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Nice,
Thanks Long!
Funny, I was also going to cite that May 2012 press release, but then I had to get a family member to a medical appointment.
The only thing I'd add is that in that press release, they state NWBO's work/changes with the FDA for that date was/were memorialized in writing the same day on Clinical Trials .Gov.
If you go to clinical trials .gov, then head to the historical changes for May 17, 2012, "side-by-side differences" you'll see under the section listed as "8," the relevant language. You'll see the before and after drafts. I'll let people go there and see for themselves.
New Language:
The primary study endpoint is PFS (progression free survival), and the first secondary endpoint is overall survival (OS). Other endpoints include performance status, immune response, and also safety. Interim analyses to assess efficacy are incorporated in the trial design.
Wow GPB, Amazing find…
"May be reasonably likely to predict clinical benefit."
In addition to using trending OS from inside the study, this is where NWBO can use recent similar historical OS (Overall Survival) data to demonstrate a reasonably likely clinical benefit.
Well done Dok,
I agree it does not make sense to "anticipate a problem," but it does seem this was the thread of logic started by some questionable posters on Yahoo.
Instead of "anticipating," like you, I think its best to be prepared. The lawsuit (plus protests) by Dendreon to get the FDA to do the right thing in their case was a very good example. Very good.
(I think Marnix Bosch's topic at the end of January will address how PFS is used appropriately as a primary endpoint.)
Anyway, I am not worried. Here's why.
1. Even though ICT-107 received that letter from the FDA in 2011 suggesting the FDA would not allow approval if PFS was a primary endpoint in IMUC's Phase II trial, that does not apply to NWBO because:
A. NWBO actually received approval from the FDA in 2011 to use PFS as their primary endpoint in NWBO's more highly powered, phase III (not phase II) pivotal trial.
B. DCVAX-L has orphan status for this trial. Many people do not know this gives the FDA more authority to approve a medication without as stringent requirements (powering) as otherwise might be used in a non-orphan status situation. Cramer, for instance, keeps shouting that orphan status only gets companies things like additional patent time protection. This is not true, it also requires the FDA to work closely with the company and reasonably accommodate matters such as trial size and powering in order to help patients with deadly/rare conditions that might not otherwise ever have companies try to work on medications for their diseases. The assignment of orphan status to a disease and to any drugs developed to treat it is a matter of public policy in many countries, and has resulted in medical breakthroughs that may not have otherwise been achieved due to the economics of drug research and development.
Orphan drugs generally follow the same regulatory development path as any other pharmaceutical product, in which testing focuses on pharmacokinetics and pharmacodynamics, dosing, stability, safety and efficacy. However, some statistical burdens are lessened in an effort to maintain development momentum. For example, orphan drug regulations generally acknowledge the fact that it may not be possible to test 500 patients in a phase III clinical trial, as fewer than that number who are eligible for enrollment may be afflicted with the disease in question.
C. Since 2011, the FDA has moved toward using PFS as a primary endpoint, even in non orphan status cases where OS would otherwise take far too much time, too many lives and resources to get a drug approved. The European (EMA) started using this metric (in many cases) as a primary endpoint several years ago.
Something on the Yahoo board I must address.
There are 2 things on the Yahoo board by questionable posters that seem like a transparent big pharma line of attack.
1. Someone posed the question….What if all the 66 events were deaths?
2. Someone else stated that IMUC posted a letter today from the FDA that stated the FDA (from way back in 2011) would not approve a biologic license application with PFS as the primary endpoint.
IMHO, these 2 taken together are the last desperate gasps of big pharma trying to slow or detour NWBO from demonstrating success while big pharma catches up.
Please bare with me.
The first question above dealing with the 66 initial events possibly being deaths is patently absurd. I'll talk about that more later, but the reason this inane question is raised is to hit at the letter from the FDA to IMUC back in 2011. You see, even though I've previously posted about the FDA moving toward greater acceptance of PFS (Europe accepted it many years ago) as a primary endpoint based upon the obvious cruelty an overall survival endpoint would place upon patients in a GBM trial study, in addition to the inhuman FDA surrender that this would slow research to a snail's pace; the big pharma argument is that that 'death is (of course) the real thing these treatments are meant to avoid, and if you don't look directly at OS as the primary endpoint (so their false argument goes) then you are really going to approve drugs that will not work as often as not.'
Read that last paragraph again. That is their argument. It is based upon an initial extreme and statistically impossible precursor, then followed with a rational sounding but absurd result.
This is a war folks, and this is where it is heading to. I didn't realize it until recently.
Let's step back and look at NWBO and what they are attempting to do. NWBO is attempting to conduct a phase 3 trial with PFS as their primary endpoint, and Overall survival as a secondary endpoint. NWBO introduced a crossover arm (for humanitarian purposes) so that the actual "control arm" for overall survival comparison will need to be something closer to the average statistics from S.O.C. findings over this decade. So, the only OS control, within the present trial data itself, to judge the treatment arm against…. is the Crossover arm. Therefore, NWBO must really use recent historical data for OS (overall survival). If DCVAX-L's data turns out like it did in Phase 1, EVEN THE PFS (Progression Free Survival), FROM THE DCVAX-L TREATMENT GROUP, WILL SIGNIFICANTLY STATISTICALLY OUTPERFORM THE HISTORICAL OS (OVERALL SURVIVAL) OF A STANDARD OF CARE GROUP!!!!
