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Thank you Mojo. Another very relevant insight in your long list of valuable posts.
Your post offers compelling evidence of why Bavi will replace Avastin in the market place based on its much better safety profile. As your article points out, all you need to have is roughly comparable efficacy, and the doctors and the insurance companies will flock to the drug with a better safety profile-- because better safety translates to lower overall health care costs from treating Adverse Events.
Based on this example, I came away with the new awareness that having better safety data than Avastin will be more important than having better efficacy data-- at least in a context where both drugs have comparable efficacy.
Mojo and CJ-- Thanks for the great work in ferreting out yet another favorable distinction between Bavi results and Avastin results in NSCLC.
Geo-- Let's remember that randomized Ph IIb trial results usually come in worse than signal seeking Ph IIa results. So in order not to disappoint the markets when randomized results come out, it was smart of SK and Garnick to understate how well Bavi did in signal seeking trial by not highlighting the ways in which our patient patient population was sicker, or received less chemo, than Avastin population.
The 3 distinctions CJ summarizes in his post 65518 give us a margin of safety that should make us all sleep better as we approach Q4 2011 and Q1 2012 reports on the randomized NSCLC results.
the signal seeking 2nd line MBC trial appears to have a valid protocol and the MOS data is overdue.
MoJo-- I am not so sure that the MOS data is overdue. Look at this review of MOS times in a variety of MBC trials. Average MOS time for breast cancer appears to be around 3 years. Data from our signal seeking trial doesn't go out nearly that long.
From the article:
"The median overall survival that tended to improve from 2.4 years during 1985 to 1994 to 3.1 years during 1995 to 2005 was not statistically significant (P=0.26), Sumanta K. Pal, M.D., of City of Hope Comprehensive Cancer Center in Duarte, Calif., reported at the 2008 ASCO Breast Cancer Symposium."
http://www.breastcancer.org/symptoms/new_research/20080909b.jsp
These long MOS times for breast cancer are another reason why the Company was smart to focus on NSCLC.
Someone might want to ask Adam how he comes to the conclusion that Avastin has suddenly become the SOC for lung cancer when it causes so much bleeding and has such a horrific AE track record.
PPHM management is extremely conservative in their PRs and likes to hide their light under a bushel. But they were not willing to go so far as to indulge the false notion that Avastin has become the SOC for NSCLC.
... and this is not because they shy away from being compared to Avastin. Clearly they showed in the ASCO Cotara poster that they are willing to be compared to Avastin when the comparison may be justified.
The FDA will look with great favor on a new drug for NSCLC that matches Avastin's efficacy without the same AEs and toxicity. This is the point Adam is not willing to admit.
I do acknowledge that the results in these 41 patients need to be confirmed in the much larger, randomized NSCLC studies now underway. But even if the randomized data comes in lower (e.g. only a 10% improvement in MOS over the CP SOC rather than 20%), the FDA will still want to give patients a choice to use a much more humane drug than Avastin.
CP-- Let's remember that the PR made no mention at all of Avastin. That is a discussion that has arisen only on this Board.
My guess is that the PR compared Bavi only to Carboplatin & Paclitaxel (CP) because CP is still widely recognized as the SOC in NSCLC due to the many published reports of Avastiin bleeding and other AEs in NSCLC.
By contrast, in the ASCO Cotara poster a footnote reference was made to a meta-analysis of Avastin's results in GBM because that data is relatively new and PPHM gave Roche the benefit of the doubt because there is not yet a large body of clinical data confirming that Avastin has similar AE problems in GBM.
There is however a significant pre-clinical study showing why Avastin use for GBM is likely to be as controversial as Avastin use for NSCLC. http://www.ncbi.nlm.nih.gov/pubmed/21321221.
The people I speak with find it both revealing and quite encouraging that PPHM management, which bends over backwards to be conservative and understated, compared Bavi in yesterday's PR only to CP results, not to Avastin data.
Given Bavi's excellent safety profile and Avastin's horrible safety profile, I bet we could get approved by the FDA if randomized results in the larger NSCLC trials show only a 10% increase in MOS as compared with CP, not the 20% that was reported yesterday.
Good point Jake. The front line randomized NSCLC trial is open label so the Company is indeed seeing the results as they come in.
You can bet the recent hires are not jumping ship from other prestigious positions without also seeing this data.
