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Etienne and Ou,
While our 3 predictions are very far apart, I believe they are all reasonable alternatives. Ou's conservative prognostication is the soundest based upon historical norms for biotech trial progress. Even if he proves prescient once again, I believe patients, caregivers and the world have reason to hope this time. With every breakthrough in cancer, it seems the past is also strewn with disappointments that make the most optimistic among us turn dubious.
Futurist Ray Kurzweil's observations regarding how the human psyche relates to technological advancement expectations is worth considering. In the short run (1-5 years), people expect matters like cancer treatment, robotics, computer development and the like to achieve much more than typically occurs. However, in the long run (ten years or more into the future), technology tends to advance in unexpected ways that go well beyond what we considered possible in one generation.
DCVAX-L and DCVAX-Direct provide a decent point and case. From 2003 until 2013, DCVAX-L was turning out data points that pointed towards a sea-change in medical care. It seemed slow and laborious to the point that human cognition started discounting the beautiful dream it once elicited. Moreover, for most of that decade, DCVAX-Direct disappeared entirely from mankind's expectations. However, by 2014/2015, there is a real chance we will see an effective broad-spectrum cancer vaccine based upon DCVAX technology!
I'll bite.
The more I read, the more I am convinced we will see results as expected from the DCVAX-L trial. Because of this, and the fact it is easier to show statistical significance early with PFS as the primary endpoint, I'll stick to the notion the trial will be unblinded at the first or second interim review. I think PFS will be 24 months or more (I do not expect the typical phase 3 falloff -- based upon reasons I gave in earlier posts.) Because of the limited shares outstanding, I expect the company will need to split their stock immediately after the results/unblinding is announced.
I expect a sporadic but relentless price increase as early DCVAX-Direct patient results are released, and I expect another split when the Direct phase 1 and 2 results are shared later this year. After digging down into the history and research, I expect to see an 80% to 100% response rate, depending on the type of cancer. I also fully anticipate seeing indications of complete, systemic and lasting immune responses (again, depending on the type of cancer). I see the phase 1 and 2 Direct results persuading the FDA to approve a large but expedited phase 3 double-blinded trial. I think that trial will be unblinded at the 1st interim analysis in early 2015.
(Prior to the two events above, I anticipate DCVAX-Prostate will be partnered with a large pharmaceutical company. That will likely take the stock above $8.00.)
If the above events all occur in 2014, and they never split their shares, I think the value could range between 200 - 400 per share. After that, I believe the share price would continue to rise and split throughout 2015.
Its still biotech, so don't bet the farm. Stay well within your risk tolerance and means.
Happy New Year!
May the New Year bring a Cure!
….or very close to it.
Answer #1: The present DCVAX-Direct platform was not used in the Triozzi study from early 2002. It was not in existence yet. The present DCVAX-Direct platform is the more potent, perfectly staged dendritic technology born out of the Maurine studies and one small human study.
Answer #2: I believe the present DCVAX-Direct is the culmination of many years work to study and enhance the dendritic technology used in the original Triozzi vaccine. NWBO took up Triozzi's challenge, and here is the end product.
I posted this a couple days ago. It is the Triozzi study. In my view it sent NWBO and probably a few other companies into dark caves for a number of years to take up the challenge he incorporated in his conclusion. Personally, I find it almost incomprehensible Triozzi would refrain from moving forward immediately with such a powerful therapy in favor of making it more potent. To me it would make sense to move forward with the therapy he used, and concurrently work on more potent dendritic cells. Instead, he basically said…"I just had the most astounding results on GBM ever, but let's wait and think about it. Let's step back to understand it. Let's go into sequestration to develop it further."