Read that last sentence again.
So now, imagine you're a slimy big pharma company that wants to give the FDA (perhaps some on their private payroll) an excuse to still deny a biologic license application to NWBO DCVAX-L (by making them do a second 4-7 year phase 3 GBM follow up study).
Imagine the current DCVAX-L Phase 3 results are actually out, and they really show that the primary PFS endpoint for DCVAX was easily met by the treatment group, and in fact, even the PFS (Progression Free Survival) in the treatment group statistically beat the "Recent Historical Overall survival for S.O.C. patients that used the Stupps protocol with and including total resection."
How do you -- a slimy big pharma company -- stop that drug (DCVAX-L) from getting approved????
You make a ridiculous but straight faced argument that gives some (not all) on the FDA a face saving but inane and statistically impossible argument in order to deny DCVAX-L approval.
What's your argument??
Slimy big pharma and a few FDA grunts' phony but straight faced argument:
"Well Linda, honey, I see you got statistical significance for PFS (Progression Free Survival)….congratulations (golf clap)….but…oh dear, how do I say this without hurting your feelings….didn't you realize that very statistically significant improvement in PFS does not necessarily indicate any improvement at all in OS (overall Survival)???? Why some big pharma companies just recently conveniently sponsored an article that proves just that -- using a few reviews.
Linda Responds: "Are you blind? Even our PFS (Progression Free Furvival) beat the recent historical average for OS (Overall Survival)."
Slimy big guys: "Oh….'recent historical average' you say….tsk tsk….that does not sound very much like it came from a control arm in your phase 3 study….that's not very scientific Linda….."
Linda Responds: "Our treatment arm beat our own crossover arm as well, and this demonstrates delayed treatment can kill."
Slimy Big Guys: "Are you sure about that Linda?" What if you had no crossover arm? What if your control arm had lived longer than the crossover stats you have right now? What if….Linda honey….what if the control arm would have even outlived the treatment arm, and the deaths were all going to happen earlier in the treatment arm rather than the control arm….I guess we just can't know dear….oh such a shame….you'll have to do another study….back to the drawing board as they say….and all the patients that will die because you can't prove what you already know -- shhhhh -- and we know too dear….DCVAX-L really is a miracle."
Linda response: "Look, we beat the primary endpoint for PFS by an incredible amount, and that even exceeded Historical OS by an incredible amount, and our Treatment OS beat the historical OS by more than double….there is no way in hell the FDA will look at this improvement as statistically insignificant. There is no way they will force more people to die, when they know for certain we have just given significantly extended life…and in some case, a cure to these patients."
Slimy Big Guys: "Oh, but Linda, you used patients with total resections and no sign of measurable tumor progression after radiation and chemo….but before starting your little biological treatment. So, that has never been done quite that way before, maybe the FDA will rule that it all could have been these perfect surgery candidates you selected and further that they did not have aggressive tumors when you started treatment. Maybe their long lives are really due to great surgeons plus timid GBM cancers."
Linda: "You know better than that, there are many large studies with hundreds of patients on total resections plus chemo and radiation….they live only a couple months longer at best, and even accounting for no tumor progression at the start of DCVAX-L treatment, they still can die in 6.9 months median survival. Roche just had these results with Avastin in their control arm."
Slimy big Guys: "They didn't select for non-progression when they started treatment…."
Linda: "Yes they did, and they conducted total resections….and still they only got 6.9 months median survival…."
Slimy Big Guys" "Well that's their control arm, you can't use it or anyone else's to prove your point….you must do a second phase three….this time without a compassionate crossover arm, and you are just gonna have to let a lot of people die in your control arm to prove your point….oh…such a shame…so much time wasted…so many lives you could be saving….if only you hadn't been so soft hearted…."
Linda: "That's the most inane argument I've ever heard, the majority of clear thinking people at the FDA will see through your bald faced lies and red herrings…."
Slimy Big Guys: "Hmm are you talking about Joey Boy, Little Frankie and Gold digging Gabe?
Linda: No…I'm talking about the FDA…..
Slimy Big Guys: "So are we…."
This makes NWBO's Marnix Bosch's presentation at the end of January that much more relevant.
Depends on the results.
1. If the data on tumor reduction in the Direct trial is complete tumor reduction plus strong indications of systemic immune responses, and these results keep trickling out week after week on cancer type after cancer type, at some point the PPS (as well as the market cap) will explode.
2. If the 1st or 2nd interim data in the DCVAX- L trial are so strong that the trial is unblinded, the price will explode.
Market Cap is important for PPS, and I regret not being more clear on my first post regarding what PPS would do without further dilution.
Regardless, the upshot of mine and the others' last posts on calculating Market Cap to PPS are in agreement.
That said….
In my opinion, we will sail beyond a 7 billion market cap in very little time with positive news on numbers 1 or 2 above (and no bad news).
So if we go over 7 billion Market Cap, we will also be comfortably beyond $100.00 per share, as long as there are no new offerings between now and then. This PPS includes what the others wanted me to include the first time around -- existing warrants and options that will be exercised long before we reach $100.00 per share. Their figures would agree with this extrapolation.
So what does a 7 Billion Market share mean? If you know these companies, and what they produce or have in their pipeline, you can get a feel for what this number means. There are better examples, but this list is just a starting point.
