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TOG, don't give up - the science behind Bavi is only increasing, not decreasing
The Big Boys, even Roche, which has 14 BTDs, (thanks to N40K for the Roche slides), still doesn't have the I/O answer.
In fact, no one does. To really put the hurt on cancer, I/O COMBO therapy will be mandatory. Upstream and downstream, AND maybe chemo in some cases, and radiation in others.
Look at the Roche slides. They're as professional as it gets. When Bavi is combined with biomarkers and exosome science, the Big Boys will come calling. They've already sunk too many trazillions of dollars into their anti-XYZers. The competition is ferocious, as cancer is more widespread than ever.
Anything that offers an edge will be acquired. I really think that's how PPHM will go. The company will just be bought out completely, everyone will cash out, and then go home.
2017 will prove an interesting year. I/O 1.0 has played itself out. I/O 2.0 promises interesting combos. And Bavi is at the right place at the right time.
Best,
Joe Six- Pack
Bio, North, CP, the UCSF article confirms what we've discussed all along. The Big Boys don't have much at all. Opdivo is not the golden goose. WAY too many non-responders, and if they do respond, they get nasty auto-immune disease like fulminant diabetes and Crohns. That NYT article is still reverberating. Oh, and yes, they're guaranteed to relapse. (No memory cells to attack the cancer's return, as CP points out.)
So Big BP doesn't have jack. With all their gazillions in cash, all their tragillions in research dollars already invested, and you know what? They don't have jack.
That's why I've always preached the patience of Job around here. Multiple labs from around the world (NOT associated with the much-maligned UTSW) are all saying the same thing.
Something is missing. Some kind of general immune light switch that provokes the development of dendritic cells and turns off the suppressor cell network.
We are all here for one reason. We are convinced, through our reading and DD, that there is an answer to that problem.
Best,
Joe Six Pack
PTL, show me where BP is doing any better
Tustin right now has a market cap of about $80M. GILD and MRK have MCs around $130-140B as in Billion. That's about 1600x the size of PPHM. What has Wolcott said about THEIR products lately?
Uh, yeah. That's what I thought. Keytruda helped out Jimmy Carter a bit, but otherwise, anti-PD1s are killing lots of patients or giving them fulminant diabetes.
When BPs start pulling away from us with new I/O drugs that really work, then I'll be a bit concerned.
But then again, I'm not concerned. Their drugs won't work well without PS blockade.
Best
Joe 6
Thanks Bio and North, for keeping the conversation going about the severe limitations of the Big Boys kazillion dollar downstreamers.
The focus here always seems to be how far behind we are, and we're haven't done this and we haven't done that, but guess what? The big boys anti-PD1'ers aren't exactly cleaning up.
In fact, mega-BPs downstream Mabs are kinda killing folks outright (but, hey, what else is new).
I hope everyone takes the time to read through North's NYT links. The big boys clearly don't have what they need to hit the zazillion dollar I/O jackpot. It's not there.
There IS lot of auto-immunity, diabetes, Crohn's, and death, though.
(Hey! We made a lot of progress against the patient's cancer; unfortunately, he's no longer here to receive the good news...)
So what's missing? Hmmmm...
Happy New Year,
Joe 6
Geo, if they refused to pay a good price before, that's fine. Now
they'll just pay through the nose.
The downstreamers (anti-PD1) won't work correctly until the upstream switch is thrown on (Bavi). Only PS-blockade will re-animate the immune system thoroughly and completely (every cell!) Then, and only then, can the downstream T-cells be recruited properly. (with MDSCs turned off!)
With the billions and chagillions already spent on downstream technology, the big boys aren't going to trash their investment, geo.
Whether they want to or not, SOMEBODY is going to pay the price to buy the central ingredient in the gazillion dollar I/O stew. (And it really isn't that pricey for these guys).
10-20-30 billion? Pocket change. In my view, it's coming. The field is moving too quickly, yet gruesome side effects are holding back the downstreamers. The big boys aren't going to stand for that.
It's coming. Ask Pascal Soriot. Ask Wolchok (privately). Ask so many other NON-UTSW researchers.
Better hold tight, otherwise you'll be on the outside looking in.
Cheers,
Joe 6
PTL, I wouldn't be too sure
about PPHM not having partnering interest.