Excellent point FTM. I had forgotten that Bavi's population included these hard-to-treat squamous cell patients.
Today's data is interesting and is consistent with previously reported ORR and PFS data as the PR points out, but the truth is that major WS players won't get involved until we report randomized data. That's the big game changer.
So the big news in today's PR may have been the statement that randomized data will be published before year end:
"We are eager to complete enrollment over the coming weeks in our ongoing confirmatory Phase II trial evaluating this same therapeutic regimen in a larger, randomized study and reporting interim ORR results in the second half of this year.
Let's remember that the MOS number is only half of what's important in the Kaplan Meier survival curve. The other half is long-term survival, i.e. how many patients are still alive at 18 months and 24 months.
Bavi's long term survival rate, i.e. the % of patients still alive at 18 months and 2 years, is likely to be much higher because, once Avastin treatment stops, the tumor comes back with a vengeance.
As a follow-up to my post just now, it is very interesting to note the opportunity that the Company has created by scheduling the FDA meeting for 4th Qtr.
The ASCO poster was made as of late May. After four more months, i.e. June, July, Aug and Sept, the three censored patients in MoJo's chart will have either lived, or not lived, for another 3-4 months.
Thus starting in Oct the Company will be able to confirm to the FDA, hopefully, that MOS is 11.5 months and long-term survival at the 12-month mark is 46%.
MoJo-- I join CJ in thanking you for this excellent explanation of how censored patients are treated.
As you pointed out in Post 64888, "if all 3 censored patients (who died before the 8.8 MOS date) end up surviving past 11.5 months, then the final MOS should move out to 11.5 months."
In addition, if these same 3 patients live past 12 months, then I calculate that the percent of patients surviving at the long-term date of 12 months would be about 46% for Cotara. Do you agree with this calculation?
Such a long-term survival figure, i.e. 46% still alive at the 12-month mark for Cotara, would compare favorably with Avastin's one-year survival rate of 37.8% still alive at 12 months.
Of course Cotara's long-term survival rate at the 24-month mark, i.e. 19%, beats the pants off of Avastin, i.e. 0%.
But its interesting to note that Cotara matches Avastin at the 9-month mark, beats Avastin by a small but meaningful margin at the 12-month mark, and completely tromps Avastin at the 24 month mark.
IMO, there is no doubt that the FDA will give Cotara a favorable Phase III registration pathway, maybe even an Accelerated Approval pathway, based on these impressive results achieved with only a single dose and much lower toxicity than Avastin.
Cotara may not be the dominant consideration for PPHM pps prospects going into 2012.
That's got to be the biggest understatement made on this board in weeks. For the record, I agree 100% with WH's post 64818: "I'm not here for Cotara" either.
Just a hint of good Bavi clinical news from the current randomized Phase IIB trials will probably have as much impact on the pps as a good Cotara FDA meeting.
The only reason I focus so much on Cotara is that a successful FDA meeting, which means a successful BP license negotiation, will enable the Company to stop selling ATM shares to fund the 2012 Bavi program. ATM-driven dilution is killing the current pps. Ultimately the value of developing Bavi so far in-house will more than justify today's pps pain, but I sure would like to know when we can anticipate the end to ATM selling.
New evidence that Avastin causes GBM tumor cells to invade healthy brain tissue.
http://www.ncbi.nlm.nih.gov/pubmed/21321221
As this abstract points out, Avastin's GBM program is indeed "controversial" as the article puts it. This research confirms that, yes, Avastin does cause a "strong reduction of large- and medium-sized blood vessels" in GBM tumors, but "Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma."
Translation: The physiology of GBM tumors is such that when the blood supply is cut off, the tumor cells relocate and invade healthy parts of the brain tissue to get the blood supply they need. This explains why the the tumor grows back with a vengeance once Avastin dosing stops.
This is one more big nail in Avastin's coffin. If I were a BP looking to restock my cancer drug pipeline, the medical controversy swirling around Avastin would convince me that there is plenty of room for Cotara's elegant MOA in the GBM market place.
I admit I was a bit hasty in saying there would be a "bidding war," but it's looking more and more like Temodor is still the SOC (not Avastin) and that greatly enhances both the likelihood of Cotara approval and the price BP will pay for a regional or global license.
JR-- You make fair points. I apologize for my remark.
