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James, nice post. But Gilead has 24.7B CASH
CEO Martin and his team are on the warpath. The reason I like "Gedanken" experiments with GILD is because of their culture. They're nimble, entrepeneurial, and bold. Just the type that buys PPHM.
insert-text-here
Regards,
Joe
Nuke, recall that all PPHM's ISTs are open-label
for the Phase I, I/b, and II trials in Breast (Her-2 negative with Paclitaxel), Stage IV NSCLC (with carboplatin and permetrexed),and Liver HCC (with sorafenib), respectively. Enrollment for those trials is already complete. PPHM has data and is already studying clinical responses.
It's up to them whether they want to share this trial data with negotiators at the table. These are HUMAN trials with HUMAN results, which I agree, are paramount.
Always remember GILD what did with Pharmhasset's phase II data. GILD saw what it wanted, and struck quickly and without hesitation. For $12 billion. For one drug. For one indication.
Regards,
Joe
James, GILD will not make Roche's mistake
Roche (a stodgy ol' Swiss company) bought 60% of Cowboy-California Genentech for just $2.1 Billion (!!) in 1991.
This proved to be a brutal, extremely costly mistake. Genentech proved to be such an incredible superstar, that just 18 years later, Roche was forced to pay $47 Billion in 2009 for the rest of the company (!!)
NO WAY does GILD make a similar mistake with PPHM. These guys are vicious. They're salivating big time over the gazillions just sitting there with immuno-oncology; they know it represents the paradigm shift away from the "cut-poison-and-burn" cancer treatment that everybody despises (i.e. surgery/chemo/radiation). Cancer is ready to surpass HEART DISEASE as the number #1 killer. Good grief.
No, GILD or some other behemoth wants the whole bag. The entire industry is fully aware of the catastrophic error made by Swiss Roche with South San Francisco Genentech (DNA) in 1991.
I expect CASH and STOCK for ALL of PPHM. But, OK James, let's replay your numbers:
CEO John Martin of GILD says, "OK, let's move." He offers $20 Billion for 50% of worldwide rights to Bavi plus a 1:1 stock exchange. (The float for GILD is 1.44 billion shares, so he'll have to offer 300 million shares, i.e. 20% of the company). Unlikely in my estimation, but I like your optimism.
Joe Six-Pack is going to pass out when this hits his portfolio: He'll get $66 per share from the $20 Billion, = $4.3M, plus 65,000 shares of GILD for a value of $6.63M (based on today's GILD pps of $102), plus appreciation of his GILD shares (at $345 pps in 3 years), which gives him $15.79M more, PLUS the annual dividend of $1.72/share for every GILD share (as North40000 stated, likely to increase in the future)
So Joe Six-Pack is looking at $4.3M + $6.63M + $15.79M + dividends = $26.72M for an original investment of 65,000 shares of Bavi. This would clock out at Bavi today at $411/share.
Well, King did mention the word "astronomical." Whether these numbers represent that word I guess is up to everyone's personal point of view.
Regards,
Joe
That's it Eb; Joe Six-Pack will make more off his GILD shares than his PPHM shares.
That's the key. In my example, Joe Six-Pack makes $4.3M off his PPHM shares, but then make $4.48M off his GILD shares.
Getting out of the PPHM box is the idea. When Bavi is approved (and the Avid maneuvers and my own DD make me think they've already got data from other trials in hand), most investors here will make the MAJORITY of their money via ANOTHER stock.
Namely, GILD.
Best,
Joe
MD, if Bavi is the cornerstone molecule GILD is looking for
then $20 billion may indeed be the initial cash offer, but no way Garnick, SK, ES et. al. will settle for that. They want a piece of the action in the future. How does that happen then? GILD offers PPHM cash AND stock.
What if GILD said, "OK, we offer $20 Billion for US rights AND 1 share GILD for 5 shares PPHM to your stockholders."
