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My understanding is the same - neither the CEGE Vital-1 nor Vital-2 trials are non-inferiority trials. In fact, since Vital-1 does not control against the GVAX arm taking Taxotere after GVAX, in many ways it is quite similar to the Provenge 9902b trial where the combination of immunotherapy plus Taxotere is so disproprtionately superior to immunotherapy alone that even if their ITT patients using the combination are in any significant minority, their results, especially at the median survival point, will likely drive the overall results for the entire ITT group.
Results in Phase 2 trials are often poor predictors of Phase 3 results, as Provenge's Phase 2 TTP results were for its Phase 3 TTP results, especially wrt to 9902a. So the Phase 2 35 month median survival results reported for the 32 GVAX patients receiving the highest dose that is now being used exclusively in Vital-1 and Vital-2 Phase 3 studies, where some of the Ph2 patients also received Taxotere after GVAX, will not necessarily be duplicated in Phase 3. The GVAX median survival results would also be less likely to be statistically significant at the interim look than at a final unblinding. However, that GVAX 35 median survival is virtually identical to that of the 51 of 147 Provenge 9901 and 9902a patients ITT patients who took Taxotere after Provenge as reported by Dr. Petrylak last November. Since Drs. Petrylak, Small and Higano are now all GVAX investigators, I would imagine they are encouraging the ITT patients to follow GVAX with Taxotere, the present standard of care. OTOH, GVAX is not an FDA approved therapy and, unlike the 9902b Provenge trial, there is no crossover from Taxotere to the experimental immunotherapy.
The median survival for the asymptomatic subgroup in the Taxotere TAX 327 pivotal trial was apparently 22 to 23 months. Assuming the same median survival for the Taxotere arm in Vital 1 holds true, I find it difficult to understand why you believe so strongly that GVAX (+Taxotere)in Vital-1 with a possible 12 month greater increase in median survival than Taxotere alone would fail to achieve a statistically significant improvement over Taxotere in the same way that the Petrylak analysis would suggest that Provenge (+Taxotere) would prove superior to Taxotere. I'm not saying that you won't be right and anything, of course, is possible, but from all that I've read, GVAX looks to have as decent a chance for success as ultimately Provenge does.
1. At the CEGE CC, their CEO stated that there were no circumstances that the 600 patient Vital-1 trial, which compares GVAX to Taxotere in asymptomatic AIPC and was fully enrolled since July, would be stopped for futility as a result of its interim look. All Vital-1 patients would have been randomized and treated at that point. The Vital-1 final look is estimated to occur in 2009. He also expressed his belief that their 600 patient Vital-2 trial that compares GVAX + Taxotere to Taxotere alone in sicker symptomatic patients will be unblinded about the same time in 2009 due to the shorter life expectancy of those enrollees.CEGE also confirmed that once a patient is randomized to the GVAX ITT group in Vital 1, there is no prohibition against them taking Taxotere after their GVAX therapy, such subsequent therapy would not cause them to be censured from the ITT survival data analysis. If an enrollee were randomized to the ITT group and was hit by a bus before any therapy, he would still be counted as an ITT event.
2. Dr. Small's report on the 34.7/35 month survival of the highest dosed Phase 2 GVAX treated patients also mentioned that some had received Taxotere after GVAX. Dr. Petrylak, who did the analysis and presentation of the 13.6 month increase in median survival of the 51 of 147 9901 and 9902a patients who took Taxotere after Provenge is now also a Phase 3 GVAX clinical investigator, along with Drs. Small and Higano who were lead investigators in the 9901 and 9902a Provenge clinical trials.Given their knowledge of the benefits of combining Taxotere with immunotherapies and the recent AACR article by NCI docs to the same effect, I would imagine that many Vital-1 ITT enrolleees will be strongly encouraged to consider Taxotere after their GVAX therapy. Thus, both the Provenge 9902b and GVAX Vital-1 trials may ultimately revolve around their combinatorial effects with Taxotere.
3. 2008 has the potential for being interesting in that at present both the interim survival looks at the Provenge 9902b trial and the GVAX Vital-1 trial should occur then. Statistical purity requires each company to separately allocate some part of their alpha of 0.05 to the interim look, which raises some interesting possibilities. A p value substantially below the allocated alpha or way above it provides s obvious and straightforward outcome. Consider, however, if the allocated alpha is 0.01 or 0.02 and the actual value is 0.03. If interim median survival were a "surrogate" for ultimate median survival, it would be both statistically significant and "reasonably likely" to predict statistical significance for the ultimate median survival at the end of the trial and the earlier result would have a causal connection to the latter, all the necessary elements of the Prentice criteria for Accelerated Approval. The conditional approval that the AC recommended for Provenge on 3/29 was, of course, quite similar to an Accelerated Approval. In addition, FDA regs allow one well controlled trial in a life threatening disease to be sufficient for Regular Approval, so presumably that could be a potential outcome.If either or both Provenge and GVAX missed their allocated alpha, but each was statistically significant would the FDA hold up any revised or new BLA until final survival results, thus denying dying men their earlier availability? What if both were statistically significant, but their alpha allocations were substantially different, and the therapy that beat its alpha actually had worse results than the one that missed its much lower alpha? If the first therapy approved has a better increase in median survival, Hazard Ratio and p value then the one that follows, does the first therapy raise the approval bar for the second? Common sense should suggest that if either or both Provenge or GVAX achieved statistical significance, regardless of their prespecified alpha allocation, that should allow their approval even if one approach, given its particular group of enrollees and follow-on Taxotere dosing, did somewhat better than the other, but are statistical purity and common sense both important FDA goals?
1.There is an interesting and surprising new study published in this month's JCI by the NCI's all star immunotherapy team: Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling
Chrystal M. Paulos1, Claudia Wrzesinski1, Andrew Kaiser,1, Christian S. Hinrichs1, Marcello Chieppa2, Lydie Cassard1, Douglas C. Palmer1, Andrea Boni1, Pawel Muranski1, Zhiya Yu1, Luca Gattinoni1, Paul A. Antony3, Steven A. Rosenberg1 and Nicholas P. Restifo1 J. Clin. Invest. 117:2197-2204 (2007). doi:10.1172/JCI32205.J. Clin. Invest. 117:2197-2204 (2007). doi:10.1172/JCI32205.
2. The NCI has previously reported using chemotherapy and whole body radiation to deplete regulatory T cells and "cytokine sinks" prior to infusing their adoptive genetically modified T cells primed against a gp 100 antigen in their remarkably successful end stage melanoma therapy.The new study reports that the major positive effect of whole body radiation may be its impact on microbes in the gut, increasing the level of LPS, which is a powerful stimulant of the innate immune system. Administration of ultrapure LPS to non irradiated mice increased immune activity against established tumors and further enhanced tumor remissions when given to irradiated mice.
