Gone for good.
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I was pointing out that your original posting
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81016462
implied that this statement somehow implicated Avid, when in fact the statement
was in the Sept 10th PR before the problem was announced.
I said the September 10th PR, before the announcement of the problem with the second-line NSCLC trial.
So this staement has nothing to do with Avid's involvement, or not. Here it is
Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding
Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the
future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forwardlooking
statements involve risks and uncertainties including, but not limited to, the risk that the overall survival data from the
randomized, double-blind, placebo-controlled Phase IIb together with other earlier reported data from the trial may not support
registration filings with the U.S. Food and Drug Administration, the risk that overall survival data from the planned Phase III trial
will not be consistent with the results from the randomized Phase IIb trial, the risk that results from the other randomized Phase
II trial will not be consistent with results experienced in the earlier single-arm Phase II trial or support registration filings with the
FDA, the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs.,
the risk that Avid's revenue growth may slow or decline, the risk that Avid may experience technical difficulties in processing
customer orders which could delay delivery of products to customers and receipt of payment, and and the risk that one or more
existing Avid customers, including those [with committed manufacturing or representing its backlog], terminates its contract prior
to completion. It is important to note that the Company's actual results could differ materially from those in any such forwardlooking
statements. Factors that could cause actual results to differ materially include, but are not limited to, uncertainties
associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the
significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials;
obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for
our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying
with governmental regulations applicable to our business. Our business could be affected by a number of other factors,
including the risk factors listed from time to time in the our SEC reports including, but not limited to, the annual report on Form
10-K for the fiscal year ended April 30, 2012 and quarterly report on Form 10-Q for the quarter ended July 31, 2012. The
company cautions investors not to place undue reliance on the forward-looking statements contained in this press release.
Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking
statements in this press release.
Total BS
This is exactly the same wording that was in the Safe Harbor Statement in the
September 10 PR on First Quarter Fiscal Year 2013. That is before the screw up with CSM.
This has been in the Safe Harbor Statement since the PR released on September 24. It is not new today.
From the SITC poster
http://www.peregrineinc.com/images/stories/pdfs/sitc_2012.pdf
ABSTRACT
Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the
plasma membrane. PS becomes exposed on tumor vascular endothelial cells and tumor
cells in response to chemotherapy, irradiation and oxidative stresses in the tumor
microenvironment. Binding of antibodies to PS on tumor endothelial cells and tumor
cells recruits immune cells and engages the immune system to destroy tumor
vasculature. The antibodies also enhance anti-tumor immunity by blocking the
immunosuppressive action of PS. A chimeric PS-targeting antibody, bavituximab, is
being used in combination with chemotherapy to treat patients with solid tumors in
Phase II trials. Using syngeneic tumors and human tumor xenografts in mice, we have
demonstrated PS targeting antibodies can specifically localize to tumors and antibody
uptake by tumors is enhanced by chemotherapy and irradiation. In addition, PS
targeting antibodies are capable of suppressing tumor growth in multiple tumor types by
several mechanisms including destruction of tumor blood vessels by ADCC
mechanisms, blockage of PS-mediated immunosuppression, and reactivation of
macrophage and T-cell cellular anti-tumor responses. The combination of these
mechanisms promotes strong localized anti-tumor responses without the side-effects of
systemic immune activation.
It is really quite different than the anti-PS platform and not a threat to Peregrine,
if that is what you want to know.
I don't see how this is relevant to bavi at all. Please cite a published paper that tests this idea, based on
network theory, in mice. It is a totally theoretical idea about how some aspects of the immune system
function that needs to be tested in the flesh.
The innate immune response is not to specific antigens but is more general, like to LPS from gram-negative
bacteria, or other molecules which signal infection but are not specific to a particular pathogens. Many times
the adaptive immune response doesn't even get activated because the innate response has taken care of the problem.
In case any of you missed it, this research is what Thorpe was talking about with the mice model that spontaneously
generates prostate tumors. This poster was presented at this year's AACR meeting.
http://www.peregrineinc.com/images/stories/pdfs/aacr_2012_prostate_cure.pdf
I agree. I have listened to sections of it 4 or 5 times. It is all there.
Andy, that about sums it up. The rest is noise.
Best post I have read in quite a while.
Mark
Thorpe wasn't at the ASM.
The whole idea as talked about by Thorpe is to switch the microenvironment so that the dendritic cells are
then allowed to mature and present antigen to T cells and start the whole adaptive immune response.
That is why he refers to "awaking the adaptive immune response", because it is blocked and then
becomes unblocked. Yes, bavi does work through the innate immune response, but it also has the ability
to utilize the adaptive immune response. You might want to reread that paper. The F98 tumor is poorly
immunogenic in the rat model. Thorpe also talks about this in his NYAS webcast. Here is the survival data.
You can see that it is only the rats that received the combination treatment of radiation and antibody that developed immunity.
The point with the serum therapy is that antibodies were being injected and they neutralized the diptheria toxin
and saved the lives of the patients. It is an old example of an immunotherapy.