1. CLDX = 1.88 Billion
2. CBST = 5.18 Billion
3. JAZZ = 7.86 Billion
4. PCYC = 9.62 Billion
5. Gilead =113 Billion
6. Roche = 242 Billion
My apologies.
Much of what you say is correct, but I said "without dilution." 3,500,000,000 / 65 million is indeed 53.85 PPS. (Whereas 3,500,000,000 / 38.5 million = $91.00 PPS) Our current amount of outstanding shares is 38.5 million. That excludes options and warrants in the amount of $25,311,431.
If you take the Market Cap right now and divide by the share price you come up with the shares outstanding that is in line with the most recent prospectus after it accounts for the offering = 38.5 million.
38.5 million + 25,311,431 = 63.8 million.
3,500,000,000 / 63.8 = $54.85 pps. So you were technically only 1.00 off, whereas my "nonsense" was much further off -- by a country mile.
So let's get rid of my nonsense.
At 35 Billion Market Cap, the PPS would be $548.50 Price Per Share:)
At a 10.5 Billion Market Cap, the PPS would be 164.55
At a 7 Billion Market Cap, the PPS would be $109.70
Another way to calculate future Market-Cap to PPS.
Short answer: A 3.5 billion increase in Market cap would bring us a share price of $96.21.
I calculated this with post dilution dates using Y chart's data.
January 8, 2013 = 4.21 PPS and 162.30 million MC
December 18, 2014 = 3.29 PPS and 126.83 million MC
162.30 - 126.83 = 35.47 million MC difference
4.21 - 3.45 = .92 cents PPS difference.
That means for every 35.47 million shares increase in Market Cap there is a .92 cent rise in price per share.
That means that a 350.47 million share increase in MC would create a $9.20 increase in PPS.
That means approximately 3.5 billion increase in MC would create a $92.00 increase in PPS.
From yesterday's price and market cap, an approx. 3.5 billion increase in Market Cap would bring us to a stock price of 96 Dollars and 21 cents.
The beauty of this method is you are using real post dilution date numbers to compare what actually happens to market cap when share price goes up and visa-versa. Then you use that ratio to project into the future.
(And yes, without further dilution, a 35 billion Market Cap would increase the PPS by $920.00)
Don't get too stuck on your numbers.
Off topic , OCA results = double take on Blucetin.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292407/
The OCA liver results made me go back and look at Blucetin (something in the back of my head told me to research this)….Sure enough…..Check out this study (two paragraphs down). I thought it was a gimmick. Recently heard about it on sports talk radio commercials. Note: It also prevents cirrhosis by helping the liver metabolize alcohol more effectively and faster. Blucetin is cheap and over the counter. It even reduces BAC very rapidly. I think it may be used in emergency rooms as well, because doctors often have to wait until a patient is sober to perform medical procedures. This will also result in reducing costs for law enforcement and jail space, because the Police Stations, Jails and Courts are full of intoxicated drivers, alcohol related domestic violence, and other alcohol related crimes. It will reduce taxes for public safety, medicare, public mental health and taxpayer burden from emergency room visits. It will decrease hospital visits. It will reduce the need for psychologists and suicide hotline volunteers. I'm not kidding. On the dark side, it will probably increase binge drinking, and therefore somewhat offset these gains -- the question will be: by how much? It may be that hospitals will be able to use it to treat liver failure from prescription drug overdose/reactions -- primarily acetaminophen.
"The laboratory mice were given excessive alcohol and then cradled in a V-shaped hammock in an intoxicated state. After consumption of alcohol, the time it took mice given BluCetin anti hangover tablets to rise up from their cradle was 10 times quicker than mice that were not given BluCetin. Withdrawal symptoms also were fewer. "
Rancho Santa Margarita, CA (PRWEB) January 04, 2013
BluCetin™, a patented (pending) natural product researched by UCLA School of Medicine and developed by Blue California, has been proven to be an effective ingredient in reducing negative symptoms of alcohol in recent animal and human studies. BluCetin-DHM, derived from Hovenia dulcis (oriental raisin tree), is considered a breakthrough over anti hangover remedies in the market place that solely attempt to relieve symptoms such as headache and dehydration through traditional supplementation.
The research team at David Geffen School of Medicine, Department of Molecular and Medical Pharmacology & Neurobiology, led by Jing Liang, PhD in collaboration with Blue California, discovered Dihydromyricetin (DHM), a unique natural molecule that targets the GABA(A) receptor in the brain more effectively than other flavonoids (natural molecules found in some plants and fruits). Alcohol binds to GABA(A) receptors cause imbalance between control and excitement. By targeting GABA(A) receptors BluCetin DHM protects the neurons on brain cells from the influence of alcohol. A patent application on the discovery was filed by UCLA and exclusive license to market the technology was granted to Blue California.
BluCetin, the patented high purity form of the DHM molecule, was used in animal studies conducted by Dr. Liang with striking and significant results. The laboratory mice were given excessive alcohol and then cradled in a V-shaped hammock in an intoxicated state. After consumption of alcohol, the time it took mice given BluCetin anti hangover tablets to rise up from their cradle was 10 times quicker than mice that were not given BluCetin. Withdrawal symptoms also were fewer.