I do not know Triozzi, so I do not want to cast either dispersions or accolades. I can only think of a few reasons he held off -- beyond what he mentioned. 1. Develop a process that will provide patent protection. (This sounds cynical, but maybe this is not as insensitive as it sounds.) 2. Make certain that such an amazing technology does not get washed away from mankind as a result of poor initial results on a slightly inferior inversion. In other words, even though he had great results on a small scale, he knows the rigors of three trial phases, and he did not want the first in-vivo loaded dendritic therapy to fail because it might deter or stop any further efforts.
http://onlinelibrary.wiley.com/doi/10.1002/1097-0142(20001215)89:12%3C2646::AID-CNCR18%3E3.0.CO%3B2-A/full
Dok, that is a fascinating observation. It also makes one wonder about the long-term safety profile for specifically anti-pd-l1 drugs.
Based upon preclinical maurine studies and at least one small human trial for DCVAX-Direct, I do not believe PD-L1 presents a significant hurdle for a far more potently staged dendritic cell injected directly into the tumor on the heels of chemo/radiation.
I do not know how DCVAX-L will fare against PD-L1 subgroups, but I suspect DCVAX-L will comfortably meet its primary endpoint and be approved as S.O.C in addition to ( but not subordinate to) chemo and radiation.
John1045, Thanks for the reminder.
This explains why NWBO designed their phase 3 trial the way they did. Only a 1/100,000 chance of the prior PFS results being random. What is also impressive is that there were 3 phase 1 trials upon which to gather this data. Moreover, since that time, NWBO designed their current phase 3 trial to exclude patients (placed in compassionate arm instead) that had progression after chemo/radiation.
Moreover, even though there was only a 4/10,000 chance the OS statistics were random, the crossover arm basically removes control group OS as an endpoint -- this wisely places all trial emphasis on PFS (only a 1/100,000 chance of previous results being random) where it should be (for scientific, ethical and reasonable development timeline concerns). The European regulatory authorities were historically slightly ahead of the U.S. in accepting PFS as a primary endpoint for cancer trials, but the FDA is now behind this metric as well. Finally, in the phase 3 trial, all patients with prior recurrent GBM were also excluded (placed in another study or compassionate program instead).
I still believe that while the data looks great, an investor must strive to understand the science behind it. This then might allow one to understand why somewhat similar companies with decent phase 1 results performed somewhat disappointedly on their later stage trials. While I understand the need to leave the science to the scientists, I stand by the premise that investing means delving into unchartered waters to find the pearls. For instance, if one strove to understand the scientific difference between ICT-107 and the DCVAX science, trial design and development strategy, one may have been drawn initially to one company more than another. IMUC may be a worthy investment in the long run, but based upon their science and previous data, they set themselves up for a setback. NWBO is still a risky investment, but from all outside appearances, they designed their current trial appropriately based upon scientific understanding (albeit incomplete) and prior data.
Biomarkers like PD-L1 can exist in healthy individuals for various reasons. For instance, to protect a fetus from mistakingly being identified as a pathogen.
I wish I could give you a scientific answer to what I perceive to be the question. There are several theories why Direct appears to be better than L. Your inquiry about potential mutation after resection being one of them.
1. The perfectly staged dendritic cells, loaded by direct injection into the tumor are more potent because they uptake and present biomarkers/antigens better than preloaded/ex vivo dendritic cells.
2. The perfectly staged dendritic cell injection into a tumor better/naturally orients (perhaps through chemical signals) the dendritic cell after uptake so that it can move more efficiently to the lymphs.
3. Dead Tumor versus Live Tumor. While I believe the dead tumor would still be displaying pd-L1, I think the live tumor would be displaying it within a tumor cell pre-emersion, emersion and post-emersion. This might in fact allow the dendritic cell to uptake and then display the biomarker/antigen to B-cells (which make antibodies) much more specifically.
Likewise, think of all the things that might happen to a dendritic cell during maturation after injection into a tumor cell versus maturing that same dendritic cell outside the body. There are all kinds of potential actuators, like hormones, that may be involved in orienting the dendritic cell, increasing dendritic mobility to the lymphs, improving uptake and/or presentation to T and B cells. I think of it like trying to grow a baby in a womb versus a test tube.
The same goes for uptaking tumor biomarkers/antigens. That live tumor (or its interactive environment) may do something we have not even thought about yet. For instance, it may temporarily display some blocking proteins then quickly withdraw them….I made that example up, but you get the picture.
gpb, Good points.