This is a more plausible way to get to the high numbers bandied about from time to time on the Board.
****EXAMPLE: Joe Six-Pack IHUB Member has been averaging down for the past 2 years and now has 65,000 shares accumulated.
CEO John Martin of GILD gets aggressive and makes the above offer.
How does Joe Six-Pack do? Well, he does quite well with the initial offer, but he'll do even better if he sticks with GILD.
The $20 billion cash gives Joe about $20B/300M shares (shares outstanding will increase in the future, hey, that's Biotech, out of the kitchen if you can't take it), which = $66/share, which gives Joe $4.3M for his Biblical patience. Sounds fine, but ah, we're just beginning.
Joe's 65K shares will entitle him to 65K/5 = 13,000 GILD shares, which X closing price today $102/share gives him another 1.32M
Ah, but do we really expect GILD to stand still at $102? Think not. With their new cornerstone molecule, Martin snaps up the best PD-1s, PD-L1s and other T-cell modulators at bargain prices for his combos. Everyone suddenly wants to do business with GILD, and Martin knows that with a grin on his face.
So GILD stock heads north as they lock up SOC in MULTIPLE solid cancer indications (see Sunstar's many laundry list posts as to how many cancers Bavi can combo against).
3 years from now, GILD is $345/share (not at all unreasonable, with GILD/Martin's killer instincts).
How's Joe Six-Pack doing now? Well, he's got $4.3M + $1.3M + the appreciation of his GILD shares which is $3.18 M, for a grand total of 8.78M for his time and effort.
Yeah, yeah, haha, wotta riot, the hell you say... keep thinking that...(smirk)
Regards,
Joe
Great job, Chris - my thoughts
Great job, Chris, as usual. Thanks for the effort.
What the science has determined for quite some time now (think decades) is that changes in the CELL MEMBRANE induced by oncogenesis place that cell outside the grasp of the immune system. In short, cancer manages to turn off the immune system's interaction with the affected cell, thereby allowing the cancer to wreak its havoc uninterrupted. The bastards.
Enter PPHM's Bavi. The key immunological challenge is to reverse the changes in the cell membrane, so the immune system can come back on-line.
THE SOLE, UNIQUE, monoclonal antibody that can effectuate this critical reversal is Bavituximab.
In biotech, you pays your money and you makes your choice. I'm placing my bet on the cell membrane. The scientific community KNOWS and HAS KNOWN for a very long time that the phospholipid bilayer is the critical interface between a cancerous cell and a threatening immune system.
Winning this critical fight at the cell membrane is the spearhead realistic for the coming paradigm shift in oncology.
Regards,
Joe
PDB, Bavi was, and still is, anti-angiogenic
Tumor blood vessels in the micro-environment DO express significant amounts of PS.
What's new, however, is the discovery that PS is also expressed greatly by the tumor cells themselves.
This is how the tumor "hides" from the immune system. The exposed PS triggers the production of MDSCs, which Mojo, BP, and myself have been noting as a very crucial element in why treatments fail.
If we can combine Bavi with downstream inhibitors, a serious hurt can be put on MDSC prodution.
Don't give up quite yet. We're actually quite ahead, being in a large PIII, as the field is just starting to develop. And it's a $35 billion field. If Bavi is in the middle of this space, and the evidence indicates that it is, you won't regret holding.
By the way, welcome back after your 10 month hiatus.
Best,
Joe
Great post, Mojo, MDSCs are the hard brakes
on the immune system. Gabrilovitch and Brekken are your key men here. Brekken knows that reduction of MDSCs when combined with downstream anti-XYZers will give the 200-300% potentiation in OS rates.
UTSW - Brekken
It's why I'm thinking PPHM could very well get scooped up. BPs have invested BILLIONS into their anti-XYZ babies, and a Mab that doubles or triples their efficacy is going to draw intense interest.
