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I'm not certain Merck's trial was very similar to NWBO's DCVAX trials.
Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5).
JJ,
Let me give you a hypothetical. Pretend the coke recipe made it onto the internet, and it did so because it was stolen, would that protect the up-loaders from violating Coke's intellectual property right? Would it protect those who reprinted it if they knew it was stolen? Simply because something hits the internet does not mean its copyright and/or patent protection is not enforceable. IMHO
John,
Thanks for your work so far. I think you also want to delete post 3970 and 3975. Thanks.
Bio, this link may help.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696565/
Tell me more about this "bank" you belong to FCB.
Looks like FCB did have some connection to the post, but there is no true confirmation…so it still is not worth the cloud its printed on -- I do have respect for FCB.
On another note, from the price action the last couple days, it appears there are some folks that do not want to be left out in the cold at the end of the trading day.
Pulled this from the Yahoo board.
Its a new poster, so I have no idea if it is accurate, I'm just wondering if anyone else can confirm JPM's thoughts?
I have some contacts at JPM that say this will be an early termination and are doing business as such.
Its practically the entire market. General pullback.
You may want to review posts 3916 and 3917 for good news.
Welcome back Ou!
and good point.
Indeed. And why would cognate want that deal expanded and written in stone prior to the first interim analysis?
I think DocLogic is correct. I was recently nosing around some of the same material in addition to other articles. I found it telling that about 1/3 of the average GBM IV population falls within the mesenchymal subgroup. If you add this to the fact that those with tumor progression or pseudo- progression after chemo/radiation but before treatment are not included in the main DCVAX-L phase III study, the chance for early termination is much higher. (Note: Further research into the very latest studies on pseudo progression demonstrate those patients fair about as well as the post/chemo non-true progression group when surgery/chemo/radiation are the sole treatments). Anyway, the high responding mesenchymal subgroup will compound the results when added to the fact that patients whose tumors are stable (albeit temporarily), after surgery/chemo/radiation, and at the time DCVAX-L treatment is initiated also respond much better -- in historical DCVAX data.
In other words DCVAX-L response is magnified by:
(Mesenchymal group) + (post-surgery/chemo/radiation group with no tumor progress when DCVAX-L trial is initiated) - (patient population with tumor progress after surgery/chemo/radiation) = higher chance for statistical significance in the trial population.
Or
High responder + high responder - lower responder = Increased chance for success.
How statisticians handle cross-over arms:
Using Provenge as an example -- Crossover analysis is extrapolated to show Provenge treatment was even more efficacious than previously determined.
The Phase 3 IMPACT trial included a crossover design that allowed patients who were randomized to the control arm and experienced disease progression the opportunity to participate in an open label Phase 2 protocol to receive APC8015F, an investigational autologous cellular immunotherapy made from cells that were cryopreserved at the time the control was manufactured. As a result, 109 out of the 171 control patients (64%) received APC8015F.
In this exploratory analysis, researchers used a rank-preserving structural failure time (RPSFT) model, to quantify how treatment with APC8015F might have impacted the overall survival of the Phase 3 IMPACT trial by adjusting for the positive treatment effect of APC8015F in the control arm. The previously published intent to treat analysis, which is described in the Food and Drug Administration approved prescribing information for PROVENGE, did not account for cross-over and demonstrated a 4.1 month median survival benefit (HR=0.775, 95% CI: 0.614, 0.979). Using the RPSFT model, and assuming that APC8015F was equally effective as PROVENGE, the median overall survival benefit of PROVENGE in the Phase 3 IMPACT trial was estimated to be 7.8 months, had there been no cross-over to APC8015F (HR=0.60, 95% CI: 0.41, 0.95).
"This exploratory analysis provides important insight into how the cross-over design of the IMPACT trial may have affected the overall survival findings," said Leonard Gomella, MD, Kimmel Cancer Center of Thomas Jefferson University. "These data support the use of PROVENGE as a foundation of care for the treatment of metastatic castrate resistant prostate cancer."
Fox,
I'm tired, but I promised to write something tonight.
(Again, I refer you to Longusa's recent post demonstrating why NWBO has multiple advantages above and beyond just statistical significance.)
Here is a link providing an example where the DMC (AKA: IDMC) was scrutinized for early termination for efficacy -- where one of two primary endpoints were not met.
This is not anything I expect to see in the DCVAX trial. I expect an 'across the room' obvious result. However, the link below demonstrates that there is more to the IDMC than statistics.
http://seekingalpha.com/article/639811-will-the-fda-dance-to-j-and-js-tune-on-zytiga
Here is a passage from the above link:
In sum, then, there are those who believe the IDMC had good reason for recommending termination, given the study had achieved stat sig PFS and the survival data were reasonably good even if they failed statistical significance.
