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Thanks for doing your homework. I stand corrected:)
A comment I wrote to "Dok Logic" on another board.
I agree. Your comment about Linda's description regarding the CONSISTENCY of cancer's response to DCVAX allowed me to connect a couple dots.
First of all, Linda Liau made a similar statement a while back about the amazing CONSISTENCY they are finding with respect to overall survival in GBM patients as this relates to DCVAX-L therapy. Percentages at 1 year, 2 years and so on.
Next, S.O.C. provides its own (albeit less efficacy) CONSISTENT response rate and overall survival rate in GBM cases.
Also, untreated GBM has its own very CONSISTENT overall survival statistics.
The point I am getting to is that CONSISTENT RESPONSES TO THERAPY seems to be a HALLMARK theme for GBM. Someone might say, "well look at IMUC," that was not consistent with their phase 1 trial. But I think, if you look at it from the proper perspective, they did have CONSISTENT results.
ICT-107 was very effective and CONSISTENT in the subclass of tumors that expressed a higher percentage of the antigens it was designed to attack. The problem is, by only selecting 6 antigens, the specific subclass population ICT-107 could affect in a small randomized double blind trial was luck of the draw. That's how it is with subclasses. Do you wonder why all those insiders sold before the results came out at IMUC? Yep, their drug was "high-brow," and they could not select "high-brow" tumors to match. The first phase allowed IMUC to select "high-brow" tumors. The phase 2 results do not mean ICT-107 did not work in those it was intended to help.
This brings me back to the concept of CONSISTENCY when it comes to GBM. With DCVAX, we are not relying on luck of the draw in the patient population. We are not trying to treat "high-brow" tumors, because we do not have a "high-brow" treatment. We have a "rainbow" treatment. Thus we should expect CONSISTENT response rates, pfs and os comparable to those found in previous clinical trials and compassionate use cases.
(Sorry for the homely analogy. I am not insinuating IMUC is prejudice against or for any HUMAN genetic predisposition.)
Speaking of rocket rides….
Market Cap. range is 241 million to 270 million -- depending upon your source.
Yes, I'm just looking at those 4-5 chart mounds (instit. entry?) of volume over the past 5 days combined with the price surge. I completely agree that retail is barely moving the needle these days -- those retail investors who know are probably near their full purchasing power. Its hard to believe, but most investors do not know about this stock. In November of last year there was approximately only 2200 shareholders or so. That was listed in the prospectus.
We've been over $5.00 for a bit now, so it's easier for instit. to justify entry and additional investment.
Koman.
You said:
And that logic of the first 33patients in this trial making the analysis longer doesn't fly- I'd expect the opposite because that group should have shown efficacy for PFS and OS by now allowing the DMC to comfortably continue the trial since everyone will get DC-VAXL eventually IF the current data supports efficacy.
Diamond.
High pitched squeaky sound.
Ou and Long,
Those are all very good points. Ou, i'm glad we had some similar reasoning before seeing each other's responses.
Tricky Koman.
You drew fat-cat in with a vague statement that might be positive, then lowered the basher boom on him. Slick.
Your logic is suspect. You said:
Prolonged interim analysis to me is not a good sign. If the data was extremely good based on 66events, it would be halted or simply continued to the next event. If there is some potential for separation of efficacy then it will be continued to see if the separation continues. BUT if there is no difference, they may wait for further events for confirmation before advising halt to the trial. Also, I'm having doubts that NWBO will meet their target date for completion of enrollment for pIII GBM trial and expect them to delay again the anticipated completion date (another bad sign).
Bio,
It looks to me like 4 or 5 institutions or mutual funds bought shares over the past 5 days. Would you agree?
John.
From looking at his curricular vitae and other information, it seems Robert Gorter is a clinical compassionate innovator. Meaning he gives full faith and credit to innovations like DCVAX, which was created before he started using the technology. My guess is that DCVAX is making his dendritic product, but reimbursement from the government, instead of patients, is just around the corner.
Those who are concerned about competition, I hardly think you need fret. Dr. Gorter has no patents on an autologous dendritic product to my knowledge. He has not sponsored/conducted large stage 2 or 3 studies, instead he is simply using parallel clinical therapy, but instead of using concurrent chemotherapy with DCVAX [or DCVAX-"like"] dendritic cells, he is using hyperthermia. Hyperthermia is being studied throughout the world -- check pubmed.
