Gone for good.
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Maybe the HCV data will be presented at this conference.
The EASL 2012 conference April 18-22, 2012 in Barcelona.
http://www2.kenes.com/liver-congress/pages/home.aspx
Here is the missing poster from CBDST 2011.
EVALUATION OF PHOSPHATIDYLSERINE TARGETING ANTIBODIES
AS A POTENTIAL TREATMENT FOR ARGENTINE HEMORRHAGIC FEVER
Grant, A.M.1; Sbrana, E.1; Popov, V.L.1; Wakabayashi, M.2; Schlunegger, K.2; Freimark, B.2; Brideau-Andersen, A. 2; Peters, C.J.1
1University of Texas, Medical Branch, Galveston, TX; 2Peregrine Pharmaceuticals, Tustin, CA
http://investorshub.advfn.com/uimage/uploads/2012/1/13/qmkqsCBDST2011_poster.jpg
Targeting of Anionic Phospholipids Exposed on Infected Cells and Virions: Potential Broad-Spectrum Antiviral Therapy
Remember this poster from the Chemical & Biological Defense Science & Technology Conference, 2010 Abstract #157
Phosphatidylserine (PS) is normally maintained on the inner leaflet of the
cell membrane. Viral infection induces flipping of PS to the outer surface
of the cell. This exposed PS causes the immune system to treat the
infected cell as a dead or dying cell rather than an immunogen, effectively
dampening the immune response to infected cells and viruses released by
the cells. PGN401 (Bavituximab) is an candidate antiviral drug that is a
chimeric monoclonal antibody (mAb) that recognizes PS. Binding of
PGN401 promotes immune recognition of enveloped viruses and infected
cells and activates antiviral defenses via antibody-dependent cell-mediated
cytotoxicity (ADCC). PGN401 has been shown to have inhibitory activity
against HIV-1 in peripheral blood mononuclear cells (PBMC) and Pichinde
virus (PCV) infection in guinea pigs modeling arenaviral hemorrhagic
fever. Further, PGN401 is being clinically evaluated for the treatment of
hepatitis C virus (HCV) and HCV-HIV-1 co-infections. Here, we
demonstrate that PS-targeting mAbs bind several virus and virus-infected
cells including Junín and Ebola. We also present in vivo efficacy data
evaluating PGN401 in combination with Ribavirin in animal infection models
involving Punta Toro virus (PTV) and PCV, both hemorrhagic fever
viruses. These combination studies strongly suggest a synergistic
therapeutic effect between PGN401 and Ribavirin. Further therapy studies
in Junín and Ebola animal models are underway. Our data further support
the idea that targeting PS has the potential to work against a broad
spectrum of viruses and other infectious agents that induce the cell surface
exposure of PS.
Here is a paper which shows that ribavirin increases the amount of PS exposed on red blood cells.
Morphological transformation and phosphatidylserine exposure in erythrocytes treated with ribavirin.
Homma M, Hosono H, Hasegawa Y, Kohda Y.
Biological & pharmaceutical bulletin. 2009 Nov;32(11):1940-2
So maybe it does also in other cells infected with HCV.
The infection of a host cell with HCV by itself should expose PS on the outer membrane of the host cell,
as is seen with other viruses. Adding ribavirin should further increase the targets for Bavi. That was
seen with the hemoraghic fever results.
The consistency of results between the animal models and the human trials has always impressed me.
I think there are very few cancer treatments that can claim that.
It does make it easier to have confidence in the whole approach. Why are they so
consistent? I think it is because using PS as a target and the whole immuno-
suppression link is a very basic feature of immune systems. Also, PS is universal to cell membranes.
I look forward to the next generation of immunocytokines which should be even better than bavi.
I think most people have not yet realized how different this approach is, how universal it is, and how
powerful the immune system can be when it is able to unleash its power.
Here is figure 4 from the AACR poster by Cheng and Thorpe on HCC and Sorafenib.
It shows the synergy between 2aG4 (mouse version of bavi) and Sorafenib. Note how 2aG4 alone is no
better than the control, but sorafenib induces PS exposure and then the combination of 2aG4 and sorafenib
is significantly better than sorafenib alone.
About the Phase II front-line NSCLC trial.
I have been looking at the past studies for this indication. The historical control
cited by Peregrine in their PRs is from the phase III trial comparing Avastin +
carboplatin + paclitaxel (ACP) with carboplatin + paclitaxel (CP). Sandler et. al. NEJM; 2006, 355: 2542-50.
