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Partnering Conference vs. Investment Conference
IMHO, the Company has passed the point where it makes sense to seek a Bavi development partner. They have paid the price (in terms of ATM dilution and Garnick's salary) to launch a randomized registration trial on their own without help from BP. Now they sit back and wait for the trial results to come in to see if that was a good decision or not. If Bavi works better than Avastin, which Mgmt thinks is the case, then they were very smart not to have wasted their time at Partnering Conferences in 2010. If Bavi works better than Avastin, then in 201l Mgmt. will again start attending these conferences, but what they will be looking for is a Bavi marketing partner, not a Bavi development partner.
So that leaves Cotara, I think they feel that there are a small number of BPs who play in the radio-pharmaceutical space and all of them already know about Cotara and are watching it closely.
Short interest being down 11% is good news. It suggests that the significant selling we saw during second half of March came from the Company selling ATM shares to raise money for the Phase II/III registration lung trial.
Hopefully they now have all the money needed to be comfortable about funding at least the first year of the registration lung trial-- which would mean Mgmt. could hold off selling more ATM shares until after ASCO when price will be higher.
Double agree here. Excellent point. Thank you.
It is my opinion that the shelf shares and the slow playing may not help the PPS but it does make us look like more of a threat to the big pharma out there who see us coming. Knowing that we can finance our own phase 3's using money from AVID and NIAID and millions of shelf shares may help push them to the table. They won't take you seriously if they think you need them.
The Investigator Sponsored Trials (IST) are the reason why we will for sure know by late 2010 / early 2011 which way this is breaking. Mgmt. has kept a low profile in Wall Street circles, but in medical circles, there are lots of Docs who understand Bavi's potential to stimulate the immune system to recognize and attack tumors. These Docs are eager to put their name on some of the early Bavi trials, especially when they get to co-develop their trial design in discussion with the likes of Drs. Chabner, Garnick and Garovoy.
Many of these small IST trials involve only one or two patient cohorts. Results can be shared with other docs and released publicly at any time. By summer a half dozen of these small IST trials will be enrolling patients.
Yes, a large randomized, blinded study is the gold standard, but when a half dozen independent investigators all start reporting similar results on different tumors in different studies, that quickly becomes pretty solid evidence as well.
Hmmm ... I wonder why AVID has already started producing and stockpiling so many doses of frozen Bavi ?
Great post MoJo--
SK is saying very clearly that what the Company needs is a sales team and manufacturing help, not a development partner.
Anyone who is thinking in these terms is obviously very very confident about what they are sitting on.
My understanding is that the "going concern" issue is determined by the auditors as of the date they sign their cover letter, which is the day the 10K financials are filed with the SEC, which will be approximately July 15.
In reading the CC transcript, I found a few interesting points. C.J. please remove prior posts on same topic that had errors. Thank you.
1. Timing for Monetizing Cotara. Two of the funds asking questions were keen on the time line for finishing the 40 patient GBM study (SK answer: this summer) and collecting survival data needed to go to FDA for approval of Phase III trial design (SK answer: “So yes, once we complete patient enrollments, this is an open label study. So we will be able to report results probably toward the end of this year or ealy next year, as we generate the data”).
Then a few minutes later Steve Dunn at LifeTech Capital asked whether the Company would take on a partner for Cotara Phase III, and SK’s answer was:
“I think we will have a much better view point once we are through the Phase II study and have the results and can have that meeting with the FDA to design the Phase III study… The key is just by getting through this Phase II study and defining what that typical trial would look like adds a tremendous amount of value from a partnering standpoint. … Obviously very happy [with the results] so far. If we [get clearance from FDA to] get into a smallish trial, then it could be something we could handle ourselves. But otherwise I think [it is] really partnerable at that point.”
So my translation is that, at most, we long-suffering longs have approximately 10-12 months more of painful ATM financing to endure assuming the Cotara results continue to be as good as they have been so far. Looks like the GBM program will get monetized 10-12 months from now either by a BP licensing event or by a substantial increase in pps due to fact data was so good that FDA approved a very small Phase III trial size. In the second scenario there would still be ATM financing but the PPS would be so high from FDA's very favorable review of Cotara that more ATM sells would not be painful.
t seems that at least two fund managers following this stock share the view that completion of the current Cotara trial with strong data (like the data to date) will be a pivotal event for the Company. Personally, I think the recognition of Bavi's anti-viral potential could be another pivotal event that happens much sooner (e.g. through Animal Approval, Duke/Haynes publication, another gov't contract, etc.), but it's nice to know we have Cotara as a back-up on a 10-12 month time line.