What's missing on the board is frank discussion of the sputtering failures of the chagillion dollar Big Boys. Just too many brutal side effects with their downstreamers.
That NYT article did a lot of damage. Sudden type ONE diabetes in a 60 year old! The best doctors in the world missed it!
Auto-immune brutality. Even smaller pharm Juno's drug killed patients outright.
SO MANY trazillion research dollars for a 20-30% responder footprint.
Oh yes, PPHM has MANY suitors. They're just trying to figure out how to pay for the diamond ring.
Happy New Year,
Joe 6 pack
Yeah, 2 downstreamers, ho-hum
Won't work HD - now combining upstream and downstream, now that's why you're here brother HD LOL
CHEERS AND FELIZ NAVIDAD
Bio, this article is HUGE
from cancer.gov - they are referencing Bavi's melanoma trial with Wolchok CLEARLY.
I'm surprised by the third-party reference at this time. Something is clearly cooking here - Wolchok's tight lips, the strange tight-lipped cc, and now this - fantastic news IMO (although well-known to so many long-timers here).
How many times need it be mentioned that PS blockade will be the central ingredient in the gazillion dollar I/O STEW.
Cancer is similar in some ways to TB. You have to go after it with multiple agents to GET it.
It remains my view that 2017 may very well mint many millionaires on this board. I mean it.
Hold tight and don't sell with the first wave - a tsunami is coming after that.
Best,
Joe Six-pack
TOG, Wall Street sees PPHM as a microcap with a failed Phase III
That is true (not really though, in my view b/c of the biomarker data).
It is also true that such valuation could change overnight.
Admit it or not, that is why everyone is holding.
Best
Joe 6
Bro, you're here because Bavi is the central ingredient in the gazillion dollar I/O stew.
I'm not saying this. Many, many top scientists outside of UTSW are saying it.
You can't give it away for stew croutons.
Biotech is a brutal investment field. Hang on with the patience of Job or sell.
That's all you've got.
Regards,
Joe 6
Big, you think the share price is low?
Try the share price without Avid.
Best
Joe 6
Now Bio, people also don't realize that Avid makes PPHM a much more attractive buyout candidate.
You can't start up this sort of incredibly technical molecular business with quarters you found in your sofa.
What's more compelling is the EXPERTISE required. Why else would Halozyme, a much bigger company, go cap-in-hand to little Peregrine, paying a 50% premium?
Answer: This sort of business is a PITA to organize. The legal hoops to jump through! The test runs! The certifications!
The acquiring company can say to their shareholders, "Yes, we paid a premium for Bavi, and we got a profitable manufacturing arm to boot."
Don't think for a second that PPHM doesn't have Avid on the table with Bavi.
Common business sense says they most definitely do.
Best,
Joe Six-pack
Pere, I dunno. Before agreeing with you, show me another small-micro cap biotech with its own attractively profitable contracting business for producing incredibly precise molecules.
Let me give you a head start. YOU WON'T FIND ONE.
It's time the IHUB Board started imagining the dilution and ATM running without Avid!
Now THAT would be something!
Best,
Joe 6-pack (Yuengling)
Nice points Corp, but you can't fire up one of these plants with spit, shoe polish, and elbow grease.
They're producing molecules, for good ness sakes.
Corp, a critical rule of business is you've got to spend money to make money.
You can't fire up one of these plants with quarters you found in your sofa or clothes dryer.
Cheers,
Joe 6
RRdog was right (RIP) Avid by itself is worth at least $1.00 pps if not much more due to its guidance.
I mean Avid has 55 million in revenue with a backlog of 70+ million more. The growth is explosive. Avid's services are in such high demand that customers are paying for trial certification runs just to "jump the line."
Did anybody else catch that?
The usual suspects will poo-poo this incredibly valuable asset, yet will remain unable to name another tiny biofirm that has anything close to it.
Cheers,
Joe 6
Congrats longs! Avid 23.37 M revenue!
And income just - 0.02! WE BEAT THE STREET
We're headed up up
Best
Joe 6-pack
JJ and Wook, the RB Birge/Rutgers paper is truly
outstanding and deserves a more thorough summary.
CP has been high on this paper from the beginning, and if you wind your way through it, you'll see why. The article was published 2/26/2016.