The response rate for CP was 15%, the MOS was 10.3 months, the median progression-free survival
(PFS) was 4.5 months; versus 35%, 12.3 months, and 6.2 months for ACP.
However, if you look at other phase III trials for front-line NSCLC you can find response rates, MOS, PFS,
for CP that vary quite a bit. There was one large trial that compared 4 different chemo regimens,
all of which were platinum based, one of which was CP. The trial, Schiller et al.,NEJM; 2002, 346: 92-98,
found no difference between them. The overall results (N=1155) were response rate of 19%, MOS of 7.9
months, and PFS of 3.6 months. My point is that the historical control for CP cited by Peregrine may be,
in fact, not representative. That is, past studies showed higher response rates, shorter MOS and PFS times,
for CP than the cited control. That would make the MOS of 12.4 months, PFS of 6.1 months for the first
phase II NSCLC bavi + CP trial look even better.
If these numbers for Bavi + CP were to hold up in a phase III trial then I have no doubt that Bavi + CP would be
approved for front-line NSCLC. Given that the results are virtually the same as for Avastin + CP, which is
approved, and that Bavi + CP has fewer side effects, then Bavi + CP could become the preferred treatment.
The phase III trial for sorafenib in advanced liver cancer was Llovet et. al. NEJM. 2008, 359, pp 378-390.
At the time there was no treatment for this indication. The results were:
median overall survival sorafenib: 10.7 months, placebo: 7.9 months
complete response sorafenib: 0, placebo: 0
partial response sorafenib 2%, placebo: 1%
stable disease sorafenib: 71%, placebo: 67%
So it seems that the approval was all based on the MOS. The UTSW trial of bavi + sorafenib uses
the same dosing of sorafenib. Looks like an unmet need to me.
Mojo, good point. In that case, assuming the same scenario of enrollment
and death, the 80% threshold would be reached on August 22, 2012. It all
depends on how soon the enrollment is completed.
I was thinking about the timeline for the pancreatic cancer trial.
The trial started enrollment on Jan 5, 2011. Assume that one new
patient is enrolled every week. The trial size is 70 patients, which
means that it will take 35 weeks to enroll 50% of the patients. This
would have occurred on Aug 31, 2011. Next assume that each
patient lives for 7 months (30 weeks). This means all of the first 50%
of patients enrolled will have died after 65 weeks. That would occur
on March 28, 2012. The last patient enrolled will be at week 70, which
would be on May 2, 2012. So, the median overall survival (50% are still
alive) would be reached before the last patient is enrolled, assuming the
above. If this were true then by ASCO in early June we could know the
results of the pancreatic cancer trial. Of course, this is being optimistic.
We need to push Peregrine to pursue breast cancer. Bavi seems to work pretty
well for metastatic breast cancer. The fact that there were complete responses
is very good. Why isn't this being pursued?
A friend of mine, a woman I went to high school with, died today of metastatic
breast cancer. Her brother and I were best friends. Her father died years ago
from melanoma, her sister is a breast cancer survivor. This cause is personal.
Here is the latest on Dr Haynes. I guess the Infectious Disease Society of America (IDSA) is part of the conspiracy!
Alexander Fleming Award Winners
Current Winner
BARTON F. HAYNES, MD, FIDSA, a thought leader in the fields of human host-pathogen interactions and immune reconstitution, is the recipient of IDSA’s 2011 Alexander Fleming Award for Lifetime Achievement. This award recognizes a career that reflects major contributions to the acquisition and dissemination of knowledge of infectious diseases. Dr. Haynes has been a pioneer in the development of a vaccine for HIV. Through his seminal work in the biology of human thymic epithelium and thymocytes, he has enriched our understanding of human thymic function and established the foundation for thymic cell transplantation for the curative treatment of DiGeorge Syndrome.
Dr. Haynes is the Hanes Professor of Medicine and Immunology and director of the Duke Human Vaccine Institute. His research during the last 10 years has focused on the development of an HIV-1 vaccine. Through his work, Dr. Haynes has demonstrated the importance of tolerance and other immunoregulatory mechanisms in hampering the development of broadly neutralizing antibodies against HIV-1, launching HIV vaccine development into a new direction.