Anyway, as you know, he apparently is finding that DCVAX-L plus radio chemotherapy can be replaced with DCVAX-L plus hyperthermia.
Thank God he is in Germany, because big pharma would likely politically destroy him in other parts of the world.
I posted an article recently that said Roche is getting very angry with the German government for its transparent drug pricing legislation. Roche gave one of their recent chemotherapies as an example. Germany tends to be the benchmark with which other countries in Europe set their drug prices. I'm told by a pharmacist with their PHd that the countries then use their nation's GDP and a few other standard quantifiable data along with German price points to calibrate what their own country will charge for drugs.
You can imagine the importance that final passage of this current German legislation will do for patients in Germany and every European country, plus you can imagine the fear that big pharma has when very large private clinical therapies exclude chemotherapy from dendritic treatment and instead use concurrent hyperthermia.
You can also imagine the importance for Doctor Gorter's patients, and patients everywhere, what a final decision concerning German Government reimbursement for DCVAX (which also includes price point standards) will mean.
Man…These pools always get complicated.
OK….
Still Tuesday
2/25/14 Halt for Efficacy
8:15a.m. EST
Closing Price?
Double Digits:)
Office Pool: When will the DMC decision be released to the public?
I reckon 2/25/2014
Tuesday Morning, 8:15am EST
Hi Austin,
You said:
at the end of the trial they (IMUC) had data that said they improved PFS by 2 months and it was not yet stat sig. I could be wrong but i believe that was the case.
A comparison of PFS between ICT-107 and placebo showed a statistically significant difference in the Kaplan-Meier (K-M) curves favoring ICT-107 (p=0.014 two-sided, hazard ratio (HR)=0.56) in the intent-to-treat population of all 124 randomized patients. The difference in the median progression-free survival times between ICT-107 and placebo favored ICT-107 and was two months in duration. For the per-protocol population (117 of 124 patients receiving at least four induction vaccinations), the K-M comparison p-value improved in treated patients to 0.0074 two-sided (HR=0.53) and the difference in median progression-free survival times increased to three months in favor of ICT-107.
Hey, I recognize those guidance rules!
I think talking in absolutes either way might be a tad heavy handed. I know, without looking, there is also a guidance rule that demands quick termination when certain safety issues arise past a certain threshold. I also know futility is highly unlikely (not impossible -- but very close to 0%), because we were told how well the compassionate use program is doing, as well as the prior trials, plus the 66 events occurred later than NWBO's own predictions.
So, while it may not be good to speak in absolutes, IMHO the trend is increasingly favorable but certainly not completely airtight.
Going into early 2011, we had 33 patients who may or may or may not have had an event by then. They'd all likely have been in the trial for 36 months by 2011. Let's just ballpark that at 25 events through today.
That means from the time enrollment restarted in early 2011 to December 2013 (aka: about 3 years), it took 36 months to obtain the additional 41 events -- or 13.66 events per year.
Of course that is when enrollment was ramping up. Moreover, there was a few month window in the first half of 2011 where very few, if any, events occurred.
The next interim review would be triggered by 22 more events from December 10, 2013.
With enrollment now both continuous and faster, I'd say the events per year probably is now somewhere between 22 and 30, but that may be conservative because NWBO really increased the number of clinics over the past 18 months.
Anyway, I'd speculate late summer to late fall.
General Expectations:
I think the volume is starting to reflect the 10th week is upon us. December 10, 2013 to yesterday was 10 weeks (70 days). I think Linda Power's public presentation projection tagged on a few days, so her outside thinking is this coming Monday. Tuesday of next week puts us at 11 weeks (77 days) from December 10, 2013.
So the slight volume uptick over recent days might be straightforward 'actuary tables' kicking in. In other words, each day we go out from here before a decision is handed down, the 'prognosis' for DCVAX-L improves.
That's not my personal investment strategy, but I could see investment firms, who watch DMC interim review dates come and go tens of thousands of times, having the average review time/delay significance built into their early entry formulas.