3. This was a particularly interesting observation: "Our finding that microbial translocation augments the function of adoptively transferred CD8+ T cells brings to mind findings reported by William B. Coley over a century ago (47). Hypothesizing that tumor regression in some patients was the result of bacterial infection, Coley designed a mixture of bacteria consisting of killed cultures of Streptococci and Bacillus prodigiosus known as Coley’s toxins. He reported occasional success using these toxins in patients with cancer. Our findings may be consistent with the notion that activation of the innate immune system can trigger tumor regression with bacterially derived products."
4. While tangential to this article, Dr. Petrylak's presentation of Taxotere after Provenge last November also stated that Taxotere preciptates a macrophage innate immune response. In any event, it is a fascinating analyis coming from an unexpected source and potentially a quite positive future element in all immunotherapies.
The fusion gene studies also seem to be developing out of “cancer stem cell" studies and indirectly from the success of Gleevec in Phildelphia chromosome related blood cancers. There is also a free access review article in the current issue of the Journal of Clinical Investigation that gives an exhaustive history of the subject. It also suggests that these prostate cancer stem cells are not effected by hormone blockade and may be the reason why ADPC invariably progresses from ADPC to AIPC. See: Stem cells in prostate cancer initiation and progression
J. Clin. Invest. 117:2044-2050 (2007). doi:10.1172/JCI32810. http://www.jci.org/cgi/content/full/117/8/2044
The current issue of the Journal of Clinical Oncology raises an interesting issue regarding the standard use of X-rays and radio-labeled markers to identify bone mets in advanced prostate cancer instead of MRIs, and reported that “MRIs identified metastases in seven (30%) of 23 patients considered negative and eight (47%) of 17 patients considered equivocal by other strategies”. Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3281-3287 http://jco.ascopubs.org/cgi/content/abstract/25/22/3281
Considering that the number of bone mets is considered an important and heavily weighted prognostic factor in the Halabi nomogram and in measuring Time to Progression changes from the time of randomization, any AIPC clinical trial measuring TTP in AIPC without using MRI’s can’t be very accurate. Surprising, considering how long MRI’s have been around.
The Journal of Clinical Investigation has a free accessible issue on Tumor Immunology at:
https://www.the-jci.org/publiTron.php?series_id=55&action=review_series
One of the articles in the Review "DC-based Cancer Vaccines" fails to even mention the Provenge clinical trials, which I thought was odd. OTOH, DNDN's presentation at the March 29th AC meeting was so devoid of any discussion of immunology factors (eg, Treg levels, CD8 T cell persistence in vivo, antigen cascade / epitope spreading, etc) that their contribution to immunology science, whether Provenge is eventually approved or not, may be considered minimal. JMHO.
ocyanblue:
1. We can both agree that Ph2 studies are primarily used for dosing and some indication of efficacy and not for extrapolation statistically to Ph3 results.You are among a handful of statisticians on the MB's whose observations are valued, which includes negative as well as positive ones. I am a strong believer in the future role of immunotherapy in cancer and believed that Provenge would be the first on the market. The reason for the post was not to create certainty, but the opposite. As the CCR article described, there may be several viable ways that cancer vaccines will come to be accepted. The two leaders with large randomized PH3 trials are DNDN and CEGE and both have strong proponents.
2. In my book, clear writing sets up the issues; lack of essential known information and the unpredictability of future events creates uncertainty. I will be the first to acknowledge that if I had known about the February Form 483 issued as a result of the FDA preapproval inspection of DNDN's NJ facility, my investment decisions with DNDN would have been dramtically different based on my past experience with the manufacturing problems of developmental biotech companies. So you can add hiding negative results of FDA preapproval inspections from shareholders to all the other risks in biotech investing, but that is one the courts may act to stop.
3.Studies of the different methods of action of the various immunotherapies unlike the black and white statistical results of a Phase 3 trial are being published continually in many medical/scientific journals.A lot of this material can shed light on whether the presumed superiority of maturing a patient's own dendritic cells with a single target antigen as Provenge does is essential or whether the combined antibody / T cell response apparently stimulated by GVAX's vaccine based around two inactivated prostate cancer cell lines or of Onyxax's vaccine based around three PC cell lines is superior. The CCR article raised such issues while leaving answers to such issues to ongoing studies. Theoretically, antibodies stimulate cell destruction by macrophages by phagocytosis, a process which is different than destruction of a cell by a CD8 T cell immune attack and is not deactivated by Tregs. Petrylak's presentation last November to the Chemotherapy Foundation hypothesized that a similar macrophage cancer cell killing process by Taxotere is what substantially increased the efficacy of the Provenge plus Taxotere combination. Thus, there is some scientific basis, although no certainty, that a combined antibody / T cell immune attack may approximate the MofA of Provenge plus Taxotere. JMHO.
1.The second Phase 2 trial apparently adds 22 patients who received high dose GVAX that is being used in Phase 3 and survived a median of 35 months. See: http://phx.corporate-ir.net/phoenix.zhtml?c=98399&p=irol-newsArticle&ID=981173&highlight...
While that only totals a group of 32 patients who survived a median 35 months, it may not prove a strong hypothetical treatment effect, but it certainly doesn't disprove it.
2. When you add developing strong MOA evidence that GVAX given in the high doses over 6 months used in the Ph3 trials precipitates a strong antibody response with consequent macrophage attack as well as a T cell response, it appears increasingly potent. IMO, it is foolish to discount the outcome of interim results. In addition, early Ph1 results of GVAX with ipilimumab, a CTLA4 blocker, also have shown bone met regression, an exceedingly difficult goal for any therapy to achieve. My point is that it is far too early to presume interim survival results of Provenge or GVAX especially when the unknown alpha spending for the interim look for each therapy is factored in. JMHO.
1. The real danger to DNDN may be the recent complete enrollment of CEGE's Vital1 600 patient trial (which began enrollment a year after 9902b) and their CEO's projection that its interim look will occur in 1H08.CEGE clains that the Ph3 GVAX dosing is at the highest dose level given in its Ph2 trials and that median survival at that dose was 35 months. This GVAX dosing without Taxotere equates to the median survival that Dr. Petrylak reported for the 51 ITT patients in 9901 and 9902a that took Taxotere after Provenge and will be compared to a Taxotere control arm where Taxotere had a median survival of 23 months in the assymptomatic subgroup in its clinical trials. CEGE's Vital 2 trial which measures GVAX + Taxotere against Taxotere alone is expected to complete enrollment by the end of the year.CEGE has not indicated whether it will be using isome of its alpha on the interim look and whether its interim look is successful could be the basis of a BLA.