Here's the link to the paper for science adventurers:
RB Birge Rutgers paper
Here's my "Top 10" from the paper.
1. RB Birge, the lead author, has NO affiliation with PPHM.
2. Other senior contributors to the paper come from Germany, Brazil, and England. Needless to say, they don't work at UTSW.
3. The paper uses the word "astonishing" to describe the number of major infectious disease pathogens that utilize phosphatidylserine and apoptotic mimicry to evade host immune responses.
4. It is well-known that PS is profoundly dysregulated in the tumor microenvironment and antagonizes the development of tumor immunity.
In this review, we discuss the biology of PS with respect to its role as a global immunosuppressive signal and how PS is exploited to drive diverse pathological processes such as infection and cancer.
The net negative charge of PS contributes structurally to membrane curvature and fluidity, and the electrostatic charge provides a docking site for proteins with poly-cationic domains such as C2 and Gla domains.9 Indeed, a number of important intracellular proteins require PS for proper localization and/or activation.
The preceding reasoning suggests that a critical concentration or topology of PS may need to be acquired for recognition as an eat-me signal.
The large amount of evidence obtained with AnxA5 and PS-targeting antibodies supports the notion that PS is a fundamental immune checkpoint akin to or upstream of the CTLA4 and PD-1/PD-L1 checkpoints.
CP, study what happened to HZNP from August, 2013 to July, 2015
The stock went from $2.13 to $37.20 in 23 months. A lot of people retired on that stock. Horizon makes ARTHRITIS drugs.
Check it here:
Horizon retirement run
Bavi is a central ingredient for the coming I/O gazillion dollar stew. PPHM won't sell it for croutons. The stock will make Horizon's run look quaint.
Either you're in, or you're not. Many, many traders lost out on Horizon's run, because they sold before its spectacular run, when it had fallen from about $8.75 to $2.13. I know. Because that's when I sold my shares.
NOT going to make that mistake again.
Best,
Joe 6-pack
AZN just became #1 suitor of PPHM
With the FDA biologics approval of Durvalumab, AZN gains serious credibility in the I/O space.
Just wait 'til the results come in for the Bavi-Durvalumab combo.
AZN will go bananas.
Best,
Joe 6
PS blockade is reaching an inflection point
The mass of research opinion on Bavi is hitting an inflection point. Wolchok's remarks have confirmed what Thorpe, Gabrilovich, Stopeck, Freimark, et, al have been saying for years.
You've got to go upstream and throw the main circuit-breaker for the immune system back on. You've got to turn the power back on before hunting for T-cells with a flashlight (downstream anti-XYZ'ers).
It's becoming increasingly obvious to everyone. The MDSCs have to be shut down. Repolarization has to occur (a magnetic term, interestingly.) Bavi does all that, and MORE. It stimulates all the right cytokines and interleukins.
It's an integral part of a gazillion dollar I/O stew that PPHM won't sell for croutons.
Thus, we've languished, learning the Biblical patience of Job.
But don't count JamesGMS out.
Something's coming, and it could be big and it could be soon.
GLTAL, as always.
Best Regards,
Joe 6-pack
Jake, Bio, the transcript shows AZN's CEO Soriot is seriously oriented toward the I/O space
...and yet his prized PD-1 and CTLA-4 babies aren't growing up. In fact, they're throwing tantrums.
To wit:
AZN drug flops
AZN halts trials
That's why I think we need a reminder here. Sure, Bavi is still in process, winding its way through many combo trials. But so are the drugs of the big boys. And they're NOT doing very well at all. Downstream checkpoint inhibitors can't do it by themselves. All too obvious now.
Gee, I wonder what additional ingredient might help them?
THE Big Boys' trials are halted because of stupendous side effects. Trials flunking big time. No discernable therapeutic effect whatsoever and dangerous side effects. Low rates of responders.
So yes, we've been learning the patience of saints with Bavi, but Big Pharma, with infinitely more resources than poor Tustin, aren't exactly wiping the floor with us.
In fact, they're starting to cozy up to Bavi.
Because it's starting to dawn on everyone that PS externalized needs to be gotten rid of. Because it's gunking up the works. It's depolarizing everything. It's putting the brakes on the immune system. Both innate and adaptive. MDSCs are suppressed.