At some point in 2005-2006 they had to go with what they knew then. So while that may have been changed if they started today, I'm thinking their protocol looks adequate -- but I see what you mean.
Doh!
'cut out for them' -- that is. (auto spell check hazards)
gpb, logical reasoning in your theory why DCVAX-l efficacy benefits more from major resection than chemo.
In your collateral inquiry regarding dosing and timing, In one of Linda Liau's reviews, she noted that booster shot timing and dosage is sometimes counterintuitive; in that, sometimes too much booster too early can cause inefficacy….she sated it had something to do with programmed cell death interference (over my head at the time). In some cases, after initial DCVAX-l therapy, it appeared that booster shots with tumor lysate alone worked quite well.
Doktor, here's a potentially helpful animation.
It might be more likely that DCVAX-Direct will have more capacity to create Anti-PD1 antibodies. I watched a Roche video on this technology a while back….I'm a sucker for animation. Scroll down to the video section.
http://www.biooncology.com/pipeline-molecules/anti-pdl1
My conjecture back then was that since the PD-L1 biomarkers do not 'pop' up on tumors until activated by anti-tumor activity, it might be that Direct takes advantage of PD-L1 pre, concurrent and post activation structure (if at all different). Whereas DCVAX-L "nibbles" at dead tumors to uptake its biomarkers, DCVax-direct "nibbles" at live tumors.
Ou, Great points. It seems that while the DMC are not in completely unchartered waters, they have their workout out for them.
Doktor, Thanks, I think Ou improved the analysis further.
Googled: Crossover Arm Overall Survival
There are many recent articles and examples on crossover arm dynamics. In my reading thus far, it appears scientists include crossover arms for humanitarian reasons. Because of this, they accept Overall Survival can become much more complicated (if not impossible) to analyze for efficacy in some cases.
One reason patients do not enter a crossover arm is because the standard of care led to safety issues.
Example: Gemcitabine plus TH-cr-404 = treatment arm, Gemcitabine alone = control, but 16% could not crossover upon tumor progression because they had serious side effects from gemcitabine alone.
(Note: Of course, the Threshold Pharmaceutical example is not apples to apples with DCVAX-L, but it serves as an illustration).
http://www.thresholdpharm.com/pdf/supplemental_info_survival_pancreas_cancer_09-12.pdf
Inability to crossover should not be a problem (for patients) in the NWBO study (because the crossover arm does not require additional SOC after progression, and because DCVAX-l is essentially nontoxic), therefore it seems very likely almost all patients from the control arm who are alive at tumor progression will crossover.
The prior studies that have done this typically compare three different survival curves -- crossover arm, control arm and treatment arm. Because DCVAX-L is so safe, I don't think we will have a third OS control curve of any significance since maybe only 0-5% will not crossover.
Consequently, with OS, there will be crossover v. treatment arm. If we accept that PFS in the original control arm is likely to be somewhere around 9 months (this is higher than the 6.9 months or 8.1 months in prior trials because I am allowing for SOC improvement), then we can also assume the OS would have been (without crossover) as high as 17 months. This means at PFS = 9 months (control arm), there should be many alive in the crossover arm that might benefit from DCVAX-L. The issue that arises for patients and the review board is that it is likely the crossover arm will not do as well, because DCVAX-L does not work as well once tumor progression resumes active measurable progression. If this is born out in the curves, and it is statistically significant, the pressure to unblind the trial will be even stronger.
Going back to the Threshold Pharmaceutical example (which has three curves), the crossover arm still seemed to benefit from delayed treatment even though administration of TH-CR-404 was administered after progression resumed. (Again, this is an apples and oranges comparison, and it is not meant to compare the drugs...only to illustrate the crossover arm dilemma.)
Conclusion: Because the primary endpoint for DCVAX-L is PFS, OS will likely only be judged based upon two curves -- crossover arm v. treatment arm. Based upon past experience with DCVAX-L and what we can glean across 21 prior Dendritic therapy studies (some more alike than others), the curve is likely to demonstrate that delayed treatment is statistically more deadly. Consequently, this (delay) statistical significance may pressure the review board toward unblinding the trial earlier and moving everyone to the treatment arm.