The entire groundbreaking study can be viewed online (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292407/).
Barnstormer, OCA will likely decrease liver transplant demand.
Right now it can help up to 12% of the population. I looked up studies on OCA for alcohol induced liver cirrhosis, and it is effective there as well.
If you consider that Gilead and PCYC recently created extremely effective treatments for Hepatitis C, the demand for liver transplants will decrease further.
The world is changing fast. Organovo is already growing livers that can be used for testing new drugs….one day they will be good enough to use in transplants (since they are derived from autologous cells).
Like NWBO's DCVAX- Direct, these new treatments will continue to reduce the need for surgery.
(If the populace also remembers not to take too much acetaminophen and/or alcohol all at once, the combined effect with the above 'inventions' will reduce liver transplants to a very manageable number.)
Thanks….let me know if you turn up anything else.
It's true. I'm a gorf:) I'm old enough to be ok with that. I'll probably spend a good deal of my next year trying to fully understand that article I recently cited on dendritic cells. I do get out though. Still, my wife, my oncologist and my son deserve a better crapshoot than Cancer and Alzheimer's disease provides. What a wonderful, tragic, bizarre and hopeful time to be alive.
New SC 13G/A on Sabby --
http://nwbio.com/sec-filings/
I think its an increase…. its an amendment to show they now own a certain percentage of shares.
The share total is 1,454,700.
Aggregate amount = 2,054,200
Someone else on this board more wise in SC 13 G/A matters may wish to elucidate us on how much this changes Sabby's and Hal Mintz' most recent position in NWBO -- if at all.
It might explain why we are around the 4.20 pps right now.
Agreed.
Article to Understand Dendritic Cell Immunotherapy. (Best Yet).
It indirectly shoots down my (last post) theory that Dendritic Cell expression to naive t-cells can also happen on the tumor, but does not preclude other dendritic cell localized tumor expression/exchanges (see innate immune system cells). It also explains why a dendritic cell stimulated at the tumor site is different than a dendritic cell stimulated at the lymph node location.
These ideas might explain the nonresponse PFS with intranodal injections, but significant (but not equivalent to L or Direct) OS response with intranodal injections.
I can't explain here in any sort of detail why this article also makes me confident about DCVAX, but maybe you will draw your own insights and ahas. To me, NWBO is even ahead of the foundational knowledge laid out in this article.
http://www.nature.com/nrc/journal/v12/n4/full/nrc3258.html
Interesting.
Below is my ham and egg interpretation of what is going on in that study. It sounds like I am certain, but its simply my humble opinion.
This was one of those studies that had a little bit of DCVax-L, DCVax-Direct and something completely different.
I am not surprised by the OS lengthening while PFS was standard.
Why?
First and foremost, these were intranodal injections. That means the Dendritic cells were injected into the lymph nodes (which the brain proper does not have, so Yang had to use cervical and nasal associated lymphs), and not the tumor (as in Direct) or the arm (as in L). This would likely account for the standard PFS response in comparison with historical TMZ/radiation therapy, but longer OS (in comparison to chemo/radiation alone but not longer than DCVAX-L phase 1/2).
In other words, dendritic cells don't just do their job (uptake and expression) in the lymph nodes, they also can and will do them directly in the tumor. When you inject intranodally, you reduce the opportunity for local Dendritic - T-Cell/B-cell/Helper T-cell exchange at the tumor site. Consequently, you reduce the chances of immediate interference with tumor progress (PFS), but you still have the opportunity for longer term interference with tumor progress (thus improving OS, but not to the level of DCVAX-L or DCVAX-Direct). When you inject into the blood stream (as in DCVAX-L), you increase the opportunity for both tumor and lymph dendritic cell exchanges with T-cells/B-cells/Helper T-cells. When you inject intratumorally (as in Direct), you highly increase the opportunity for dendritic cells to exchange with T-cells/B-cells/Helper T-cells in the tumor and the lymph nodes.
Think of it like the dendritic cells, T-cells, B-cells, helper T-cells being placed down stream in the lymph nodes and having to swim upstream (which the dendritic cells are not really meant to be good at), versus them being placed upstream in the tumor (like direct) or easily shuttled to the tumor from the bloodstream (like L). The trip for dendritic cells, to start up stream then move down stream, is much more natural. Dendritic cells are all over the body (especially in the blood), but their primary action with a tumor is to go there first, nibble, mature and then either stay put and express and/or move to the lymphs to express. (Note: ICT-107 was injected subdermally, thus like L, it has a more profound affect on PFS than an intranodal injection).
Second, the tumor lysate in this experiment only selected for IL-12 expression on the matured Dendritic cells (Direct selects for IL-12 and CD-40).
3rd, the stage of the dendritic cell was unclear, but appeared to be fully matured (not partially matured as in Direct).
As Linda Liau stated in her 2010 review, the place where the dendritic cells are introduced is extremely important. Subdermal and particularly intratumoral seem to have the best affect.
The Yahoo site NWBO chart is partially broken.
Let's just stick to the interactive chart for now.
1 Day = NWBO works
5 Day = NWBO works
1 Month = Broken
YTD = Broken defined as nothing on the chart
3 Month = Broken defined as chart stops on November 14, 2013
6 Month = Broken defined as chart stops on November 14, 2013
1 Year = Broken defined as chart stops on November 14, 2013
2 Year = Broken defined as chart stops on November 13, 2013
5 Year = Broken defined as chart stops on Week of November 11, 2013
** I am not a trader, I am an investor. However, it is interesting to look at the pattern that formed from December 9th through January 2 and January 9.