After receiving his medical degree from Baylor College of Medicine in 1973, Dr. Haynes completed his medical residency and internship at Duke Hospital in Durham, North Carolina. From 1975 to 1980, he worked in various roles at the National Institute of Allergy and Infectious Diseases. In July 1980, he began teaching at Duke University in the Departments of Medicine and Microbiology and Immunology. In 2005, he was named director of the National Institutes of Health Center of HIV/AIDS Vaccine Immunology (CHAVI), an international consortium of scientists with the task of developing an effective HIV-1 vaccine. Under his leadership, CHAVI has defined the early T cell responses to HIV and their protective nature, provided the most extensive assessment of HIV antibody responses during acute HIV infection, and developed vaccine candidates that are entering clinical trials. Dr. Haynes has published more than 480 journal articles and served on the editorial boards of numerous scientific publications such as the Journal of Clinical Immunology and Blood.
In recognition of his outstanding contributions to the field of infectious diseases and immunology for more than 30 years—from his groundbreaking research to develop thymus transplantation for T cell deficiency to his work to develop a vaccine for HIV/AIDS—IDSA is proud to present Dr. Haynes with the 2011 Alexander Fleming Award for Lifetime Achievement.
http://www.idsociety.org/Alexander_Fleming_Award_Winners/
I don't see it that way at all. I believe that Haynes et al has done the research,
using Gates Foundation money, to figure out the MOA of the anti-lipid
antibodies in HIV infection. Duke may get the patent for how this MOA can
be used in a microbiocide, but Peregrine still has the antibodies and so would
get some sort of royalty. It might be possible that Gates would pay for a
clinical trial of the microbiocide in Africa. The pay off for Peregrine would be
a huge validation of their anti-phospholipid approach, and publicity, but this would
be years away. By then Bavi should be approved for a cancer indication.
This is from the SEC form 10-Q, quarterly report for quarter ending July 31, 2010.
Filing date: Sep. 9, 2010.
ITEM 6. EXHIBITS.
(a)
Exhibits:
10.26
License Agreement between Stason Pharmaceuticals, Inc. and Peregrine Pharmaceuticals, Inc., dated May 3, 2010.**
10.27
Assignment Agreement between Stason Pharmaceuticals, Inc. and Peregrine Pharmaceuticals, Inc., dated May 3, 2010.**
These have to do with the TNT antibody stuff. So, I think it is a coincidence.
There could be something to this, or just coincidence? These two patent
applications were filed as a pair on the same day, Sep. 8, 2009, by Haynes et al.
US Patent Application US 2011/0262526
Publication Date: Oct 27, 2011
title: METHOD OF INDUCING AN ANTI-VIRAL IMMUNE RESPONSE
PCT Filed: Sep. 8, 2009
PCT No.: PCT/US2009/005024
Deals with anti-lipid antibodies but does not include any Peregrine antibodies,
but specifically antibodies CL1, IS4, P1, among others.
---------------------------------------------------------------------------------------------------
US Patent Application US 2011/0318360
Publication Date: Dec. 29, 2011
title: ANTI-LIPID ANTIBODIES
PCT Filed: Sep. 8, 2009
PCT No.: PCT/US2009/005023
Deals with anti-lipid antibodies and now includes Peregrine antibodies
(PGN632, PGN635, PGN634, PGN401), and the others from above.
Here is a figure from the first application above which summarizes what is going on.
Entdoc, like you I look forward to the future when bavi is paired with something else.
I am thinking the Bavi-IL2 immunocytokine as in the Vaccine paper from 2011:
Enhancing the potency of a whole-cell breast cancer vaccine in mice with an
antibody-IL-2 immunocytokine that targets exposed phosphatidylserine
by Xianming Huang,DanYe,PhilipE.Thorpe
I think this second-generation could be much more efficacious. Maybe Bavi-IL12,
or Bavi-IFN-gamma. The plan is obviously to get bavi with chemo approved and
generating money to pay for more research and trials of bavi combined and used
in other ways. There is much, much more potential than just bavi alone. Don't forget
the other antibodies either, i.e. PGN632.
There is a major difference between infection with HIV and infection with HCV.
The people who are treated for HCV have been chronically infected for decades in
many cases. The goal there is to stimulate the immune system to help eradicate
the virus, along with other directly anti-viral approaches. In HIV you want to prevent
the initial infection in the first place, or game over. That is what PGN632 does. The
antibody binds to monocytes and stimulates the production of chemokines, it is
not clear exactly how, but it does require the whole antibody, i.e. the Fc end, not just
the Fab part. These chemokines bind to the receptor CCR5, which is the coreceptor
for HIV, on T cells and macrophages. In effect, enough of these chemokines are
produced to saturate the CCR5 so that the HIV can't use the CCR5 for binding and
prevents infection.
