front line NSCLC failed
front line pancreatic failed

There has not been one trial where you can show statistical significance.

That combo paper already has Yervoy at >80%, the remarkable powers of Bavi are certainly due to Yervoy.

Oh yeah, those checkpoint inhibitors work in frontline unlike Bavi the supreme universal upstream checkpoint that doesn't do anything.

Steve King has neither a PhD nor an MD.
He does have a failed phase II and a product Cotara that is doing virtually nothing except losing patent life if it even has any left at this point.

yes the FDA permitted them to go to Phase III because Bavi appears to be safe. Efficacy is not proven only a lack of harm. That is why the stock didn't move after Phase III was announced. FDA is one thing, having a BP put their money in is something else and that has not happened.
I hope all you longs get rich off of PPHM I just don't see how that can possibly happen with the current mgmt.

you're right about the greedy incompetent mgmt but I would say the jury is still out as to whether Bavi is effective or not.
One issue I see with Bavi is its target- PS. Just because PS is on the surface of apoptotic tumor cells does not mean that something binding to it has any effect. CTLA4 and PD-1 are part of defined pathways. PS does not have a great model IMO. This class switching of macrophages is a phenomenon and the proposed reason for it is just a theory not something that has been thoroughly tested.
Add to that Bavi is not actually binding only PS but beta2 glycoprotein which is present in the serum as well. Because of that it is hard to know how much bavi actually gets to the site where it is supposed to have an effect. Also add in Bavi is a chimeric antibody which generates antibodies to it ( HACA). This technology is way out of date and is fraught with issues.
So after all this time, unproven technology, suspect MOA, and incompetent mgmt adds up to low share price and ATM sales further contributing to low share price.
Alls I'm saying to the longs is caveat emptor. I don't think mgmt cares about success as much as you do.

Instead of generating clinical data they go hiring Worsley, getting names to call a scientific advisory board etc, paying money to defend a lawsuit. PPHM is a constantly changing publicity stunt. If bavi is for real then act like it. Go on with the Phase III, stop worrying about preclinical and more Phase I trials you can hype.
Has there ever been a company stuck at Phase II longer than PPHM?

good points. you lose your leverage when you start the trial alone. There is now no compelling need for any company to get involved. Even if the trial is successful PPHM has no way of selling Bavi and they will still have to partner then.

It is kind of sad that PPHM has always stated or implied they would be able to get a partner on board before the start of the Phase III. I believe they wanted to have a partner that could have helped design the Phase III and may already have had relationships with various clinical sites.

Going it alone, despite Garnick's protestations, is not a winning strategy.

the judge says that if they don't amend it will be dismissed with prejudice. doubtful that the judge would permit a third amendment. It is interesting that the judge seems to think that there is something there but not enough evidence. PPHM is hardly getting a clean bill of health.
Again, PPHM cannot be culpable if they are just incompetent so they have that in their favor.

IMO the scientific advisory board is a publicity stunt. there will be no followup these hired guns are getting paid to have their name out there and give PPHM some favorable publicity. You know what's better than publicity, having a drug that actually works. and if it works you don't need to hire rent a consultants constantly that have no skin in the PPHM game ( for that matter neither does mgmt!)

PPHM often says things that never happen. I like how they use the CC to do introductions now. Worsley this time implying he can close a deal for Bavi. Can't Garnick or Boyd do that? Thought there should be some exciting new data about the synergy of Bavi and other therapeutics. Does Brekken know that if you already have %80 response you can't go to %200. I also like the way Shan and King were indignant about updating how the Phase III trial was progressing.
When you dilute loss per share goes down. When you have record revenue and same monetary loss you are spending too much, probably too much on rent-a-consultant and lawsuits

what are the odds that PPHM will allow questions from people without direct financial ties to PPHM? In the interests of transparency they should invite comments from any analyst that takes the trouble to listen to the CC as time permits.

go check what they say on the PPHM website about what Avid provides, there is a different story.
quote---Final product filling (including labeling and packaging services)

not surprising that PPHM is putting out confusing information. Please ask at the next CC who filled the vials that were allegedly mislabelled by CSM.
CSM does not fill protein vials. So if they don't vial, and no one has heard of any other party involved in the filling of the Bavi vials in question, don't see why it is so hard to conclude that Avid was responsible. And of course, this is something that a transparent organization would have told you already.