Indeed, I was also disappointed by the lack of an ASCO pop. In fact I bought some at $2.30 on the way down. It's only in hindsight that I recognize that I could have / should have foreseen this downdraft for the reasons in my post 64784.
Hate to say it, but I miss Moby. At least he understood what he was arguing.
LOL. WH, you crack me up. How sad but true !
Yes, it's true that all the new Genentech hires and Dr. Thorpe's stunning MOA revelations in Barcelona both point strongly to Bavi's success. However, the pps may not be that strange when you realize that professional investors/shorters could figure out easily that this summer will be a good time to shake the tree and close out a short position (or alternatively pick up cheap shares for the long run) because :
1. The ASCO news was always limited to a Cotara update and more of the same Interim Cotara data doesn't move markets; only the outcome the the Q4 FDA meeting, and the resulting BP license, will move the PPS in a big way on the Cotara front;
2. The Company is currently running 4 of its own trials (2 lung; 1 pancreatic; 1 HCV) and coordinating 4 IST trials; all these trials require a steady source of new funds-- hence steady ATM sales can be counted on to assist the shorts' strategy for several more months.
3. Market-moving data from these 8 Bavi trials will most likely start to flow in the fall, not during the summer; and
4. Many retail investors who expected a pop at ASCO will have to sell some of their shares over the summer to make ends meet in this hard economy.
Conclusion for professional investor: Bring the price down and rattle the confidence of retail holders who bought the stock on a tip and don't understand the science and will unload a fair number of shares in a steady drip, together with the ATM drip, throughout the summer.
MoJo-- Thanks again for the Avastin PDF link in your post:
That article (albeit a self-serving Genentech publication) nonetheless makes clear why the picture for Avastin in GBM is not at all rosy.
Point 1. Avastin was dosed continuously for many months: 3.7 months in one arm of the trial and 5.1 months in the other arm. Then, even after disease progression occurred, 51.8% of the patients continued to receive Avastin. See pdf page no. 61 to confirm this info.
Point 2. The list of serious adverse effects for Avastin in the GBM trial reads like a train wreck and includes 5 deaths unrelated to disease progression. See pdf page nos. 59 - 68 and then compare these AEs to what you see on the Cotara Poster now found on the PPHM website. The Avastin article goes on to admit at top of pg. 64 that "Fourteen patients (17.7%) discontinued Avastin because of an adverse event."
I guess we know now the source of 14 of the 16 "censored" patients MoJo mentioned. They dropped out because they couldn't tolerate the toxicity resulting from 3-5 months of continuous Avastin dosing. The "successful" patients, i.e. the ones who caused the MOS figure to go out to 9 months, are the lucky ones who were able to keep taking Avastin for a few more months even after disease progression showed up.
As the medical community already knows, Avastin gives cancer patients a brief reprieve, but once you can no longer tolerate the nasty side effects and stop dosing, the tumor comes back with a vengeance.
Sounds to me like there is plenty of room for Cotara in the GBM market place.
Here's the link again to Genentech's article on their Avastin GBM study.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM148788.pdf
Thank you MoJo. Very interesting. Did that graph come from the 2011 JNCCN article mentioned in the Poster? I haven't been able to get a copy of that article yet so I appreciate very much any further comments you can make on the article.
For example, does the article disclose how long Avastin dosing continued? Does it disclose how soon death happened after dosing stopped?
Thank you.
JR-- You are confusing the "median" with the "mean" . The mean is the average of all the survival times and of course is not available until everyone has died. The MOS time can be determined much sooner because only 50% of the patients need to have died to determine the MOS.
The 86-week survival time for 14 of the Cotara patients would absolutely pull up the "mean" or average survival time, but might have no effect at all on the median survival time or MOS. Here's why:
In a trial of 41 patients, if 20 live for 37.9 weeks and 20 live for 86 weeks, and the last patient dies in week 38, then the median MOS is 38 weeks even though the average or mean number would be something like 62 weeks.
It would be very interesting to know Cotara's average or mean survival time and be able to compare that to same number for Avastin. The closest you can come to guessing at the "mean" number is the long-term survival figures published in Fridays PR:
"Currently, patients alive at six-months, 12-months and 24-months are 73%, 38% and 19%, respectively, and two patients have survived three years after a single treatment with Cotara."
Conspicuously, Roche has not published comparable long term survival figures for Avastin.