If you want to do some reading the paper you cite is freely available to anyone
http://www.neoplasia.com/abstract.php?msid=5083
The "inflammatory intratumoral infiltrates" in this case are neutrophils and macrophages. Both
were mostly in the N1 and M1 state which are immunostimulatory and are able to phagocytose the tumor
vasculature cells opsonized with bavi. The neutrophils, which are granulocytes, are involved probably
because in this case surgery was done first, and then bavi and cisplatin given. The effect of surgery
is like a response to a wound when neutrophils quickly arrive at the scene. These cells are described as
inflammatory because of the types of cytokines they release. In Thorpe's NYAS webtalk he talks of these.
The whole idea of switching the macrophages from a pro-tumor M2 state to a anti-tumor M1 state lies
at the heart of understanding the MOA. If this does not occur then the macrophages won't
be able to phagocytose the tumor vasculature endothelial cells which have PS exposed on them.
So bavi first has to enable this switch by a process Thorpe talks about in the NYAS talk and I have
diagrammed here
So the tumor microenvironment is switched from a immunosuppresive state to a immunostimulatory state.
Then the arriving neutrophils which enter the tumor remain in their N1 state and are not switched to a N2 state.
It is thought that the presence of the cytokine TGF-beta does this. When the tumor microenvironment
is in the immunosuppressive state TGB-beta is produced by the macrophages, but when the macrophages
are switched to the M1 state by bavi then TGF-beta is not produced. The concept of how the immune cells
behave, either pro- or anti-tumor, depending on the local conditions in and around the tumor site, i.e. what
cytokines are present, is crucial to understanding how bavi works.
Bavi linked to iodine-131 should still work the same way. I think the issue is more
of the complications of using a radioactive isotope for treatment. It brings up a lot
of regulatory issues dealing with the disposal etc. that might not make it very
attractive for use on a large scale. Isn't that what happened to the two cases you cite?
It is working at the local level where the tumor is. It does not necessarily have to induce systemic responses.
Well, serum therapy from over a hundred years ago was first used to treat children with
diphtheria and save their lives. That was an immunotherapy.
I suggest you read Thorpe's paper using radiation in the rat model of glioblastoma.
The radiation increases the amount of PS on the tumor vasculature and tumor cells, as
does the chemotherapy. That is why bavi has to be used with one or the other, to increase
the amount of target PS. In that paper, and Thorpe also showed a slide of the survival
in the NYAS webcast, it is shown that 13% of the rats became immune to the glioblastoma.
Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma
FREE: http://clincancerres.aacrjournals.org/content/15/22/6871.long
When you cut your finger and it gets infected do you get a fever? Usually not, it is
only when the infection can't be controlled locally by the immune system and it spreads.
Then prostaglandin E2 (PGE2) gets in your blood and travels to the hypothalamus in your
brain which controls your body temperature.
For one thing human evolution does not extend back 50 million years. Fever and chills are systemic responses.
Fever is controlled by the hypothalamus when acted upon by the molecule PGE2.
Bavi has its effects in the tumor microenvirnoment and tumor vasculature and does
not seem to trigger such systemic responses when it is acting locally.
A complete response is when the evidence for a tumor, such as seen in imaging, is not
detected during the treatment phase when the clinical responses are evaluated. Many
complete responses don't last but relapse because there are still tumor cells around
that have survived the therapy and then proliferate and are resistant to the therapy.
The only way to tell if patients have developed immunity is to wait and see if they are
cancer-free over a long period of time, free of relapse. Obviously you can't inject
tumor cells into the survivors to see if they are immune as you can with mice.
It is not true that
bavi helps the innate immune response triggered by the chemo/radiation damage, but by itself does nothing tangible because the cancer cells have learned to evade the immune cells and PS molecule is just one of several mechanisms of evasion
I believe it will create immunity to cancers, as it has in mice. What difference is
there that would prevent that from happening in humans? Based on the mechanism of action
proposed just exactly would stop it from working the same way on mice and humans?
The radioisotopes used in imaging, here iodine-124 and zirconium-89, emit positrons (anti-electrons).
That is why they are used in PET (positron emission tomography) for imaging.
http://en.wikipedia.org/wiki/Positron_emission_tomography
The radiation that is used to treat cancer is ionizing radiation, that is x-rays or gamma-rays,
as in Cyber Knife or Gamma Knife.
http://en.wikipedia.org/wiki/Radiosurgery
The human immune system is not far more complex than the immune system of mice.
All the same immune cells are there, neutrophils, macrophages, dendritic cells, T cells, you name it.
Fever and chills are general responses to an infection. Bavi does not work that way.
It is very specific to its target and the tumor microenvironment.
Wouldn't it be nice if Peregrine released the data from the trial once the revisions have been made.
This could be done if all identifying data is removed. I don't think any company does this, but it would
be nice to have the actual data.
The Kaplan-Meier analysis is an estimate which takes into account the censored patients. I want to see the percentage
of actual patients who are alive after one year on the different arms.