Thanks for the post,
Joe
PPHM is going to get scooped up: 40% MDSC reduction
Moreover, cells that suppress the immune system from recognizing tumors, such as myeloid-derived suppressor cells (MDSCs), were reduced by more than 40% in the combination with the PS-targeting antibody versus anti-PD-1 alone.
Stone, you're not following the I/O thread
It's a rapidly-changing, dynamic field.
PPHM itself didn't understand Bavi's MOA 24 months ago.
So what if you've been waiting 15 years like (what seems) everyone else here?
For 13 out of those 15 years you've been holding, you didn't even know what you had.
And neither did PPHM.
And neither did the scientific community.
It's a whole new YOUNG ball game, my friend.
We're only just getting started.
Your thinking is a bit "soooo 15 years ago...."
Joe
Only in the U.S. does instant gratification take too long
Your list will come, Stone. (with the exception of the BOD change. Don't count on it. They know what they have and they're not showing their poker hand to ANYONE.)
Bavi has great scientific rationale, breast results were super, second-line P2 results were awesome despite the sabotage, and Gabrilovitch loved the liver results, clearly calling for a P3.
Promise me. No. more. tantrums.
Regards,
Joe
No. P3Data. Yet.
Let Sunrise progress already.
Joe
IFU, there are oceans of anti-PS articles
Here's one I'm reading now:
phosphatidylserine in brain cancer
Check the 3rd paragraph:
Increased exposure of phosphatidylserine characterizes the membrane surfaces of tumor cells and tumor-associated vasculatures [14, 15], and represents an attractive target for anticancer therapies.
Am I supposed to do your research for you -
I already gave the link to Gabrilovich's authorship on the Bavi paper.
Please pay attention.
Gabrilovitch anti-PS platform
Joe
OK, IFU, but since only PPHM has the patent on anti-PS,
any mention of antibody-mediated coverage of phosphatidylserine externalization is, by default, a citation on Bavi.
There are no others.
Any literature reference that cites phosphatidylserine's harmful polarization of macrophages to M2, or promotion of MDSCs, or increase with Tregs, is in fact referencing Bavi's MOA, which, not surprisingly, reverses these harmful changes.
And, my friend, there are THOUSANDS of such articles.
Regards,
Joe
For the doubters, this man knows Bavi works
Here's his profile:
Wistar Institute, Philadelphia, PA, Gabrilovitch, M.D., Ph.D.
Perhaps a tad smarter than the some posters here.
Perhaps.
Regards,
Joe
IFU, KOL Dmitry Gabrilovitch is named with Bavi
Check the link (read the list of authors at the top)
Gabrilovitch - Bavi, anti-PS
Here's Gabrilovitch's profile from the Wistar Institute. (in Philadelphia, about as far away from Tustin as you can get)
Profile: Dmitry Gabrilovitch, M.D. Ph.D.
You can say what you want, man, but based on the photo of that guy, he doesn't look like the bottom of the scientific barrel.
Regards,
Joe
That's true enough, Abe, but it doesn't legitimize
"off-the-cuff" remarks on the science that are readily refuted.
I invite you to read PubMed with the appropriate search terms.
Nothing in the market is a foregone conclusion. Everyone knows that. It's a bettor's game.
You do your research, "you pays your money, and you makes your choice", as the old saying goes.
My money is on a horse named Bavi.
I, like pphmtoolong, like our chances. Very, very much.
Regards,
Joe
Abe, your original quote was
i certainly believe thorpe said the stuff works, but the fact remains that it is not generally accepted yet by any means.
Exactly, pphmtoolong, thanks. EOM
Abe, the SUNRISE trial is not yet complete
You do get that, don't you?
Please say "Yes."
Regards,
Joe
Abe, it's NOT my opinion; these are the studies out there
You can't just say, "Hey, that's your opinion, fine, but I've got mine."
I'm not giving any opinion. I'm just citing the literature. And all the science is there to support the hiding of phosphatidylserine externalization.