Regardless, in my view, overall survival can not and will not be used to reflect negatively upon DCVAX-L efficacy. Why? Because OS will not include a meaningful control arm. Thus, the only meaningful OS comparison is S.O.C. treatment followed by immediate DCVAX treatment v. S.O.C. with delayed DCVAX treatment. Even if delay did not effect OS efficacy, it would not reflect negatively upon DCVAX-L treatment.
Thus, the only statistically significant endpoint that can reflect both.... either positively or negatively upon DCVAX-L is PFS. Because PFS is a much quicker and complete endpoint (compare against ICT-107 OS primary endpoint), the review board will have an easier time determining whether statistical significance is met. The review board will not be forced to extrapolate survival curves to determine efficacy. The only effect OS can really have on the review board is in the case if treatment delay with DCVAX-L proves deadly. If that is the case, it would likely place additional burden upon the review board to unblind the trial.
Ou, I feel like I am speaking to a mentor, but I must admit the crossover arm (secondary endpoint OS) issue, plus the one person --1 versus 2 events -- are confounding questions to an amateur like me, and I'm sure they could otherwise be answered by a pro/trial statistician in seconds. Maybe I need to make another call. I've been in touch with the FDA on a couple unrelated questions, and their answers typically lead to more questions. Still I have confidence in some conclusions I've drawn thus far. Be well everyone.
Did you calculate it based upon 1 person presenting the potential of 2 events?
At a rate of 19.5 total enrollment per quarter. If the 33 were trial arm, statistical analysis would demand increasing rate of control enrollment in 2011 until 3/1 ratio is back in balance.
That's more than 7 control arm enrollees per quarter. Take just 7 of those quarters = 2nd quarter 2011 to last quarter 2012. 7 x 7 = 49. 49 x .9 = 44.1 tumor progressions by end of this quarter if 90% reach Tumor progression within control arm in 12 months (It was 8.1 months back in phase 1. (Very conservative.)
Then , unfortunately, you must include event deaths, even if they include someone who already rated with a tumor progression event. The crossover arm mercifully almost certainly reduces death events. So say 10 from the control arm since the study began. Total events from control arm until now -- approximately 54. That leaves 12 events to take up the balance from the much larger trial arm.
Next updates expected between now and the end of January:
* Opening German Clinics for L.
*Opening European Clinics for Direct.
* Initial data regarding Direct's efficacy on first 2 or 3 patients.
* Recommendations from Review board on DCVax-L.
A few things we know/believe from various sources.
1. Germany is still gearing up for opening its clinics/manufacturing/quality control/compassionate use for DCVAX-L -- should happen any day.
2. The Brits are up and running their DCVAX-L phase III trial, manufacturing and parallel compassionate use program.
3. Sarah Cannon -- and perhaps MD Anderson's European sites -- are preparing to begin DCVAX-Direct trials.
4. The equivalent of a less potent version of DCVAX-Direct was used successfully on 10 Humans -- (not just mice)--patients in the Triozzi study way back in 2000, and an amazing 6 out of ten very sick patients had tumor reduction and signs of immunity. In that study, Triozzi amazingly held off on using that product at that time in favor of scientists developing a more "potent" version through development (think about that for a moment). 11-13 years later, NWBO announced through patents, press releases and presentations that it has that more potent version.
5. DCVax-L reached its first interim event juncture when NWBO thought it would. Because NWBO is using a better trial design in phase 3 that allows them to exclude post radiation patients with concurrent tumor progression, we might, might, might submit that the first event juncture and timely prediction thereof was predicated almost exclusively on control arm events. Whereby the trial arm might benefit far more than the control arm ( as anticipated based upon our understanding of past preclinical, clinical and third party experience/results) from the synergistic advances of improved near total tumor resection, chemotherapy/radiation and undetectable tumor progression in the selected patient population at the moment DCVAX-L/placebo treatment is initiated.
etienne 555, un deux trois quatre quatre cinq
C'est vrai!