Just thought I'd mention Larry Smith has an article on his attendance at the Waldorf Astoria Biotech Conference in New York (same one Linda Powers just presented at). Its proprietary so I will not give hints other than to state he did not share any bad news on NWBO. It came out on February 14th, 2014, but I just read it. Just FYI.
(Note: He does cover NWBO and a number of other companies that presented there.)
Now you're talking.
My guess is that NWBO and Germany already know the price point that is competitive, fair and consistent with their system. Like other drug companies, after launch, cost savings from economy of scale will become very critical. That brings us back to the large expansion in manufacturing capability NWBO recently financed. We also must remember the cost savings this medication will bring to Europe based upon overall reduced hospital time, reduced loss of work and reduced government costs -- especially if cost-effective treatments like they are using in Cologne replace adjunct chemotherapy as the superior combination with DCVAX-L.
If Ou is correct, and German approval for compassionate use is de facto commercial market approval for Germany, then the time NWBO spends getting FDA and EMA approval will be effectively partially compensated by the German, British and Israeli Compassionate Use reimbursements. NWBO will also save administrative costs in avoiding endless country by country price negotiations.
Ou.
I have the same question you do regarding the negotiated price difference with Germany. I guess its simply good we are watching it.
I agree with the rest of your statements, especially this one:
If the German regulatory body pays anything toward compassionate use, to me it's de facto approval. It would be huge news.
German Compassionate Use Reimbursement Connected to European Price?
To some degree, I think NWBO's request for compassionate use status and Germany's upcoming decision regarding DCVAX-L compassionate use reimbursement will give us a good idea what the continent of Europe will pay for DCVAX-L.
Drugmakers are allowed to set a list price for a new innovative medicine for the first year it’s on the market; the association negotiates rebates after a cost-benefit assessment run by the Federal Joint Committee, the German body that makes drug reimbursement decisions.
The revised law will make it clear that the list price isn’t what’s paid in Germany, she said. German prices are influential because other countries use them as a reference.
The German Connection.
http://www.bloomberg.com/news/2014-02-17/german-proposal-to-report-drug-prices-has-roche-concerned.html
Drugmakers have had to negotiate rebates on new innovative medicines with German insurers for the past three years. Now instead of referring to rebates negotiated between drugmakers and insurers, the law will refer to reimbursement. The shift may seem small, but it means the talks are really about price, not discounts, Pfundner said.
February 18, 2014
Finally, as Huntington disease and other neurodegenerative disorders progress, there is a gradual loss of brain tissue or atrophy. In Reach2HD, brain imaging using magnetic resonance imaging (MRI) was performed in a small subset of patients (n=6) to map anatomical changes in brain structure. In the combined PBT2 groups (n=4) a reduction in atrophy of brain tissue in regions of the brain known to be affected by Huntington disease was observed compared to the placebo group.
Dr. Diana Rosas, Associate Professor of Neurology at Harvard Medical School and the study's co-Principal Investigator who conducted the imaging sub-study commented: "Despite the very small number of patients in the sub-study, the data are suggestive of a beneficial effect of PBT2 in regions of the brain that are known to be vulnerable to Huntington disease."
http://www.marketwatch.com/story/prana-meets-primary-endpoint-in-phase-2-reach2hd-clinical-study-of-pbt2-for-treating-huntington-disease-2014-02-18?reflink=MW_news_stmp
Shorts getting burned at Prana (PRAN) today.
Short interest had gone up 700,000 by January 31, 2014 (from 15 days earlier), but guess what? This morning at 6:04 am, PRAN announced its PBT2 treatment against Huntington's disease met its primary safety endpoint, plus demonstrating statistical significance in improvement for executive function, plus demonstrating a significant benefit on cognition.
Pran already up 25%.
Maybe I'm wrong, but I do not believe you can get day-to-day shorts. It's not my area of interest, but don't you have to wait 15 days to get the data? (Nice graphics by the way -- is it a mirage?)
I wrote a longer analysis earlier this weekend, but IHUB ate it.
So, I am going to give the short version.
Methylated MGMT is a subtype tumor that responds well (initially) to aggressive chemoradiation for GBM cancer -- the relationship is statistically significant and the response rate in these types of tumors is about 90%.