Injection site reactions are reported so having the buffer the same for the placebo is important cause then you have a real control.

Also what the Avid website says now may not be the same as what it said prior to the labeling disaster. Maybe they got out of the vial filling business when they screwed it up for PPHM.


Herceptin is provided as a lyophilized powder. Prior to use it is reconstituted with sterile water but the powder contains

L-histidine hydrochloride
L-histidine
a,a-trehalose dihydrate
polysorbate 20

Avastin is not formulated in saline. The formulation contains phosphate buffered to pH 6.2, trehalose and polysorbate 20

why do you presume saline?
that is not a typical formulation for a commercial antibody.
whatever Bavi is formulated in is the placebo.
Look on the Avid website they do filling, finishing and labelling.
Look at the CSM website they do not fill protein vials.
Avid is the logical choice to produced placebo, 8 mg/ml ad 24 mg/ml Bavi as that is the job of a commercial biomanufacturer.
as I stated previously, an 80 kg patient would receive 2 vials of bavi per weekly cycle. if they weigh more a portion of a third vial would be used to make up the difference. the remainder of material in that vial would be discarded.
This is not logic or a guessing game this is simply the way things are done.

why does everyone think they sent it out in bulk. PPHM clearly must have sent out individual vials containing either formulation only, 8 or 24 mg/ml Bavi. By the dosing schedule and number of patients there would have had to been at least 6000 vials prepared.

You can't use Bavi in "bulk". After the first dose the rest of the bulk would not longer be considered sterile.

King obviously sent out that panicked PR before he actually knew what had happened.

The placebo has to have the exact buffer components as found in the formulation of Bavi. FYI most commercial antibodies are not formulated in PBS. The placebo would certainly have been produced by PPHM as they are the ones that know what is in the Bavi formulation. The placebo would also have to be vialed as well. Since it is double blinded the placebo, 1 and 3 mg/kg vials must look identically.

I was wrong. According to the trial protocol there are 6 21 day cycles of docetaxel with weekly Bavi inections. That is 18 weeks of Bavi so 3x the vials I thought were needed. It's over 6000 vials now. maybe PPHM couldn't ship them all in one run and sent them at different times. That could have been where the screw up occurred. Either way you have 6000 vials shipped. You would think someone would have been curious if they got that right, especially someone with 17 approvals under his belt, Never heard of this kind of a fiasco happening at Genentech. Maybe Garnick didn't know how they did clinical trials since he was only in regulatory.

120 mg/ 5 ml = 24 mg/ml

I think a 120kg person would have to be on the heavier side as that is 264 lbs.

So let us assume the average patient is more on the order of 80kg (176 lbs)

for the 3 mg/kg arm that would be 240 mg/dose or 10 ml or two vials.

for the 1 mg/kg arm it would be 80 mg but also 10 ml or two vials of 8 mg/ml

I believe there is 6 weeks of treatment per patient. So to start the trial it would be reasonable to have an excess inventory. Each arm has 40 patients. 40 patients x 6 weeks x 2 vials/ week = 480 vials/ arm
3 arms = @ 1500 vials.

To make sure there are enough vials a conservative approach would allow for 3 vials/ dose thus 720 vials for each arm would be needed. That is over 2000 vials.

CSM does not do the dilutions. Their website lists no capability to do so. A dilution must be done under cGMP conditions and documented. I am therefore assuming that PPHM will supply all the vials containing the placebo, 8 mg/ml (for the 1 mg/kg) 24 mg/ml (for the 3 mg/kg).

presumably each vial would be coded by PPHM and relabeled by CSM.

Presumably CSM would then be in control of the inventory and would ship out the vials as needed. Since there were over 50 sites and 120 patients, some sites may have only received one type of vials.

This seems pretty complex. If Garnick is the expert he should have insisted the vials be reconciled before the results were disclosed to the public. Given the complexity of the operation you would think everyone would have wanted to know if the right doses were given.