The science here was included in the paper from last year
Anti-phospholipid human monoclonal antibodies inhibit CCR5-tropic HIV-1 and induce ß-chemokines
in the Journal of Experimental Medicine
http://jem.rupress.org/content/207/4/763.full.pdf+html
The patent lays out some possible uses of the antibodies, such as
a microbiocide. Someone would have to run a trial using the developed
microbiocide to get it approved. Several microbiocides have failed in
trials done in Africa in the last year or so.
PGN632 is a fully human mAb, but it differs from bavituximab in that
it does not bind beta2-glycoprotein I (which binds PS), but instead binds
to PS directly.
New patent application using PGN632 to inhibit HIV infection.
United States Patent Application 20110318360
Haynes; Barton F. ; et al. December 29, 2011
ANTI-LIPID ANTIBODIES
Abstract
The present invention relates, in general, to anti-lipid antibodies and, in particular,
to methods of inhibiting HIV-I infection using anti-lipid (e.g. anti phospholipid) antibodies.
Inventors: Haynes; Barton F.; (Durham, NC) ; Moody; M. Anthony; (Durham, NC) ;
Liao; Bua-Xin; (Durham, NC)
Assignee: DUKE UNIVERSITY
Durham NC
From the text...
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention relates, in one embodiment, to a method of inhibiting infection
of cells (e.g. T-cells) of a subject by a CCR5-tropic strain of HIV-1. The method comprises
administering to the subject (e.g., a human subject) an anti-human cell antibody (for example,
an anti-lipid (e.g., anti-phospholipid) antibody), such as mAb 11.31 (PGN 632) or CL 1), or
fragment thereof, in an amount and under conditions such that the antibody, or fragment
thereof, binds to cells of the patient that: i) can produce CCR5-binding chemokines, and ii)
have on their surface an antigen recognized by the antibody. Binding of the antibody, or
fragment thereof, induces the production of the CCR5-binding chemokines by the cells, either
in the absence or in the presence of the CCR5-tropic strain of HIV-1, to a level sufficient to
inhibit infection of HIV-1 susceptible cells that utilize the CCR5-receptor (e.g., T-cells).
Advantageously, the antibody, or fragment thereof, is administered within 48 hours of
exposure of the subject to the CCR5-tropic strain of HIV-1.
...
[0030] In accordance with the invention, the anti-lipid antibodies can be administered prior to
contact of the subject or the subject's immune system/cells with CCR5-utilizing HIV-1 or
within about 48 hours of such contact. Administration within this time frame can maximize
inhibition of infection of vulnerable cells of the subject (e.g., T-cells) with CCR5-tropic HIV-
1. This mode of inhibition of HIV-1 is particularly effective for modifying or inhibiting the
transmission event, since virtually all of the transmitted HIV-1 viral quasispecies are CCR5-
tropic (Keele et al, Proc. Natl. Acad. Sci. 105:7552-7557, Epub 2008 May 19 (2008)).
[0031] One preferred antibody for use in the invention is mAb 11.31 (PGN 632). This
antibody was derived from an antibody library generated from PBLs of healthy donors.
Whether it reflects an antibody that was being made at the time of production of the antibody
library is not known. The original antibody isotype was IgM or IgD that was then converted
to IgG and was further matured to optimize for high affinity PS binding. The potency of mAb
11.31 (PGN 632) for inhibition of CCR5-utilizing HIV-1 infection of PBMCs is broader than
any other antibody reported.
[0034] The antibodies, and fragments thereof, described above can be formulated as a
composition (e.g., a pharmaceutical composition). Suitable compositions can comprise the
anti-lipid antibody (or antibody fragment) dissolved or dispersed in a pharmaceutically
acceptable carrier (e.g., an aqueous medium). The compositions can be sterile and can in an
injectable form. The antibodies (and fragments thereof) can also be formulated as a
composition appropriate for topical administration to the skin or mucosa. Such compositions
can take the form of liquids, ointments, creams, gels and pastes. Standard formulation
techniques can be used in preparing suitable compositions. The antibodies can be formulated
so as to be administered as a post-coital douche or with a condom.