THAT IS NOT MY OPINION. That is the result of SCIENTIFIC studies outside of PPHM, and outside of UTSW.
As for your stock price of $1.28, that is a question of the commercialization of the science, not an indictment of the science itself.
You know Biotech, Abe. You know how quirky it is. You know that Wall Street has a Jerry Maguire fixation: "SHOW ME THE MONEY!!!!"
I/O is indeed an emerging field. And Wall Street is still trying to get its head around it.
$1.28, $1.38, $1.58....
The question I have for you is this:
If PPHM were $1.68 right now, would you have more confidence in the science?
Do you see how absurd that is? You are basing your confidence in the science on the vagaries of the market.
Please read more.
Hit PubMed and start searching. Might I suggest "MDSC" "antitumor immunity" "phosphatidylserine" and "M1 polarization" as search terms to start.
Regards,
Joe
Abe, the cell membrane has been acknowledged to play a central role in cancer transformation for almost 40 years
i certainly believe thorpe said the stuff works, but the fact remains that it is not generally accepted yet by any means.
Accumulating evidence suggests that the success of some anticancer therapies not only relies on their direct cytotoxicity on tumor cells but also on their ability to promote anticancer immune responses
"Immune System Cancer Drugs = $35 Billion Market
Check the link: I/O is $35 Billion Market
Don't sweat the pennies, brothers. SUNRISE will put PPHM in the middle of this space.
And that's a BIG space.
(The biggest in pharm history, actually.)
Regards,
Joe
"We'll be in the middle of the space"
Will someone please show me data that contradict this assertion -
(OTHER than whining about the PPS) (Bolding is mine.)
I think maybe even most importantly is that our data is very consistent with what people are showing with other test systems. So, it really is resonating with people in a way it hasn’t in the past.
But, it’s a ground effort – it’s publications, presentations. And then, of course, clinical data will eventually trump all that, and that’s the reason that executing on the Phase III SUNRISE trial is so important as a backbone to getting the recognition for this program.
It’s just going to be continuing to execute, be on the road. I think, the more the word gets out there, we think the more we’ll be clearly in the middle of the space.
As I said in the prepared remarks, to me we’re in a really unique position because, while there’s a lot of interest in immunotherapy, there’s not many that are in the middle of their pivotal Phase III study like we are. We view that is a real benefit and I think something it will drive a lot of interest because once a drug’s on the market now, of course, it opens up all kind of avenues for combinations and others ways to use the drug. We’re really looking forward to continuing to execute on that and take advantage of sort of that position being more advanced than a lot of the other immune checkpoints at this point.
"Paradigm shifts don't come around often"
I also don't complain because I understand paradigm shifts and they do not surface often.
Right on, dia. Never mind the fact that all of oncology knows a paradigm shift is coming, that the cell membrane is crucial to signaling of the immune response, and that PPHM holds all the IP with the ONLY upstream checkpoint blockade that happens to be exactly on that cell membrane.
No. Never mind all that. Just worry that doubling up Avid capacity spells DOOM.
I'm afraid investors tend to have the maturity of junior high school students.
**Sigh**
Best,
Joe
GoodJohnHunting, your cytokines are a bit off.
INF-alpha is VERY immunostimulatory. Always has been. That's why it's used been used for decades to fight Hepatitis C (Interferon alpha 2a i.e. "Pegasys").
While I agree that IL-1 and IL-6 are essentially immunosuppressive (they are in fact Th2 promotors of antibody-mediated immunity), IL-12 definitely is not.
Check the article below on INF-alpha:
RESULTS:
Treatment of peripheral blood mononuclear cells with a combination of CpG ODNs and IFN-alpha resulted in enhanced cytotoxicity and activation of natural killer cells. Administration of CpG ODNs plus IFN-alpha elicited superior antitumor activity in a murine model of B16 melanoma compared with either agent alone.