2. IMO, Gold and his rubber stamp BOD are blazing a new trail in non disclosure to shareholders and other Provenge supporters by not only not disclosing the February 12 preapproval inspection and the resultant Form 483, suggesting in the March 14 10K that it hadn't occurred yet, Gold selling shares with 2 other directors, and refusing to release with possible redactions, the Form 483 and the Complete Response Letter. At this point why should anyone believe anything Gold has to say? While I find it hard to understand the basis for the efficacy lawsuits from what has been publicly disclosed, that is no assurance that the CRL did not contain more specific information to explain the FDA decision. I believe that Walkenizer pointed out that Waksal mininimized the FDA reasons for the FDA issuing its Refusal to File letter for the original Erbitux filing, which were then spelled out when the letter was leaked to The Cancer Letter. It's a lot easier to spin an FDA action ("minor CMC issues") when you omit what the FDA actually wrote.
3. The recent Clinical Cancer Research article by NCI authors pointed out that there is evidence to suggest that possibly every prostate cancer vaccine will benefit from post immunotherapy Taxotere. According to Dr. Petrylak. the 51 of 147 patients in the ITT 9901 and 9902a (34.7%) who received Taxotere after Provenge had a median survival of 35 months, which logically means that a good portion of the increase in median survival would be due to the combination P+T impact as would be 36 month survival (roughly 47% survival at 36 months for T+P vs 26% for P alone.) BTW, for all conspiracy COI buffs, Drs. Higano, Small and Petrylak are all involved in CEGE's GVAX prostate cancer trials.
4. IMO, the FDA would have been far more likely to back its Advisory Committee and give conditional approval to Provenge were it not for the CMC issues, which I believe would have pushed even that approval into 2008. Combine that delay with the beneficial, but confounding effects of Taxotere and the larger Vital 1 trial and the FDA might have decided that an interim survival look at both immunotherapies during the same year with little impact on faster availability to PC patients due to DNDN's CMC issues might be a better way of getting the best immunotherapy to PC patients quickly. Since the final decision was made behind closed doors, there is no way of knowing exactly why the FDA did not back their Advisory Committee unless some suggestion of that thinking was in the CRL. Pazdur may have played a big role, but he is not in the CBER chain of command / recommendations leading up to vE.
5. Both CEGE and DNDN and better biotech disclosure would benefit if both companies would tell the investing public what alpha allocation they intend to use in looking at interim survival data in 2008. JMHO.
walldiver:
Came across this on the CEGE MB:
http://abclocal.go.com/kgo/story?section=edell&id=5469010
Lots of ouches. Not 16 injections, but 6 every two weeks is enough to get anyones' attention. The patient described in the article received chemo after the vaccine. Wonder if that means he will be censured from the trial statistically if he was enrolled in Vital-1 if the chemo was Taxotere or was enrolled in the Vital-2 trial?
Iwfal:
1. Generally, I agree that it doesn’t pay to fight city hall. However, there apparently is an FDA white paper that says that in the last ten years, the FDA has accepted and acted on a positive recommendation for approval from an Advisory Committee some 37 of 38 times and the applicant withdrew its NDA in the one case where there was no approval. Under such circumstances, a procedural appeal should almost have been expected by the FDA. While the non approval on CMC issues might have remained until corrected, a Court might have thrown out the need for additional efficacy data since there will be no other AC on that issue, especially if it was thrown in the CRL by the FDA Reviewer since there would be a delay in any case on the CMC issues, as croumagnon speculated.
2. The hullabaloo over on the IV MB about DNDN shareholders suing the FDA when only DNDN clearly had the standing and opportunity to do so, and over the conflicts of interest of Scher and Hussein, who, after all, openly cast two of the four minority votes against Provenge on the efficacy issue seem irrelevant or tangential at best to a reasonable goal of exploring the action behind closed FDA doors where the law specifies that the FDA can only officially take advice from a validly constituted Advisory Committee.
3. >> Ok. Still not an accepted endpoint. Also note that the FDA is steering away from TTP in general - so going in and trying to modify the SPA, which at that point had survival as the primary endpoint with all the alpha, back to TTP, especially a totally new paradigm of TTP, is completely unrealistic.<<
The CRL reportedly asked for additional clinical efficacy data and didn’t specify that it needed to be statistically significant survival data. Since the 9901 TTP data miss as a primary endpoint under the old rules was the reason that the FDA statistician wouldn’t even answer Scher’s question as to the risk of the survival data being a false positive, if statistical significance for increased TTP were reached with new data from a much larger number of enrollees following the same protocol, it seems to me that would be additional efficacy data that would support the AC's decision to consider the survival efficacy data in spite of it not being the primary endpoint in either 9901 or 9902a. Perhaps there was still another undisclosed reason for the CRL and the FDA's request for additional efficacy data (other than Gold's dismissive comment about human nature) that was a reason why Gold elected to place the BLA on the shelf until the interim look at 9902b survival data.
4. BTW, FYI, I was once a large DNDN shareholder, but presently have no investment long or short in DNDN. I am an attorney and a plaintiff in the 483 lawsuit, but I am not an attorney handling this case. I have spent most of my business career in an entirely different field and have not actively practiced law for many years. If there is any recovery, I will receive the same percentage of recovery proportionate to my losses as any other DNDN shareholder damaged during the class period, as the Federal statute is careful to provide. Under 9th Circuit rules, the attorneys handling such cases are limited to 25% of any recovery. Good firms and attorneys don't take cases where there is little hope of recovery. My belief is that there may be a decent amount of recovery in this case, but that will be up to a Federal judge and jury. I am also unaware of any attorney handling any of the 10b-5 class action lawsuits actively posting on this MB or any other, although I would not have any way to confirm that. If a successful lawsuit causes DNDN to change its way of doing business, existing shreholders could benefit more than from the impact of any uninsured damage award that DNDN might incur itself. Whether or not that happens, if directors did breach fiduciary duties to shareholders, they should be held accountable. JMHO.
>>Name 3 cases where a company has published a 483, redacted or otherwise.<<
1.Google FDA Form 483. Among the tens of thouasand of hits there will be enough Form 483's for you to read to your heart's content. The vaccine operations of Sanofi Aventis and Wyeth tend to be best sellers.
2 >>What percentage are successful? Vs how many build up exceedingly bad blood at the FDA? Given these odds this is not evidence of a meaningful 483.<<
First, should DNDN really care about offending the likes of Pazdur and his trolls from those in the FDA who would have respected the recommendation of the AC? The appeals process and the Federal Admin Code are there for a reason to assure a fair process and eliminate procedural irregularities. If an applicant isn't prepared to defend its basic rights, no one should complain if those rights get trampled. This issue is independent of the Form 483 issue which is a question of inspection facts, not basic procedural rights.