2. Confidence that Bavi will be Approved Shown in Avid Plans. In SK’s opening remarks I loved this statement regarding plans for the future of Avid: “We plan to launch and commercialize Bavituximab out of our existing facility.” I like it when our CEO is taking concrete steps now to plan for Bavi's approval. As CJ pointed out in his post 48494, 15,000 vials of Bavi already in the freezer is a pretty concrete step.
3. India and Georgia Phase II Patients Continue to Receive Bavi. Twice in his opening remarks SK was careful to emphasize that in the three Phase II cancer trials it is the “planned combination treatment” that has completed. He did this to distinguish the number of patients who had a meaningful tumor remission and elected to continue treatment with Bavi dosing alone. Seems clear that some percent of the Phase II patients were so encouraged by their remissions that they elected to continue on with solo Bavi dosing. This augurs well for the survival data we will see out of AACR and ASCO.
CJ- Excellent point. 15,000 vials is way more than needed for two trials of 120 patients each.
I wonder if the stock piling of Bavi that is now happening relates to SK's comment that
"We plan to launch and initially commercialize bavituximab out of our existing facility."
It looks like they are investing hard manufacturing dollars on the assumption Bavi will be approved and they want to pump out as much profit from their own sales as they can before turning production over to a BP partner.
Geo-- Completely agree. Omission of any question during CC about Animal Rule status is staggering especially because:
(1) The PR yesterday morning said "Bavituximab Anti-Viral Program: In the first half of 2010, Peregrine expects to report additional preclinical data from its ongoing bavituximab anti-viral program"
and
(2) The information this week on JBM blog-- http://anti-ps.blogspot.com/ -- is the most direct confirmation of Bavi's anti-viral MOA that we have seen to date.
Regarding (1), my view is that the Company is getting ready to release its own new, pre-clinical anti-viral data with 11.31 regardless of whether Nature has published or not. Mgmt has given Duke and Haynes more than enough time to be first out of the gate and get the media attention for the anti-PS paradigm shift in anti-viral therapy. I think the Company just announced in yesterday's PR that they are going ahead with a release of their own data in May or June with or without the Nature publication coming out first.
Regarding (2), I am amazed there has been no discussion on this Board of the excerpts from this week's IAVI Report reproduced yesterday on JBM's blog. You will recall from the Moody's Capetown presentation that 11.31 works its magic in large part by using its FC region to stimulate other cells (often referred to as "killer T cells" or macrophages) to stimulate the Beta Chemokines that stop HIV cold in its tracks.
Well as this week's IAVI report discloses, the whole HIV community is now waking up to the awareness that these chemokines that 11.31 happens (coincidentally) to stimulate by its FC tail wagging in the breeze, are now the hottest new breakthrough in AIDS research.
I agree Jonny-- It was nice to see some new blood asking questions. Interesting to see that each of the funds in the Q&A session came into the call with a prepared list of questions.
Clearly some knowledgeable players are doing their homework on PPHM and asking the important questions.
Personally, I like how they are using Dr. Garovoy and the IST program to generate interim results from small open-label trials-- maybe 5 -10 patients each -- that can be released during the first half of 2011 if I heard correctly. With a registration trial pending, this interim data from a bunch of IST trials will keep a fire lit under the pps. I'm not sure the Company will need a partner to finish the lung registration trial if the IST program is able to generate concurrent data that re-confirms great Phase II data announced at this year's ASCO meeting.
Remember, there is an independent review panel of Docs who are constantly monitoring the data as it comes in from the blinded study. That panel can declare the trial finished after 60 patients (instead of the full 120) if the data is outstanding. With cancer in the news every day, the IST program will put the public eye and some heat on that independent review panel to cut a year off the duration of the registration trial if the first 60 patients generate blow-your-socks off remissions. That's what Accelerated Approval is all about.
Mojo, That was purely speculation on my part.
I have no data to back up my last post. All I'm trying to say is that you don't get two shots at creating a new Board. A new Board of Directors, once established, will have a tendency to perpetuate itself of many years to come. I think everyone agrees with that. So if the Company is strong enough now to attract a new grade B or B+ Board, but by waiting one more year for our anti-PS platform to prove out its enormous potential we could attract an A or A+ Board, my vote is to hold out for another year.
From people I have spoken with who talked with ES at the annual meeting, he is completely willing to step aside when he is sure he is leaving the Company in the hands of very experienced BP executives and/or some of the folks from Bill and Melinda Gates Foundation who are currently funding the Company's anti-viral work.
If ES turns over the reins of of power while PPHM is still a speculative biotech, we may end up with an O.K Board that is better than the mistake made with Bonfiglio and Bimaster a few years back, but not nearly as good as what we could do once our anti-PS platform (and supporting patent portfolio) has established itself as the biggest medical break through since penicillin.