Systemic IL-12 administration modulates dendritic cells to overcome the immunosuppressive microenvironment of the liver
Furthermore, the cells activated in the presence of both TGF-ß and IL-12, and not of TGF-ß only, stimulated macrophages to produce nitric oxide. Altogether, these results indicate that IL-12 is a superior cytokine that has the ability to skew the already ongoing TGF-ß-dependent iTreg or Th17 developmental program into Th1-like direction.
Wook, my ticker=$1.35 - what gives? EOM
EBS, the question is why the rotten cohort?
Yopp's open-label liver trial in advanced HCC had a rotten-to-the-core cohort.
You know that.
So what's PPHM's strategy? Well, what are you going to do, take a much better performance status cohort, and prove what?
Nothing. The size (n=38) is too small to prove much of anything in a healthy group. The study will also take too long.
PPHM wants fairly quick results that can allow them to move Bavi on to the next phase.
Yes, yes, it's terrible that Bavi didn't knock out a home-run. But if the baseball itself is in terrible condition, it won't go far anyway.
The liver trial WAS a base-hit, however, and that's all PPHM wanted.
Best,
Joe
IFU, the ONC consensus is that more has been learned about cancer in the last 10 years than in the previous 2000 years.
Dr. White (director, UC Davis Cancer Center) adds that we've learned more about cancer in the past 10 years than we had learned in the previous 2000 years.
PR, I appreciate your struggle greatly, but I cite FACTS not opinion. Chemo and radiation haven't changed cancer mortality statistics in 50 years.
Oncologists KNOW that the age of chemo is ending. Article: No More Chemo
Cancer is an industry, PR. You know that. The American Cancer Society has a HUGE interest in promoting this industry. That's why they went ballistic over this ENORMOUS 25 year study (n=90,000) that showed definitively that mammograms are worthless.
Vast study doubts mammograms
Yep, the whole Susan G. Komen "Run for the Cure" show is nothing but. All those 5k races. All those pink ribbons. All those "Fight like a Girl" tee-shirts. Yep, a FARCE.
Now yes, PR, you're right, chemo does work well with a few cancers e.g. childhood leukemias, Hodgkins lymphoma, and testicular cancer. But not much more.
It's undeniable that chemo and radiation have put millions into early graves. Suffering, vomiting, hairless, and exhausted ALL THE WAY to the end. Why? Because the very system they needed to fight their cancer, their immune system, was totally annihilated by their "treatment." Ever wonder why you can't bring fresh flowers into a cancer ward?
Please recall that THE central bias in American medicine is this:
"DO SOMETHING."
What is NEVER acceptable is to promote health through alternative means. Instead, the dictates of the medico-pharmaceutical cartel must be followed. Give her the poison! Zap that cancer! Get the gamma knife! Get the Neupogen! Inject the Procrit!
THIS is the reality for millions of cancer patients. I respect your story. But your trial size is N=1.
There ARE treatments out there for Sue right now that won't destroy her immune system.
More on that in a forthcoming post.
Best,
Joe
Sunstar, great post and indicative of a central aspect of immuno-oncology.
It takes time. LOTS of time.
We live in a culture of instant gratification (now more than ever). My brother jokes that "Only in the U.S. does instant gratification take too long."
If a person has cancer, they want that cancer GONE. As in, "yesterday." Doctors have this mentality even more so.
Think about your typical oncologist. Poor Sue has breast cancer and is in tears. She's had a mastectomy, feels traumatized already, and now here come her "white knight" (literally, in a white coat).
Doc says "Don't worry, dear, we're going full-steam ahead, full-attack, and hopefully (he knows better, but doesn't say anything) we'll have your cancer in remission in 3 months." Sue brightens up immediately, placing all her hope in Dear Doctor's chemo.
What Sue doesn't know, and what Dear Doctor fails to tell her, is that BREAST CANCER MORTALITY HASN'T CHANGED IN 50 YEARS. "Cut, poison, and burn" i.e. surgery, chemo, and radiation, will, 100 years from now, be seen as BARBARIC. But right now, Sue thinks she's found her white knight.
