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px: yeah. We gotta go there (PhIII), and when we start there, that's when the real action begins. We have an entirely different set of market makers. This guy (invisible hand) has actually been pretty benevolent. It's that precept that keeps us in our chairs instead of stalking.
Nice post. Agreed until you said, "I believe they [PPHM]are going to partner, and a partner IMO is not going to care what exchange they're on." I think there's a sub rosa partner already [the invisible hand] with a goon squad tasked with feeding us [ducks] just enough to keep us from squawkin'. This thing will bust wide open at a positive announcement along with the opening of stage III [expedited?] trials.
dia, nice post. Does anyone know of progress on remodeling Cotara? Humanized? Shrunken some?
A recent discussion with a very active clinical oncologist: He had never heard of PPHM, Bavituximab, anti-PS, or the PS inversion phenomenon. He thought Rituxin the best thing down the pipeline; expressed reservations about Avastin; and was dismissive of Erbitux. When I briefed him on above, he looked at me [literally]with wide-eyes and asked, "Why are you so interested in all this?" I told him there's a better Avastin,
and all about Cotara. Makes me appreciate how long it takes and how difficult to get the word out.
honestabe:you are that:honest. I have given this subject some minutes this morning. Specifically, evaluating Nature Medicine and the value of publication in that magazine. Who wrought the fixation on that publication? Not anyone friendly toward scientific progress. The HIV rehash we've been waiting for includes (I'll list only two for fear of boredom): "Structural definition of a conserved neutralization epitope on HIV-1 gp120", and how about "Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells". It's a different world, and not a bavi new world. A different attack strategy. Important, but not PPHM or Duke. A different league. PPHM and Duke could put these guys out of business. Probably some of the posters here. Hey a love the board here but the scene is still cluttered by big pharma goons. Let's move the ball forward. PPHM has incredible momentum now. The "New Scientist" article says it all. Look at who is financing Nature. It isn't the guy on the street payin' a dime for that news. It is big Pharma tootin' it ancient horns. Let's stay focused and get the message through.
errata..."heretofore UNpublished papers"...
Would someone bring me up to speed on this Nature Medicine situation? I don't get it. The online "Nature Magazine" website states, "This (HIV) special collection presents a selection of papers published in Nature highlighting the progress that has been made towards conquering this enormous challenge over the past couple of years." The only papers included are those that have already been published in Nature which would eliminate any heretofore published papers. The introduction editorial was notable by its absence of overall perspective on the subject, but that's about it.
honest abe: the best parallel is ImClone. I bought it at about $18 when it was in early stage III trial openings would lead PPHM to equivalent evaluation. It peaked at about $120, and then split, and meandered around for a while before settling in the $30s before being purchased by BMY. With PPHM it is a matter of "critical mass," which is overwhelming public and institutional focus and belief. So far PPHM has not missed a beat. It is an infinitely better property than Imclone, and should be as good as DNA. Right now the trading is laughable, but certainly a buying point in the .70-1.00 range.
Thing: fantastic find. Good article everyone should read, if only the last 1/3 of the article...and I mean everyone.
dia, I suppose more specificity is what's happening: Tissue factor (TF) is a potent thrombosis-inducing agent that, tamed a bit, may be used for severe bleeding (read hemophelia). However, TF has obvious deleterious effects in normals even though it binds to PS. How to get it to cancer PS?
Tear TF apart at appropriate intervals...prune the branches so to speak...design a branch or coupling to fit a two-fisted MAB missile that is safe (!), and may be targeted only to cancer tumor vessel lining...and the vicious clotting cascade begins. How much longer can the roche hide behind avastin?! I say give 'em Cotara..then Bavi..and for dessert an anti-EGF to further discourage local stragglers and recurrence.