3. >>And even if this were an accepted endpoint there is NO WAY to do it for 9902b patients - who stop being checked after they progress relative to the measurement made at randomization.<<
Go back to the FDA /NCI February workshop where the new paradigm was discussed at length.Patients who progress during the first three months after randomization would be censured; only those who progress later would be counted.
4. Factual evidence not emotion points to the Form 483 and the February FDA preapproval inspection not being disclosed until after the receipt of the CRL and to three directors selling shares who presumably were aware of the pre-approval inspection and its results.
5. >>I'll bet that in a year Gold is still in charge and has not been indicted. << I never said that he would be indicted, although if a Court finds that he improperly profited from the use of insider information, it would be nice to see him disgorge any such profits. Actually, something like 99% of 10-b-5 actions that successfully reach the discovery phase are settled, so managers have many ways to avoid exposure. Here many on the DNDN BOD seem to have even ignored the language of the annual 10K that they signed and sent to the SEC. In the absence of a strong BOD, execs can have a free hand to do what they like. Unfortunately, lawsuits are effectively one of the few tools left to shareholders to correct the situation.
>>Since the filing would not begin until 2006, let's wait till the last minute to get the jersey plant up and running - because Gold etal thought CMC would not be a problem.<<
Actually, I asked Gold just prior to the start of the 2005 ASM whether DNDN was waiting for the results of 9902a before starting work on a production facility. Gold told me that a production facility was not required to file a BLA, only a production plan. That, of course, was incorrect. A production facility has to be in place and ready for an FDA inspection for a BLA to be considered complete.
>>I would tend to trust Urdal who said something to the effect that the mention of the CMC issues in the CR letter was just a reminder to get it done.<<
1. Right. 483 issues are violations of FDA regs, typically involving cGMP issues. Experts report that cGMP inspections concentrate on issues such as recordkeeping, training, maintaining sterile conditions and the like rather than on merely observing operations during the course of the inspection since such "human factors" can easily get out of hand during a step up to large scale production, especially where it's obvious an applicant is intending on a substantial increase in people and equipment post any FDA approval. Follow-up surveillance inspections occur only every two years on the average.
2.Dave Urdal is an immunologist, not a production QA expert, and remedying such people issues might seem minor to him, even thogh the impact in schedule and tens of millions in added costs before first commercial revenues is hardly minor. In addition, Urdal did not sell shares before the 483 issues were disclosed.
2. OTOH, Bogdan Dryzinski (sp?), a selling Director is a retired Quality Assurance Director from Medimmune, a vaccine manufacturer in the same regional district of the FDA's Office of Regulatory Compliance (reputedly the toughest) as DNDN's NJ facility and an officer of a national regulatory affairs organization. Logically, I think that the actions of a quality assurance expert selling shares prior to disclosure of FDA Form 483 issues after a positive FDA AC meeting and less than 6 weeks prior to a PDUFA date says a lot more than the words of an immunologist after those same issues were repeated in an FDA CRL. Ultimately though, these issues will not be decided on a MB, but in a Federal District Court proceeding.
1. The true status of the CMC issues can be easiiy cleared up by publishing a redacted form 483 to remove "proprietary" items and reporting when the FDA has accepted the required written corrective action plan that would have restatrted the PDUFA clock. My guess continues to be that the nature of the 483 problems are those that even when viewed in February would require a follow-up unanounced FDA inspection that taking into account the time for FDA acceptance of a written corrective action plan and the 6 month resetting of the PDUFA clock at that time would have taken DNDN into 2008.
2. I think that croumagnon's response is closer to what may actually have occurred. DNDN could have appealed the FDA CRL with little impact on the much delayed schedule caused by agreeing so rapidly to await the interim survival results and even taken the FDA to court for procedural irregularities under Federal Administrative law. There is probably no other action that could have strengthned the position of Provenge supporters in the FDA and at the NCI, but even if it removed the requirement for further efficacy data, the spotlight would be shifted on the time to resolve CMC issues.
3. There would have also been the possibility of reopening the TTP issue if DNDN hadn't rushed to reaffirm the interim look for survival as the next regulatory event, as allowed in any event by the existing SPA. Under the new paradigm for clinical trials of cancer vaccines and immunotherapies, an initial ramp up period for an immune reaction to become effective(suggested at three months) is allowed, which would have made 9901TTP statistically significant, but was not allowed in 9901(retrospective and long since passed) and would not have helped 9902a. 9902b TTP data, allowing six months from randomization, should be fully mature in early 2008, as should be some early survival data. The Prentice criteria for surrogacy would require that TTP be stat significant, that it be reasonably likely that survival will ultimately also be stat significant at the trial's conclusion and that the cause for the increase in TTP be the cause for increased survival. It seems to me that causation requirement could be met simply by testing long term survivors of 9901 and 9902a for continued reactivity to PA 2024 (OK that still raises the human PAP vs.PA2024 reactivity issue). Since a FDA Accelerated Approval based on such analysis would be equivalent to the conditional approval recommended by the AC, and with a Federal Court looking over the FDA's shoulder, this process would have allowed DNDN to skip the more risky interim survival look with a reduced alpha to await 2010 final data while allowing commercial sales.
4. Since we have so many fine statisticians posting today, a question. Without digging deeply into the reference material, my recollection is that the Petrylak Halabi based analysis of Provenge + Taxotere was based on 81 patients in 9901 and 9902a who took Taxotere and reported that median survival increased by 14 months. Dr. Small's Halabi analysis reported in 10/06 was that the increased median survival of the 9901 was 5.8 months. 202 9901 and 9902a patients took Provenge either initially or on crossover. Putting aside for simplicity's sake any non crossver control patient who may only have had Taxotere, approximately 40% of 9901 and 9902a enrollees would have had Provenge + Taxotere. Simplistically multiplying that 40% by the 14 months increase from Petrylak's data comes to an average for all treated patients of 5.6 months increase in MS per Halabi, which, in tirn suggests that the combination treatment may have been overwhelmingly responsible for increased median survival. DNDN reported that the average time interval between the completion of Provenge treatment and Taxotere for those patients who took both was 4 to 6 months and a full course of Taxotere is a 7 month process, which seems to tie into the period when the survival curves begin to separate. The point of this line of reasoning is that if increased survival is largely the result of the combination therapy, shouldn't that hypothesis be tested in a clinical trial and potentially yield greater statistical significance than the 9902b trial where the use of Taxotere after Provenge in the ITT and control group is uncontrolled? The combination therapy also happens to be much more similar to MOA ideas of the NCI's Drs. Niederhuber and Rosenberg, where chemo is used to deplete Tregs, and of course with the suggested protocol of Dr. Petrylak.