Studies strongly correlate Pseudo-progression patient's tumors with methylated MGMT. This relationship is also about 90%
As Linda Liau points out, there is a strong correlation between tumors that respond to chemoradiation, and tumors that respond DCVAX-L, such that they are synergistically related. Probably because DCVAX-L dendritic cells can uptake more biomarker/antigens from the dead andy dying tumor cells the resulted from the early aggressive chemoradion.
However, in the alternative possible trial design, the pseudo progression patients would not be used to determine the primary endpoint.
Question: Do the above points mean all the patients with methylated MGMT tumors are not included in the group of (probably) 240 patients being used to determine the primary endpoint -- under the possible alternative trial design?
Answer: No.
Reason:
1. The rate of methylated MGMT in GBM IV tumors is consistently about 45%.
2. The rate of pseudo-progression in GBM IV patients (based upon a huge comprehensive retrospective review of multiple studies) is about 18%.
3. The percent of methylated MGMT tumors in pseudo progression tumors is about 90%.
4. Therefore, based upon this info, there are only 16.2% of combined pseudo-progression/methylated MGMT in the overall GBM IV general tumor population.
5. Therefore, under the possible trial design I am considering in this post, if you took 240 patients x 45% methylated MGMT, you would have (approximately) 108 patients with methylated MGMT. This amount would be reduced by 16.2% x 240 = (about) 38.8 methylated MGMT patients that would otherwise be in the primary endpoint group, but were placed in a tertiary endpoint group instead.
6. Therefore, in trial arms 1 and 2 combined, there would be (about) 69.2 patients with Methylated MGMT out of the 240 patient pool -- if the patient population fell into global statistical averages.
Conclusion: I expect the primary endpoint pool in the phase III DCVAX-L trial to have a very robust percentage -- 29% -- of methylated MGMT patients. When combined with the fact that this pool excludes early acute real tumor progression (aka: chemoradiation non-responders and thus also less likely to respond to DCVAX-L according to Linda Liau and Dr. Kim), this primary endpoint pool should ultimately have very good responses to DCVAX-L for reasons stated in this and earlier posts.
Note: Because DCVAX-L has an 80% response rate, I certainly do not think it exclusively depends upon Methylated MGMT tumors in the patient population pool. However, Chemoradiation does rely very heavily (about 90%) upon Methylated MGMT patients. Thus there should be good separation between S.O.C. versus DCVAX-L plus standard of care. Thank heavens for the crossover arm.
I didn't see this post earlier. I think you're putting my feet to the fire unnecessarily. I guess I could have have said, "this is really really important to know." Its also important to know for patients who are in each subtype so they can make the right decision. I respectfully disagree with you, I think my bar is quite high.
I look at it this way. Linda Powers does not intentionally waste money. IMHO, they are expecting a big crowd, and they want capacity to handle the potential flood.
RRRichmond.
I am very sorry for your loss. Thank you so much for sharing your thoughts with this board.
Ou.
Clinicaltrials.gov unintentionally gives us a couple ways to interpret the full extent of the trial design, because it (the clinical trial.gov posted design) is not specific enough for the public to know exactly which fleshed out design to rely upon. (This is likely true for all brief versions of trial designs they have ever posted).
A couple patients posted on the internet how the pseudo-progression arm protocol works up to the point of enrollment. Public message boards and the internet were also recently confronted with something that may or may not have been a much more specific version of the trial design....but it was apparently proprietary info, so message boards and the public were instructed by the company not to reprint the document or link it. I am not trying to confuse matters. I am a public investor following the rules by only discussing the possibility of how a second interpretation of clinical trials.gov limited info might affect things. I'm not going to be passive....I have to think. In the end there is only one written official trial design -- and one thing I believe very strongly, clinical trials.gov only gives us the equivalent of an abstract. As for NWBO, they have probably not fleshed out the full extent of the trial design to the public, but they have given a few more 'glimpses' in their press releases.
I can't put myself in the shoes of a hypothetical CEO looking to purchase NWBO.
I am still fully invested in NWBO, and I have always been diversified.
(Note: Tomorrow, I'll try to give my thoughts on how the methylated MGMT factor might be affected when seen through the prism of a (possible) second fleshed out trial design (the one with five arms I have been considering in my most recent posts). My conclusion is that it does not change my thinking on the phase III chances for a favorable outcome.