That said, about 50% of the patients were known to take subsequent therapies such as Taxotere or Provenge by the time the interim analysis was performed. So, there now is a question how these therapies impacted the trial. The 18-month overlap of the survival curves might have been an indication these treatments were as effective as Zytiga during that period. Then, too, even though the curves managed to open up, now that the trial has been unblinded, patients could overwhelmingly start secondary treatments, including crossing over to Zytiga. This would have the effect of causing the curves to close. Put another way, we may ask this question: can the trial achieve statistical significance for OS if many of the patients cross from the placebo arm and take Zytiga? These are but a few of the many issues upon which the debate regarding FDA approval will almost certainly be focused in the months ahead.
I'm speaking about the other way around. The DMc continues in spite of meeting primary end points. This is allowed for, but I don't think it will happen here for the reasons long mentioned. I'm on my cell phone, but it's important to mention the DMc does not work in a vacuum. There is also the 6 month fence potential issue. I'll post tonight if somebody dosnt beat me to it.
Yes, of course the primary end points were set. The dmc does not simply examine the stats to make their decision. That is the point of the last conversation. The guidelines also have them looking at need, subgroups (which may or may not have specific end points), they may or may not take into consideration external data like a really good safety record in their compassionate use program, etc. Stats are absolute for the end points and are the primary tool, but if you read the regs and interviews with former DMc members from extensive surveys, you'll know the primary and secondary end points and p values are not the only factors they consider. It's a bigger job than that.
Thanks FCB.
I agree with your analysis on the statistician side of the DMC. However, I do not believe the statistician is blinded from the discussions with other members of the board. Therefore, it seems the statistician is required to compartmentalize his two tasks. 1. Statistics. 2. Obtain enough information to vote. If he lets #2 creep into #1 then there is a problem. The statistician is also not likely blinded from "open session" sponsored meetings, where the sponsor can share important external data.
So my thinking is that the board likely already attended an "open session", and its just my guess, but I bet the sponsors made very clear the distinguishing factors between the Provenge and IMUC trials. If not, the physicians likely already studied the two prior cases in depth.
"many DMC meetings include an "open" session in which information in the open report is discussed. These non-confidential data may include, for example, status of recruitment, baseline characteristics, ineligibility rate, accuracy and timeliness of data submissions, and other administrative data. Sponsors may also use open sessions to provide external data to the DMC that may be relevant to the study being monitored."
Does anyone know if the DMC will likely look at Dendreon and IMUC trial results to help them establish a pragmatic window for their deliberations re: DCVAX?
Thanks.
I read them quite some time ago, but I've been focused on DCVAX-L approval (if things go well) so much that it took someone to remind me DCVAX-Direct has a real shot at approval after stage I/II if the results turn out as we hope. Thanks again.
Calls…. and April is up 22% for $7.50 calls, March is up 28%, and July is up 28% (at this moment).
John, I'm not an option guy, but did you see that July 2015 $7.50 options are up over 23% to today? Wait a minute…now they are up over 28%
You're right LongUSA…
I should have looked up the response timelines instead of going from memory. Shortest PDUFA date is 6 months (not 60 days).
Also Hodge, the FDA recently gave some new information on compassionate use. Longusa is correct, you really should see if the company could make this happen. Your Doctor will ultimately need to help you if you go through "single patient access," (or any other process).
This link should help.
www.cancer.org/treatment/treatmentsandsideeffects/clinicaltrials/compassionate-drug-use
Finally, Yes….Long is correct, they could approve this drug on phase (I/II) combined data. With this in mind, there are ways to shave some time off Long's estimate, but I think the window (after taking into account my error and Long's excellent point) is November 2015 to June 2016….best case scenario -- for commercial availability of Direct (IMHO).
I second Long's recommendation that you call NWBO and see if you can pursue compassionate use on direct.
Hodge, I think the best case scenario should be given as a range.
Just to be clear….we are talking about Direct. Let's also hope, in the meantime, if all goes well, it is possible the compassionate use programs around the world will be expanded to include Direct.
Let's assume the final primary results of the phase I/II unblinded study come out between September 1, 2014 and November 30, 2014. (Note: since there is no control or cross-over arm, it will not be concluded earlier than enrollment, treatment and response allow for.)
If the results are what we hope for, there will be significant tumor shrinkage and/or eradication with signs of immunity in 80-100% of patients.
If memory serves me correctly, Direct also has orphan status and fast-track status (or it will), and because the next stage trial -- whether that is classed as a 2b or 3 -- will almost certainly use tumor regression as the primary endpoint, the route to final approval would be be sped up enormously -- again, if all goes well.