Thanks C.J. for posting SK's answer to that important Board-seat question.
My translation of King's answer is that overhauling and re-inventing the Company is a 4 step process:
(1) First, you need outstanding clinical data.
(2) Second, if you have outstanding clinical data you can attract an outstanding, world-class clinical and mfg. team like Drs. Garnick, Chabner, Garovoy and Truc Le.
(3) Third, when you have the likes of Drs. Garnick, Chabner, Garovoy and Truc Le, you can attract outstanding institutional investors.
(4) Finally, when you have had complete success in (1), (2) and (3), you are in a position to attract a truly outstanding Board of Directors.
If you try to do (4) before (2) and (3), which is what some posters on this Board seem to want, the post-split value of the pps may go to $100, but it won't go to $200 or $300.
Now in some companies the clinical data and the clinical advisors are not as outstanding as they are at PPHM. Very few biotechs can boast the likes of a Dr. Garnick or a Dr. Chabner on their team. So at those companies you may need a stronger Board before you can attract the likes of Goldman Sachs. But if the clinical data is half as good as it seems to be, and we will know that by the end of ASCO, the big funds won't wait for new Board members before they take a position.
Patience my friends. Rome wasn't built in a day. :)
Great list. Thanks.
The only thing you left off is Accelerating World-Wide Scientific Confirmation of the Anti-PS Platform as a major new paradigm for stimulating the immune system to attack viruses and tumors.
The accelerating pace of PS-related publications is shown well in the bar chart on this page of PPHM website: http://www.peregrineinc.com/index.php?option=com_content&task=view&id=79&Itemid=147
If the number of major new PS-related papers posted on JBM's blog in Jan and Feb of this year is any indication, the new bar posted on this graph for 2010 will be off the chart. http://anti-ps.blogspot.com/
In my view, the most frustrating thing about owning this stock is now becoming it's biggest advantage. For the past 5 years really important R&D advances have been happening with Peregrine's anti-PS technologies, but the Company has not waived its own flag and has kept these important advances off the PR radar screen. These R&D advances have only been appreciated by a small and highly-specialized community of molecular biologists and only recently by a few clinical MDs and only very recently by a few industry leaders like Garnick and Garovoy.
Now that the scientific foundation for this paradigm shift in disease management has been well laid, the bonfire of support from FDA regulators in the U.S. and clinical investigators around the globe will ignite quickly.
Important to Note:
The research posted today on the JBM Anti-PS Blog (http://anti-ps.blogspot.com/ ) comes from the Brazilian National Cancer Institute in Rio de Janeiro. This is the same Institute with which PPHM has an active Bavituximab collaboration.
Go to the "Infections Diseases" page on PPHM website: http://www.peregrineinc.com/index.php?option=com_content&task=view&id=79&Itemid=147
... and scroll down to the Table of Bavi Collaborations under the bar graph. It's the 6th Collaboration listed in that Table.
The article summary excerpted by JBM includes at the bottom the following reference to Bavi, but the current studies described in the article were probably done with with Bavi as well:
"Bavituximab, a humanized anti-PS anti- body, is capable of curing guinea-pigs lethally infected with Pichinde virus [16]. In addition, bavituximab has been described as also recognizing infectious VSV virions [16]."
PROOF OF THE ANTI-PS MOA IS HAPPENING NOW ALL OVER THE GLOBE. In Brazil they call it Apoptotic Mimicry. Haynes calls it his Tolerance Hypothesis. Others refer to it as the "Immune Escape" mechanism. It's all the same thing. :)
Major journal highlights Bavituximab. This article may have influenced today's volume. JBM's blog says it was published on line 12/16/2009, but it may have become available only today to non-subscribers.
From the Journal of the American Chemical Society:
"there is increasing evidence that the membrane surfaces of certain cells and particles of biomedical significance, such as apoptotic cells,2 activated cells,3 tumor vasculature,4 microvesicles,5 bacteria,6 and viruses,7 expose unusually high levels of negatively charged phospholipids. Proteins and antibodies that can selectively target these anionic membrane surfaces and distinguish them from the near-neutral membrane surfaces of normal human cells have promising potential as imaging probes,8 drug delivery agents,9 and targeted molecular therapeu- tics.10 Notable examples are the protein, Annexin V, which is under clinical investigation as an imaging probe for dead/dying tissue,11 and the antibody, Bavituximab, which targets viruses and tumor vasculature."
See link to full article at JBM's bog: http://anti-ps.blogspot.com/
It's been a long while since the last time I helped prepare a Form 10-K, but I believe the vesting milestones will have to be disclosed as part of that Annual Report document. So we should learn Mgmt's expectations for pps appreciation when 10-K is filed around July 15.