Ou717,
I agree with your observations.
Moreover, in its phase 2 study, IMUC did not exclude post chemo/radiation patients with tumor progression at the time ICT-107 therapy was initiated. This is extremely significant.
Doktornolittle,
From 2000 to 2005, consider that, even after initial s.o.c. chemo and radiation therapy, Dr. Liau's trials (and many other dendritic trials under the same time frame) included a significant population of patients with verifiable tumor progression present at the time they started DCVAX therapy.
Now, in the phase 3 trial, those with tumor progression (or even pseudo-progression) present after chemo and radiation, but before DCVAX therapy is initiated, are not included in the primary study.
There is considerable consternation by certain authors, analysts, posters and others who state that NWBO "cherry picked" in their first 3 phase 1 trials.
Quite the opposite.
In fact, it was not until phase three that NWBO was able to exclude patients exhibiting progressive disease after s.o.c. but before DCVAX therapy was initiated. (those patients with concurrent progression were either moved to compassionate care or a separate study).
So, unlike most trials, NWBO was able to ethically and appropriately 'cherry pick' their patients for the phase 3, 312 patient study.
DCVAX-L works significantly better on patients with stable disease at the time therapy is initiated. This includes Response Rate, OS and PFS v. s.o.c..
While I could address most if not all of your other concerns, I just gave you a golden ticket.
Doctor Know (relation to Doctor Who?)
You must remember, this lead investigator may sound unphased, but she is speaking with the heart of a mother and the faith of a loving daughter. If she exaggerates her findings, she would not be in her current position at UCLA. She also would be doing a disservice to her brave patients (living and passed).
The key is that L.L. is meticulous about getting to the heart of advances and missteps. She knows the lessons thus far. She has incorporated every nuance into the GBM phase three trial. The worst statistic thus far regarding anything close to her procedure is 90% OS at 1 year, 50+ at 2 years and 47% at 3 years. These are not the percentages we hope for from direct, but if these showed up from the phase 3 DCVAX-L, mankind will take a giant leap.
She stands on the shoulders of giants.... but countless others -- angels and loved ones -- will dance on the head of her scalpel and pen. The Direct trial, while conducted by V.S., will owe pure gratitude to Liau's dedication and ingenuity. I have nothing but admiration for her colleagues and friendly competitors in this field.
As of 2013, 403 patients were included in peer review studies for Dendritic cell therapy on GBM alone! http://www.ncbi.nlm.nih.gov/pubmed/23790634 It is sound science. DCVAX-L has saved birthdays, weddings, births and childhoods. DCVAX-L is not a silver bullet, it is a soldier in a tough ground game. However, it is a prelude to victory for all mankind.
Follower,
Here is a very nice review of dendritic cell therapy over the past decade 2002-2010, and it includes some theory/clues by Liau regarding ways to improve matters. One thing that I keep reminding myself lately is that there were actually 3 phase 1 trials.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810429/
Watching another video of Liau, she stated the results were fairly consistent throughout those trials. 90% overall survival after one year, 75% after 2 years and 50% after 3 years.
Anyway, she used DCVax recently in three pediatric patients, and it extended the lives for 2 of them.
See a list of her extensive studies.
http://people.healthsciences.ucla.edu/institution/personnel?personnel_id=8887
With dcvax-l, radiation plus chemo enhance efficacy.
As does total removal of tumors...
This was not originally thought to be the case. Linda Liau has a nice 2010 review of the things they have learned thus far. I'm on my I phone and have thick fingers and relatives all around. So you'll have to find it. Also, radiation has been found to enhance direct intratumoral injections treatment of carcinomas. Merry Xmas all.
What a dignified man. I showed the BBC interview to my extended family, and they agreed he exemplified what we all aspire to if potentially faced with an early exit from this hallowed ground. There is something preordained about all this. May God (or the Universe) bless you and yours. Happy Holidays. Live long and prosper.