I believe the FDA meeting was scheduled for 4th Qtr. to allow the long term survival numbers (i.e. the space to the right of SOC in the Kaplan Meier curve) to grow even more dramatic as compared with Avastin. We all know that colon and breast tumors treated with Avastin grow back with a vengeance a few months after the treatment stops. Why should it be any different with GBM tumors.
Assuming Avastin has become the new SOC (which is a big assumption given its toxicity and many AEs), happily there is still plenty of room for the FDA to approve Cotara as well. Avastin's MOA requires multiple and continuing doses to achieve a 9 month MOS. Cotara requires a single dose to achieve approximately the same MOS but enables 1/4 of the patients to live much longer than Avastin, e.g. approximately 18-24 months and maybe these long-term durable responses will grow even higher by the FDA meeting this fall.
In my mind there is no doubt that the FDA will approve a registration pathway for PPHM at the 4th Qtr meeting. For patients it is highly desirable to have both the Avastin and the Cotara MOAs out there in the market, whether used separately or in combination. It's like giving the doctor both a hammer and a saw. Two tools are better than one.
IMO, the only question remaining is whether the FDA will approve a SPA registration pathway requiring 100 or 150 or 200 Phase III patients, Very few small biotechs take their drugs to this SPA (Special Protocol Assessment) stage. Once the FDA goes firm with bright line as to the Phase III no. of patients, and outcomes for X% of those patients, that must be achieved to get market approval, the BP's will be able to do a precise risk/reward analysis and the bidding war will begin. :)
From today"s Wall Street Journal:
"The Pfizer drug reported on at the meeting is called crizotinib and it blocks a mutated gene called ALK that is found in up to 7% of cancer patients with NSCLC."
From looking at the Poster, it seems the Company is indulging the possibility that Avastin could be the new SOC even though the JNCCN abstract (cited in Poster footnote) makes clear that "The lack of a dose-response effect would require confirmation in a prospectively conducted clinical trial."
What we know about Avastin/Bevacizumab is that it is a very effective anti-angiogenesis drug (i.e. stops tumor capillary growth) but has serious side effects and the tumor comes back with a vengeance a few months after the treatment stops.
This would seem to be why the company is emphasizing Cotara's long term survival benefits ... and especially emphasizing that these long-term survival benefits are achieved from a single dose, i.e. no need for the patients to make multiple trips to the hospital for continuing doses of Avastin.
Finally, lets not forget how cancer therapy is moving more and more in the direction of multi-drug cocktails that combine different MOAs. There is every reason to believe that Cotara and Avastin could work together in a drug cocktail since they have such different MOAs.
SK summed it up nicely: "As a single-treatment approach showing promising signs of overall survival and a good safety profile to date, Cotara may offer advantages when administered alone or in combination with other therapies for patients with this deadliest form of brain cancer."
This is not a race to prove we are better than Avastin. Many years of using both drugs in the marketplace will be needed to establish the relative merits. Rather it is a race to get the FDA to approve a definitive registration path. That meeting has been scheduled and SK has clearly laid out the criteria for why Cotara merits registration: better safety profile than Avastin; better administration profile than Avastin due to single dose; and apparently better long-term survival data than Avastin, although Avastin long-term survival numbers at the two-year mark are conspicuously missing.
The key to tomorrow's Cotara news will be seen not in the PR but in data in the Poster that hopefully will be added to the website at the same time the PR goes out. Hopefully the Poster will show the survival waterfall chart as compared with SOC.
If our survival line in the Poster chart has lots of space above and to the right of the SOC line, then the good times for the pps have arrived-- or nearly arrived. Space above the SOC line means a better MOS (Median Overall Survival). Space to the right of the SOC line is equally important because it shows that at a given point in time like 18 months after treatment, for example 35% of Cotara patients may still be alive but only 3% or zero percent of SOC patients are still alive at that date. Such a survival fact is just as important as the more traditional MOS figure and the FDA will surely take note if we have lots of space to the right of the SOC line.
From looking at historical Cotara data, the "space to the right" success of Cotara seems to be it's strong suit. In other words, for whatever reason, we beat beat the MOS for SOC by a significant margin, but the really dramatic news is that there seems to be in every trial about a third of the patients who outlive SOC by leaps and bounds.
I'm not predicting the stock will jump tomorrow, but if there is lots of space above and to the right of the SOC line, this means analysts and the funds they work for will be able to figure out that the FDA is going to give us an easy Phase III registration path-- perhaps only 100 more patients in the Cotara arm and 100 in the control arm.