5. BTW, one does not have to be bitter to be disgusted with DNDN's management and to want the very best therapy available to cancer patients as quickly as possible. Insistence on management transparency is hardly a radical idea.
1. If the 483 issues were so minor why did Gold say at the annual meeting that they will take until the end of the year to clear up? Why not report what the 483 issues are now or at the time they were received? Why hide the fact the the pre-approval inspection had even occurred in the annual 10K SEC filing while describing the outcome of such inspection as a material investment risk? A legal presumption under the 10-b-5 securities law that awareness of a negative fact equates to the reason for a sale requires a lot more than that to rebut. With just six weeks to go from the time of the sale to presumed FDA approval and an even higher pps, why the rush to sell? There were just too many Press Releases and Regulatory Filings after DNDN's poor (and only) pre-approval inspection of its production facility in February purporting to report on important events without any mention that it had even occurred to conclude that there wasn't a conscious decision not to report for fear of its impact.
2, There's no question that the access now that every investor has to the internet and search engines such as GOOGLE gives an increased awareness to important material information where many executives would think that no investor would have the knowledge to realize that an insider was using critical inside information to their trading advantage. Did the wealthy ex CEO of Medarex ever think that the spotlight would shine on his backdating of options that lead to his ouster? It's just getting harder for executives to take advantage of their fiduciary obligations to their shareholders to make a buck.
p3analyze:
1. I have no idea what the total amount of damage claims that the various class action attorneys have signed up, nor am I aware of how many plaintiffs may have joined the Susman Godfey "483" lawsuit. The first time that may become known is when the 60 day statutory period from the time the first law suit was filed ends on July 23 and the supervising judge has a hearing to consolidate the actions.
2. Published literature suggests that only about 1% of all successful class action lawsuits ever go to trial, with the vast majority being settled after various legal motions are decided. Settlements can be structured in a number of ways including, for example, a combination of liability insurance payments and the issuance of new shares. It would be highly unlikely that any settlement would culminate in class suitors taking control of a company.
3. I was a great believer in the science of Provenge if not in DNDN's BOD and management. I have become increasingly convinced, however, that the biggest factor in prospective Provenge efficacy is the proper sequencing of Provenge and Taxotere as Dr. Petrylak spelled out last November. Much of this relates to the important complimentary effects of long lived primed memory T cells circulating in a patient's blood and macrophages unleashed on established tumors by the action of Taxotere, as Petrylak pointed out and as work of Ulrich von Andrian of Harvard that was unrelated to Provenge predicts. Since DNDN has all that PA2024 in storage and the FDA is allowing them to ship clinical trial Provenge while they work out production problems, a compassionate use, open label trial using Petrylak's suggested protocol could be a good way to rehabilitate DNDN's science as well as its reputation in the oncology clinical investigator community without burning too much cash. JMHO.
Saul:
1. There are two issues wrt to a 10b-5 action: when is a fact material, and when is there is a duty to disclose?
2. The most straightforward way to establish a material fact is when a company says that it is, as DNDN did in their 10K's when describing any delay in FDA approval wrt to the outcome of a FDA manufacturing inspection as a material investment risk. In addition, the proportion of Form 483's in relation to the number of facilities and surveillance inspections a company handles annually can be a factor. Thus, the only pre-approval inspection of DNDN's only and start-up production facility during a 6 month priority review cycle of their first BLA is a far cry from the hundreds of inspections and many Form 483's that a large pharma deals with over the years (this, for example allowed Abbott off the hook when they received a large fine for not clearing up recurring 483 problems). Was it just a coincidence that the Quality Assurance expert on the BOD was one of the selling shareholders? Another factor is the proximity in time of a regulatory event to another important event with significance to investors. A prediction that a clinical trial will be enrolled during the following year is very different, for example, from not reporting an event near a May 15 PDUFA date that would likely delay FDA approval when DNDN said they expected to launch commercial sales of their first product.
3. A duty to disclose arises when a regulatory event occurs with potential negative impact and is not reported when a company purports to review all material facts to that date and /or an insider or insiders sell shares. There is also a legal presumption that if an insider was aware of the undisclosed fact, that is presumed to be a reason for the sale, A 10b-5 sales program that one of the selling directors filed and sold pursuant to is a good reason for a sale so long as it was filed prior to the bad event; if filed afterwards it becomes a red flag.
4. David Miller may be a fine biotech analyst, but he is no attorney with experience and a record of success in 10b-5 actions.
5. One final observation: If you were the only DNDN shareholder and one of your employees didn't tell you about the failed preapproval inspection, sold $2.7 million of his shares while you believed that he had told you everything of relevance, and later told you at a shareholders' meeting that the Form 483 issue could not be cleared up until the end of the year, which he knew about for 3 months before the PDUFA date and less than two months from the time of his sales, would you continue to trust him, pay him $700K a year in salary and bonuses, and give him another 100,000 options? When is enough enough? The fact that it may have influenced the DNDN desision not to raise funds at a more opportune time and not to challenge the FDA decision wrt to clinical trial efficacy and take Pazdur and his cronies into a Federal Court to explain their actions is just another reason to be ticked off.
BTW, dwightd pointed out in msg 140582 on the IV MB that Gold stated at the ASM on June 6 that the Form 483 issues would be cleared up by the end of the year.So much for their rapid resolution and the fact that they would not be material wrt a May 15 PDUFA date. No wonder that the contents of the CRL and Form 483 have become such a "proprietary" deep dark secret.
1. Not as far as I know. At the followup CC after the CRL, DNDN reported that the CRL letter listed the Form 483 as a reason for not approving. Gold said that they had been working on the issues raised in it since the FDA pre-approval inspection during the week of February 12. I didn't realize until after the CC, that a Form 483, a Notice of Inspectional Observations, is given to a plant manager at the conclusion of an inspection before leaving. It does not list recommendations or guidance but violations of FDA regulations. FDA regulations incorporate tough cGMP standards, and according to Quintiles Consulting, nearly 20% of biotech companies fail their preapproval inspections. There are thousands of references in Google to FDA Form 483's.