Speaking of nanoparticles, remember tTF and this one? [Science 24 January 1997,Vol. 275. no. 5299, pp. 547 - 550
Tumor Infarction in Mice by Antibody-Directed Targeting of Tissue Factor to Tumor Vasculature, Huang,Molema,Steven King, Linda Watkins, Thomas S. Edgington, Philip E. Thorpe]
Selective occlusion of tumor vasculature was tested as a therapy for solid tumors in a mouse model. The formation of blood clots (thrombosis) within the tumor vessels was initiated by targeting the cell surface domain of human tissue factor, by means of a bispecific antibody, to an experimentally induced marker on tumor vascular endothelial cells. This truncated form of tissue factor (tTF) had limited ability to initiate thrombosis when free in the circulation, but became an effective and selective thrombogen when targeted to tumor endothelial cells. Intravenous administration of the antibody-tTF complex to mice with large neuroblastomas resulted in complete tumor regressions in 38 percent of the mice.
Sunstar, nice. I had not thought of reading a company future by looking at its "help wanted" ads, and the numbers of people being hired. It is difficult to imagine anything but a positive spin from that info...especially in this economy. And the nanoparticle business...Bavi loaded with a nano-...now we're cookin'!
NCB2K, Wikipedia has a pretty good discussion of viral recombination: "Antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human viruses. Viruses undergo genetic change by several mechanisms. These include a process called genetic drift where individual bases in the DNA or RNA mutate to other bases. Most of these point mutations are "silent"—they do not change the protein that the gene encodes—but others can confer evolutionary advantages such as resistance to antiviral drugs. Antigenic shift is where there is a major change in the genome of the virus. This occurs as a result of recombination or reassortment. When this happens with influenza viruses, pandemics may result.
Genetic recombination is the process by which a strand of DNA is broken and then joined to the end of a different DNA molecule. This can occur when viruses infect cells simultaneously [each of the virus' DNA strands break apart and recombine with each other]and studies of viral evolution have shown that recombination has been rampant in the species studied. Recombination is common to both RNA and DNA viruses.
"Recombinant DNA" is a form of DNA that does not exist naturally, which is created by combining DNA sequences that would not normally occur together. Recombinant DNA (designated: rDNA) is introduced through the addition of relevant DNA into an existing organismal DNA to code for or alter different traits for a specific purpose, such as antibiotic resistance. It differs from genetic recombination, in that it does not occur through processes within the cell, but is engineered. A recombinant protein is protein that is derived from recombinant DNA.
The Recombinant DNA technique was first proposed by Peter Lobban, a graduate student at Stanford University Department of Biochemistry...a method to isolate and amplify genes or DNA segments and insert them into another cell with precision, creating a transgenic bacterium. Recombinant DNA technology was made possible by the discovery, isolation and application of restriction endonucleases [enzymes that can specifically break DNA/RNA chains at specific points] by Werner Arber, Daniel Nathans, and Hamilton Smith, for which they received the 1978 Nobel Prize in Medicine.
sidestyle, it will be the law of unintended consequences that determines the answer to your question, and the prize will not be at the original destination.
hey sunstar, really good stuff, thanks. And CJ, as usual, a hearty doff o'me hat to ye.
the state of virology in the United States is such that nobody has a clue about the etiological agents causing acute and subacute viral infections. It's all a guess. How many out there have had viral cultures taken for the last URI or GI bug? Probably got an antibiotic and a large bill. Try Googling the symptoms of swine flue. That should be enough to convince anyone that we have not the slightest idea of the virus' penetrance in this country. I think I had swine flu a month ago. Ghastly!@! Nothing like it in my long life. Expiratory wheezing like I've never had. Cough. Scary. Did I report it? Stay home from work? Spread it around to patients? Where did I get it? On an airplane from SanFran to Houston? Or from all the illegals I work with out in the yard? Who knows? And I am a doctor. That's where we are folks. And to think of the implications of rushing a vaccine onstage to combat something we are clueless about with sumpin' else we are even more clueless about. Oh, if it could only be so easy to get Bavi on the treatment table.
the thing: thank you. I read with great interest the entire programs of the two meetings at which Dr. Thorpe is a presentee, and both the meetings are first rate. It was a rare treat to read the summaries of presentations, the presenters involved, and see Dr. Thorpe among them. The presenters and subject matter are of the first order. We can all be proud to be associated with this crowd. Reading through the presentations makes me even more confident that we are in the right place at the right time re. PPHM shareholders. The "take-away" from reading the synopsis of the presentations (aside from above) is that things are moving with bewildering speed in this arena, and the problem is (and always has been) where to put down a stake in the ground and say, "This is the future. Let's go with it." My sense of it is that anti-PS mab Tarvi and its offspring will be around for a long time.