The curves are crossing each other and on top of each other even after 3 months, so to me they have
not separated until 4 months or so, just about the time the treatment cycles finished.
It has now been over a year since all patients completed treatment in the second-line NSCLC phase IIb trial.
When the revised data is released it will be interesting to know the one-year survival rate. Regardless of whether
the patients received 1mg/kg, or 3 mg/kg, or some combination of the two, the percentage of patients
surviving after one year, compared with the control arm patients, should be a good indicator of how
well bavi works. That would be valuable information for any potential partner.
Silver lining to the problem?
Let us assume that the phase IIb NSCLC trial data is corrected and released and still shows very good results.
We will know that the trial data will have been examined more thoroughly than most any other phase IIb trial, ever.
The FDA will have agreed to the release of the corrected data since they approved the initial trial and licensed CSM, Inc.
In this regard I think investors could put more faith in the results than before this happened.
It won't any longer be "too good to be true", but just "great".
Doesn't really matter. If nothing works over the next 9 months then game over.
Just for accuracy, the third quarter of calendar year 2013 is through September of 2013, not March.
From PR 10/17/12 "and assuming the company does not receive additional proceeds from other potential sources of capital, this funding should provide the company with sufficient capital to reach potential upcoming clinical and development milestones through the third quarter of calendar year 2013."
Here is a picture of the structure of a capillary. Imagine these throughout a tumor and then bavituximab
binding to PS exposed in the lumen. The wall of the capillary has a layer of endothelial cells that is just one cell thick.
If macrophages bind to bavi and then eat holes in that layer of cells you can imagine the structure collapsing.
Probably just some IT guy screwed up. That happens often enough!
I was thinking that they might learn something about PS and cardiovascular disease that has wider application than just APS.
There is this oral presentation next month at the annual American Heart Association meeting.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=78993901
There might be something interesting about PS and cardiovascular disease.
Session: AOS.703.02a-Novel Signaling Pathways in the Regulation of Endothelial Function
Presentation: 13186 - Development of Novel, Mechanism-Based Therapies to Prevent the Cardiovascular Complications of the Antiphospholipid Syndrome
Pres Time: Wednesday, Nov 07, 2012, 10:00 AM -10:15 AM
Location: Hall A-8
Specialty: +703. Endothelium, Vascular Tone and Nitric Oxide
Keywords: Endothelial function; Nitric oxide; Cardiovascular therapeutics; Thrombosis; Angiogenesis
Authors: Victoria Ulrich, Philip Shaul, Philip Thorpe, Chieko Mineo, UT Southwestern, Dallas, TX
Disclosures: V. Ulrich, None; P. Shaul, None; P. Thorpe, Peregrine Pharmaceuticals, Inc., Significant,Other Research Support; Peregrine Pharmaceuticals, Inc., Significant,Ownership Interest; Peregrine Pharmaceuticals, Inc., Significant,Consultant/Advisory Board; C. Mineo, None.
This is what PGN635, the fully human antibody would look like. It is then linked to the near-infrared (NIR)
probe IRDye800CW to make 800CW-PGN635.
The top part of the antibody, F(ab')2, is the part of PGN635 that is called PGN650. It is then linked to
the radioisotope iodine-124 to make I124-PGN650.
The Fab end, or variable region, of the antibody is what binds to beta2-GP1, which binds to PS.
A macrophage would bind to PGN635 via the constant region, or Fc end, of the antibody using the Fc-gamma
receptors on the macrophage. Note that this cannot happen with PGN650 since the Fc end has been cut off by using
the enzyme pepsin. So I124-PGN650 won't interact with macrophages and DCs, but will block the exposed PS.
I see CJ beat me to it.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=80298325
New conference presentation on imaging.
SPIE BiOS, part of SPIE Photonics West, where the latest on biomedical optics, diagnostics and therapeutics, biophotonics molecular biology and genetics, optical microscopy, optical coherence tomography, and optogenetics research are presented and discussed.
2 - 7 February 2013
The Moscone Center
San Francisco, California
Imaging of tumor vascular endothelial cells in living mice
Paper 8596-3
Author(s): Dawen Zhao, Jason H. Stafford, Heling Zhou, Philip E. Thorpe, The Univ. of Texas Southwestern Medical Ctr. at Dallas (United States)
Abstract
Phosphatidylserine (PS) is normally intracellular but becomes exposed on the luminal surface of vascular endothelial cells in tumors. Here we optically imaged exposed PS on tumor vasculature in vivo using PGN635, a novel human monoclonal antibody that targets PS. NIR imaging was performed after injection of IRDye800CW-PGN635 into mice bearing glioma or breast cancer. A clear tumor contrast was visible 4 h later and became maximum 24 h later. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive tumor vascular endothelial cells. Our studies suggest that tumor vasculature can be successfully imaged in vivo to provide sensitive tumor detection.
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Looks like a presentation of their recent paper, but with more results in a breast cancer model too.
http://www.transonc.com/abstract.php?msid=234