To sum up
thousands of vials prepared by PPHM
no dilution done down the supply chain
complex operation that screams for double checking that things were done right
CSM denies any wrongdoing. I still say if they had screwed up they would have settled with PPHM already.
Also no one would get anywhere near 100 ml / dose much less 300 ml as mojojojo suggests.

in point of fact PPHM has to label the vials it shipped out to CSM. They didn't send out vials with nothing on them. Very possible in my mind that something about the way PPHM shipped out the vials, packaging of vials, number of vials for each dose, labeling of packages etc. could have caused the error. CSM claims it did nothing wrong and they are sticking with that. If they think they screwed up my guess is they would have settled with PPHM already.

Two parties were responsible for labelling, PPHM and CSM. It has not been determined who messed up. The mistake could be PPHM's.

Regardless. Oversight on the part of PPHM was lacking.

the case against PPHM as I understand it, requires evidence of PPHM being intentionally misleading rather than merely grossly incompetent.
That is how PPHM will beat this suit- they can claim they just messed up cause they didn't know what they were doing. I do not think that should make anyone feel any better.

everyone here expresses an opinion relative or otherwise.

stock price is better compared to all time lows not so much to all time highs. I think someone posted a graph of stock price when SK took over to now. It is not pretty.

an 120 patient Phase II took over two years. I don't think it is unreasonable at all to think a 600 patient trial would take substantially longer.

BMY Roche and Merck know the MOA or their molecules and have for a long time. PPHM just pronounced they now know the MOA. As a practical matter PPHM should then be able to explain why Bavi doesn't work in front line or show any preclinical difference when used by itself. If PS is such a powerful immunosuppressant why does Bavi work "better" when there is more PS exposed? It should have an effect when there is less exposed as well. In terms of the dose do you or anyone else have any idea of the total number of PS on the tumor cells. Does the amount of Bavi given come close to blocking all PS sites? With PD-1 or CTLA4 you can know these things.
Even in the preclinical data Yervoy worked great on it's own. Bavi didn't work at all. Hard to imagine how it would help.

When the "discrepancies" in the Phase II were discovered PPHM came out firing that CSM was at fault. Since then the rhetoric has toned down. Now it is described as labeling issue. Whose labeling issue? They aren't saying now it was CSM's fault and CSM has not accepted responsibility for the problem.
Do you know when and where the mixup occurred? That is clarity to me. Not SK saying we looked into it thoroughly and there is nothing to see here. It might be kept under wraps because PPHM will payoff CSM not the other way round.

I think the bottom line is you trust SK and I don't.

The position is low share price, no funding other than ATM.
No realistic approval scenario in under 4 years
Emphasis on nonchemo combo is a pipedream.
There is no clarity as to what occurred to cause the faulty labelling even after more than a year. What happened to the third party audit. And if PPHM has salvaged the trial what financial loss can they sue for?

And if PPHM had done its homework it would not be in this position. Even if they are not guilty of fraud they aee guilty of gross negligience and incompetence

Every part of the trial is PPHMs responsibility. They failed to adequately monitor the trial. Did CSM also tell them to not check on their work. PPHM did not live up to FDA requirements

This so fake. They are counting Bavi in both infectious disease and oncology like there is a difference. Misleading. Typical PPHM trying to imply expertise instead of actually having expertise

why does everyone make fun of Mary Boyd. She is actually the most qualified employee there. She has an excellent education and has worked for major BPs.

I was looking on the iHub PPHM page and noticed a long long list of patents held by Thorpe. King's name was on a few of them. I then went looking for the list of SK patents, the ones he did by himself and without Thorpe. Didn't see that. A real coinventor would have his own patents. Can someone explain that to NH and Zavoico?

The more PPHM emphasizes immunotherapy the slower the Phase III will go. If PPHM doesn't believe combo with chemo is the answer long term, do you think any BP does. That is probably why they are shifting. Also if they don't do a full blown Phase III they can make their money last a little longer and ensure a few more years of inflated salaries for the King and his men.

He's not spotting a gem. He is not independent. He works for the company doing the ATM. They get a nice percentage of those proceeds. At 15-20 million shares per quarter MLV is making 2-4 million on commissions from PPHM a year. I would take his words with more than a grain of salt.
I would ask what would it take for you to lose faith in SK and company?

you do realize Zavoico works for the company that does the ATM? He has millions of reasons to pump up SK as they peddle the stock. Would a car salesman tell you the car you were about to buy was a lemon?