hayward, mere coincidence!?* PPHM securities marketing has been stellar...this year. Response in unison: "Yes, but what has the invisible hand done for me lately?"
sunstar: great post. thanks.
jessme, pardon me for the occasions of hyperbole, if not downright exageration. Maybe 95% of the scientific community doesn't know about anti-PS MABs. Most (the majority) probably have heard about monoclonal antibodies [MABs] if they were in medical school in the 1980s, but that leaves a huge number who graduated before all this has been worked out. It is difficulty enough for practicing oncologists to keep up with "standard of care" and some of the "protocols" which are available to their patients. We won't go into that tirade.
And while we're talking about exagerations, I retract what I wrote about "peer review," and pecuniary interests. I think most reviewers are honest and inquisitive. Not all are well informed on the subject being reviewed, but they will do some homework and "talk it around" to the experts.
You wrote that anti-PS has been around for decades. Probably forever, but that doesn't mean a scientist, say, interested in cancer genetics or stem cells, or traditional chemotherapy spin-offs, would have heard about Bavi or anti-PS MABs.
AntiPS,the antigen is the basis for the serological test for syphilis which dates to 1906, but I doubt if scientists then were calling the reactant anti-PS. According to Wiki, at about that same time, the turn of the 20th century, the idea of a "magic bullet" was proposed by Paul Ehrlich: that if a compound could be made that selectively targeted a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity. Voila, Bavi.
In the 1970s the B-cell cancer multiple myeloma was discovered to produce a pure, single type of antibody, a paraprotein, a monoclonal antibody, which stimulated study on the structure of antibodies, but it was not then possible to produce identical antibodies specific to a given antigen. Then a method was devised to produce monoclonal antibodies using human-mouse hybrid [genetic mosaic] cells [1973-75] which is the process used in a modified form to produce first generation MABs Avastin and Erbitux, and the process for which Köhler, Milstein, and Jerne shared the Nobel Prize in Physiology or Medicine in 1984. So 1984 brought some focus on MABs. In 1988 Winter et.al. pioneered the techniques to humanize monoclonal antibodies, removing the reactions that many monoclonal antibodies caused in some patients.
The observation that PS underwent cell membrane eversion was probably made in the same decade, and the decade of the 90s saw reapid expansion in strategies to use the PS inversion observation to therapeutic advantage.
abe: Bavi is a "cancer answer"? 99% of the scientific and medical community has not heard of anti-PS...or PPHM...and that is more or less true of oncologists and virologists as well. Most know about monoclonal antibodies.
Oops...last line. Cotara, not Tarvacin.eom
CJ, thank you for the extreme effort.
First thought after skimming the date-lined PRs you provided?"Yippee!"
Second thought? How linear the narrative of PPHM CEO SK. All his PPHM anti-viral (HIV)discussions were positive, and became more positive with time. All the PRs struck me as thoughtful and truthful [as in an "ethical pharmaceutical house"]; well-couched, well-hedged, and solid strategically. SK intimated (nee promised) that anti-PS has awesome antiviral properties--that anti-PS has a gigantic future.
So Bavi and Bavi's offspring have a bright and hopefully future as well. The "crackpot/GatesFoundation/theorists" look more credible as "The Moving Hand than even Roche, at this point. I hope Dr. Seuss strikes SK dead if he is lying, or he gets sacked if he's only being overly enthusiastic, but the lure and line SK is spinning re. Bavi anti-viral would make any fish bite.
Is the whole idea/concept sensible? Yes.
He says our (PPHM/UTSW) investigators and DukeU/GatesFoundation group have "moved on" in collaborations re. anti-PS therapy since submitting a publication to Nature Magazine re. anti-PS v. HIV. Weeks pass while an author awaits the vote of the group of "peers".