Look at the 6 month chart on NASDAQ:
It is clearly a cup and handle pattern.
Here is an example of that pattern:
http://i.investopedia.com/inv/dictionary/terms/Cup_and_Handle.gif
Prior to that, from November 14 to December 2, it is clearly a distinct head and shoulders (that was from the fundraising).
Here is an example of that pattern:
http://www.chartpatterns.com/headandshoulders.htm
Note: Early on, when NWBO made it onto the NASDAQ, Yahoo's chart for them was broken for a few months. I do not know what all this means. No other sites that post NWBO charts have had this problem. It does not seem random, as I have never found this to be the case with any other stock chart on Yahoo.
etienne,
Ou is correctement! All for one and one for all.
I agree. At this point its about the Patients, Doctors, Caregivers, Scientists and the data. GLTA GS.
Webcast - 01.13.14 Monday, 4:00 P.M.
Northwest Biotherapeutics at Biotech Showcase 2014
San Francisco
I know what you mean about the Triozzi study.
I must be dense, because each time I read it, I discover something new.
For instance, Patient #6. He had 25% tumor regression at week 4. He also had a response in every other category, making him technically the second best responder if 25% tumor regression had been the cut off point.
Also, we are talking about patients that only had normally 2 weeks until the tumors were removed. A couple had 4 weeks until their tumor was removed. And one had 6 weeks.
Think about that….
If you look at the other responses and indicators, it looks like they really might have had an 80% response rate had they simply waited long enough.
How many studies do you know that do not bother to tell us patient outcomes no later than 2 to 6 weeks after treatment?
Now, think about what NWBO has been saying. It believes most if not all tumor regression will start to be see "within a few months."
It is possible -- I'm not saying it happened -- that even with an inferior product, Triozzi may have seen tumor regression in 100% of his patients had he waited "a few months."
I'm not casting criticism on the brilliant work of Triozzi, he simply performed the pilot study the way it was designed.
Now I must start a new post, unless someone else has, because I just noticed NWBO is going to present at a biotech conference on January 13, 2014!
Long,
The NDA filing for 2nd generation DCVax-L under your proposed timeline is why I think our congress needs to look at updating their stem cell and immunotherapy dendritic cell (autologous) approval legislation. Japan has done this, and the procedure you propose -- including a mandatory post market confirmation study -- would be allowed. IMHO. If things go well for the current versions of DCVax-L and Direct, I hope NWBO does not have to go to Japan first to get early approval for 2nd generation L.
Red,
I think you may be right. Even if both 1st and 2nd generation DCVax-Prostate are available to license, if DCVax-Direct runs the table….and that table includes 80 - 100% efficacy on prostate cancer, a purchase of DCVAX-Prostate now by big pharma might be premature.
You know, I bet big pharma is watching NWBO extremely closely right now. They are probably more on the edge of their seat than we are.
DCVax Prostate: Does licensing offer include 2nd generation?
Red,
I thought I'd throw this out there.
Red,
Brilliant. It will be interesting to see how the FDA and NWBO proceed with the new and improved DCVax-L and Prostate once the current DCVax-L results are in on phase 3. The new legislation wording regarding stem cell and immunotherapy from Japan may flow into the U.S.. I think the new DCVAX-L and Prostate versions may get orphan and fast track status due to the overall remarkable safety profile of dendritic immunotherapy, the diseases themselves (need for new trx.), and the (hopefully) stunning efficacy results of their predecessors.
I've slightly updated my thinking on the difference.
Direct is likely better because:
1. Intratumoral dendritic injections have proven superior.
2. DCVax-Direct is/are dendritic cells matured to their most effective state -- partial maturation.
3. DCVax-Direct is stimulated to become the most effective type -- identified by cd40 expression and il-12 production.
4. Sometimes its ok if the king wears no clothes (like when he's taking a shower)….In other words, its no secret ultimately DCVax Direct -- if proven very successful -- will be used on operable as well as inoperable tumors.
5. DCVax direct is loaded with antigens from dying (but not dead) tumors. This is where I am updating my explanation. Thus far it appears that a dying/weakened tumor is even better at presenting antigens/biomarkers to DCVax-Direct than a healthy or dead tumor is.
6. It does not require surgery, tumor preservation and processing.
The benefits of numbers 1,2 and 3 above make the dendritic cells better at:
a. Going directly to the antigen source of a dying tumor.
b. Responding better to the immunosuppressive environment the tumor immediately throws at it.
c. Taking up antigens and biomarkers in their most relevant states.
d. Orienting and mobilizing DCs back to the lymph nodes.
e. Expressing their antigens/biomarkers to the natural killer t-cells, b-cells (which make antibodies) and helper t-cells more effectively because dendritic cells perfected in stages 1,2 and 3 above were not down regulated by the otherwise immunosuppressive environment of the tumor.
