Gone for good.
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Thanks for pointing that out. I listened to the NYAS Q & A session and heard that about leukemia and lymphoma.
ENTdoc, I think of the PS as just a target. In the figure I drew the important point is what happens in the
macrophage (or DC), which is what would be to the left of the long membrane with the PSR and Fc-gamma-R (FcgR) on it.
I am going to try to describe this in detail for others who might be interested.
When the PS receptor (PSR) binds to the exposed PS a signal transduction pathway is activated in the macrophage.
This pathway results in the expression of genes which code for anti-stimulatory cytokines, as shown in the figure.
These cytokines are secreted by the macrophage and then affect other nearby immune cells putting them into
a state which is non-stimulatory. This would happen if the macrophage encounters a cell that has undergone a normal
death by apoptosis and needs to be removed, i.e. cleaning up the garbage.
Now if there were pathogens present and antibodies to them also present then the antibodies would bind to the
pathogen. The macrophages then bind to the antibody through their Fc gamma receptors. This activates a
different signal transduction pathway which results in a different set of genes being expressed, and then the
secretion of pro-stimulatory cytokines. These different cytokines alert the surrounding immune cells
that there are pathogens present so to go on the attack. What does that have to do with bavi?
Bavi is just an antibody that binds to its target PS. The important point is that the macrophage binds to
bavi using its FcgRs which then activate the production of the pro-stimulatory cytokines and cause
the activated macrophage to eat whatever is connected to the antibody. When the DCs also do this then
they can present antigens to T-cells and lead to development of long-term immunity (natural antibodies
against the pathogens or tumor cells). In the figure you can see that both the PSR and the FcgR are present. I show how
the signal from both are integrated in the little box and the resulting signal comes out. This shows that the pro-stimulatory
signal over-rides the anti-stimulatory signal. Think of many receptors and how the resulting effect depends on
a majority of one type of signal or the other. Of course it is not this simple as there are many other such
receptor-ligand combinations that can also contribute to the overall resulting signal. So adding bavi can
overwhelm the immunosuppressive signal that the PS by itself would trigger in the macrophage, and switch
the signal to a pro-stimulatory one, i.e. switching the macrophage from the M2 state to the M1 state.
Of course adding bavi will also mean that it will compete with the PSR for binding to PS and so that will also
contribute to the net result. Enough bavi could result in competitive inhibition of the PSR binding to PS.
If you look at things this way it comes down to turning signals on and off so you just need to find the best
way to do that. Using bavi is just utilizing a natural pathway that already exists to activate the immune system.
Bavi is working at a fundamental level here and that is why I find it so powerful.
I hope I haven't totally confused everyone!
I have been thinking about how the understanding of the mechanism of action (MOA) for bavituximab has
evolved over the last decade. In the beginning the MOA was thought to be the destruction of the tumor
vasculature by macrophages which engaged the bavi antibodies bound to PS via the beta2-GP1 molecules on
the surface of the vascular endothelial cells. There was also an early understanding that exposed PS can be
immunosuppressive for macrophages and dendritic cells (DCs). Over time there has developed an understanding
in the cancer immunotherapy community that the tumor microenvironment is manipulated by the tumor
to a state which is advantageous to tumor survival, as you might expect. This shows up in the ratio of macrophages
which are in the M2 pro-tumor state versus the M1 anti-tumor state. This has now been extended to a similar
N2 to N1 ratio of neutrophils, and of DCs. This new knowledge of the tumor microenvironment changes
the understanding of the MOA for bavi. The central idea now is that the tumor establishes a microenvironment
that promotes its own survival, as you would expect from an evolutionary viewpoint. I now see the
main MOA of bavi as reversing this immunosuppressive microenvironment by the effect bavi has on macrophages.
I drew this figure before to show how this can happen when bavi binds to microvesicles (or exosomes)
or PS on the tumor vasculature.
Once this change has been effected from a pro-tumor microenvironment to an anti-tumor microenvironment
then the immune system is enabled to bring its full power to bear against the tumor. This entails the switching
from the M2 to the M1 state of macrophages ( and neutrophils and DCs), which then are enabled to phagocytose
(eat) the tumor endothelial cells which have PS exposed. So it is this switch which makes possible the initial
idea for bavi's MOA, that of destruction of the tumor vasculature. Dr. Thorpe talked of this in his NYAS webcast.
This switch also reduces the immunosuppression of the T cell response, that is the adaptive immunity arm, which
can lead to long-term immunity.
To me this change in emphasis of bavi's MOA leads to the idea that bavi can be used on more than just solid tumors.
The use on only solid tumors followed from the initial understanding of the MOA. Now we can see that the MOA is
much broader, that of reversing immunosuppression and awakening the total immune response to cancer.
This might mean that bavi could be useful in leukemia and lymphoma if there can be shown to be an immunosuppresive
environment that could be reversed by bavi. Perhaps these types of cancers also produce microvesicles to
thwart the immune response which can be neutralized by bavi. I hope you find this as interesting as I do.