IMHO
Turns out from reading the PNAS publication that LJ001 works in a petri dish but not therapeutically in mice. Read the paragraph below from the Article's conclusion.
Moreover, even if LJ001 did work therapeutically, it would be at least 3-4 years behind Bavi in terms of its clinical development. They haven't even had a successful experiment in animals yet, let alone started a PK work-up in humans.
Far from being competition, seems to me the take away point is the one made by JBM at the top of his blog: http://anti-ps.blogspot.com/ The real point is that the petri dish work being done with LJ001 means that yet another group of distinguished scientists at important universities have confirmed that host cell lipids on enveloped viruses are a valid therapeutic target.
Here's the quote from discussion at end of PNAS article:
"The actual ef!cacy of LJ001 for the prophylactic, postexposure,
or therapeutic treatment of enveloped viral diseases probably will
depend on formulation and pharmacological considerations as
well as on the pathogenic pro!le of the virus. Thus, we conducted
preliminary Ebola postchallenge protective ef!cacy experiments
by dosing once daily with LJ001 in 100% DMSO at 50 mg/kg i.p.
after lethal challenge with maZEBOV and initially were discouraged
when LJ001 did not show ef!cacy in this postchallenge
assay (Fig. S7A). We subsequently developed a liquid chromatography/
atmospheric pressure chemical ionization/tandem MS
method for quantifying LJ001 in serum, and analysis of the pharmacokinetic
data we eventually obtained (Fig. S7B) explains this
failure. Serum concentrations of LJ001 did not approach in vitro
IC50 concentrations ($1.0 "M) until 2 h after i.p. injection, and the
biological half-life of the compound appears to be about 4 h.
Clearly, once-daily dosing was not suf!cient to maintain therapeutic
steady-state plasma concentrations of LJ001. However,
our results suggest that reasonable serum concentrations can be
obtained if formulation, potency, or pharmacokinetic properties
can be improved (Table S1)."
IMHO:
1. Bavi's 1st MOA would not be relevant to the NEOP diagnostic device because that MOA only works by spotting PS on tumor vasculature and the tiny tumor bits not already caught by the surgeons eye would not have such vasculature.
2. Bavi's 2nd MOA renders NEOP's device moot and unnecessary because this 2nd MOA triggers the body's natural "adaptive immune response" to recognize and destroy even the smallest single cancer cell. Through the 2nd MOA the killer cells in the body's own immune system get trained to recognize the antigens on the surface of each tumor cell as "bad guys" that need to be destroyed. Once this training of the immune system has happened, even a tiny single tumor cell, i.e. the one that leads to metastasis, can no longer hide. There is no reason to guide the surgeon to it -- it's already gone. :)
Thanks Geo for making this inquiry directly with Nature Medicine.
The first author in the list of authors will be "Moody, M.A." and the last will be "Haynes, B.F."
The content of the article will include a discussion of the 11.31 MAb.
The title of Nature article is likely to be similar to the title of the Moody / Haynes presentation in Capetown, S. AF., which was: "Anti-lipid Human Monoclonal Antibodies Inhibit HIV-1 Infection of PBMC By Binding to Host Cells."
Eager to hear what Nature has to say. Thanks.
Good point. I had the same thought. No one wants to be used as a pawn to help close a different deal.
So here's my speculation as to one possible answer: Maybe, just maybe, the Cotara survival data really is spectacular compared to SOC and getting more so with each passing month. Maybe Stason knows they are second in line behind the Japanese BP, but would rather be in second place to take down Asian TNT rights than not in line at all.
I haven't done any research on Stason, but I'm guessing if they were founded in 1994 they are much smaller than the BP we have been dealing with. Sometimes the Avis company is "willing to try harder" than the Hertz to land a sweet license.
This line of thought only makes sense if Cotara really has strong supporting clinical data and would be a sure money-maker in the Pacific rim. -- From everything SK has said, and now Dr. Garnick is confirming it, Cotara fits this profile in these times when pharma. is starved for innovative new drugs.
_______________________
Separately, here's another thought about Cotara. I always assumed the problem in the licensing negotiations is that the BP didn't want to pay what PPHM was demanding -- and that may indeed be the case.
But it's equally possible that the big holdup has been about the scope of the license rights rather than the size of the upfront license payment. I understand that PPHM only wants to give up Asian-Pacific rim marketing rights to Cotara at this time. Thus, another reason why Stason may be the perfect partner, is that they are small enough to be willing to accept only Asian marketing rights. If the Japanese BP knew that there was another marketing group willing to accept only Asian Cotara rights as opposed to world-wide Cotara rights, that might be enough to get the BP negotiations unstuck.