The more space above and to the right of the SOC line, the less risk for our BP partner, the sooner the bidding starts, and the higher the price that PPHM will be able to command for a regional or global Cotara license.
Once that upfront license payment arrives, which could be $50 to $150 million (depending on whether is a regional or global license), the ATM selling stops and we're off to the races. The actual Cotara license may not be announced until late 2011 or early 2012, but the anticipation of this license event and what it means for the Company will start tomorrow and grow steadily over the summer and fall.
RRDog-- Your Ode to Dr. Thorpe is well sung. I agree completely. The market doesn't appreciate the MOA "tour de force" Thorpe has pulled off here. However, for the FDA, the analysts and the medical community considering Bavi trials, Thorpe's presentation in Barcelona will be hugely compelling for years to come. I bet many aspiring PhD candidates are already making plans to replicate new versions of this break-through Phil Thorpe accomplishment.
An immunology maven I spoke with emphasized the importance of Slide #41, which tells the whole story in one picture. Everyone who owns stock in PPHM should print Slide 41 and keep it by their bedside. If Bavi indeed triggers either of these MOA mechanisms, it's the launch of huge new therapeutic platform-- certainly in cancer and perhaps in viral therapy as well. But if both of these mechanisms of action are operating, the effects of Bavi as an immunotherapy will be nothing short of sensational. The fact that Thorpe has nailed down these TWO separate ways that Bavi "breaks the grip of tumor on the immune system", indicates huge promise for Bavi !!!
________________________________
On a separate subject, I am now confused about the relevance-- at this point in time-- of MOS data from the Georgia and India signal-seeking trials. The following link indicates that under SOC the MOS for breast cancer (apparently via various chemotherapies) seems to be around 2.5 to 3 yrs.
http://www.breastcancer.org/symptoms/new_research/20080909b.jsp
If the info. in this link is correct, the interim MOS achieved so far in PPHM's two MBC trials would not yet be relevant. Comments on this topic are invited.
CJ-- Thanks for this very informative link re meaning of both the horizontal gap and the vertical gap in a Kaplan-Meier Survival Curve. You omitted to quote a subsequent paragraph in your link which I think is key:
"Often we will compare curves for two different groups of subjects. For example, what is the survival pattern for subjects on a standard therapy compared to a newer therapy. We can look for gaps in these curves in a horizontal or vertical direction. A vertical gap means that at a specific time point, one group had a greater fraction of subjects surviving. A horizontal gap means that it took longer for one group to experience a certain fraction of deaths."
In other words, MOS data tells you only about the horizontal gap, and says nothing about the vertical gap.
Until your post today I had been focusing only on the horizontal gap in Mojo's chart that measure the difference between the time when 50% are dead with SOC vs. the time when 50% are dead with Cotara.
But as your link points out, equally important is the vertical gap between SOC and Cotara at a later point in time like 18 months out. In other words, it's very important to know, for example, that 18 months after treatment perhaps 40% of Cotara patients are still alive but only 5% of SOC patients are still alive.
The way to picture this vertical gap dramatically is to imagine the significance of the vertical gap if Mojo's guess about the slope of the Cotara red line in Post 64053 were to run higher up on the chart as it moved down and to the right after the 8.8 month MOS moment. This could greatly increase the vertical gap between the Cotara line and the SOC line that is the other half of the importance of a Kaplan Meier Survival Curve.
We get a big clue about the importance of Cotara's vertical gap from the PR the Company put out last week, which states: "we have seen median overall survival of close to 9 months, and importantly have followed long-term survivors after a single, generally well-tolerated infusion of Cotara."
I think the Company is throwing us a clue that in the June 3 Poster we will see some dramatic vertical gap info. that could dwarf the importance of the MOS horizontal gap.
There are 2 ways to invest in PPHM: Follow the buzz others make OR read and understand the science yourself. For those in the second group, today's Immune Reactivation Poster (hit link at bottom of PR) was a huge step forward in documenting Bavi's MOA.
When combined with last year's big MOA poster at AACR on how Bavi mediates maturation of dendritic cells, we now have two major studies both of which explain Bavi's MOA and both of which point in the same direction. Both of these AACR studies explain at a molecular level how it happens that PS causes the immune system to tolerate the presence of tumors and how it is that Bavi "overcomes PS-mediated immune tolerance of tumors" (quote from today's PR).