[url][/http://io9.com/5883180/why-havent-we-cured-cancer-yeturl][tag]Article: Cancer mortality hasn't changed in 50 years[/tag]
So what's wrong with this picture? Easy. Everybody thinks we're gonna get this "cancer thing" in 3 months, and then get Sue back to drinking lattes with the girlfriends at Starbucks.
As we all know, it doesn't work out that way. The very thing that can save Sue from her breast cancer, her immune system, is being systematically destroyed by the very chemo and radiation she is so eager and anxious to get. She, and even more so, Dear Doctor, are gonna get this breast cancer "quick."
But the immune system doesn't work that way. It's a loping elephant, taking plenty of time to get up and get organized. Now with sustained support and prompting, it can be turned into a CHARGING elephant (with Bavi in the mix, of course).
Now a charging elephant is going to beat the stuffing out of Sue's breast cancer and either cure her outright, or put her into a 30 year remission. She'll probably die of something else first. Kinda like the slow-growing, indolent prostate cancers that don't kill older men because their hearts wear out first.
So what's the answer with immuno-oncology? Answer: time, time, time.
But the trick is that a patience-centered approach (sorry for the pun), runs counter to the culture.
We want "quick-cures," so we can get back to our fast-paced lifestyles.
But maybe it's precisely that fast-paced lifestyle that led to the cancer in the first place....
Joe
Exactly, jim - the CT scans are AWESOME
I've been trying to point that out - 18 months PFS with HCC?? !!
Absurd.
I encourage everyone to LOOK at the 3 CT scans in the poster closely.
Best,
Joe
MD, true, Liver (Bavi) is not Brain (Cotara)
Millions have Hepatitis C, which is a huge risk factor for HCC. Liver is in a TOTALLY different category than Brain.
Many big BPs would be VERY interested in securing SOC in HCC.
Interesting to note that Yopp's poster mentioned HCC as THE fastest growing cancer out there. WHY?
Hep C.
Regards,
Joe
The CT scans of the 18 mo PFS patient are striking
I think what people are forgetting here is that HCC is an absolutely FATAL cancer. You just don't "recover" from it. It's vicious. When you lose your liver, you're toast. Cancer weakens your body incredibly.
The CT scans on the poster of the patient with the PFS of 18 months (!) are unusual. I mean, LOOK at them. No wonder this patient had a PFS of 18 months. People don't live with HCC and fail to have progression for a YEAR AND A HALF. They just don't. Look at the cancer wasting away. In HCC, that just doesn't happen.
Yopp poster with CT scans of 18 mo PFS patient
Best,
Joe
MD, if you do a little algebra, you can see that
The 7 patients still alive must average 14.4 months TTP for the total 38 patients to average 8.2 months TTP. Remember, the study is powered only to detect this far out, not more.
For example:
31 patients (6.8 TTP obtained ) + 7 patients (x) = 38 patients (8.2 TTP average)
7x = 311.6-210.8
7x = 100.8
x = 14.4 months TTP (time to progression)
Can these 7 patients do it? Well, they're still on their way. They would all have to live until September 20, 2015 for the average to occur. Present median trial time is 6.1 months, which means to make 14.4 months TTP, they have to live another 8.3 months. 8.3 months from now is about September 20, 2015, give or take. We'll see.
Regards,
Joe
Careful, MD, the study was POWERED to detect 8.2 months TTP (time to progression), but Bavi up til now has clocked in only 6.8 months TTP.
Now it's true that 7 of the original 38 patients are still alive, so that number HAS to improve. But let's wait and see what Yopp says about that later this week.
Best,
Joe
The exact link for the poster (C14) should be at
PPHM Yopp Liver Results, I think.
Thanks, Irish, for getting us there.
Let's all keep checking.
Thx,
Joe