This is the only thing I can find from NWBO regarding the ongoing results for DCVAX-L in Israel.
Approximately July 17, 2013.
Regarding Compassionate Use Program.
"Although we do not have reportable data on the success of administering DCVax-L for patients with recurrent GBM, we have some anecdotal evidence of good results." -- NWBO Patient Liason
http://www.cancercompass.com/message-board/message/all,72718,0.htm
If it were reportable data, it would undermine the FDA and EMA trials. So I think this is the furthest NWBO can go in sharing compassionate use success. However, an investigative journalist might be able to get further with the medical staff in Israel, or former patients, if they were so inclined.
When speaking to the former patients in the compassionate use program, they might be willing to share what the medical staff thought about DCVAX.
john1045,
Affirmative. Of course, a bit more data will come in soon for NWBO. This will change the market cap. DCVAX did not navigate the predictable route that most products take to market. At least since Linda arrived on the scene, they have taken the road less traveled. Infrastructure and manufacturing capacity built well in advance of trial results. Compassionate use programs expanded around the world. Collaborations with prestigious international institutes and governments. FDA approved first in human phase 1/2 trial on All Solid Tumors for DCVAX-Direct. DCVAX-L 2008 follow of 33 patients on phase 2, converted to phase 3 in 2012 with the FDA's blessing. An associated business with an eleven year old canine program for a DCVAX-like program that successfully treats all solid tumors in dogs (probably in every other animal). Linda seems bound and determined to stop big pharma from a hostile takeover (many times CEO's are more interested in a quick buyout).
These are shrewd moves to bring a disruptive technology to market.
Linda managed to keep NWBO shares outstanding low through small frequent dilutions that were not excessive. The market cap is a reflection of a company with a disruptive technology that tried to fly below the radar for a decade while they improved their product and infrastructure. It is little surprise to me that the market place has not been able to establish a value for this company -- simply due to the fact that it breaks the mold.
From what I understand, there are several players in the immune system. The dendritic cells activate the helper T cells, Killer T-Cells and B-Cells. The B-Cells give rise to antibodies that also attack the cancer. Macrophages are a lot like dendritic cells, but they do not present antigens as well to the above players. There are many more aspects and players in the immune response.
One way, but not the only way cancer tricks Killer T-Cells is to shut of their ability to inject their tumor killer toxin into the cancer by blocking the PD-1 antigen on the T-cell with their PD-L1.
Biologiques that block the tumor from doing this make the Killer T-cells more effective at killing tumors, but it is not enough. The cancer uses other techniques.
The key to DCVax is that:
1. Dendritic cells are exponentially grown outside the body.
2. They are grown to their most potent stage.
(If they are too young, they can't effectively express antigens to the Killer T-cells, helper T-cells and B-cells. If the dendritic cells are too old, they can't effectively uptake the antigens and thus are also ineffective. I may have that reversed)
3. In the case of L, the tumor is presented to them outside the body and then re-injected. (despite best practice, it is difficult to get a tumor to present all antigens once it is effectively dead)
4. In the case of direct, the perfect stage dendritic cells are presented to the live tumor by "direct" injection, and thus all antigens are presented to the dendritic cells -- once the tumor recedes the injections are placed into the blood stream (like a flu shot).
5. The perfectly staged dendritic cells create the most potent killer t cells and helper t-cells, and they go after every antigen expressed by the tumor. The DC's do this through up regulation and presenting the other immune system cells with the full set of antigens on the tumor to attack.
6. The perfectly staged dendritic cells also activate the B-cells to create the broadest set of antibodies. It is possible that they are so complete in the DIRECT form, that they also provide anti-PD1L antibodies thus eliminating the need for a cocktail. Right now that latter theory is simply conjecture, but if proven accurate, every other cancer therapy company will have difficulty surviving.
7. The additional exponentially produced dendritic cells also provide an overwhelming immune response that the body could not replicate on its own. Kinda like the Powell Doctrine.
Osprey,
I am not a trader, I am an investor, so if you want to jump in and out, and in and out, be my guest -- the law allows you to do that. That's what traders do.