[0036] That anti-lipid antibodies only inhibit the infectivity of CCR5-utilizing primary isolates
has significance for the mechanism of inhibition of infectivity and for the setting of utility of
anti-lipid antibodies in inhibiting HIV-1 infection. That select anti-lipid antibodies (e.g. CL1
and 11.31 (PGN 632)) can inhibit HIV-1 infection up to 48 hours after addition of the virus
show that they do not block virion binding and attachment. The data provided in the Example
are compatible with the mode of action of the mAbs being induction of chemokines from
monocytes and other chemokine producing cells. (See FIG. 13.) That the anti-lipid antibodies
act up to 48 hours after infection show their utility for prophylaxis in, for example, the
following settings:
[0037] i) in the setting of anticipated known exposure to HIV-1 infection, the anti-lipid
antibodies described herein (or binding fragments thereof) and be administered
prophylactically (e.g., IV or topically) as a microbiocide,
[0038] ii) in the setting of known or suspected exposure, such as occurs in the setting of rape
victims, or commercial sex workers, or in any heterosexual transmission with out condom
protection, the anti-lipid antibodies described herein (or fragments thereof) can be
administered as post-exposure prophylaxis, e.g., IV or topically, and
[0039] iii) in the setting of Acute HIV infection (AHI) with an CCR5 transmitted virus, the
anti-lipid antibodies described herein (or binding fragments thereof) can be administered as a
treatment for AHI to control the initial viral load and preserve the CD4+ T cell pool and
prevent CD4+ T cell destruction.
New imaging paper just out, Near-infrared Optical Imaging
of Exposed Phosphatidylserine in a Mouse Glioma Model,
by Zhao, Stafford, Zhou, Thorpe.
Translational Oncology, vol 4, number 6, Dec 2011, pp 355-364.
From the Discussion
Clinical applications of optical imaging are currently limited to the
detection of tumor margins or deposits during surgery, to the detection
of superficial tumors, and to the detection of deep-seated tumors
by endoscopy. The current study is also a proof-of-principle study, indicating
the potential of this unique antibody for detecting deep-seated
tumors using PET, SPECT, or MRI. Other labels besides optical dyes
should be considered for attachment to PGN635 F(ab')2 fragments.
PGN635 is particularly impressive as a targeting ligand because of its
high specificity, lack of uptake by the liver or any other organs, rapid
acquisition by its vascular target, and its persistence on the vascular
target for days. It is an excellent candidate, for example, for labeling
with DOTA and 64Cu for PET or 111In for SPECT. It should have
applications not only in tumor imaging but also in the imaging of
thrombi or sites of ischemia for cardiovascular investigations. It will
also be interesting to correlate PGN635 optical imaging data with functional
MRI studies of apoptosis by diffusion-weighted MRI and vascular
perfusion or permeability by dynamic susceptibility contrastMRI.
In summary, we have combined NIR optical imaging with
PGN635, a novel monoclonal antibody that binds to PS, to monitor
in vivo dynamics of exposed PS on mouse gliomas. We show that irradiation
increases the PS signal, predictive of the response to therapy.
The high tumor specificity of PGN635 in the present study underscores
the prospects of using PGN635 and related antibodies to treat
cancer in humans.
Here is the survival curve from the trial which established docetaxel as the "gold standard" for second-line NSCLC.
Shepherd et.al. J Clin Oncol 18:2095-2103. (2000).
The median survival is 7.5 months. P= 0.10 compared to best supportive care (BSC). The response rates were CR: 0%, PR: 5.5%.
The time to progression is given as 10.6 weeks. Note that there are only 104 patients in these arms of the trial.
The Bavi trial uses the same dosing. Since the median survival time is so short we should know this by ASCO in June.
I think people are overlooking the possibilities of the Bavi pancreatic cancer trial.
By the time the last patient is enrolled unfortunately many of the patients
will have already died. The median overall survival is the primary endpoint
and may be reached a few months after the last patient is enrolled. This phase
II trial is using the same dosing of gemcitabine as in the 1997 registration trail.
In addition the 1997 trial only enrolled 126 patients. Is it possible that if the Bavi
phase II trial has a good outcome (~7 month survival) a double-blind phase III
trial could be started a year from now, and the results known in 2.5 years?
From December Nature Medicine
Have no interferon: interferon-free HCV therapies in mid- and late-stage development.