2. FDA regs state that if a reinspection is required, the PDUFA clock is reset by one review cycle, six months in the case of a priority review, after the FDA accepts a corrective action plan that is implemented by an applicant.Since cGMP problems tend to be recordkeeping, training errors and the like where promises just won't work, an unannounced reinspection requirement is likely. The DNDN non-disclosure problem is compounded by the fact that in the 10K issued in March and signed by every Director escept Susan Bayh, they not only fail to list the preapproval inspection and its outcome in the Section describing Ongoing Regulatory Activity, but describe the requirement for the inspection as something that hadn't occurred yet. Both the CEO and the CFO certified the 10K per Sarbanes Oxley as being materially accurate.
3. Actually, I assume that there were no leaks of the Form 483 problems, but it is likely that many of the employees in New Jersey and possibly some family and friends knew of them and what they meant while working to correct the problem areas. I just assume that these folks didn't follow the example that the BOD members set, but given the huge trading volumes in DNDN shares, the chances of detection if improper trading had occurred would be minimal.
4. A question for you. Do you think that a few FDA docs who knew about the poor preapproval inspection outcome also noted that DNDN's CEO sold $2.7 million of DNDN shares without telling his shareholders about that problem?
1. Yes. I have zero tolerance for BOD members and execs who are well paid and incentivised and who somehow think that their shareholders / owners are not entitled to know what's really going on in their company that is important and material to investment decisions, whether it be bad or good. The Federal District Court in Seattle will ultimately decide whether the CEO and the two selling Directors improperly profited from their awareness of the undisclosed poor outcome of the February preapproval inspection when they sold shares and whether investors were damaged by such non-disclosure.
2, The point of my last post was that such factors may influence decisions that ultimately may hurt investors and prospective patients in unanticipated ways.
3. While you and I have rarely seen eye to eye, I am reminded of the "summertime event" of 2005, DNDN's July 22 report of the top line results of 9902a as being supportive of 9901 and followed by an impressive Cox analysis of the integrated results, which briefly pushed DNDN's pps over $7. The FDA did an instructive job at the AC in pointing out how malleable a Cox analysis can be, and depending on how it is done yield widely varying results. I doubt whether any serious investor in DNDN wasn't somewhat shocked at the 0.331 Kaplan Meier p value for 9902a that was disclosed in Paris in late October of 2005. You and PGS did raise questions before that disclosure, and of course, that series of events was ultimately followed by a low ball secondary at a pps of $4.50.
There is simply no substitute for intelligent and transaparent leadership especially in an industry as volatile as biotech. Withholding important facts, corporate spin and hype ultimately does no one any good. JMHO.
1.IMO, if the CEO and two directors hadn't sold shares in April while being aware of the undisclosed problems with DNDN's pre-approval inspection during the week of February 12 and the misleading statement in the March 10K indicating that it had not yet occurred, DNDN would have had little to lose in appealing the FDA decision and/or going to court seeking a show cause order under Federal Administrative law. Those sales may have also been the reason why DNDN did not update its shelf registration by disclosing the February inspection and the likely delay in approval and selling shares in April when the absence of FDA contact and last minute labeling discussions made it increasingly obvious that there would be no approval by May 15. Unlike AIPC patients or DNDN shareholders, DNDN itself would have had clear legal standing to seek redress for the procedural irregularities. Since there is a SPA in place for 9902b anyway, there would have been little to lose timewise. Such action would have supported DNDN's friends in the FDA while making things decidely uncomfortable for its opponents. IMO, a Federal judge would be appalled by the obvious trumping of fair procedural standards by backroom letters and politics in light of the recommendation for FDA conditional approval by a FDA appointed Advisory Panel and the facetious reommendation by Hussein and others that Provenge be made available on a compassionate use basis, but not be paid for it. A cross examination of Pazdur and vE would probably have been Washington theater at its best. The conflict of interest issues of Scher and Hussein raised by so many DNDN shareholders would be of little concern since they were officially waived by the FDA and the two were overwhelmingly outvoted.I think the TTP endpoint miss in 9901 would also be of little concern since it would have been stat significant under the new rules, but the p value of .0046 for 9901's tripling of 36 month survival of the ITT vs. controls, supported by 9902b's doubling would have impressed any judge.The need of AIPC patients for new therapies would probably be conceded.
2. IMO, the outcome would have been an elimination of the CRL requirement for additional efficacy data, but a continued delay in any FDA conditional approval (pending completion of 9902b) until DNDN got its CMC issues under control, which, IMO will probably involve a facility reinspection by the FDA and as much as another 6 to 9 months to clear up. A decision would have eliminated the need for an interim look at 9902b and increased the likelihood of Regular Approval in 2010 when the full alpha could be used on 36 month data.
3. Such outcome, for better or worse, would have had the effect of focusing a major spotlight on the CMC problems and the whole issue of their non disclosure and subsequent insider sales. Under the present circumstances, the PDUFA review clock will not be reset until the interim look at 9902b data so corrective action at the NJ facility is technically no longer material so long as it's finished over the next year or so.Ironic isn't it how circumstances can line up so that the interests of Pazdur and some DNDN insiders once so diametrically opposed are now effectively aligned? All JMHO.
walldiver:
You may have better info, but the CEGE GVAX prostate vaccine Phase 2 study posted at at ASCO 2006 by Drs. Small, Higano and others reported better median survival when actual numbers were compared to the Halabi predictions than the 5,8 months that Dr, Small reported in 10/06 for the 9901 trial, that the Ph3 dosing requires two injections on a biweekly basis for 24 weeks and that all Vital 1 enrollment will be in North America. Considering CEGE's strong connections with Novartis. John Hopkins and Harvard, I imagine they will get help with enrollment and money. Also while Vital 1 doesn't have a crossover prorocol to Taxotere, I believe that the trial is uncontrolled after the vaccine dosing is completed much like the Provenge trials, allowing docs to prescribe Taxotere or other taxane. Also, their April analysis of the antibody and antigen reactivity precipitated by their vaccine was scientifically impressive. DNDN moght have delivered a near knock out blow to CEGE if Provenge had been approved, but some feedback that I have been getting is that they are definitely back in the game.
“Of interest, those patients who developed an immune response to native PAP had a longer time to disease progression (TTP; 34 weeks v 13 weeks; P = .03).” From Dr. Small’s Phase 2 report.
“The PA2024 T-cell stimulation index is a measure of specific T-cell responsiveness against the target antigen. This exploratory analysis was performed in a subset of patients for whom cells could be processed within 24 hours of collection, thus precluding the need to freeze the cells before analysis. All analyses were performed before study unblinding. The median ratio of the T-cell stimulation index at 8 weeks versus baseline (preinfusion) was approximately eight-fold higher in sipuleucel-T- versus placebo-treated patients (16.91 Wilcoxon v 1.99; Wilcoxon rank sum P < .001).’ (Emphasis mine)
1. These remarks are quoted from last July's JCO article by Small et al. The Phase 2 study by Burch et al from the Mayo Clinic published in 2004 in The Prostate commented on the difficulty in getting any T cell stimulation to human PAP in Provenge treated patients, suggesting several possible reasons for it. Dr. Small never explained how a reaction to PA2024 is “a measure of “ human PAP. This issue was pointed out in the FDA Briefing Materials. The follow-up question at the AC as to why there is little or no T cell stimulation to human PAP was entirely predictable. When asked, DNDN did not even have a hypothesis to explain it.