SK said, "things have moved on since submitting the paper". Translated: "Pockets must be lined, and in proportion to the expected bigness of a new drug." How many reviewers can possibly be up to speed on anti-PS science? How will they be "lobbied"? Who pays their grants? Where are they in the big Pharma web?
What should stockholder strategy be?
PPHM's last fiscal year was convincing. Am I "all in?" No. Bought BMY a couple days ago. Do I have reservations about PPHM? A few. Time frame. Wondering about the problems with Bavi and hepatitis. Could be that killing hepatitis virus kills too many liver cells.
What would I be doing in the lab right now? Missile Bavi will require not only humanization, which is being dealt with [i.e. Affitec], but also an improved guidance system. We're talking even more specificity. Double-armed Bavi will speed through the bloodstream with an MAB missile seeking inverted-PS cells with one fist, and with the other a specific-HIV- seeking coupling for docking sites on HIV-infected cells.
You know what they would have me doing in Thorpe's lab? Counting how many zillions of inverted-PS cells there are inside a 100kg. cancer patient with AIDS, herpes, and human papilloma virus...etc...and how to direct the wonderful new anti-PS seeker.
Strategically, we have three players at the MAB table now.
No question. The anti-PS strategy is too compelling to credit naysayers. There is no plausible deniability.
Where is PPHM in the MAb cancer treatment troika? IMO, integral.
Why? Virtually ALL solid tumors can be attacked with Bavi.
Major competition: MEDX/BMY: Humanized anti-EGF MAB, a good ticket. It will be used. BMY got it right finally.
Avastin? A goner. History. When? When DNA 'fesses up to 2C3 and Bavi. Checkmate.
Surface agents: MEDX's AntiEGF + PPHM BAVI MABs.
Vascular agents: PPHM's 2C3 + PPHM Bavi
Core cell agent: PPHM's anti-TNT MAB
PPHM on every line of attack.
Caviat: Surface cancer cells may remain even after Bavi does its job. They don't need blood supply. Nourished by surrounding tissue fluid osmosis. What then? MEDX's anti-EGF. And the dormant cancer cells at the necrotic tumor core? Too far inside for an anti-vascular agent to reach? Tarvacin. The irony? The economy. Guns or butter.
Bull, good sign. It's going to start costin' the invisible hand, huh.
Interesting, adjuvant enhanced? Oil in water? An anti-phospholipid? I don't get it. Maybe they should use only the adjuvant and forget the vaccine if the vaccine requires a boost. What clinical trials are to be/were conducted on this anti swine-flu construct? Anyone? I don't think I'll be the first on my block to get one. I tend toward getting my vaccine-induced immunity by passive-immunity...by piggybacking off the herd that faithfully gets their immunization shots. There's always one in every crowd...
NCB2K: perfect post.
dia, yes, when you're on a roll in the lab your published data lags behind because...well because...the competition is on your heels, and you don't have a publicity MACHINE or elves at your fingertips, and you're better at discovering and playing with electronic gadgets than putting your thoughts into a manuscript.
BMY recognized a better Erbitux and bought it. MEDX Second generation MAB. Same with 2C3.
Bavituximab though is not so much a new generation MAB as a differrent one because it uses an exclusive docking site on the diseased cell, inverted PS. And the spin-offs from examining that discovery (inversion of PS)...are mindboggling.
Bavi is safe. Bavi works. Bavi trials will be financed. It is with finance and science gods now, and will move forward in its many permutations in many different labs in many fiancial hands because a newly discovered and widely needed medical treatment brings out greed and high dollars like you cannot imagine.
AT this point the race is to fully humanized anti-cancer MABS, and BMY/IMCL/MEDX are there. Their relationship cost BMY billions and profited IMCL and MEDX stockholders, although not enough for MEDX "long-sufferers." How about the ROCHE/DNA/AFFITEC/PPHM alliance?
Early phase beauty pageants are over for Bavi safety and evidence of efficacy. The most difficult and risky part is behind us. And here we are off 4% today.
We know Bavi does not cure late-phase cancer. But the effect garners respect. And in early trials its numbers were as good or better than Avastin.