On the other hand, L is first partially matured outside the body, then fully matured outside the body with grounded up tumor lysate. It is unlikely NWBO was able to modify the L partial maturation process in-between phases 1/2 and 3 to otherwise reflect the superior dendritic cell maturation (used in direct) to (a more) correct stage and type. This is because the learning and benefits put into DCVAX-Direct were only really known after the first phase of the L trial began. It is unlikely L was allowed to further improve its product after the trial started, but I am not certain about this. Further, L is not injected into the tumor bed, and as you know, uses dead -- not dying -- tumor lysate. I could explain those things in more detail, but I think you get what I'm trying to say.
The eventual outcome will tell the real story, and we will see what transpires.
P.S. Of course, I still think that DCVax-L will prove superior to any non-DCVax platform.
I tried to figure out what Pfizer was working on with their Rinat division ala MD Anderson. I did not find the pipeline products.
Anyway, I think the take away here is that Big Pharma is following NWBO….not leading.
If you look at the benefits from the MD Anderson MOONSHOT Program, they are allowing some companies to inject into the tumor/body "before" removal.
DCVAX direct already takes that a great deal further, in that they inject into tumors that will not be surgically removed.
One of the things that I thought would happen, when NWBO started getting close to big announcements, is that other pharmaceutical companies would start to attempt course correcting their big ships, even going to the extent of simply appearing to already be on the same track as NWBO.
It started about a year ago with big pharma announcing Chemo is not the future in cancer research and development -- immunotherapy is.
Now, with NWBO moving quickly toward their big announcements, the "me too" sounds from much larger companies is almost deafening.
I hope they all succeed of course, but I think we know what/who motivated them to turn their big ships in the right direction:) By now, they know what is going on.
(I have a problem with big pharma using patent protection as a way to extend high costs in one product whilst they slow introduction of a better product for the same illness so as not to cannabilize their products still on patent. I hope NWBO will make the drug industry rue the day they started thinking like that, but I also hope we get a cure very soon, no matter who finds it. Personally, I think it will be DCVAX-Direct.)
I looked back at some of his writings (postings). A very thoughtful fellow. My condolences and prayers go out to his friends and family.
The University of Miami has a long road ahead of them. GLTA. They are on the right track in using tumor lysate as the follow-up booster. However, should Direct provide the same results as it did pre-clinically, the days of tumor surgery may be numbered.
For the patients' sake, let's hope NWBO gets some stellar results from Direct and L, so that people have something to hold on to in the near term.
The one factor NWBO might overlook is a sense of urgency. In my opinion, they likely have a far superior product that will initially be merged into a protocol with chemotherapy and radiation (and surgery in the case of DCVAX-L).
However, while big pharma likely has inferior products to offer as their proposed adjuvants, they can market their upcoming products as if they were comparable to DCVax.
In other words, I hope NWBO does not try to get cute with their timing, and instead proceeds full steam ahead.
I understand most of the upcoming catalysts are pretty much out of their timing control right now, but the catalysts that can be placed on fast forward should be.
I understand regarding theoretical promise -- it does not always pan out, but understanding this can help me determine what the data means when it comes out.
I'll just add that CD40 ligand and IL-12 prove a very important point. By themselves they do not help the immune system, but on the exterior of a 'skilled' dendritic cell, they are safe and efficacious. This dendritic cell 'knowhow' demonstrates why NWBO might have a leg up on other companies that are instead trying to isolate biomarkers, specific proteins and genes.
So you also want a dendritic cell that expresses:
IL-12
and produces:
CD40 Ligand.
So what are these substances?
Wikipedia to the rescue.
"IL-12" http://en.wikipedia.org/wiki/Interleukin_12
"CD40 Ligand" (also called CD154) http://en.wikipedia.org/wiki/CD154
January 2, 2014.
I also found that passage very interesting.
"It has now become apparent that DC maturation can result in either immunostimulatory or immunosuppressive DCs…"
The rest of that passage wasn't too shabby either.
"but it is generally accepted that immunostimulatory DCs produce IL-12 and express CD40 ligand (Albert et al., Nature Immunol. 2:988-989, 2001; Lanzavecchia, Haematologica 84 Suppl. EHA 4:23-25, 1999). Therefore, partially matured DC should be used for IT injection, especially if the stimuli used for maturation of immature dendritic cells are known to result in expression of CD40 ligand and in the production of IL-12."
So, they are not just maturing a large volume of dendritic cells to the right age, they are stimulating those dendritic cells to simultaneously become the right kind.
Inject the wrong type of dendritic cells, and you shut down the immune system. Inject the wrong age dendritic cells, and they can't do everything they need to do -- uptake antigens, mobilize to the lymph nodes and express biomarkers to B-cells, killer T-cells and helper T-cells.
One more note about the DCVAX-Direct patent.
It is important to keep in mind that while Direct technology matures and selects specific dendritic cells outside the body for eventual intratumoral injection back into the body at a later date, the dendritic cells continue to mature once placed back into the body.
So maturation is continuous. First inside the body, then outside, then back inside again.
A homely analogy?
I think NWBO's analogy that their technology places the equivalent of a "teenage" dendritic cell back into the body is quite symbolic.
(In the more humorous sense, a child is raised in the home, leaves for college (or elsewhere) than invariably returns home to live in the basement.)
In the more poetic context, a child is raised in the community -- mostly by his/her family, but others as well. Upon coming of age, they sever their apron strings and enter the big-wide-world. Upon return, they share their experiences, gifts and teachings with the community. We also see this with a honey bee when it dances flower coordinates to the waiting and welcoming hive. Not being particularly religious, I am still reminded of Jesus and/or the Jews tempted or lost in the desert.