Gabrilovich knows this. (Wistar)
Wolchok knows this. (MSK)
Freimark knows this. (UTSW)
Stoppeck knows this. (Stony Brook)
Soriot knows this. (AZN) (thus, the collaboration)
John Martin knows this. (GILD)
John Milligan knows this. (GILD)
I don't think money is holding PPHM back. Gild could drop $20B on Bavi in a heartbeat and barely miss it.
I think it's control. I/O is still VERY much in its infancy. But the big boys know it's gonna run. That tantrum-throwing infant is gonna grow up to be a BRAUNY MUSCULAR BRUTE.
PPHM is somehow still around. Incredible for a mosquito-sized company going against the Goliaths (who still have nothing).
I wonder why.
It's because they want control of a key ingredient in the gazillion dollar stew.
And PPHM ain't giving it away for breadcrumbs and stew croutons.
THAT'S the problem.
Regards always,
Joe Six-Pack
CP, here's a post of mine from 5/14/2013
The key to cancer is the cell membrane and that's where Bavi makes its stand. I'm not sure most investors realize how important that is.
Cell membrane repolarization is an absolutely critical component of its defense. Once PS is "flipped" externally, it changes the electromagnetics of the membrane and renders the cell susceptible to cancer infiltration, attack, and takeover.
Bio, Wolchok was one of just six (6) I/O Institute heads at Sean
Parker's huge Immunotherapy party back in April, 2016 at his estate.
The institutes were/are as follows:
Memorial Sloan Kettering
Stanford
UCLA
UCSF
Penn
Texas MD Anderson
Celebrities attending the event were:
Tom Hanks and Rita Wilson (who's had a double mastectomy with reconstruction due to invasive lobular carcinoma)
Lady Gaga
Katy Perry
Lenny Kravitz
Bradley Cooper
Red Hot Chili Peppers
Princess Beatrice of York
Not exactly a B-list.
Wolchok was quoted at the event as saying "Immunotherapy is a disruptive technology", and expressed optimism at Parker's initiative.
Uh, that would be THAT Wolchok who just validated and affirmed Bavituximab as a "meaningful" player in the emerging I/O combination therapies.
We've got to keep our eyes on the prize, brothers. Tune the nervous energy out and FOCUS.
Parker's $250 million donation to I/O essentially matches the entire budget of the NCI toward I/O. Parker invited Wolchok for a very specific reason.
Wolchok just pronounced on Bavi.
Parker knows about Bavi. You'd better believe it.
Hold on to your hat.
Best always,
Joe Six-Pack
Geo, I think James is considering that a breakthrough deal could come at any time. Never before has PPHM been validated by such a world-class third party as it has been recently -
Look, Geo, you've been here for years as I have. For how many of those years were people crying for third-party validation OTHER than UTSW???
Well, it's here.
Now people are crying why then are we at 0.32 cents??
Well, Biotech doesn't work that way. McDonalds works that way.
Nothing will disabuse Americans faster of their "get-rich-quick" mentality than Biotech.
You can make a fortune in biotech alright, but you'd better fasten your cigarettes and extinguish your seatbelts.
James is right - turbulence (the good kind) could come at ANY time.
Why so?
Well, PPHM has never been in the position it is now.
Best,
JOE SIX PACK
Stone,we know you too well
You're not selling. I understand the aggravation. But PPHM has a way of digging into your bone marrow. I've sold some and bought back even more.
Hang in there.
Joe Six Pack
P.S. I know you will.
IAT - nice post and a good reminder how dynamic and fast-moving the field is. Opdivo monotherapy looks so quaint now!
This is why dedicated longs and all the old-time friends here know very well how things could turn on a dime here. All the big-time BPs know VERY WELL how fast the field is moving and are going to want to lock down the important pieces for the next I/O wave. Biopharm posts on this constantly. (Many thx to him for all the hard work.)
Now do you think PS blockade is a key part of that future?
Yes, that indeed is why you are still here.
Wolchok agrees, too. To him, Bavi most likely has a "meaningful" role to play. (His word, not mine)
Best,
Joe Six Pack
Good John I like your intensity
I don't know if I can match it (haha).
I would only suggest that you check out Alison Stopeck's
Her-2 negative breast cancer study on 3.31.2015.