Phase Company Investigational drugs Drug action
3 Pharmasset PSI-7977 Polymerase inhibitor
2 Abbott Laboratories ABT-450 plus ABT-333 or ABT-072 Protease and polymerase inhibitors
2 Boehringer-Ingelheim BI-201335 and BI-207127 Protease and polymerase inhibitors
2 Bristol-Myers Squibb BMS-650032 and BMS-790052 Protease and NS5A inhibitors
2 Gilead Sciences GS-9451, GS-5885 and GS-9190(tegobuvir) Protease, polymerase and NS5A inhibitors
2 Inhibitex INX-189 Polymerase inhibitor
2 Novartis DEB025 (alisporivir) Cyclophilin inhibitor
2 Peregrine Pharmaceuticals Bavituximab Phosphatidylserine targeted antibody
2 Roche Danoprevir and RO5024048 Protease and polymerase inhibitors
2 Santaris Miravirsen MicroRNA-122 inhibitor
2 Vertex Incivek (telaprevir) and VX-222 Protease and polymerase inhibitors
Totally!
PDF of slides presented by Dr. Thorpe at IBC Antibody conference on Wednesday.
http://files.shareholder.com/downloads/PPHM/1517209363x0x526581/805447db-defc-46d4-9d03-214bf496e134/Thorpe_IBC_2011_Bavi_Slides.pdf
It is snowing and I am delaying my trip to work so I am posting this. In my opinion the HCV game is just a side issue for Peregrine.
Nature Reviews Drug DIscovery, December 2011
An all-oral and interferon-free future for HCV therapy?
The current standard of care (SOC) for hepatitis C virus (HCV) infection involves treatment with ribavirin and pegylated interferon (PEG-IFN). This stimulates the immune system rather than targeting the virus directly, and is associated with severe side effects. Earlier this year, the first two direct-acting antiviral agents (DAAs), the protease inhibitors telaprevir (Incivek; Vertex/Johnson & Johnson) and boceprevir (Victrelis; Merck), were approved by the US Food and Drug Administration; however, these still have to be administered in combination with ribavirin and PEG-IFN.
Now, data presented at the American Association for the Study of Liver Diseases (AASLD) 2011 Annual Meeting show that the goal of achieving an all-oral and IFN-free treatment regimen is achievable and might be close. In particular, clinical trial results with HCV polymerase inhibitors have generated excitement. Michael Manns, Medical School of Hannover, Germany, explains: “The advantage of nucleoside polymerase inhibitors is that they are pan-genotypic, which means that they show activity against various — maybe all — HCV subtypes, which is in contrast to most HCV protease inhibitors. Moreover, they have a high genetic barrier to resistance, strong antiviral potency and a favourable safety profile.” He is particularly excited about the uracil nucleotide analog polymerase inhibitor PSI-7977 (Pharmasset). “A two-drug combination, PSI-7977 plus ribavirin, was shown to be successful for HCV genotype 2 and 3 patients and another study with PSI-7977 in combination with PEG-IFN and ribavirin showed promising results for HCV genotype 1, which is currently more difficult to treat.”
Pharmasset announced the initiation of a Phase III programme that will evaluate PSI-7977 in a 12-week, all-oral, IFN-free regimen in combination with ribavirin.
Another nucleoside polymerase inhibitor, INX-189 (Inhibitex), was shown to achieve robust and dose-dependent decreases in HCV RNA levels after 7 days of monotherapy or in combination with ribavirin in treatment-naive patients with chronic HCV genotype 1. The company announced that it will now expand its clinical development programme to include IFN-free combinations of INX-189 with other DAAs in patients with HCV genotype 1, 2 and 3.
Pharmasset will test PSI-7977 in combination with the small-molecule NS5A replication complex inhibitor BMS-790052 (Bristol-Myers Squibb). BMS-790052 showed promising results in combination with the protease inhibitor BMS-650032 in an early-stage, all-oral, IFN-free combination study, achieving a 100% cure rate in all nine Japanese patients with HCV genotype 1b who completed treatment. Manns points out that this provides proof of concept for all-oral IFN and ribavirin-free anti-HCV therapies.
Finally, Roche and Anadys Pharmaceuticals have announced a merger agreement, in which Roche acquires Anadys for US$230 million in an all-cash deal. This follows promising data for Anadys’s setrobuvir (ANA598), a non-nucleoside oral small-molecule HCV polymerase inhibitor that is currently in a Phase II study in combination with PEG-IFN and ribavirin. Again, the aim for this drug is to ultimately form part of an IFN-free oral DAA treatment regimen.