Find someone in biotech/ academia that is a first author in either a patent or a publication and ask them if the other authors are coinventors. You don't have to believe me.

Just curious about the bavi/yervoy trial. yervoy is $120000 for 4 rounds of treatment. Multiply by 24 and PPHM is on the hook for 3 million right there.
You also may want to look at the publications that describe the Phase I of Yervoy. It would be remarkable if any definitive data can be obtained from the 24 pt 12 control/ 12 treatment.

What is true is that PD-1 and CTL4 are changing things. Look at the latest from Merck

http://www.bloomberg.com/news/2013-11-18/merck-drug-boosts-survival-of-advanced-melanoma-patients.html

that is the bar now.

no problem HDG

mgmt has zero experience commercializing a human therapeutic
SK along with Lytle and Shan have either little or no experience other than PPHM.
The BOD with no scientific expertise decided SK has great scientific expertise. SK is also head of Research in addition to being CEO.

Philip Thorpe discovered Bavi. Look on the PPHM website they never make the claim that SK is a coinventor of Bavi. Do not read too much into someone being on a patent if they are not the first author. It is like a batboy getting a world series ring. Yeah he helps but is his contribution equal to guys that actually play the game.

Track record
Cotara has never gone anywhere under SK despite promises dating back 10 years that is is almost ready for commercialization, looking for a partner etc.
Bavi Phase II was a disaster. The buck stops at the CEO and SK has not taken ownership of the problem.
The ATM is destroying shareholder value. Pretty soon there will be 200 million OS. This is limiting what the SP could go to in the event of a buyout.
Imaging? big deal last year nothing updated
and now back to pre clinical and piggybacking on the success of Yervoy.
In the meantime SK and upper mgmts take way too much money- money that would be better spent on actual research.

I find it unacceptable that PPHM has not with complete transparency resolved this. After more than a year the story needs to be told. If it puts management in a bad light so be it. Someone has to take responsible for this debacle.

Think of what the botched trial meant for the patients. They put their health on the line to participate in this trial. They deserved to get what they were supposed to get.

NOTBOB17 I want you to get the best drugs to help you. I want you to get the best care. I do not want you to get an inferior product that will not help you. I think you deserve better than false hope. I think you deserve to have the company providing you with a drug to have done the best job that can be done in understanding the drug and conclusively demonstrating its utility before it is given to you.

You guys think bashing PPHM will prevent them from developing a life saving cure. I am saying that if Bavi or Cotara will ever be a beneficial approved product SK and the rest of the "team" need to go and let competent people develop it. In the end that will be the best for the patients and the shareholders.

I'm pretty sure what he means is that he will publicly call out what he perceives as dishonesty and incompetency on the part of PPHM. I took there to be nothing sinister about that.

I would hope PPHM management would take responsibility for the Phase II debacle. Say what you want but this issue has been going on for more than a year. Those who believe management take their explanation at face value. I do not believe their explanation. if the facts were that clearly on their side this would be over. The fact that it is dragging on causes me to question whether or not PPHM is telling the whole truth-- I hold them accountable for this i.e. they need to give an honest account of what happened.

as far as SK fully understanding what he was saying at Credit Suisse I would side with MicrobeMan. His speech, which at this point is like a campaign stump speech, was rehearsed. I cannot think of a forum where SK has had to answer probing questions. The CC's are populated by representatives doing business with PPHM ( and getting great commissions from PPHM). SK is not a good enough scientist to ever give a talk at the NYAS for instance, where you have to display complete knowledge of your subject and get asked questions by folks that may be more knowledgable than you are. When SK does something like this I will retract my comments about him not really being a serious scientist.

(while I was typing this M_M was crafting his own reply, so my explanation of "accountable" is superceded by his)

I think it is highly debatable whether PPHM's conduct surrounding the Phase !! trial was industry standard. That may end up being settled in a court of law. The law says that ultimately they are responsible for the trial and can't pin the blame on a vendor. The vendor's mistakes becomes PPHM's mistakes as PPHM chose the vendor and should have been supervising their work. I don't know what is more fundamental to a trial than verifying that the doses where given correctly. Whenever I got a weird result in the lab the first thing my PI would ask is whether or not I mixed up the tubes.