2. The new AACR article is interesting in that the authors, all NCI docs, were heavily involved in the failed Therion prostate cancer vaccine and probably in many of the some 30+ therapeutic cancer vaccines that the NCI has tried without success over the last 10 or more years. The scientific analysis of the antigen cascade effect of the Phase 2 trial of the Therion PROSTVAC vaccine targeting PSA was first rate, even if the results were less so, showing that it also targeted human PAP and three other AIPC antigens, but with even less avidity than its 3.3 T cell stimulation index against PSA. In comparison, all the Provenge T cell stimulation index data against the PA2024 antigen, which is after all not native to the human body, is far higher, but what does it mean? Since DNDN’s entire antigen cassette technology relates to joining cancer antigens with GM-CSF in large fusion molecules, one would have thought that this issue would have been exhaustively studied.
3. Dr. Niederhuber, the head of the NCI gave a great talk at the opening of the second day at the FDA / NCI workshop, where he predicted that the first successes for cancer vaccines and immunotherapies would come in combination therapies. Even the renowned Dr. Steven Rosenberg, mentor of Dr. Mule' of the Provenge AC panel, and his NCI associates use chemo and radiation to deplete Tregs to enable their genetically engineered adoptive T cells to cause partial and complete remissions in some 50% of their end stage melanoma patients having large well vascularized tumors. His adoptive T cell protocol only targets one melanoma antigen. However, it is remarkably successful against all established melanoma tumors, suggesting that it is uniquely expressed in all such tumors, or, alternatively, that it is also assisted by the antigen cascade process the AACR authors describe. Rosenberg makes no secret that his adoptive T cell protocol should be applicable to all epithelial cancers, including prostate cancer. The need to break a patient’s tolerance to established tumors to make immunotherapies effective regretfully for patienrs does not equate to the more benign “silver bullet ”prospect of three doses of Provenge with flu like side effects being all that is necessary for substantially increased survival. It does, however, reflect the complex, dynamic biologic system that our immune systems are. The AACR article reflects the probability that Provenge, as a stand alone therapy, like many other therapeutic cancer vaccines, may extend survival for some without causing the regression of established tumors, but that does not necessarily equate to establishing statistical significance when applied broadly to larger groups in the absence of supportive combination therapies.
4. The likely truth is that assuming Provenge primes T cells against some antigen characteristic of AIPC cells and assuming that these primed effector CD8 T cells continue to circulate for relatively long periods in a patient's blood, the T cells still require combination use with Taxotere or some other adjuvant to allow them to extravasate from blood toward target tumor cells and overcome established Treg defenses. This was a primary element in Dr. Petrylak's presentation last November recommending a new Provenge protocol utilizing Taxotere after Provenge and therafter followed with a Provenge booster. Petrylak pointed out that Taxotere’s initiation of macrophage attacks on AIPC cells may be synergistic with a vaccine primed T cell attack. If anyone thinks that an increase in median survival for the Provenge + Taxotere combination of 14 months as compared to the Halabi projected survival for those not taking that combination for the 81 patients who took both therapies in the 9901 and 9902a trials had no effect on Provenge's long term survival results, there's a bridge in Brooklyn for sale.
5. Where does this leave AIPC patients? CEGE is conducting a 600 patient Phase 3 Vital 1 trial of GVAX for prostate cancer vs. Taxotere, as well as a 600 patient Vital 2 study comparing GVAX + Taxotere against Taxotere alone, in both cases with survival as the pimary end point. While both trials are enrolling slowly, they also provide for interim looks. My prediction is that Vital 1 may be marginally statistically significant, while Vital 2 will definitely be so. Even the Therion PROSTVAC data showed that its use prior to Taxotere increased TTP over either alone, and probably will ultimately show some increased overall survival. Combination therapies will be vital in the development of all immunotherapies. While they might not eliminate chemotherapies, they will reduce and optimize their use. Before long, the NCI and Dr. Rosenberg’s genetically engineered adoptive T cells will be tested in critically ill AIPC patients, achieving prior Treg depletion with chemotherapy. DNDN should back Dr, Petrylak in an open label salvage trial since his analysis and suggested protocol is many years ahead of that used in 9902b and points to the role that Provenge, used in a combination therapy, can play in prostate cancer over the long term. Competition is definitely coming. Then again, the absence of Drs. Small and Petrylak at the AC and their silence since then is hardly reassuring. Have the attacks of Provenge supporters on fellow clinical investigators in oncology who lead studies of different therapies and the silence of DNDN in calming the rhetoric gone on for too long?
6. Fascinating science and all JMHO. Since this is a national holiday for all Americans I will not comment on DNDN’s BOD and CEO, but simply wish everyone, especially our service men and women and their families, a great 4th of July.
I have no position in DNDN, but have great respect for walldiver, ocyan and many of the other posters on Ihub, so I will depart from my intention not to post and make a few comments on the science and MOA of Provenge:
1. The multi institution rapid auropsy program in AIPC showed that patients died from slow growing metastases in visceral organs that were largely undetected until the autopsies.
2. The Provenge clinical trials exclude patients with known visceral mets, but as noted above, most are undetected in any event. Logically, sicker patients could be expected to be more likley to have undetected visceral mets.
3. Any immunotherapy based on adoptive T cells or the priming of T cells by dendritic antigen presenting cells, such as Provenge, is subject to the body's immunosuppressive effects, primarily caused by regulatory T cells, assuming, of course, that the T cells last long enough in vivo to be impacted by Tregs.
4. Provenge itself might have some impact on metastacizing PC cells unprotected by Tregs, but acting alone, IMHO, it is unlikely to be able to overcome the Treg defenses of established tumors. This appears to be substantiated by the absence of any statistically significant impact of Provenge (or of any experimental therapeutic cancer vaccine acting alone)on eliminating known lesions. If in later stage patients the mets have already been established in visceral organs, but remain undetected, the prognosis for any Provenge only treatment would be poor.
5. Dr. Niederhuber, the NCI chief, stressed at the FDA / NCI workshop that the first FDA approved immunotherapies would likely be combination therapies. The efforts of the NCI's Dr. Rosenberg and others suggests that a primary goal of combination therapies would be to deplete Treg defenses. Any analysis of the Provenge MofA and the combination effects with Taxotere suggests that this need to overcome Tregs will also be true wrt to Provenge.