If you actually take the time to read todays AACR poster, you can understand why Phil Thorpe has been selected as the featured keynote speaker at the prestigious European Antibody Congress May 24-26 in Barcelona. http://www.informaglobalevents.com/appdata/downloads/antibodies1/CQ3455_Recombinant_Antibodies.pdf
Scroll down to page 5 of this pdf and see the description of Dr. Thorpe's keynote address on May 26 that is advertised as the featured reason to attend this Conference. It says he will talk about how:
"Bavituximab causes macrophages to polarize into tumoricidal M1 macrophages that destroy the tumour vasculature and tumour cells by ADCC. In addition, it stimulates the generation of tumour-specific cytotoxic T-cells."
Dr Thorpe is presenting in Barcelona, as the featured work of the conference, the same study that is disclosed in today's AACR poster. Of course he will jazz up his talk with recent clinical data from the current Bavi Phase II trials. But what makes Dr Thorpe's work so compelling, and why he was selected as the featured keynote speaker in the antibody development world today, is that Dr. Thorpe can now explain with confidence to world class doctors Bavi's amazing MOA. Between today's AACR poster and last year's dendritic cell maturation poster, Dr Thorpe has proven what is happening at the molecular level to give Bavi its magic punch. This solid molecular explanation of Bavi's MOA is meaningless to Wall Street but means everything to the FDA and the medical world and the BP world that invests in new cancer technologies.
The last sentence of this part of today's PR says Bavi's ability to "reactivate the immune system" to recognize and destroy tumors will "... have broad implications for the future of cancer immunotherapy." When the emerging Phase II clinical data comes out concurrently with ASCO next month, lots of folks will wish they had paid more attention to that statement.
UMass-- I would think your doctor pow-wow tomorrow is 4 days too soon. The really big paper coming out at AACR is by Thorpe on April 5 explaining how Bavi works to "... reactivate innate immunity in tumors."
Maybe your coffee tomorrow is just to warm the other docs up for next weekend when you discuss Thorpe's new paper-- the one linked in Company's Feb 28 PR:
Phosphatidylserine-Targeting Antibody Induces Differentiation of Myeloid-Derived Suppressor Cells into M1-Like Macrophages
Introduction: The phosphatidylserine (PS)-targeting antibody, bavituximab, is currently in Phase IIb clinical trials in patients with lung cancer. Bavituximab, and its murine counterpart, 2aG4, induce the attack of monocytes and macrophages on PS-expressing tumor vascular endothelium and tumor cells and inhibit the immunosuppressive effects of PS in the tumor microenvironment. Myeloid-derived suppressor cells (MDSC) are one of the major cells responsible for the immunosuppressed state in tumors. In this study, we tested the influence of 2aG4 on the differentiation of MDSC into M1-like tumor associated macrophages (TAMs). Methods: MDSC were isolated from 4T1 tumor bearing mice with anti-Gr1-coated magnetic beads. The purified MDSC were then cultured for 5 days in the presence of 2aG4 or control C44 antibody. For in vivo studies, PC3 tumor-bearing mice were treated with 2aG4 for 30 days and MDSC and TAMs in tumors and spleens were analyzed by FACS and immunohistochemistry. Results: 2aG4 treatment of purified MDSC switched their cytokine production from an immunosuppressive IL-10-dominated response to a pro-inflammatory IL-12- and TNFa -dominated response. The percentage of Gr1+ cells decreased to 8% in the 2aG4-treated cultures (P<0.0001) but only to 50 - 57% in the PBS and C44-treated cultures. Treatment with 2aG4 induced the differentiation of MDSC into M1-like macrophages that expressed lower CD206 and produced more NO than control cultures. Treatment of mice bearing PC3 prostate tumors with 2aG4 decreased the percentage of MDSC from 7% to 4% (P<0.001) in the tumors and from 28% to 20% (P<0.001) in the spleens. The antibody treatment also increased the ratio of M1 to M2 TAMs in PC3 tumors from 0.7% to 1.4% (P<0.001). Conclusion: Taken together, our results suggest that 2aG4 causes the differentiation of MDSCs into macrophages having an M1-like phenotype. 2aG4 treatment decreased IL-10 production and increased IL-12 and TNFa-production. These results suggest that 2aG4 treatment reactivates innate immunity in tumors.