Part 3 of 3: February 2013 response to Feuerstein by Larry Smith.
:While I favor the chances for success of DCVax-L over ICT-107 based on everything I know, investors should not think that I am slamming ICT-107. The most important thing to remember is that both ICT-107 and DCVax-L have shown unusual, powerful median overall survival and median progression free survival benefits in glioblastoma, an extremely aggressive cancer in which the average patient dies in about 14 months. There is a large unmet medical need for new and better treatments for brain cancer, and as I have previously written, both drugs have the potential to be successful in their clinical trials and subsequent commercialization. If their clinical trials are successful, both drugs have blockbuster potential. It is not a zero sums game between the two products."
Part 2 of 3 Larry Smith reply from February 2013.
"Because ICT-107 only works in a certain immune type (HLA A1 and A2 positive) it is not applicable to the entire glioblastoma population. In the phase I/II trial of ICT-107, the company screened 278 patients, but only 124 patients were randomized and enrolled in the trial. Over 50% of patients screened were excluded, primarily because of the immune typing issue. Some investors have not understood that this is a 124 patient trial, not 278 patients.
5. NWBO's phase III trial has a better chance of reaching statistical significance because it is so much larger. The size of IMUC's trial (number of patients) is relatively small in relation to the anticipated difference in treatment outcome (6 months of additional survival), and may be underpowered.
6. NWBO's trial has been approved as a Phase III trial by two different regulators: the US FDA and UK MHRA. IMUC's trial has only been approved as a phase II trial by one regulator (the FDA).
7. NWBO has extensive collaborations with large marquee partners in both the US and Europe, which provides significant third party validation. There is no such validation for IMUC's technology.
8. NWBO has completed phase I/II trials in two other cancers besides brain cancer (prostate and ovarian) cancers, and both of these trials had encouraging or striking results. IMUC has not conducted any other clinical trials with any other product besides the one 16-patient Phase I trial in brain cancer with ICT 107.
9. NWBO has received more regulatory approvals for more and larger trials than IMUC. NWBO received an extraordinary scope of approval from FDA for its first-in-man, combined phase I and II trial of its DCVax-Direct product for direct injection of dendritic cell precursors into any type of solid tumor that is inoperable. This trial starts with 36 patients, and includes dose escalation and confirmation, and efficacy endpoints, not just safety. NWBO also received FDA approval some time ago for a 612-patient randomized, controlled phase III trial in prostate cancer.
IMUC has received only small phase I trial approvals beyond its current phase II trial with ICT 107. IMUC received FDA approval of a small phase I trial in recurrent GBM brain cancer (the same type of brain cancer as is already addressed in its current trial), and a 20-patient phase I trial in ovarian cancer.
10. NWBO's product lines have broader applicability to diverse cancers than IMUC's products. NWBO's DCVax-L is applicable to all solid tumor cancers that can be surgically resected. NWBO's DCVax-Direct is applicable to all solid tumor cancers that are inoperable - and FDA has approved it that broadly for trials. IMUC's products hopefully will eventually be shown to apply to several cancers, but as of now, IMUC's ICT-107 is only applicable to brain cancer and ICT-140 is only applicable to ovarian cancer. IMUC's ICT-121 targeting a single biomarker believed to be on cancer stem cells may eventually be applicable to many cancers but that is unclear as of now.
11. NWBO is positioned to be able to apply for product approval in both the US and Europe, while IMUC is only positioned in the US. NWBO is not only conducting its phase III trial in Europe, it has also established a manufacturing capability in Germany and the UK, a process that took more than two years, while IMUC is manufacturing only in the US.
In view of the above factors, I find it difficult to understand why Mr. Feuerstein is open-minded about IMUC as a company and close-minded about NWBO. I would also expect that Mr. Feuerstein would be more positive on DCVax-L than ICT-107, but for unexplained reasons he is more positive on ICT-107. I draw the opposite conclusion and find DCVax-L to be the product more likely to be successful in the current clinical trials." Continued in part 3
Ospreyeye, Response Post 1 of 3.