I can just hear the CEO of the Japanese BP saying to SK: "There's no way you will find another BP who will accept only Asian rights -- no respectable BP wants to get involved in GBM unless they can have the whole globe."
Well, today we learned SK's reply to that position.
Light bulb just went on !!!
This Stason move gives PPHM a huge tactical advantage in its infamous pending negotiations to license Cotara to a BP. Several have suggested that the BP negotiating for Cotara rights is a Japanese Big Pharma.
Think how this development with Stason sends a loud signal to the Japanese BP that PPHM has other ways to get its Cotara ball across the Pacific Rim goal line if the BP wants to play cat and mouse with us.
The fact that the Stason agreement is still non-binding (for a few more months?) tells the Japanese BP that it still has a window for closing a Cotara deal but that window is closing fast.
Now the disclosure on PPHM website looks like more than just a roadshow move -- it was also a convenient way for PPHM to signal to the other side in the long-lasting Cotara negotiations that PPHM has other options for Cotara and will go in another direction if it has to.
It is a done "framework" deal. I'll bet the framework agreement they signed is at least 10-15 pages and took several months to negotiate. It's just not a done product development and/or product marketing deal until Stason wires PPHM $XX million to get TNT rights to develop/market its first set of TNT-based products for the Pacific rim.
I suggest you Google "Framework Agreement" and learn a little more about this common business practice. It signifies a mutual intent to collaborate that goes way beyond just someone "we had talks with."
From previous experience with these agreements, I am guessing that some of its key framework provisions would be (a) confidentiality regarding all product development discussions, (b) ownership/proprietary rights, e.g. who owns the remaining rights in rest of the world to a TNT diagnostic product developed by Stason for the Pacific rim market, and (c) exclusivity, i.e. Stason needs to be assured that if if starts down the path of developing and commercializing certain TNT products, it will have exclusive rights to all sales in the identified Pacific rim countries and PPHM has to agree that it won't allow anyone else (including PPHM) to sell into those Stason territories with competing TNT-based products.
Once Stason and PPHM have negotiated and agreed on these overall framework provisions that will apply to all products that Stason develops, then Stason has the legal comfort it needs to begin work. But until Stason actually begins work (i.e. pays PPHM a TNT license fee and then spends more money to market and launch a particular TNT product), the framework agreement is non-binding and either side can walk away from it.
I don't see any foul play or screw up in the Stanson and PPHM website updates.
If PPHM and Stason had entered into a collaboration agreement, then a PR would have been the appropriate announcement. But this is not a collaboration. It is merely a "PROPOSED collaboration" in the future. The parties are simply in the exploratory phase where they created a "non-binding" framework agreement to facilitate discussions that may or may not lead to a definitive collaboration agreement.
These non-binding "framework" agreements are common in business. It would be misleading to give this exploratory phase the status of a PR because no material event, i.e. no binding agreement, has occurred yet. On the other hand, both sides thought it was worthwhile to let the world know that serious discussions are in progress.
I say bravo that PPHM has progressed to the point in it's media / roadshow savvy that it is actually telling the public in advance about things that may happen soon.
_______________________
Regarding the text of the statement itself, I find it fascinating that the first sentence says PPHM is seeking partners for clinical programs "where the Company does not plan to pursue clinical development ON ITS OWN."
Translation: Here is one more signal that PPHM may be willing to license or co-develop TNT/Cotara in a region like the Pacific Rim, but Mgmt seems to be signaling that it has some big ideas for commercializing Bavi "on its own" --- and maybe managing Cotara "on its own" in the rich easy markets like the U.S. and Europe.
More on how Bavi works to destroy tumor vessels ...
Entdoc: If you are trying to understand how Bavi, a naked antibody without any "payload", works to destroy tumor vessels, a good place to start would be Thorpe's publication that was PRed by the Company in connection with last year's April 2009 AACR conference.
Here's the link to the PR: http://pphm.client.shareholder.com/releasedetail.cfm?ReleaseID=378435
Here are a couple of relevant quotes from that PR:
"... today reported that two preclinical studies presented during the AACR 100th Annual Meeting 2009 provided further confirmation of the immunomodulatory mechanisms contributing to the anti-tumor activity of its phosphatidylserine (PS)-targeting antibodies. One study confirms the anti-tumor effects ..."
"These preclinical studies further elucidate the unique immunomodulatory mechanisms contributing to the observed anti-tumor activity of anti-PS antibodies in preclinical and clinical studies," said Dr. Philip Thorpe, professor of pharmacology at UT Southwestern Medical Center in Dallas, a scientific advisor to Peregrine and co-author of one of the AACR presentations. "These presentations provide additional insight into the mechanisms that act to selectively destroy the blood vessels supporting tumor growth ..."