It's surprisingly technical. She discovered that Bavi, despite being a procoagulant in vitro, actually protects against thrombosis in vivo by prompting down-regulation of PS-bearing microvesicles.
The link to her paper is in my response post to Hornet Driver. I can't link it here b/c I'm on my mobile right now.
Take care, man - keep up the good work
Best,
Joe Six-Pack
IFU, there is no better way to disabuse
Americans of their "get-rich-quick" mentality, then to have them invest in biotech.
We are all learning the patience of saints, no doubt.
I'm with you.
But biotech in general, and PPHM in particular, is a slowly-developing Polaroid photograph. (Remember those cameras?)
When the picture is finally clear, BAM!, the stock rockets, and everyone in the market says, "Wow, those people got rich quick!"
Anything but. Years of patience are behind every fortune. It's axiomatic.
The main questions I have for you are:
1. Is the PS platform gaining more acceptance or less?
2. Are multiple studies coming out that confirm and reinforce each other, or not?
3. Are all the studies being done at one particular research center (e.g. UTSW) or are multiple research centers producing similar results?
These are the bigger questions that need consideration. Biotech isn't about moving the needle with a "silver bullet." It's about being well-invested, so when that photo comes into view, you're on the train when it rolls out or is bought by another company.
Cheers,
Joe Six
Horn, the language you question is actually pretty typical
in pre-clinical trials. In fact, you say so yourself in your "mouse" post. The SITC poster is a pre-clinical murine model. It's not a human model. It's therefore obligatory to use language such as "may', "might" and "it appears", given that the particular translation of Bavi, XRT, and anti-PD1 has not yet been proven in humans. The scientists CAN'T use convicted language. They're working with Mickey!
You are right to question the translation of results from murine models to human. I have no problem with that. You are right.
While the two models are immunological neighbors, they are NOT the same, and results are often not immediately transferable, if transferable at all.
But this is not Bavi's first ride on the turnip truck. Bruce Freimark's prior pre-clinical work with Bavi in triple-negative breast cancer is very consistent with today's Wolchok melanoma results.
You can read the study here.
Friemark also did a pre-clinical melanoma study that was published this year as well, and you guessed it, was consistent with Wolchok's MSK study.
You can read it here.
Now I know what you're thinking. "Mickey, Mickey, Mickey. Where are the HUMAN studies?"
Well, bring on Alison T. Stopeck, M.D. from Stony Brook, NY. Nationally-recognized. Not on Wolchok's team. Not on Freimark's team. Oh no. She's a heme-onc breast cancer doctor who does big-time research.
Want a picture?
Tough broad.
Her HUMAN breast cancer study with Bavi, published 3/31/2015, concluded this:
RR for the combination of bavituximab with weekly paclitaxel was 85% (11/13 patients) with two patients having complete responses (CR), nine with partial responses, and two with progressive disease (PD). Duration of responses ranged from 1.5 to 13 months (Fig. 3).
GoodJohn, I see where you're going with this
Beta 2 glycoprotein 1 autoantibodies are ANTI-phospholipid in nature. So do high levels attack phosphatidylserine expression in the phospholipid bilayer, just like Bavi?
Excellent question.
beta 2 GP1 antibodies occur in patients with antiphospholipid syndrome (APS). APS is associated with a variety of clinical symptoms, notably, thrombosis, pregnancy complications, unexplained cutaneous circulatory disturbances (livido reticularis or pyoderma gangrenosum), thrombocytopenia or hemolytic anemia, and nonbacterial thrombotic endocarditis. Beta 2 GP1 antibodies are found with increased frequency in patients with systemic rheumatic diseases, especially systemic lupus erythematosus.
Thanks CJ - you can't find a median when 60% of the cases are cured. Mathematically impossible.
Well, now we know why Bavi failed with Doxy - just pair Bavi up with some x-rays and anti-XYZers and watch cancer croak.
Nice graphic.
Best,
Joe 6-pack
SITC poster couldn't show median survival for Bavi + XRT + ANTIPD1 because 60% of the cancers were cured outright.
PPHM is already in negotiations in my view.
Best,
Joe Six-pack
NO EXPERIMENT IS EVER A FAILURE
We thought we were toast with SUNRISE termination, but that failed trial may hold the key to PPHM's success.