So PPHM, Inc enters another phase, one for which we must change our thinking along with that of company managers. Some of them have to change to. If PPHM science has gained critical mass and velocity (congratulations everyone, espec. Dr. Thorpe);if financing of trials is assured; if our gamble now is "how large the market" for Bavi; then share price should be changing too. Why not?
An infusion of "retail" interest? The untold PPHM story is compelling. And not only the science. That PPHM announced a relationship with Roche, via Affitech, a Roche "holding" company which shares some uncanny similarities to PHHM, with a stockprice of $.20 and knockout humanized MAB pipeline. Smells like a Roche.
Will PPHM ever trade better than a public utility before it is bought out? That's up to us. Dynamite price right now, especially if a buy-out only gets us a 5x multiple. Interesting forces at work. The price could snowball rapidly if PPHM stockholders spread the word. It appears there is an invisible hand guiding the executive suite as it relates to "going public with the PPHM story"...and part of the story is the pounding each rally takes by the the same invisible hand.
geo, agreed. Interesting about Bristol-Myer. The company made a huge mistake on Imclone and Erbitux to begin with, and then doubled-down when they bought the second half of the company. However, I think they got it right with MEDX because if BMY is going to be in anti-EGF, and if anti-EGF Abs are to be used in cancer treatment, and they probably will be for a while (until Bavi is armed/humanized and ready), BMY saw the handwriting on the wall: MEDX has a better antiEGF than Erbi-, an agent that was always marginal in its efficacy and side-effect profile.
DNA's Avastin, an anti-angiogenesis MAB, is better than Erbi, but not a knockout, and it burdened by side-effects. Where does DNA/Roche go for next generation Avastin? I think they have already gone...to Affitec/PPHM....to retain hegemony over anti-angiogenesis.
And then the wild card...Bavi. It's possible that Bavi is not for sale. License out Cotara? Then PPHM will be free to focus on anti-PS. Humanize Bavi, load it up with cancer killers...anti-viral...
KT: PPHM financing is assured, but that is not the picture being painted by those doing the financing. That "iffy" financial picture serves to scare away the investing community so that Roce can take over PPHM at a much lower price per share [and multiple?] than even MEDX. And that is not to take anything away from MEDX. I've said here that MEDX and PPHM are the two biotechs to be reckoned with in the next generation of MABs. MEDX has a better anti-EGF than IMCL's Erbitux, and PPHM has a better Avastin than DNA...with Bavi, Cotara, tTF, and other gems in the mix. At this point the financials are a technicality that keeps the price down. Last year that was not the case. Increasingly it looks as if Bavi is good enough to be financed all the way to the end, whatever that turns out to be.
Why is it that I see Roches everywhere I turn? The deal with Affitec (or whatever its name) is a deal with Roche, bottom line. And as said before, how long before the genie is out of the bottle? We break the pps logjam when the public sees the truth and crashes in...when Roche can no longer control the price. At that point they will have the shares...and a buyout on their terms will be a done deal. Throw the shareholders a "twofer" bone. My strategy is to get more now.
Whoever is "doing" PPHM stock price the past several months has a wrecklessly ironic sense of humor.
Rumble, rumble from stockholders here. Price goes up a nickle.
Trickle trickle. Share price drifts downward.
Funny story, this, if I didn't have so much invested.
Perigrine and Exxon moves up .06 on Friday. Exxon traded about $2 billion dollars worth of stock. PPHM traded about >$2 million. Exxon was up .09%. PPHM was up 7.6%. Miniscule amounts of money, comparatively, will dance PPHM stock any which direction. No sweat. Gripe a bit more. Grumble, grumble. Accuse Roche/DNA of criminal deeds. Price goes up for a while.