“IFN has numerous side effects and many patients cannot be included in SOC treatments because of exclusion criteria,” notes Ralf Bartenschlager, University of Heidelberg, Germany. “These problems are circumvented with combinations of DAAs and, therefore, more patients can be treated and side effects are lower.” He sees the future of IFN-free anti-HCV treatments in DAA combinations such as an NS5A inhibitor (as these have shown high potency), a nucleoside polymerase inhibitor and eventually a second-generation protease inhibitor, which has higher potency, fewer side effects and less genotype dependency compared with the first-generation protease inhibitors.
“An IFN-free (and also ribavirin-free) therapy is the main goal, and given the very promising data from clinical trials, this seems to be realistic. The prospects for curing a patient with HCV by an IFN-free treatment regimen will become very high,” he concludes.
There is more to it than anti-PS. In this paper they talk a lot about host defense peptides. Such as, again from their Discussion section:
Definitely, PS constitutes an Achilles' heel of cancer cells, because
the anionic lipid represents a cancer type independent target for host
defense peptides that rapidly kill cells exposing negatively charged
lipids.
Recently, Thorpe published a paper on PE and PS in the journal Neoplasia,
which is freely available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071078/?tool=pubmed
Increased Exposure of Phosphatidylethanolamine on the Surface of Tumor Vascular Endothelium.
In this paper they used the PE-binding peptide duramycin, which is specific for PE.
Thorpe also has a recent patent application on this subject:
United States Patent Application 20110033454
Kind Code A1
THORPE; PHILIP E. ; et al. February 10, 2011
Methods For Treating Diseases Using Antibodies to Aminophospolipids
Abstract
Disclosed are surprising discoveries concerning the role of anionic phospholipids and aminophospholipids in tumor vasculature and in viral entry and spread, and compositions and methods for utilizing these findings in the treatment of cancer and viral infections. Also disclosed are advantageous antibody, immunoconjugate and duramycin-based compositions and combinations that bind and inhibit anionic phospholipids and aminophospholipids, for use in the safe and effective treatment of cancer, viral infections and related diseases.
Inventors: THORPE; PHILIP E. ; (DALLAS, TX) ; RAN; SOPHIA; (RIVERTON, IL)
So you can see how all this comes together very nicely.
The other reference cited in the Discussion text I presented, Utsugi et al. [11], is:
[11] T. Utsugi, A.J. Schroit, J. Connor, C.D. Bucana, I.J. Fidler, Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human bloodmonocytes, Cancer Res. 51 (1991) 3062–3066.
The second author, A.J. Schroit, is a Scientific Advisor to Peregrine.
You should have recognized the reference to Ran et al [13] is one of the fundamental papers produced by Thorpe's group.
[13] S. Ran, A. Downes, P.E. Thorpe, Increased exposure of anionic phospholipids on the surface of tumor blood vessels, Cancer Res. 62 (2002) 6132–6140.
More, from their Discussion section:
After several decades of cancer research no common marker for
malignant cells has been identified so far, which would offer many
possibilities, not only for therapy, but also for fast and accurate
diagnosis. Already in 1991 Utsugi et al. [11] reported about elevated
expression of PS in the outer leaflet of human tumor cells. In 2002 Ran
et al. [13] showed that the monoclonal antibody 9D2 and Annexin V,
the natural ligand to anionic phospholipids, specifically localized to
tumor vessels and tumor cells in and around necrotic regions after i.v.
injection into tumor-bearing mice, whereas none of the blood vessels
in normal tissues had detectable externalized anionic phospholipids.
Our study strongly supports these findings and more importantly
clearly demonstrates that exposure of PS to the outer leaflet of
membranes is not restricted to blood vessels but is a general
phenomenon for cancer plasma membranes independently on cancer
type and is also valid for metastases and many cancer types including
those with poor outcome or treatability, like glioblastoma or
malignant melanoma. Thus, the anionic phospholipid PS could serve
as a common cancer marker as well as a therapeutic target.