" ... anti-PS antibodies stimulate the tumor microenvironment to recruit monocytes and other immune cells to the tumor with resulting anti-tumor effects, most likely via cell-mediated mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). Their data further define the role of anti-PS antibodies in mediating tumor cell cytotoxicity and the tumor microenvironment, showing that the anti-PS antibody induced a sequential release of cytokines and beta-chemokines and stimulated enhanced macrophage recruitment to tumors."
A nice bonus feature of this PR is that also refers to Bavi's other MOA, ie. its "immunomodulatory mechanisms contributing to the anti-tumor activity of its phosphatidylserine (PS)-targeting antibodies."
Entdoc-- You did not hear that quote on the Thorpe video because Thorpe did not say that, which is why I did NOT put that statement in quotes.
The statement comes from an immunologist with whom I speak about Bavi. This statement is not controversial; it's a straight forward description in immunology terms of what is seen in the animated portion of Thorpe's video. However, after putting up my post, I was corrected by another friend who pointed out a minor correction to what I wrote: the "receptor" is on the Macrophage, not on the FC. The tail of the MAb that wags in the breeze is simply called the FC.
By the way, the scientists with whom I speak have reviewed the public Bavi data and believe this MAb has amazing tumor destruction powers just as it is without need for attaching any radioactive or chemical "payload."
As the old saying goes, "If it's not broken, don't fix it." Bavi doesn't need "fixing" with a "payload" or otherwise. It's working great. Let's get on with the trials.
Thanks MoJo. Nice find. This data from last year's ASCO confirms nicely why PPHM is going after refractory NSCLC in 2nd line patients.
It's clear from your post there is a huge unmet need here and an easy path for FDA approval for a drug that has a clean safety profile and can improve on a 10% tumor response rate or 10 month overall survival in these refractory NSCLC patients. Looks to me like Vandetanib had some real toxicity so Bavi would only have to beat a 17% response rate if it had safety issues, which it does not.
Thanks C.J. There is so much excitement about Bavi's second MOA -- i.e. it's ability to trigger an immune response by covering up PS and thereby promoting chemokines (MIP1a and MIP1b) that facilitate an adaptive immune response to the pathogen -- that it is sometimes easy to forget the original tumor-vessel-destruction science that led to Bavi's development in the first place.
Of course Bavi's second MOA -- i.e. enabling the immune system to recognize and destroy virions and tiny metastatic tumor cells as the foreign pathogens that they are -- is ultimately more important in creating a lasting therapeutic effect.
But if you want to understand why the pending registration trial is likely to generate Overall Tumor Response Rates way above the 6% or maybe 10% remission rate that is needed to get accelerated approval for Bavi in refractory 2nd line NSCLC patients, then it's all about Bavi's first MOA, not its second MOA.
Here’s why PPHM is expecting accelerated approval in the upcoming NSCLC registration trial.
Let’s go back to some basic science about Bavi’s MOA in destroying tumor vessels. To understand why the Company is expecting great tumor response rates (i.e. shrinkage) even in these refractory 2nd line patients, you have to understand Bavi’s original MOA. Probably the best explanation of this MOA is seen in the old Thorpe video that is still on PPHM website here: http://www.peregrineinc.com/index.php?option=com_content&task=view&id=29&Itemid=45
What you need to hear again is Dr. Thorpe’s 2 minute fireside chat on Bavi’s MOA that starts 1 minute into the video. He emphasizes that PS targets the tumor vessels not the tumor cells. Thus it makes no difference to Bavi whether the tumor cells have become resistant to chemo. What makes Bavi effective is the ability of chemotherapy and radiation to upregulate (i.e. increase) exposed PS on the surface of tumor vessels but not on the surface of other vessels.
As SK said in his 1-13-10 presentation last week, the increase in exposed PS on the tumor vessels happens just the same whether the tumor cells have become refractory to the chemo treatment or not. Here’s the quote from the presentation last week:
“Perhaps why we’re most excited about this is this drug is an ideal combination with chemotherapy, and we think it has an excellent potential in the treatment of refractory disease. ... And, it’s simple because chemotherapy & radiation actually up-regulate our target on tumor blood vessels, increasing the effectiveness. Secondly, even in refractory disease or chemo-resistant tumors, the chemotherapy and radiation are still are able to up-regulate the [PS] target on vessels and we still get the same increased benefit from the therapy.”
Note in the above text how SK twice emphasized that he was talking about the increase in exposed PS on tumor vessels.