Yep. Its the other scenario given the wording of the clinical trials.gov and the protocol potential pseudo-progression patients reported (Thanks to John's link). It also seems somehow…..more possible since the hubbub here a little while back….say no more…say no more. Its the other trial design option.
Its not as complex as it sounds, since only arms 1 and 2 are used statistically for the primary and endpoint. You already knew about the cross over arm, that's arm three. That leaves the enrolled pseudo-progression suspicious tumor patients, at post chemoradiation week four MRI, who have real tumor progression ruled out around week 12 or so. Of course, if these folks are analyzed separately, as clinical trial.gov states, and they are blinded as a couple patients report, then their experimental and trial arm would very probably be used as a tertiary endpoint. Maybe the 240 patients are arms 1 and 2, and the added 71 patients in arms 4 and 5 are the former pseudo-progression patients. The 66 event trigger would only come from the 240 patient group.
I should mention that possible scenario made me go back through my thinking again….but all is well, at least in my mind. I have not moved a penny of my investment for NWBO. See last few posts.
I will also address what such an alternative possible trial design means for f3tt3f's concern regarding
methylated MGMT. It took me a while to figure it out this weekend, but I am now confident such an alternative possible trial design still works just as well regarding that subtype. (Probably tomorrow or sooner).
Caveat: Its still all good.
Just processing an alternative:
My prior thinking (recent connecting posts) were based on the pseudo-progression patients being randomized into the primary endpoint arm of the trial once real progression is ruled out. Since I am very confident that those tumor-pseudo progression patients who get retested approx. 12 weeks after chemoradiation and show no real progression are randomized and blinded (based upon some internet cancer boards I saw) an alternative trial design is that they might be placed into a separate arm but randomized, blinded unto themselves, not the primary endpoint related group.
So we could possibly have this alternative situation:
1. Arm 1 -- Experimental arm-- patients who showed no signs of pseudo or true progression up to 4 weeks post chemo/radiation get DCVAX-L.
2. Arm2 -- Control Arm -- patients who showed no signs of pseudo or true progression up to 4 weeks post chemo/radiation get placebo.
3. Arm 3 --Crossover Arm -- patients from arm 1 or 2 who truly progress after more than 4 weeks post chemoradiation or 12 weeks post
4. Arm 4 -- Experimental X -- pseudo-progression patients who ruled out further signs of progression through week 12 post chemo/radiation get DCVAX-L.
5. Arm 5 -- Control X -- pseudo-progression patients who ruled out further signs of progression through week 12 post chemo/radiation get DCVAX-L.
If the trial followed this set-up rather than the one I previously described, I believe the only 2 arms that would be used to determine the primary and secondary endpoint would be arms 1 and 2.
If this is the case, then we'd probably have less mesenchymal patients in arms 1 and 2. At first blush this might seem not as helpful because in one of her two phase 1 trials, Linda Liau found that mesenchymal patients responded well to DCVAX-l.
However, one needs to know that trial only had enough patients to compare mesenchymal and Proneural. The classic and neural subtypes were not represented specifically, and in the 2 patients where we know they were different from mesenchymal and pro neural, one lived over 50 months who was treated with DCVAX-L.
So, if we are looking at perhaps mainly the "classic" subtype to determine if DCVAX-L treatment meets its primary endpoint, we are still very likely in the same shape, because:
1. Linda Liau and other researchers noticed that in many smaller clinical trials, where chemoradiation had a strong effect (initially), it resulted in DCVAX and other dendritic therapies having much more profound efficacy.
*In my prior analysis, I reported that mesenchymal might respond somewhat more (judged against its own subtype) than Classic (does to its own subtype) to aggressive chemo/radiation. However, after more research I find that the both respond (rate of response) very well (initially) and there is no statistical difference. Proneural does not appear to respond at all, and neural responds in far fewer cases than classic and mesenchymal.
Linda Liau's theory is that the DCVAX-L dendritic cells are able to get better biomarker/antigen uptake where the in vivo tumor is no longer able to protect itself because it is weakened or dead.
2. In the large number of compassionate use cases and trial cases combined, there was an 80% response rate to DCVAX-L. Mesenchymal only makes up about 30% of the (4) subtype population. This means the other main responder to dendritic therapy, classic -- according to retrospective studies -- is also responding. Proneural does not repond to DCVAX-L in the research that I reviewed.