The consensus continues to build on a multi-angled attack on the tumor microenvironment. Repolarize M2 macrophages back to M1 with Bavi, radiate locally, and then add in your anti-XYZers. Bang. The tumor crumbles AND adaptive memory keeps it from coming back. (Remember, that as of today, a tremendous number of breast cancer "survivors" go on to get cancer in the OTHER breast.)
Avid record profits, cancer diagnosis kits pending, and Bavi synergizing beautifully as the Board has always known it; the pieces are coming together.
Now add in our failed SUNRISE. The protein biomarker data will identify those patients most like to respond. With cancer at epidemic levels, don't worry, brothers. Bavi will find its place in so many solid cancers.
Wolchok knows this!
Best,
Joe Six-Pack
p.s. sorry I went missing for a few months there. I'm back, buying more than ever, and as optimistic as EVER. Cheers.
What date is the next cc? Thanks EOM
Joe Six-Pack
Cheynew, while I can see your POV and frustration with the BOD,
just consider that one positive PR out of Wolchok's lab at MSK re Bavi can turn things over in an instant.
If Jed says "Go" with PS blockade, then watch the sentiment change around here in a hurry.
We don't know the timetable over at MSK (who does), nor how far they may have moved things along.
But Wolchok wants to advance I/O 2.0 - as do all the Biotechs. Monotherapy was I/O 1.0; funny how he invited PPHM's upstream PS blocker ahead of the 2.0 curve.
Say what you like, but the future of Bavi lies in I/O 2.0; and NO ONE has that information yet.
Say that you do know - but in fact, no one does.
Best Regards,
Joe
Vin, the study involved LYMPH node spread
after breast biopsy, which by definition, is not local.
So a 663-pt study showed a statistically significant increase in lymph node spread after needle biopsy instead of safer surgical excision.
You mentioned the spread is "local and short-lived." I don't normally associate lymph node spread with being "short-lived."
Your own citation from cancer.gov EXPLAINS that metastases are spread into local tissue and lymph nodes!
How Cancer Spreads
How Cancer Spreads
Cancer cells spread through the body in a series of steps. These steps include:
1.Growing into, or invading, nearby normal tissue
2.Moving through the walls of nearby lymph nodes or blood vessels
3.Traveling through the lymphatic system and bloodstream to other parts of the body
4.Stopping in small blood vessels at a distant location, invading the blood vessel walls, and moving into the surrounding tissue
5.Growing in this tissue until a tiny tumor forms
6.Causing new blood vessels to grow, which creates a blood supply that allows the tumor to continue growing
Most of the time, spreading cancer cells die at some point in this process. But, as long as conditions are favorable for the cancer cells at every step, some of them are able to form new tumors in other parts of the body. Metastatic cancer cells can also remain inactive at a distant site for many years before they begin to grow again, if at all.
It was a REVIEW of seeding studies
One study of 663 patients that showed statistically significant evidence of seeding is enough for me.
Why do you thinnk they recommend a vacuum-assist device for biopsies?
Doh!
Some "myth." 663 patients.
North, seeding from biopsy is not a myth at all
Br J Radiol. 2011 Oct; 84(1006): 869–874.
doi: 10.1259/bjr/77245199
PMCID: PMC3473763
Seeding of tumour cells following breast biopsy: a literature review
C F Loughran, FRCR, FBIR1 and C R Keeling, BA(Hons), MSc2
There is conflicting evidence around the suggestion that metastasis to the sentinel lymph node may occur more frequently following needle biopsy.
Hansen et al [5] examined 663 patients treated for breast cancer who had had sentinel lymph node biopsy (SLNB). They correlated the SLNB findings with the type of pre-surgical diagnostic technique employed (FNA, core biopsy or excision). They noted that the
incidence of lymph node metastasis was statistically significantly greater in the FNA or large core needle
Metastases can be large or small
or micro:
Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Adjuvant treatment for breast cancer involves radiation therapy and systemic therapy (including a variety of chemotherapeutic, hormonal and biologic agents).
Breast cancer cells that have escaped....
The concept is the same no matter what the cancer; you stated that
adjuvant therapy was not used in metastatic disease. That is clearly wrong, and has been wrong for decades.