If you watch Thorpe’s video again on the PPHM website, you will see that Bavi’s primary anti-cancer MOA works like this: One end of the Bavi MAb sticks to the PS. The other end of the Bavi MAb is called the FC Receptor and is wagging in the breeze as various white cells in the blood supply float buy. These white cells (in particular Macrophage and Natural Killer Cells) stick to the FC Receptor on Bavi and immediately cause a cytotoxic reaction that “attacks and destroys the tumor blood vessels” (Thorpe’s words in the video). Vessel destruction means the tumor cells don’t get the oxygen and nutrients they need and this lack of oxygen quickly destroys the whole tumor.
If you understand these basic principles of Bavi’s original MOA, it becomes easy to understand why SK is willing to stick his neck out and predict that Bavi will reduce tumor size “just the same” in refractory 2nd line tumors as in 1st line tumors. Yes, in refractory tumors the chemo no longer has the same ability to kill tumor cells, but SK confirmed last week some great news: chemo does have the same ability to increase (upregulate) exposed PS on tumor vessel walls in both refractory and non-refractory tumors. Therefore Bavi is expected to work roughly the same – i.e. “we still get the same increased benefit” -- in both refractory and non-refractory tumors.
Herein lies our path to accelerated approval. :) :)
Regarding the interesting comments that Steve King makes at about 5:44 or so on the UStream video,
I felt these were the most important comments in the whole presentation. I hope C.J. will add them to the very helpful transcript he made of certain excerpts.
Here is what SK said:
"Even in refractory disease / chemo-resistant tumors, chemotherapy and radiation still upregulate the [PS] target on vessels and we still get THE SAME INCREASED BENEFIT from the therapy."
SK introduces this remark in the preceding sentence as the aspect of the upcoming registration trial that "we're most excited about."
Seems to me he is saying that they have some preclinical and perhaps clinical data from work with refractory tumors that has shown they are likely to get "the same increased benefit" out of Bavi's MOA in refractory, 2nd line patients as in 1st line patients.
A bit surprised to hear SK give details on the NSCLC trial without a PR ahead of time.
Moby, I noticed the same thing but I wasn't surprised. It's done that way to give the funds a chance to get in before the price pops. This way they have time to do some due diligence during the breakout session and again this evening -- so they can still get in at a ground floor price tomorrow morning.
I do see the winter 2010 roadshows as being different.
Yes, the content of the PPHM story may only be 10% better (e.g. great FDA meeting in Nov to review Bavi data, upcoming definitive Lung tial, Avid revenues are soaring), but the story teller -- Dr. Garnick -- is now so much more credible and persuasive.
If you are trying to attract institutional investors, you don't pop the stock with a big PR the morning of your presentation to them so that they miss the buying opportunity.
Rather, after today's 8 minute pitch and during balance of this week you whisper ideas in their ear of what's about to happen ...
and then next week you put out a bunch of PRs and make it happen.
If we see the pps rise Thurs and Friday of this week on no news, then we know good things are going to happen second half of January.
Yup ! :)
I also think the PR tomorrow announcing the CC next Thursday will mention that Garnick will be one of the people on the Dec 10 call. Dr Garnick is the best PR asset the the Company has and he is willing to go bat for the Company. He put his name on Cotara this morning. Next Thursday we will get to hear what he thinks of the Bavi platform and the Biosimilars program he and Truc Le will run at Avid.
IMO
"Mindful of the fact that obtaining data on clinical outcomes can take a long time, in 1992 FDA instituted the Accelerated Approval regulation, allowing earlier approval of drugs to treat serious diseases, and that fill an unmet medical need based on a surrogate endpoint. ... Use of a surrogate can save valuable time in the drug approval process. For example, instead of having to wait to learn if a drug actually can extend the survival of cancer patients, the FDA might now approve a drug based on evidence that the drug shrinks tumors because tumor shrinkage is considered reasonably likely to predict a real clinical benefit. In this example, an approval based upon tumor shrinkage can occur far sooner than waiting to learn whether patients actually lived longer. The drug company will still need to conduct studies to confirm that tumor shrinkage actually does predict that patients will live longer. These studies are known as phase 4 confirmatory trials."
Thank you, Dia76. This is a very helpful article which I printed for future reference. Not only is this a good overview of the accelerated approval process, but the example they pick may very well be a perfect description of why Bavi will get accelerated approval for lung cancer.
CJ can correct me if I am wrong, but I believe we had a least one 100% complete remission in the Ph II lung patients. As others have pointed out, PFS is a meaningless statistic because if Bavi caused on average an 80% tumor remission (i.e. the tumors shrank to 20% of their original size), and then these tumors grew back to 30% of their original size, that would count as "progression" (i.e. no longer in the "progression-free-survival" group), but this is meaningless because what really counts is the fact that such dramatic tumor shrinkage from 100% to 20% or 30% is a surrogate indicator of long-term survival.