Separation from loved ones is painful, and yet it sometimes proves necessary for complete self-development and community survival. The dendritic cell may be the ultimate biological prodigal son. In fact, the dendritic cell is often cryo-preserved before replacement back into the body. Upon return the father throws a party for his wayward son's jubilant return. His sibling asks his father, why do you celebrate my brother's return when I have been responsible and present all along? The answer a dendritic father may give his first-born may go like this: "For this, my dendritic son, who was cryo-preserved, is living again; he had gone away from me, and has come back. And they were full of joy."
United States Patent Application 0120251561 (Filed June 4, 2012):
This really tells the story. It explains:
1. Why companies did not pursue whole dendritic cell vaccines with the zealousness that NWBO did.
2. Proprietary motivations as to why companies [IMUC for example] thought they needed to go after specific antigens.
3. DCVAX-direct (In-vivo intratumoral loading) has attributes that reduce cost/complexity compared to ex-vivo tumor lysate loaded dendritic cells.
4. Why it took so long to develop this technology.
5. Why and How NWBO improved upon/modified Triozzi's pilot study/platform and developed a far more potent "invention" in DCVAX-Direct. (For instance but not limited to: improving upon maturation stage resulting in better antigen uptake AND expression, escape from down-regulation as well as improved dendritic mobilization to the lymph nodes)
I've included a relevant excerpt.
Note: I must have read and unconsciously absorbed some of this back when it was published, because I've been dancing around these thoughts for sometime. Now it makes far more sense to me. I hope rereading it helps all of you as well, as I'm certain it was posted on ihub previously.
"0002] Dendritic cells (DCs) are recognized as the vehicle of choice for active immunotherapy of cancer. Animal experiments have demonstrated the potential of DC based immunotherapy in both protecting mice from tumor formation and eliminating established tumors. These successes have been at least partially duplicated in humans in small clinical trials. The transition from small safety- or proof-of-concept trials to larger trials in which activity or efficacy can be demonstrated has been hindered by the laborious and cumbersome nature of DC preparation (see below). As a consequence, few companies have been interested in developing DC-based cancer vaccines despite the large potential therapeutic of such products.
[0003] Intratumoral (IT) injection of DCs is a special form of DC-based immunotherapy. Upon injection, the DCs take up antigen from apoptotic or dying tumor cells, and present the antigen to T cells after migration to the lymph nodes. Indeed it was found that the efficacy of such treatments in animal models correlates with the degree of apoptosis in the tumor (Candido et al., Cancer Res. 61:228-236, 2001), which suggests that this approach is fully compatible with treating tumors with chemotherapeutic agents or radiation prior to the injection of DCs. In addition, several groups have demonstrated that such combination therapy is particularly effective against established tumors (Nikitina et al., Int. J. Cancer 94:825-833, 2001; Tanaka et al., Int. J. Cancer 101:265-269, 2002; Tong et al., Cancer Res. 61:7530-7535, 2001).
[0004] Since the tumor cells are the source of antigen, Intratumoral (IT) injection foregoes the need for both the selection and manufacturing of tumor antigens as they are currently used in most in vitro DC based therapy approaches. Selection of a tumor antigen is often driven by the need for companies to have a proprietary position and the few tumor antigens identified to date have yet to be proven to provide significant clinical benefit. In addition, the use of such tumor antigens often results in a monovalent vaccine, which can lose its effectiveness if the tumor cells down regulate the expression of the antigen used in immunization. Of course, the need to manufacture the tumor antigen under conditions required under Good Manufacturing Practices (GMP) adds additional cost to classical DC-based immunization methods.
[0005] IT injection of DCs subjects the dendritic cells to an immunosuppressive tumor environment. Tumors are known to produce cytokines that inactivate the DCs or that have the ability to skew T cell response toward a less effective Th2-type response. Several groups have used genetic modification of DCs to attempt to overcome these suppressive effects, especially through the production of the cytokine Interleukin 12 (IL-12; Nishioka et al., Cancer Res. 59:4035-4041, 1999; Melero et al.; Gene Therapy 6:1779-1784, 1999) or expression of CD40 ligand (Kikuchi et al., Blood 96:91-99, 2000). The encouraging results described by these groups further demonstrate the viability of IT injection of DCs as a therapeutic approach.
[0006] Triozzi et al. (Cancer 89:2647-2654, 2000) described IT injection of DCs in patients with metastatic melanoma or breast cancer. They obtained tumor regression in 4 patients with melanoma and in two patients with breast carcinoma. Biopsies of the regressing lesions demonstrated infiltrating T cells, suggesting that the DC had indeed activated an immune response against the tumor cells. Overall these data demonstrated that IT injection of DCs was feasible in humans, and could provide significant clinical benefit. However, significant down regulation of MHC class II antigens and of the B7-2 costimulatory molecule on injected DCs has been observed. Down regulation of these critical molecules would be expected to reduce the immunostimulatory potential of the DCs, but as provided in the present invention this can be avoided through partial maturation of the DCs prior to administration.