FTM
ENTdoc, Listening to the webcast again you can hear when King is talking about the first-line NSCLC trial that
there were differences in PFS between the "central reads" and the "local reads at the hospital". This to me
means differences between the independent evaluations of PFS done later by the central reviewers and
the reads done by the investigators on the patients when they came into the hospital for evaluation. It does not
imply anything about differences between foreign and domestic evaluations.
I have read a couple of estimates for the first-line NSCLC treatment arm to be at about 15 months and counting.
It has been 13 months since the enrollment was completed. If you look at this chart for the range of control arm
MOS that I had previously posted you see that the mean is 9.8 months with a standard deviation of 1.3 months.
This suggests the most probable value for the control arm MOS is in the range from 8.5 to 11.1 months. Assuming
that the 15 months for the treatment arm is correct, then currently the treatment arm is probably exceeding the
control arm MOS in the range of 35% to 76%. If the treatment arm MOS were to be reached in January with a
value of 18 months then the treatment arm MOS would be exceeding the control arm MOS in the range of 62% to 112%.
So a doubling of MOS is still possible in this scenario. RRdog do you have an update on your estimate?
Nuke, I heard what you did. I was surprised to read what ENTdoc wrote. I think he just got things a little mixed up.
Loofman, I am glad you won't do this. I don't want to read a bunch of stupid bragging about how many shares people own,
or say they own. I will say that after attending the ASM I will buy some more shares as the price drifts lower before news
about the investigation is released.
Back from the ASM.
First of all I want to thank everyone I met for their kind words about my posts. I was overwhelmed by their gratitude.
I especially want to thank Dan (Mahoney1) for transportation and sharing his dinner on Wed night, also
Paul (eb0783) for sharing his dinner too. I also want to thank Robert Jonson and his lovely daughter for
their hospitality and company. A big thanks to North40000 and his wife for my dinner Thursday evening, it was quite good.
I have read Mike's (gandolph120) account of the meeting and agree with everything he said. I am glad someone
was taking notes. I spent the time during the presentation looking at the back of Dr. Garnick's head and
watching the bored board members. Nothing new there, just the usual corporate presentation that Steve King has memorized.
After the Q&A I talked to Dr. Jeff Hutchins the new VP for preclinical development. I was interested in his take
on an idea I had for future uses of bavituximab. He seemed open and interested in my ideas and contributed some thoughts.
I talked to Jay Carlson a few times. I have known Jay for a few years through e-mail and was glad to finally
meet him. He talked to me as a friend and not as the IR guy with an investor. He seemed open and just as
shocked by events as all of us are. My overall impression of the meeting was positive despite the circumstances.
I feel the company was telling us all they could, and wanted to say more, but were constrained by legal and regulatory issues.
However, the best part of the whole experience was meeting the investors who were there from iHub.
It is great to have a face and name to go with their online handles. They have given me motivation to keep posting.
I was wondering that too. Does it mean something? Some news perhaps, or just trying to put
a positive face forward? I'll be there tomorrow.
The grant is from the State of Texas to Thorpe, a professor at University of Texas Southwestern Medical Center.
The patents are assigned to the University of Texas system and are then licensed to what ever company they want.
Future patents are not necessarily going to be licensed to Peregrine, although there may be a lot of overlapping patent
claims which would make it easier to license them to Peregrine. Just my take on it.
I think you are correct. Strange coincidences with the names, sort of like Peregrine Financial
and Peregrine Pharmaceuticals.
In case you missed it, it says this at the bottom of the webpage.
Oxford Asset Management does business under the names Oxford Financial Trust,
and Oxford Financial and is a separate company from OneSource. Mr. Palumbo is
principal of both companies and most of our advisors are registered with both companies.
Entdoc, I will be there. Thanks.
Here is the timeline as far as the paper goes.
Article history:
Received 29 June 2012
Received in revised form 6 September 2012
Accepted 6 September 2012
From the Acknowledgments section of the paper
We would like to thank Philip Thorpe and Nicholas van Bruggen
for helpful discussions, Peregrine Pharmaceuticals, Inc. for providing PGN635,
I would obviously think that using PGN635 or PGN650 in an imaging agent would require
that licensing would have to be obtained and royalties paid. It doesn't really matter
what isotope is linked to the antibody. Depending on its use one isotope might be better than the other.
Remember this about PGN632, PGN635 and a type of AMD.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=75520883
Entdoc, you never know. Maybe Genentech would be interested in a partnership for imaging?
The paper does have this at the end of the discussion section.
...
the presented PS-targeting antibody (89Zr-PGN635)
has a potential to become a broadly applicable imaging agent
independent on cancer type since PS is a generic component of the
plasma membrane.
New paper on imaging using PGN635. Available online 10 Oct 2012.
