term=Leishmaniasis%20phosphatidylserine
It is definitely an area of investigation and anti-PS is a good bet.
One of the things I would like to see explored, along with other parasitic diseases.
There would have to be a bunch of preclinical work done before you could do a human phase I trial and so
far I haven't seen a sign of that.
It might have some use. I have invested in a lot of small biotechs over the years, but at one point sold them all
and put the money into Peregrine because I believed so strongly in the biology behind it. I did have a few
rules about what companies I would invest in. One of them is no investments in biotechs who only work on
Alzheimers (sorry Thurly). Another is no anti-depressants, and no obesity drugs! No Alzheimers because
the biology was/is too unknown still. I don't know if what they think they are treating is the symptom or the cause.
Also, as they are finding out, by the time a person shows signs of Alzheimers I think it is too late, which means
you would have to treat much earlier to make a difference, which means trials that would last for 10-20 years! No thanks.
The problem with anti-depressants and other such drugs is also that the biology is too unknown and the data is
too subjective for my tastes. I think obesity drugs are bad too because I think they are going to have too
many side effects for a non-fatal (at least in the short term) condition to be useful.
Entdoc, the new phase I trial in stage 2 & 3 rectal cancer before surgery might answer some of your questions.
I do think bavi would have more success with smaller tumors. Seeing how the MOS for the second-line
NSCLC treatment arms have not yet been triggered I would say that bavi works fine in stage 4 cancer,
which is quite amazing.