"Pay attention to the "biomarker" language."
Agreed. In particular, pay attention to the exploding amount of cancer research focused these days on mircroparticles that are shed from tumors and circulate in the blood in large concentrations in advanced metastatic cancer. Thorpe and company have determined that these mircoparticles expose PS. It appears that Dr. Stopeck wants to see if some correlations can be made between reduced levels of microparticles (due to fact Bavi targets them and mediates an immune response against them) and better PFS and better overall tumor response rate.
My understanding is that a large number of published pre-clinical microparticle research articles suggest that microparticles may contribute significantly to the immuno-suppressive environment in which tumors flourish. Dr Stopeck now has an opportunity to advance these pre-clinical findings in a clinical environment.
You say "no revenue targets to digest." Try this one. Sales for SOC therapy in HCV in the U.S. are $4 billion. My understanding from a clinical doc is that Interferon represents half of the drug cost.
We will know by early summer whether Bavi is on its way to replacing interferon in this $2 billion annual market. What would that do to the share price?
Vertex is already trading at 40 times PPHM's market cap and they have just one of the several possible anti-viral drugs that must be used in combination with an immune stimulatory drug like interferon or Bavi.
... and this Vertex valuation analogy completely omits Bavi's massive anti-cancer potential.
See post 59739 and other posts cited there for more on Bavi's anti-viral potential.
48 weeks may be the duration of SOC for HCV, but the drop in viral load can be measured just a few days after dosing, so it will only takes a few weeks for the Company and the clinical trial centers to know if Ribavirin plus Bavi works as well as Ribavirin plus interferon. If Bavi is looking to be a viable replacement for interferon (a drug with nasty side effects) the buzz will be all over the Street in just a few months. Assuming the trial starts in Jan., I'm guessing you will hear the excitement in SK's voice by the March Conf. Call. But it will be April or May before we see interim data, because it will take a few months to enroll and dose 50 patients and assemble the data.
Regarding your post 59739 earlier today, I believe insurance coverage for off-label cancer uses of Bavi will come, not from HCV data, but from the many IST investigators who publish over the next year "careful research studies written up in well-respected ... medical literature" regarding the results of their Bavi clinical trials in multiple cancer types. This is one of the main reasons for the large and diverse IST program.
You forgot the biggest near-term Iron in the Fire:
Market finally on verge of recognizing PPHM as a serious ant-viral play as company launches HCV trial to establish Bavi as replacement for interferon in $2 billion interferon HCV market.
IMO, launch of the new Bavi-Ribavirin HCV trial will be announced in January 2011 and interim data can be expected this spring.
See posts 59690 and 59695
IMO this is setting the stage for the next major inflection point, Cotara phase 3. They need to have funds available to start phase 3 if they can’t make a good deal. Simple as that.
Certainly Cotara phase 3 is a major inflection point and this offering will give Mgmt great negotiating leverage with BP as we approach those talks this summer.
But IMO there is a much nearer inflection point, namely, the announcement in January of the new HCV clinical trial with ribavirin where Bavi could replace interferon in the SOC. HCV SOC is now interferon plus ribavirin. It's a $4 billion market. Interferon is half of the cost of SOC, or $2 billion. Results from the trial will be known in just a few months after it starts.
From the Nov 17 PR: "Additionally, Peregrine reported bavituximab in combination with the antiviral drug ribavirin improved survival by up to 50% compared to either drug used as a monotherapy in several models of VHF. ... These data are particularly encouraging and relevant to our future planned clinical studies in HCV as we near completion of enrollment in our Phase Ib trial in patients coinfected with hepatitis C virus (HCV) and HIV."
IMO, the HCV trial starting in January and reporting results in May is the NEXT BIG INFLECTION POINT.
IMO, the Company is positioning to raise some capital as the Street wakes up to the fact that PPHM is both a major cancer play and a major anti-viral play. There won't be any shortage of buyers to absorb the new shares, whether they be Mr. Dart's friends or newcomers.
... and if DTRA's current work on Ebola (which should complete by March) goes as well as the already-completed studies on Yellow Fever, Punta Toro and Pichinde-- WATCH OUT. THE GOV'T WILL BE ALL OVER BAVI.
What kind of PPS movement will we get when they PR "in the very near future" new Bavi IST and new Company-sponsored Bavi trials.