Important new journal article. Biochimica et Biophysica Acta (BBA) - Biomembranes Article in Press, July 26,2011
In search of a novel target — Phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy
Abstract:
This study was performed in the aim to identify potential targets for the development of novel therapy to treat cancer with poor outcome or treatment efficacy. We show that the negatively charged phospholipid phosphatidylserine (PS) is exposed in the outer leaflet of their plasma membrane not only in tumor cell lines, but also in metastases and primary cultures thereof, which contrasts with a lack of PS exposure by differentiated non-tumorigenic counterparts. Studied tumor cell lines were derived from non-tumorigenic and malignant melanomas, prostate- and renal cancer, glioblastoma and a rhabdomyosarcoma. Importantly, also metastases of melanoma expose PS and there is a correlation between malignancy of melanoma cell lines from different stages of tumor progression and PS exposure. The PS exposure we found was neither of apoptotic nor of experimental artificial origin. Finally potentially malignant and non-malignant cells could be differentiated by sorting of a primary cell culture derived from a glioblastoma based on PS exposure, which has so far not been possible within one culture due to lack of a specific marker. Our data provide clear evidence that PS could serve as uniform marker of tumor cells and metastases as well as a target for novel therapeutic approaches based on e.g. PS-specific host defense derived peptides.
http://www.sciencedirect.com/science/journal/00052736
One last point to make here is that the EOCG study showed no benefit for women when Avastin is added to C+P, or very little benefit. If Bavi does show more benefit for women than men, or it shows they both equally benefit, then this could be an advantage.
There is one thing more that I have noticed that has not been discussed yet. As with all of these points we have to remember that the Bavi trial has a fairly small number of patients and so the results are probably not statistically significant. The one thing that hasn't been looked at is the difference between the ORR between male and female patients. If you look at figure 3 from the 2010 ASCO poster (the Forest plot) you can see that there was a 57% ORR for females and a 37% response rate for males. Compared to the other sub-groups shown this is the biggest difference except for the difference between squamous and non-squamous. From the NEJM paper on the EOCG phase III study we have in figure 3 that the difference in hazard ratio for males and females is also large (male: 0.70 vs females: 0.98), but this is opposite from the Bavi results. Also, in discussion section of NEJM paper we have this: median overall survival
control arm (C+P)
male: 8.7 months
female: 13.1 months
treatment arm (C+P+Avastin)
male: 11.7 months
female: 13.3 months
which shows that there is really no difference in MOS for females when Avastin is added to C+P, consistent with the hazard ratio of 0.98. In the NEJM paper they discuss this difference but have no explanation for it.
It is interesting that the ORR for the Bavi trial is so much better for women than for men. Does this also transfer to the MOS? Again, I caution that the numbers for the Bavi trial are too small, but it is something to look for in the future.
This says that "The median survival for that subset of patients with Stage IIIB NSCLC (locoregional disease) was 30.6 months for patients treated with Stimuvax plus best standard of care versus 13.3 months for the patients treated with best standard of care alone." You can not compare to the Bavi+CP NSCLC trial which included "Histologically or cytologically confirmed non-small cell lung cancer at stage IIIB (with pleural effusion), stage IV, or recurrence". The patient groups are not the same. Maybe you should do a little investigation before you post things.
This is nonsense, the only thing that matters is the status of the patients enrolled in the trial, not the health of the general population.
The Avastin study, E4599, specifically excluded squamous NSCLC patients. Looking at the reported Bavi NSCLC trial on clincaltrials.gov, the Bavi trial did not exclude them. I would like to see the MOS for the subset of non-squamous patients only to get a better comparison. As for the difference between 12.4 and 12.5 MOS, there is none within the statistical uncertainty.
Mojojo,
Thanks for this graph. Looks like Cotara and Avastin are equivalent. Their confidence bands overlap, and with the fact that the Cotara study has about half the numbers of patients as the Avastin arm, I would say there is no difference in the survival. What about the side-effect profiles? Makes you wonder if more treatments with Cotara, maybe every 6 months for 2 years, might work better than just one.
The key is the side effects. The article stated that only about 25% of patients with metastatic pancreatic cancer can tolerate the side effects of the new 4-drug regime. It is nasty, so even if bavi + gemcitibine shows no advantage over the new SOC survival, if the side effects are much less then it has a chance to be adopted.
Bavi will now have to beat this new SOC for metastatic pancreatic cancer. From the NCI Cancer Bulletin for May 17, 2011
http://www.cancer.gov/ncicancerbulletin/051711/page2
"A four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer. Patients who received the regimen, called FOLFIRINOX, lived approximately 4 months longer than patients treated with the current standard of care, gemcitabine (11.1 months compared with 6.8 months)."