3. Linda Liau stated that where there was early-acute-progression, DCVAX-L was not effective. Those type of patients were excluded from this phase 3 trial.
4. If the trial design is more like the one in this post, the "no longer" pseudo-progression group (arms 4 and 5 above) would still provide further validation even though it would not be for a primary or secondary endpoint.
5. A retrospective analysis concluded that both mesenchymal and classic respond to dendritic therapy. This is just like the different chemoradiation effect among those two subtypes, so this bolsters Linda Liau's theory ( that dead or dying in vivo tumors provide DCVAX-L dendritic cells even better uptake of biomarkers/antigens).
6. Not all mesenchymal tumors would show pseudo-progression.
Therefore, those patients would be placed in arm 1 or 2 above.
I think the physical layout angle is interesting. They may expect to be swamped with people at the ASCO conference. If so, they'll need more room.
ASCO Booths.
One possibility, if it is allowed at Asco, is that NWBO is setting up separate booths for Brain (L), Direct, Prostate, Ovarian and HIVx2. Which I would see as smart.
FCB, you inquire about any concerns I might have.
Of course my main concern would be the difference between the first trial and the 3rd trial. But as I continue to "drill down into this," I am rationally exuberant. A few years ago I heard an interview on NPR (I think) with MD Anderson. The representative from Anderson said phase 3 was almost never as good as phase 1. He gave examples without naming the actual companies. He sounded like a veteran in the war against cancer. Those 2 concerns are about it. We are waiting for "just the facts" man….I could reason matters until I'm blue in the face, but we are all waiting. I think we have Steve Nash on the free throw line, and he only needs to sink 1 of 3.
Good Point!
Just a thought for those particular compassionate use situations. Maybe the added benefit of better surgery techniques combined with the understood synergy with DCVAX-L play some role in this outcome.
I'll try.
No, I don't believe the DMC believes a well designed trial in phase 3 is problematical under these circumstances.
The FDA worked with NWBO to move this to a phase 3 trial, keep it on track, cooperate as it should with an orphan treatment designation -- which included oversight when the interim analysis dimension was added in. (One reason for interim analysis, especially in very fast fatal diseases with no significant treatment options, and where safety is basically a foregone conclusion, is to make it possible to terminate the trial early and save more patients from death as long as statistical significance is present.) Consequently, the DMC should be satisfied that this trial is well designed, even if such design may possibly demonstrate better results than the phase 1 trial.
Note: In many ways, the exclusion of the early-subacute-true-progression patients (with the possibility of compassionate treatment) is also a blessing to those patients, because they can then step back and evaluate their options.
In my opinion, this is the most humane way a trial could be designed and still achieve profound data to reach an accurate conclusion.
Yes, given enough time, scientists will continue to find multiple ways to categorize GBM tumors. Here is the take away for me, and probably more important than the 'holy grail'. Tumors that demonstrate pseudo progression (inflammatory response to chemoradiation) are almost always the same tumors that will respond best of all to aggressive chemoradiation (in the short run) and DCVAX-L.
The trial design in this case will not randomize pseudo progression patients into the main body of the trial until they can determine for certain that the patient is not suffering from true progression.
The early subacute true progression patients typically do not suffer from inflammation due to chemoradiation therapy, and they will typically end up being pro neural and possibly neural.
The pro neural patients with true progression will not be randomized into the main body of the trial.
Classic subtypes will not typically show pseudo progression nor early subacute true progression yet they also respond quite well to chemoradiation (at least initially) and DCVAX-L.
In other words, this trial is likely to weed out pro neural and perhaps neural subtypes to a greater extent. Because neither chemoradiation nor DCVAX-L can help these groups much at all, and because pro neural does relatively well by itself, the opportunity to show a better comparison between the S.O.C. v. DCVAX-L in the remaining (mostly) 2 to three subtypes is enhanced. Thus the ability to focus on the statistical significance in the patients actually enrolled in the trial is enhanced and will, imo, most likely come down to the two subtypes.
Note: Bearing in mind, of course, the patients are not being selected based upon their subtypes, this simply happens because their exclusion and inclusion process happens to draw in more of some subtypes than others.