From SK in the 12.09.10 CC: "... we are planning to initiate additional Company and investigator-sponsored trials in the very near future."
Looks like the Street is finally waking up to the depth and breadth of the Company's pipeline:
GBM
broad-spectrum anti-cancer
broad-spectrum anti-viral
Bio-Similars
I estimate we need about 3-4 more months for that wake-up call to spread from Mr. Dart's desk to the rest of Wall Street. Certainly by ASCO time, the Street will have caught up with the buzz among clinical docs that is causing such rapid enrollment of the Bavi Phase IIb trials.
Getting the DTRA funding extension in March will help too.
Some funds won't see the whole picture until it hits them in the face this spring. Others started to smell the coffee yesterday.
CJ-- Excellent observation. Thank you.
Thanks MoJo- I have been wondering about that number.
I have notes from a call several months ago with a person who works with cancer trial data. My notes say that different trials of Avastin plus docetaxel have yielded OS times of 8 months, 10 months and 14 months. But I'm not sure if that data comes from a front line or refractory patient population.
Does anyone out there have more or different clinical data on how Mojo's estimate of Bavi OS lung data-- currently at 16 months-- would compare to SOC or Avasitin plus SOC ?
Lafont-- You make an important point and one that I've been thinking about as well. There are lots of industries where hostile bidders can target a company with weak management, put in their own team after the takeover, and see the stock do well. Biotech is not one of those industries.
Biotech companies require unique management skills and loyalties that cannot be replaced easily by a hostile bidder. So if you acquire a 7% position, you better like the management team that's already in place.
Ken Dart knows that the likes of Garnick, Chabner, Garovoy and a host of former Genentech people are coming to PPHM because they like the science and they like the culture. I can't believe a smart guy like Dart would invest with the intent of upsetting the management culture that attracted the likes of Dr. Garnick. It's much more likely that Dart is here to support and help build the next Amgen.
Chey-- You are woefully lacking in basic investment knowledge. "Record holders" of which there are under 6K, include brokerage firms like E-Trade. Behind one record holder like E-Trade there may 10,000 beneficial owners, i.e. individuals, like you and me.
Thanks PW. Great article. Yes, he is smart and aggressive, but he also likes exciting new science. He could be genuinely intrigued by the novelty of the anti-PS platform. This sentence in the article caught my eye:
"Outside of making money and playing the piano, Ken is intensely interested in the workings of the brain. He has funded several scientists' research through the Darts' charitable foundation. Ken is an "obviously intelligent layman," says J. Christian Gillin of the University of California at San Diego, who conducted a Dart-funded study of how sleep deprivation affects brain function."
I bet Mr. Dart catches a few shorts by surprise at the open tomorrow. :)
All Dart needs is for a few of his yacht club friends to invest on his coat tails-- and its squeeze time.
To hear the full interview including Thorpe's discussion of new Vascular Targeting Agents (i.e. Bavituximab) you have to go to the In-Thought website at http://www.in-thought.com/ and sign up for a trial subscription.
All you can hear on the link Terry posted is Thorpe's introductory explanation of the old and crowded field of VEGF inhibitors like Avastin.
Excellent point WH-- Given that we know PS is exposed on HCV virons and infected cells in the same way it is exposed on the VHF virons and infected cells, it seems Bavi would have the same additive effect to ribavirin in the HCV environment that it has in the VHF environment.
I'm sure you are right in saying this is why SK finds today's VHF data so "encouraging and relevant" to the upcoming new HCV trial.
Given the company's limited funds and primary focus on cancer, your speculation makes sense that the next HCV trial is likely to be done with a strategic partner.
I agree that success with Ebola is the key for closing on major gov't funding and political support.
In this regard, I was encouraged by this quote from today's PR:
"Our antiviral research on our PS-targeting technology platform affirms that a goal of one drug for many viral indications may be achievable. Evaluation of our antibodies in more advanced models of VHF is ongoing and we look forward to completing additional studies as part of our advancing antiviral program."
Sounds to me like they are already well underway with testing Bavi against Ebola and like what they see so far. Fig. 7 in the Poster seems to indicate that Ebola and Junin are the the "more advanced models of VHF" in which new studies are "ongoing" and which the Company "looks forward to completing" soon.
My guess is that completion of the current Ebola and Junin studies is the reason why a decision on the scope of new gov't funding was extended out to March 2011.