So the big secret that SK and Chabner and Garnick know, but almost no one esle knows yet, is how dramatic was the tumor shrinkage in the Ph II lung patients? If many of the Ph II patients came close to having a Complete Remission, then Bavi is a blockbuster and SK can raise all the money he wants north of $10.00/share after the data is released at ASCO.
IMO, the plan is for Chabner and Garnick to tell the story to institutions and Wall Street funds this winter and get them in cheap (under $5/share) while the funds use bashers to beat down the price, then SK releases the lung remission data publicly at ASCO and the whole world gets to join the party north of $10/share.
After ASCO is when PPHM will sell a bucket full of shares to fund Ph III cancer trials, and maybe a Ph III Cotara trial as well. I believe we will see in the CC on Dec 10 that the Company already has enough money in the bank now, when combined with Avid revenues and gov't contract funding, to file the Ph III lung study IND with the FDA in January and get started on the trial and finish paying for it when they raise $30M in June at prices north of $10/share.
Moby, IMO you are almost correct about something you post roughly once a month, and this may be one of those posts.
I agree that Cotara Ph III trial will only be funded after Bavi Ph III cancer trial. But what you post is only half correct because Bavi 11.31 anti-viral trial is likely to be funded primarily by some combination of Duke or NIH or Gates funding. Duke/NIH/Gates funding of 11.31 anti-viral clinical trials follows naturally from the fact that these third-party institutions have already funded 100% of the Company's anti-viral r&d and pre-clinical work so far and they will want to seal their PR fame by funding the Bavi AV clinical work as well.
But I agree that the Company's first priority for use of its own money will be to fund Bavi Ph III lung trial before it launches a Ph III GBM trial. The Cotara GBM data is truly outstanding compared to SOC, but the time line needed to show better Overall Survival rates in GBM patients is much longer than in lung patients.
What the Company needs is to get across the FDA goal line with one product quickly-- and clearly the fastest way to the goal line is lung cancer not GBM. If BOT is correct that more than half the Ph II lung patients are still alive, and if this can be repeated in a controlled Ph III trial, then I would expect the FDA to accelerate Bavi approval after just half the Ph III lung patients have been treated.
Actually WH, I don't mind the posts of the paid bashers these days. Now that the r/s is behind us, they have many fewer areas to create confusion and it's sort of amusing to watch them squirm.
When one of them tries to use an IR response about Emergency Use (a rule intended to address pandemics like H1N1) to confuse people into thinking it's the same thing as the Animal Rule (a rule applicable to horrific diseases where human clinical trials would be impossible) ...
... you can only laugh and draw the conclusion the bashers are becoming increasingly desperate.
So far no downside or safety issue has been identified in either the Bavi animal or Bavi human studies from the fact that some Bavi (probably very little) is attaching to exposed PS on apoptotic cells.
I probably oversimplified the second explanation. What I was told had to do with a series of Thorpe papers back in 2003 and 2004 where he examined closely PS on tumor vasculature and determined that cells exposing PS in the tumor environment behave in fundamentally different ways from apoptotic cells that expose PS.
In other words, all cells exposing PS are not equal. Depending on the character and function of the cell, it seems the PS (and the other signaling mechanisms on the cell membrane) will throw off different kinds of signals to the immune system.
Lastly, it appears there is a third mechanism at work that has to do with the sheer volume of PS. In HIV, there is so much PS floating around on microparticles and the outer coat of virons that the immune system gets overwhelmed and shuts down in different ways than when it is facing a small volume of PS.
Lots of room here for more research.
Good point. I have received two types of answers when asking the question you raise.
The first answer has to do with the speed at which the body's street sweepers (i.e. macrophages cells, etc) clean up normal apoptotic cells,. (Apoptosis is simply a fancy word for normal cell death.) Part of the clean up and elimination work of normal apoptosis is done by adjoining cells as well as by circulating macrophage. The net effect is that cells which are in the process of dying a normal death get swept away very quickly, even before the cell membrane disintegrates and releases the stuff inside that would cause chaos if it went circulating in the blood.
The second answer I've heard has to do with the fact that the PS exposed on healthy cancer cells and virons seems to be of a somewhat different character than the PS exposed on dying apoptotic cells.
Truth be known, all of the PS work being done today is very new and there are still many questions, like the one you asked, where they are still doing work to understand better what is going on at the molecular level. All they know for sure is that it is now an empirical fact, from both clinical and pre-clinical studies, that Bavi does not interfere with normal cell apoptosis.
Remember, I am just a lay person trying to translate what I have heard from a few scientists working in this area.