I have a few questions for this group-

I was looking at the cartoon on the poster PPHM presented at the recent SITC conference. I did not notice beta-glycoprotein included on the cartoon and was wondering why. Since bavi actually binds to beta-glycoprotein why is that information not shown on the cartoon. Does beta-glycoprotein enhance binding to the PS receptor? There are other proteins reported in the literature to bind to PS. How does their binding to PS affect the binding to the PS receptor?

Also on the graphs showing cytokines produce in the presence of control and ch1n11 on the MSDCs do you feel their should be error bars? The y-axis shows mass/ml. Is this normalized to the number of cells growing in the culture that the cytokines where obtained from.

In closing what does everyone think of this from the Dana Farber cancer institute that describes PS as an "eat me" signal"

The principal immune components charged with this task are macrophages and dendritic cells, the key mononuclear phagocytes. These antigen-presenting cells use a multiplicity of receptor/ligand pairs to recognize and engulf apoptotic cells (20). Whereas scavenger receptors, complement components, and collectins all play important roles in clearance, a primary “eat me” signal seems to be phosphatidylserine. T).

It is scientifically dishonest to say proven fact in science. That kind of mentality is inherently unscientific. That is hype.
PPHM walks a fine line. I am sure the Journal that published their results would not be impressed that PPHM was using that publication as proof of validation and proven fact in a financial conference.
Likewise, acceptance of a Phase III trial design does not mean that the FDA thinks Bavi works just that Bavi is safe.
King has promised you combination immunotherapy and will contort any data and any study to fit that need.

The good thing is science will not let this distortion go on forever

which is why they should be more forcefully pursuing the imaging and Cotara. The ultimate payout may not be billions but these products could do 100-300 million and generate positive cash flow for a long time. cash flow that could fully fund all bavi projects.

right now it appears that the energy is going towards this combo obsession. When Mr. King says the science is settled he has to be joking. This new MOA they are promoting is based on one paper- seemingly the last paper with Thorpe's name on it. It is entirely possible that these results will not be reproduced. I mean that would be like someone touting the results of a Phase II trial for half a year and then having to retract them. I mean, that couldn't happen could it?

and your excitement is based on exactly what? How do you know that the "complete" response to the combo was not just due to poor cell growth of the injected tumor cells?
PPHM is certainly not in the driver's seat and to act like they are is pure hubris. How about a little modesty? then maybe you would not rush into the public record studies that show your Phase III molecule has no activity.
Do you honestly believe that one mouse study would be enough to start a Phase 1? and where would PPHM even get the money for that ambitious trial? They have their hands full trying to get a Phase II started.

Also, all this emphasis on combo with immunotherapies seems like they are throwing in the towel in the docetaxel/ Bavi combo. Maybe they are realizing that in a few years immunotherapy will be replacing chemo and in that world there will be no place for Bavi.
At least with docetaxel there does seem to be a reason for Bavi to be there i.e. there is more PS exposed with chemo. The way Bavi is supposed to work with the immunotherapies is different. So will the real MOA stand up.

all those authors are being paid by SK and know what they have to deliver. This is PR disguised as science. You don't believe me that's fine. Here is a much better dissection of PPHM's poster than I could ever do. Pay particular attention that there is a lot of heterogeneity in the tumor model itself. This makes it very difficult for unequivocal interpretations. Leastwise that is what an honest scientist would say but having SK tell you what to say results in a distortion of the truth.

From: nathan oshanessy

The PR released by the company today, regarding tomorrow's poster presentation at SITC, deserves comment due to obvious deficiencies in the data of this marginal preclinical study. It is assumed that these experiments have been repeated and the scientists are presenting their "best results".