Feuerstein believed in ICT-107 over DCVAX for a very long time before the disappointing (but not necessarily fatal) results from ICT-107's phase 2 results. Now he feels obligated to scream twice as loud and illogically against NWBO.
On February 15, 2013, Feuerstein saw enough difference to favor ICT-107. Mr. Smith however, in a February 19, 2013 reply defended DCVAX chances.
Here is the relevant conversation.
"11. Adam Feuerstein: I'm skeptical about ImmunoCellular but with an open mind waiting for data at year's end from the first adequately designed study of ICT-107. Northwest Biotherapeutics is much more difficult to take seriously given the company's checkered past and present.
SmithOnStocks: Of all the comments that Mr. Feuerstein has made, I find this to be the most puzzling as to why he is open-minded about IMUC and close-minded about NWBO. Let me go through some important points to consider.
1. Both ImmunoCellular and Northwest Biotherapeutics are basing their studies on small phase I/II data sets. There were 16 patients in the ICT-107 study and 20 in the trials of DCVax-L. The results (as reported by the companies in their investor presentations) were remarkably similar as progression free survival was 16.9 months for ICT-107 and 26.4 months for DCVax-L. Median overall survival was 38.4 months for ICT-107 and 36.4 months for DCVax-L.
2. Both IMUC and NWBO are comparing the results of their phase I or I/II trials to the clinical results in matched patients treated with standard of care. The companies use different methods of portraying the comparison but both are doing so. Mr. Feuerstein was fiercely critical of the chart in which NWBO compared its Phase I/II data with matched controls.
3. NWBO is now in a Phase III trial while IMUC is in a Phase II trial. In his presentation at the BIO CEO conference in early February, the CEO of ImmunoCellular described the ongoing 124 patient ICT-107 trial as a phase II trial and stated that he believed the company would have to do a confirmatory phase III trial before seeking regulatory approval. Mr. Feuerstein did not indicate whether he believes this is a phase II or phase III trial, but other bloggers have mistakenly stated that it is a phase III trial.
4. NWBO's current 312 patient phase III trial is nearly three times the size of IMUC's current 124 patient phase II trial. There is a widespread misconception about the patient size of the IMUC's current trial." -- February 19, 2013 -- Continued next post.
Etienne,
I do believe the trial could be halted/modified early in order to unblind it and give the control arm DCVax-L right away instead of waiting for progression in the control arm patients. While there is a cross-over arm, sometimes that is still too late. So, because DCVAX-L for GBM has orphan status, contrary to Cramer's ( he thinks it just gives some patent protection and market incentives) opinion, the FDA can lower their statistical powering requirements. This, plus the other improved techniques, booster shots and patients from 2008 could move the board to make an earlier decision. Here is another question I would ask at the upcoming January presentation, 'how does the cross-over arm affect statistical analysis of OS against the control arm?'
Ou,
Thanks. I stand corrected, the secondary endpoint is tumor regression. However, this still might mean a very accelerated trial in these 2 unblinded phases.
I guess I need to go back and study how they can judge adverse events for the primary endpoint. Since these are inoperable tumors, I'm stymied. I know death would be one adverse event, but....I guess if I do not find the answer, I will learn it on January 27, 2014 at NWBO's discussion. Again, it is fortunate these are open trials.
Thoughts?
OU,
I agree, a partnership with a larger company to complete a phase three trial on DCVAX-Prostate would be amazing. I was a little tongue-in-cheek about Inovio having the ability to bid against BMY. Dr. Kim curiously threw NWBO in with synthetic treatments, and my guess he is that he simply misspoke. However, by misspeaking, he shared volumes about why NWBO is a superior strategy (and I believe will have superior results to ICT-107 and Provenge). That said, Inovio may offer great synergy to DCVax. In the end, I think we will see a immunotherapy cocktail that will likely be primarily based upon DCVAX with other immuno-adjuncts. Whether these will be administered simultaneously or in some critical order is yet to be determined.