Here is another thing, if the results are really good as we enter into spring and summer, NWBO can start phase 2b screening and enrollment before final primary results are 'official.' There is precedent for this.
The phase 2b or 3 trial design will be paramount in determining the speed at which it moves. Assuming strong results from phase I/II, even though the the size of the imagined pivotal trial may be large for an orphan drug -- let's ballpark 600 -- nonetheless, the enrollment rate will be faster than any prior cancer trial (IMHO).
So let's project the pivotal trial for Direct is announced September 1, 2014. There will be no start time bottleneck (as was the case in phase I) because the drug has already been used in a first in human study. Thus, sponsor trial execution, number of clinics and doctors will be the only rate limiting factor other than response time.
The responses for Direct are blindingly fast for tumor reduction. Here is the part that many of us forget from time-to-time. In most trials, we are waiting for a certain number of negative events to occur before we take an interim look, but with tumor reduction as the primary endpoint, we are waiting for positive events to occur. In this case, if those positive events are to occur, they will happen within days to weeks.
Let's project enrollment (in our example pivotal trial) is full within 6 months….due to incredible demand, and because we have and will have so many clinics available between the U.S. and Europe to handle the screening, enrollment and treatment.
Let's say the 1st interim look is at 6 months from enrollment initiation.
60 Days for analysis.
Next, in the best case scenario, they unblind the study.
Linda states it can take about a year for FDA approval following a successful pivotal trial.
However, here again, we can have a better case scenario. Let's say Linda gets an NDA application to the FDA 90 days after the phase IIB or 3 results come in.
Normally the FDA would have a decision within 6-9 months, however, because this treatment is for inoperable terminal cancer patients (the highest immediate need possible), The FDA can shorten their decision window to 60 days.
Hopefully NWBO has ramped up production capacity so that there is little to no delay in launch.
If all goes very well, In my opinion the earliest one might be able to get DCVAX-Direct commercially prescribed is somewhere between October 1, 2015 - December 30, 2015. Prior to that, one would need to try and get into any available trial or compassionate use program (when/if those are made available).
Compassionate use in the U.S. -- Great find John!
It makes me wonder if the compassionate use program in the U.S. will expand to cover additional cancers (as it already does in Israel and elsewhere).
Red,
Thanks for breaking down the competition within the sector. It is very helpful. The latest press release on expansion went a long way toward convincing me NWBO is working very hard to stay in front, make a successful launch feasible and position itself as the lead (and best) immunotherapy treatment fighting cancer.
If we do need to wait until the second or final analysis for statistical significance on the primary endpoint, our capacity to launch should be that much stronger. I will say, IMHO, while it is very reasonable and prudent to set manageable expectations for investors; the silver lining related to a slightly increased level of investor hope in a chance for early success at interim 1 or 2 is this: NWBO and investors seem to be training their resources and focus much more intensely on the next steps.
Another way to put it is that we are hoping for the best and (consequently) planning for the best.
Brilliant. I can't believe I skipped over this post.
Now, I have four posts in a row. I need to adopt a pet. He/She would not abandon me on a chat board….would you Bengie….Bengie????….Bengie!?!?!
Alrighty then!
It just occurred to me that a simultaneous announcement on L and Direct would be considerate to patients and long timers like Red, Ou, Etc. (I really get a kick out of Etc)
Anyhoooo, no matter if there are 2 "wins," 2 fails or 1 thumb up and 1 down, a simultaneous announcement might be merciful.
Its looking more and more likely.
Hello….hello….hello…..?
Its my breath…isn't it. You all went away because dolphins waft unrelenting halitosis.
FYI: Short interest discrepancy between End of year and January 15th was almost nonexistent. My interpretation is that it means nothing leaked (positive or negative) during that time.
Dissemination date was January 27th.
*****************Shares*********A.D.S.V.***Days to cover
1/15/2014*****3,491,828*****684,048***5.104653
12/31/2013****3,358,212****680,096****4.937850
Red,
I missed the link on this post back in December. Thanks for posting it. I'd note at the end of the video, the doctor stated right now, with immunotherapy, stopping the cancer is their goal. Down the line, he states, shrinking the cancer would be the goal.
http://www.nature.com/nature/outlook/cancer-immunotherapy/index.html#editorial
Note: If Direct shrinks and eradicates the tumor while conferring immune memory, that goal is achieved.
Hodge, if you read some of the recent posts on the subject, I think we established that the Biopharmcatalyst site folks are making mistakes and bouncing around. Please do not let that be the source of your anxiety.
I think you should contact the patient ombudsman at NWBIO to find out if they are trying to set up Direct in a hospital or clinic nearer to your location. God's speed.
NWBIO: Phone: 240-497-9024
Actually 66 of 110 = 60 %, but who is counting?