1. The K1735-C3H syngeneic mouse model has been studied extensively for possible immune intervention as therapy. Melanoma is a somewhat promising malignancy for immunotherapy and both preclinical and clinical trials have taken place in this model for a couple of decades.
2. The preclinical model as presented in this poster is flawed, as quickly observed for the data of the control group (receiving the C44 control antibody). Injection of the indicated dose of tumor cells subcutaneously resulted in such heterogeneous growth in the group of mice, it was impossible to determine effects of any agent. 2 mice had (desired) logarithmic, rapid growth of tumor; 3 mice had slow growth of tumor, so it must be surmised that the remaining mice (bottom of graph with measurable "bumps") had virtually no progressive tumor growth. Hence, the model, as used in this experiment does not work.
3. Treatment of mice with the anti-PS antibody, Ch1N11, resulted in no effect whatsoever in tumor growth (so much for that fantasy of anti-PS), and actually resulted in somewhat more favorable tumor growth (at least 9 mice has discernible progressive growth of tumor).
4. Treatment of mice with the much-studied CTLA-4 antibody resulted in little tumor growth in 10 mice, whereas 2 mice had progressive tumor growth. But, keep in mind, the model doesn't give uniform tumor growth to begin with...
5. The combination therapy showed no progressive tumor growth in all 12 mice (2 mice different than the use of CTL-4 alone).
6. In light of the absolute no effect of the anti-PS Ch1N11 upon tumor growth, it is difficult to believe that the combination therapy actually resulted in beneficial combination effects...which always brings up the fallacy of studies from PPHM, the lack of statistical verification of any result.
7. The histology studies lack any conviction due to complete lack of information regarding exactly what tumor did they dissect for examination; the progressive tumor, the tumor that grew poorly, or the tumor that showed necrotic features.

The statements regarding a favorable basis for clinical intervention are flawed. A poster session for one hour is 59 minutes too long.

so for the antibodies used in the study

G44 control - unknown murine/human
anti-CTLA4- unknown murine/human
ch1N11 human Fc, Fab half murine half human

for a murine study you should use all murine Abs to avoid an immune response.
my point is that if the intelligent but ignorant reader is looking at that poster they aren't given enough information to make sense of it. Or maybe PPHM knows they rushed this study and didn't use the correct reagents so they didn't mention their origin.

The key combo missing is antiCTLA4 and G44. This is the real control but is not included. and if it is a real control G44 should be chimeric as well.

Just saying this is sloppy work that IMO is not worthy of a PR saying anti-PS improves anti-CTLA4. And since there is a good chance this modest (at best) result will not be borne out by further studies it ultimately will make PPHM look silly and dishonest for issuing a premature PR.

This data is being overhyped

we do not know a lot about the antibodies used in this study

are they human or murine versions? what is the control? where was the anti-CTL4 antibody obtained? what is ch1N11?

Objectively you could also make this conclusion from the same data

Anti PS has no effect on tumor volume as compared to control.

Do you really want to release data that shows your Phase III product does nothing?

No one ever said testing the blood samples lead to the discovery of dose switching.
Whatever happened to the third party that PPHM was going to use to get to the bottom of the dose switching?
Don't you think it's strange that if CSM was clearly to blame PPHM would not be more aggressive in going after them?
Outstanding shares now at 155 million making it highly unlikely share price will get much above $3-4 even with good news. Further dilution- which of course is coming- will only drive down the share price more- and they haven't even started the Phase III.

Considering that the market for second line NSCLC is substantially smaller than first line, any deal would not necessarily be enough money wise to move the share price more than 2-3x. Mgmt can make more not doing a deal cause whoever takes over PPHM would have zero reason to keep King and Co. around

The science is they are preclinical with these 'combo' therapies. They are talking about doing combo with drugs that have not even been approved. It is all a distraction so you don't notice the Phase III will take 5 years

it would take a lot for another company to let PPHM use their potentially multi billion plus drug in a clinical trial. If a patient dies for whatever reason it could adversely effect that drug. All adverse events for a drug regulated by the FDA have to be reported to the FDA. Thus you only want to do trials that you know are going to work. Doing a trial with PPHM would represent a drastic loss of control for BP. So, unless they ask us to join them I don't think any BP will permit PPHM to use their drug in any kind of pre clinical and/or clinical work.

PPHM would never tell you that. They only want you to think 200-300% improvement based on trials that are never going to happen. Don't believe the hype. Ask yourself whether PPHM is really being honest with the shareholders.