ImmunoPET imaging of phosphatidylserine in pro-apoptotic therapy treated tumor models
Nuclear Medicine and Biology
Annie Ogasawara 1, Jeff N. Tinianow 1, Alexander N. Vanderbilt, Herman S. Gill, Sharon Yee, Judith E. Flores,
Simon-Peter Williams, Avi Ashkenazi, Jan Marik
Genentech Research and Early Development (gRED), Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
http://www.sciencedirect.com/science/article/pii/S0969805112002302
-------------------------------------------------------------------
ABSTRACT
An immunoPET imaging probe for the detection of phosphatidylserine was developed and tested in animal
models of human cancer treated with pro-apoptotic therapy. We hypothesized that the relatively long plasma
half-life of a probe based on a full-length antibody coupled with a residualizing radionuclide would be able to
catch the wave of drug-induced apoptosis and lead to a specific accumulation in apoptotic tumor tissue.
Methods: The imaging probe is based on a 89Zr-labeled monoclonal antibody PGN635 targeting
phosphatidylserine. The probe was evaluated pre-clinically in four tumor xenograft models: one studied
treatment with paclitaxel to trigger the intrinsic apoptotic pathway, and three others interrogated treatment
with an agonistic death-receptor monoclonal antibody to engage the extrinsic apoptotic pathway.
Results: High accumulation of 89Zr-PGN635 was observed in treated tumors undergoing apoptosis reaching 30
%ID/g and tumor-to-blood ratios up to 13. The tumor uptake in control groups treated with vehicle or imaged
with a non-binding antibody probe was significantly lower.
Conclusions: The results demonstrate the ability of 89Zr-PGN635 to image drug-induced apoptosis in animal
models and corroborate our hypothesis that radiolabeled antibodies binding to intracellular targets
transiently exposed on the cell surface during apoptosis can be employed for detection of tumor response
to therapy.
-------------------------------------------------------------------
Note this is a different imaging agent than used in the imaging trial, which uses 124I-PGN650
http://www.clinicaltrials.gov/ct2/show/NCT01632696?term=bavituximab+OR+Peregrine&recr=Open&rank=5
You are exactly right. I haven't claimed I know much about censoring or how Kaplan-Meier analysis really works.
The point is you shouldn't be arguing about a subject you don't really know anything about. So I am going
back to watching and waiting.
My point was that people are arguing about things they know nothing about.
What is the difference between left-censored and right-censored data?
I am taking a long break from this board to retain my sanity and health.
I believe that some day the science will be vindicated, perhaps sooner rather than later.
There are still the pancreatic and liver cancer trials plus the ISTs. We can hope.
If there was foul play involved in any of this I hope those involved get cancer, it would only
be fitting.
I don't know the details of what is allowed or not. I would assume they can inspect the sites from time to time,
but they shouldn't have any access to data and the sites would receive blinded materials for the patients
and not know what patients are getting what treatment. That is the whole idea of a blinded trial, nobody along
the chain should know anything.
No, they don't have access during the trial to any data, that is why it is blinded and the FDA approved
the protocol, just like for all the other phase 2 studies run by any company.
I was looking at the plot and can see about as many censored patients on the control arm as on the
1 mg/kg arm, and very few on the 3 mg/kg arm. It is difficult to see them. What is your count?
This is part of the protocol that tested for antibodies against bavi that might occur because of the chimeric
nature of bavi. I don't think this particular test had anything to do with the reported problems. As I said before
I think the problems were detected in preparing the final documents for the end of phase II meeting with the FDA.
Don't waste our time with this BS
The patient demographics from the study show 42 Asian patients.
Where did you see that India had 60 patients?
I see an office in San Diego, not Orange County.
8899 University Center Lane, Suite 400
San Diego, California 92122
The link is broken right now. Tried multiple times.
I found this on the WHO database, but it is for the FIRST-LINE NSCLC trial.
http://apps.who.int/trialsearch/trial.aspx?trialid=CTRI/2010/091/001402
This is an example of a CRO that covers the world. PAREXEL.
http://www.parexel.com/services-and-capabilities/clinical-logistics-services/
They can do everything needed for a clinical trial.
Contract research organizations
http://en.wikipedia.org/wiki/Contract_research_organization
List of CROs
http://en.wikipedia.org/wiki/List_of_contract_research_organizations
You are probably correct. Peregrine would have to hire some CRO to do an audit, and
probably get FDA's approval of them. It may be a problem to find one that isn't busy
doing other trials at the moment. These are pretty specialized firms and may be booked
up some time into the future. I suppose if you paid enough you could move to the head of the queue.
That makes no sense at all. If the Bavi low dose group got no bavi then it should be
just like the control arm and the survival curve for the low dose group would be very
similar to the control arm.
NO, where did you read that?
Found this FDA document which might shed some light on how these errors were discovered.
Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance
http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/ucm219488.htm
page 63 (of 63). The first document listed
So I assume that in the process of compiling this document they found the errors and that triggered an audit to be
done by an independent organization. I assume the errors were discovered during this phase to wrap up everything
before talking to FDA about phase 3 trial.