In a nutshell, I agree. I would add that the (very similar) precursor to Direct worked extremely well in humans. See Triozzi study -- Cancer. 2000 Dec 15;89(12):2646-54.
Of course there is much more to say than this, but many of us already said it.
Come on results!
I think its just a case of form. No reason to use adjectives to negatively describe a person. Once one restrains themselves from using negative adjectives -- like "pumper" -- I find that their reasoning typically facilitates better exchanges and critical analysis.
For instance, while you suggested Linda's speech in San Francisco basically mimicked her Oppenheimer presentation; I, on the other hand, would take issue with that -- even allowing for your caveat. She also gave statistics regarding the compassionate use program Overall Survival and Progression Free Survival, she told us "glimpses" on Direct results were likely in the near term as well as the spring, summer and fall; she told us NWBO would start to draw upon the German Grant in the coming week(s) and she gave us the overall response rate for DCVAX-L in trials and compassionate use program (in addition to the German financial contribution/DCVAX prostate silence you already mentioned). I would certainly not use an adjective to describe you simply because you have a different take on this review.
I'm certain if you combed my posts you'd find that I violated this rule (aka. no negative adjectives) as well.
Regardless, compounding that by calling one "too sensitive," (another negative adjective for some), while apologizing, implies that you now view someone as an "overly sensitive pumper." These adjectives are unnecessary and tend to label and globalize a person who probably would not be described this way if he disappeared from this board in the manner John's friend did….may he rest in peace.
Negative adjectives may go by the wayside for the person distributing them, but they tend to cheapen the debate at hand -- and stick in the recipient's craw.
I highly suggest Wittgenstein's Poker: The Story of a Ten-Minute Argument Between Two Great Philosophers. I certainly do not mean that their debate tactics in any way resemble anyone on this board. I simply found it interesting and topical. IMHO
You're right. Things are far too silly.
We need our fallen comrades back. (Frankly, I behave like a derelict minion when Ou and GPB are absent)
I think a valuable lesson was learned through your email efforts FatCatBanker. The calendar shenanigans were the work of trolls at the company that creates the calendar. Imagine the paranoia they can facilitate in the hearts of nervous investors by jumping dates back and forth. You think that has payed dividends for them with a less savvy group of investors? Could be. (That's right Roche…we are savvy.) Now, FCB would you kindly pass the Grey Poupon so I might slather it upon my steamed cabbage? Thank You.
Europe kicked Monsanto out (Monsanto conceded), but cabbage gives me gas. Say….maybe Monsanto already struck.
Proof of Concept -- as it were.
I am not a trader going in and out, but I'd caution against seeing a continuation as a reentry point. For one, as you know, there may not be a continuation because the trial may be successful at the first interim. Perhaps new money can go in if there is a continuation. Second, Smith on stocks is clear that a German announcement may cause a DRAMATIC upswing in price, therefore, for instance, if a continuation was announced but it was concurrent with or immediately followed by an announcement on Germany, the best laid trader plans may be for not. IMHO GLTA
At the Oppenheimer conference in December, Linda Powers said that we should stay tuned for further information on approval in Germany for compassionate use (it is actually somewhat different than what we in the US think of as compassionate use). For various reasons I think that this will have a dramatically positive impact on the stock.
Even though this video is from Dendreon….
It gives a palatable and short animated explanation (simplistic) of the various techniques being used in immunotherapy against cancer.
Even though this video is from Gentech and most of it is over my head, those who persist all the way to the end (get out your red-bull) may be amazed at what we know and don't know about dendritic cells. The speaker, Ira Mellman, is clearly impressed with the abilities and overall function of dendritic cells within the immune system.
Note: There are some really cool parts hidden amongst the extensive molecular science.
This is probably from around November 13, 2007 (Video Below). It is still relevant today. I suggest you do not skip through it. He does start out with a history on antibodies, but transitions from there to Dendritic cells. The undercurrent of contempt he had for the manner in which the FDA mistreated dendritic technology is palpable. Yet that was 2007; and since then, patients, doctors, nurses scientists, lawyers, investors and many others saw Dendreon through approval despite FDA bias, and perhaps, FDA malfeasance.
I did not invest in IMUC nor Dendreon for subtle reasons, (this does not mean I think they will not recover), but I akin Dendreon and IMUC to lead blockers in a football game. The real ball carrier is hidden from view by the rest of the team until he makes a cut upfield to score. The one really carrying the original intended technology is NWBO.
Anyway, that's it for analogies tonight. If you have time, this classic "informal" talk may give some investors a tad more perspective. IMHO
Note: The world changed again and again and yet again after this video….and now, somehow the torch that he and other institutions lit is still flickering towards its final destination. I assume he is very pleased with NWBO.