But at some point the game moves on. Shorts cover. That's offshore (Roche/DNA) money. Then a deal. If Roche isn't too late. Poker. After enough pressure builds from below this farce will start moving toward a reasonable conclusion. Hopefully those who have supported PPHM will benefit financially and medically, that is before Washington fires a disabiling torpedo at big pharma.
dia76:Proof? If it looks like a Roche; if it smells like a Roche; if it acts like a Roche... Come on. Put yourself in the executive suites of DNA or Roche. Sitting on a total dud like Avastin. If you can get that one through clinical trials and expanded indications for its use, you could probably influence/control the competition.
dia76: I thought it was common knowledge that Roche was not only looking at PPHM, but controlling its stock price.
bigworld, nice post. I'm in your corner. PPHM is my biggest holding now, with MSFT and XOM close behind, and that is about it except for an occasional flirtation. Thinking about MEDX. I've been in and out of that stock for about as long as I've been in PPHM. Here we are mid-July and the usual summer break/swoon has been pretty mild, if not downright encouraging. The question at this point is not the science or the market for it; product safety; or even efficacy, but whether or not the corporate fabric can withstand a marketplace increasingly desperate, brutal, and bloodthirsty, competing furiously for every retail dollar it can garner. The tired old-guard, Avastin and Erbitux, have had it. Obviously. Who is the invisible hand guiding us. Three guesses.
cj: thanks for posting the interview with Dr. Thorpe. The end of the interview was prelude: he is a gentleman and a scholar according the the interviewer. Anti-PS therapy and future Bavi- clones should make this ride interesting for a long, long time. The interviewer alluded to "...all this interest in Bavi..." Always good to have "outside" validation of our prejudices.
thanks cj, appreciate your efforts. I was looking for exactly that info. this morning. Anticipate double-armed Bavi- used at its ultimate potential: "naked" AND armed with a tumorcidal agent. Maybe in our lifetime.
Thurly,good,informative post. Agreed. Thanks. Your timing appears fortuitous.
better than an excisional biopsy? When dealing with small tumors whether benign or malignant, instead of taking "a piece" or a punch biopsy and sending it to the lab, a surgeon attempts a procedure both curative and diagnostic... by removing the lesion with an adequate cuff of normal tissue around it so that when sent to the pathologist all the problem is in the specimen container...solved--cured. Knowing what we do about Bavi-, its selling points as a diagnostic tool are safety, specificity, and its chemo-attractant properties of calling immune-mediating cells to tumor when needed. It is a "double-armed" MAB too, with the capability of carrying contrast agents (and/or tumorcidal) agents on the arm not used for docking. Mind-boggling IMhO.
north40k,thanks for the post on Medarex. It is a good company--good competition for PPHM with a good product. Also an MAB production facility.
too funny...last 5 seconds 43k shares...price goes from up .02 to up .06. I realize it is a function of day-end settlement, etc., but it's still pretty strange.
China Syndrome? "On the days of our last 2 Cotara PR’s (May28 & June16) we traded a total of 55,532,900 shares..." (cjgaddy), and none of that Cotara news was truly "new." Is this a not-so-"nuanced" shift of focus, a coverup for a meltdown? I like cj's conjecture better, that it is an elaborate "flasher" doing some churning, calling attention to an (obviously) good company, and picking up some cheap retail stock, just as today's "lawn mowing" has clipped off shareholders with tight stops in place. It does appear that someone (all of us?) is trying to get this clunker over one dollar, and someone is trying to stop it. Most likely the same person(s) doing the "mowing, flashing, and churning." Other possibilities? I like the China theory and not the syndrome: Someone there knows sumpin' about Cotara and lung cancer? Makes PPHM's courtroom drama with Epstein more important, and explains a lot to me.
cj:my hat is off to you for the recap you just posted. Thanks. I understand theThat huge amount of time and savvy it takes. The ASCO info raises more questions for me than it answers. My literature search last night, which was admittedly cursory, indicated that in terms of responders Bavi+chemo does compare favorably to chemo alone. There are slightly better responses with chemo alone in the literature, and considerably worse with chemo alone, but on average,Bavi+chemo DID fare comparably, if not slightly better. Your findings were somewhat more positive (and impressive). Interestingly, Avastin+chemo seems to have fared worse on almost all scores. This raises the question of WHEN to use MABs (earlier!of course), and whether or not they should be used in combination with chemo. Seems that using Bavi to prime for irradiation is probably where we are going to settle in...and for disease where the immune system is still intact. These results keep Bavi in the running, IMO, but further clarification seems necessary before any of us can be "all in," and that makes it more and more likely to me that more time and money must be invested via partnership. Your thoughts?