[0007] DCs exist in peripheral tissues in an immature form, ready to take up and process antigen. It is this immature cell that is most closely mimicked by the DCs generated from monocytes in the presence of GM-CSF and IL-4. Various stimuli can initiate the maturation of DCs, during which process the cells lose their capacity to take up antigen efficiently, and gain their T cell stimulatory functions. This process is complex and at least in vitro can take up to 48 hours to complete. One other consequence of maturation is a change in the migratory properties of the cells. For example, maturation induces several chemokine receptors, including CCR7, which direct the cells to the T cell regions of draining lymph nodes, where the mature DCs activate T cells against the antigens that are presented on the DC surface in the context of class I and class II MHC molecules.
[0008] The induction of tolerance has been linked to the cross-presentation of (self) antigens by DCs (Kurts et al., J. Exp. Med. 186:239-245, 1997), and the current prevailing hypothesis posits that immature DC continually present antigens to the immune system to maintain tolerance (Kurts et al., J. Exp. Med. 184:923-930, 1996), suggesting that maturation of DCs in vivo is required for efficient immunostimulation. It has now become apparent that DC maturation can result in either immunostimulatory or immunosuppressive DCs (Chakraborty et al., Clin. Immunol. 94:88-98, 1999). The precise nature of the maturation stimuli that produce either outcome has not been elucidated, but it is generally accepted that immunostimulatory DCs produce IL-12 and express CD40 ligand (Albert et al., Nature Immunol. 2:988-989, 2001; Lanzavecchia, Haematologica 84 Suppl. EHA 4:23-25, 1999). Therefore, partially matured DC should be used for IT injection, especially if the stimuli used for maturation of immature dendritic cells are known to result in expression of CD40 ligand and in the production of IL-12."
Gpb, great post.
You make some very good points. I do think great success in phase 1 may force some serious decisions regarding how best to move forward (or not) on multiple additional cancers. The funds will be there (with stellar results). Enrollment speed will be a nonissue (on inoperable tumors). If tumor regression were then picked as a primary (not secondary) endpoint….
I think they left themselves several avenues with which to move forward depending on the quality of response and rate of response. Certainly 60 patients will not get them across the finish line, but reasonable modifications could make phase 2 the pivotal trial.
It will be interesting.
I also agree NWBO is not out of the woods yet. It it biotech after all, and there is no telling until we are told.
I'll read your post again tomorrow when I have more time. I'll probably have a few more thoughts/questions.
Thanks again.
P.S. I'll go back and look at those preclinical studies again….they are very technical. I agree colorectal was otherwise a logical choice based upon your reasoning.
Lots of information in the last few posts. Thanks Dok, gbp, ou, long and others.
I think the insight, that many other catalysts might be held back until Direct or L results at least confirm continuation of the trials, is quite possible. This is because many of those catalysts must be primarily carried forward by outsiders.
The analysis/hypothesis identifying likely cancers treated by direct in phase 1 is also quite reasonable.
Here's an additional thought.
We already know passage of DCVAX-Direct for phase 1 is a given re: safety and determining dosage. As long as there is some sign of efficacy, it will expand immediately therefrom to colorectal in a phase 2 trial.
However, NWBO previously established a precedence in the L trial. That is, the ability to beef up a phase 2 trial mid-stream, and in fact convert it into a phase 3 trial.
I'm just spitballing here, but I think NWBO anticipating the best results in colorectal cancer treatment (probably from their preclinical complete immune responses and other signals in maurine models) and thereby are protecting themselves from public disappointment if the treatment for multiple cancers narrows down to only one type in phase 2.
However….they also left themselves room to convert their phase 2 trial into a phase 3 trial for all solid tumor cancers -- depending upon the response quality and rate.
NWBO clearly planned way ahead to manage FDA and public expectations These expectations must be managed in order to get the best product with the broadest application to market first without losing funding when the burn rate is at its highest.
Remember, the FDA is legislated to demonstrate some flexibility when dealing with orphan drug prospects. It was a brilliant ethical plan by NWBO to move Direct forward for inoperable tumors.
The FDA is not stupid, they know that direct, if wildly successful on inoperable tumors will be applied to operable tumors as well. In fact, technically it already is. "Inoperable" has a broader definition than one might otherwise think.
I do not believe the FDA would hesitate to convert the Phase 2 trial mid-stream if the phase 1 results are very impressive. I also do not believe adding operable tumors to a phase 3 trial would result in a loss of orphan status, as 2 arms could be delineated and/or addressed with some other reasonable arrangement.
I guess what I am saying is that it appears NWBO took great care to leave themselves room for almost any contingency. Furthermore, due to the safety profile and orphan status for Direct, I believe the FDA can accommodate NWBO.
Larry Smith is really good, yet one must not miss the finer points he makes (I usually reread what he writes at least once). The devil is in the details. He'll also be the first to admit when he is wrong. I don't subscribe to Smith on Stocks, but I'm considering it.
It was written by an amateur who does not understand the science. His analysis has been so incredibly inaccurate in the past. He does not understand the difference between injecting a cell versus a nonliving synthetic drug. Sorry, I don't mean to be harsh, but the last time he wrote an article, it took all day for me to get his attention that he gave completely reversed data (even though he quickly responded all day to his budding admirers), and even though it was an easy fix….he said "I'll look into it." His comparisons are shallow, unscientific and misleading. If he's going to publish, he needs an editor, he needs to check with various sources, and he needs to think.