6. Crossover Provenge made from thawed white blood cells does not appear as effective as Provenge made from fresh white blood cells, presumably giving the ITT patients a therapeutic as well as timing advantage over control patients. However, after an ITT patient or crossover patient receives Provenge, his therapy choices are no longer controlled, although survival continues to be monitored. The nature and timing of any post Provenge therapy for 9902b patients between ITT and placebo patients may have a substantial impact on survival statistics, especially in the case of sicker patients where quicker and more dramatic rescue is vital.
7. The fact that natural PAP does not precipitate a strong T cell stimulation response, as Dr. Burch of the Mayo clinic reported in his Phase 2 report, and that the reported strong T cell proliferation data resulting from Provenge therapy is only to the fusion antigen was an obvious question to expect from the AC panel (BTW, I emailed DNDN to expect this), and was raised in the FDA Briefing Materials, but inexplicably when DNDN presenters were asked this question, they did not even propose an hypothesis to explain it (as Dr. Burch himself had proposed). DNDN was also asked at the AC meeting for some suggested biologic marker to differentiate those who would benefit from Provenge from those who might not, a question also asked at the AC panel for Xinlay in AIPC. Dr. Petrylak asked the same question at the BIO2007 conference, to which Gold responded by suggesting that CD54 upregulation was such a biologic marker. Thankfully, Dr. Prevost cleared that misunderstanding up at the AC meeting by pointing out that CD54 upregulation was only a manufacturing potency marker and not a biologic marker, but neither she nor any DNDN presenter could offer any possiblities for a single or composite biologic marker predicting therapy success for a given AIPC patient.
8. In the absence of any DNDN hypothesis or substantiated explanation of its MofA, the AC panel was left to rely on mixed statistical support. The 13-4 vote on substantial evidence of efficacy was heartening in that regard, and in the absence of the unacceptable CMC preapproval inspection of DNDN's NJ facility, might have carried the day. When faced with CMC delays in any event, it was not surprising that a conservative and risk averse bureacracy such as the FDA would ask for more clinical efficacy data while CMC issues were being resolved. Remember that it was not only Drs, Scher, Hussein and Fleming that objected to the statistical basis for the AC vote in the Cancer Letter, but also the incoming President elect of ASCO.
9. For the sake of every AIPC patient, I hope that DNDN is working hard to provide a well substantiated MofA to support any mixed statistical data from its future interim survival analysis. DNDN, its patients and shareholders, should appreciate, however, that the relative impact of follow-up therapies (Taxotere, other taxanes, CTLA-4 blockers, etc.) may have unpredictable impacts that extrapolation of statistical results from the 9901 and 9902a trials to projected 9902b results may not account for.
10. I will once again withdraw from active posting, but I very much appreciate the science, statistical and other solid debate that Ihub posters now seem uniquely inclined to bring to any analysis of DNDN and Provenge.
rancherho
Just wondering in light of the continuing heavy volume if anyone has any good reason why DNDN doesn't just pay some IB a small fee to sell the balance of the shelf registration into the market. If, as is likely, DNDN must wait until next year at the earliest to get usable data from an interim 9902b, the market realizes that and the volume dries up, a delay could make last year's $4.50 secondary pricing look good.
This post and the video link by dendreonrich on the IVillage MB is worth repeating for IHUB readers.
Uncut video
http://uncutvideo.aol.com/videos/639d0c2859cb46f2d4962c47388b36c9
There is apparently no sound track with the video. My separate commentary follows:
dendreonrich:
1. It seems that the first part of the video is the activities of Mr. Garcia, a long term AIPC survivor treated with Provenge, who spoke with Gold during a presentation at last year's ASM.
2. One of the processes shown is centrifuging. According to Dr. Small's Phase 2 report on the "method of Hsu" processing, this is done twice with a patient's leukapherisis product, and the result is washed after each centrifuge step to remove platelets. The resultant "immunity pellet" is then shown placed into a container with other growth media and some 10 micrograms per mL of the fusion antigen is injected into the solution that is then pulsed under proper heat and mixing conditions for 40 hours to expand the number and mature the dendritic antigen presenting cells. After another washing step, the product is then diluted with "Ringers solution" to make a readily infusable product (likely the final plastic bags being shown being placed into a freezer). The lab work done thereafter is probably just to illustrate the quality assurance testing done before its release to a clinic. The whole video appears to be shot at DNDN's Seattle facility.
3. This is the first that I have seen various steps in this process. I was told that one of the beauties of the process is that DNDN's processing, independent of the production of the fusion antigen, is its relative simplicity. Although processing is done on an individual dose basis, disposable plastic bags and containers are used in clean room conditions, so the required sterility and product purity is maintained, and yet, the process is relatively inexpensive and easily scalable. When I inquired about the possible use of some of the NCI's sophisticated T cell genetic engineering processes for the 50% of the Provenge dose that are T cell precursors, the response was that that might be tried in the future, but that the very simplicity of the present process and its applicability across a wide range of cancers with different antigens to achieve an initial plateau of efficacy for all addressable cancers strongly suggested that DNDN should rapidly try to get their vaccines in first use across many cancers while increasing efficacy later through more difficult and expensive processing steps. This uncut video seems to support this strategy.
4. This video was shown in the 2005 ASM. My concern with the message of the video is with the likely most expensive part of it, the artist's rendition of the process of the dendritic antigen presenting cells priming of T cells to attack cancer cells in vivo. The problem is that it is so simplistic that it does nothing to distinguish the fundamental differences in the method of action of DNDN's autologous vaccines, and that of the vaccines prepared in bulk for all patients using allogenic vaccines, recruiting dendritic cells at the site of injections, such as the GVAX vaccines of CEGE and the vaccines of Onyvax. Also, neither the video, nor DNDN itself, make any reference to the critical role that regulatory T cells play in the process, nor of the great strength of the DNDN approach, the longevity and persistence in vivo of the primed T cells as was reported with early results from the P11 trial. Minor criticisms on what if finsihed and polished could be an extremely valuable informational tool.
5. Overall, my congratulations on a fascinating and valuable post. You demonstrate once again how valuable the information that can be accessed through internet MB's can be.
Good luck to all DNDN longs.
Walldiver:
1. In addition to acceptance of the Provenge BLA as apparently complete, the FDA Priority Review decision is interesting for a couple of other reasons: (1)CBER requires a pre BLA inspection of a proposed production facility. While this might be no big deal for a J&J, Abbott and the like who manufacture drugs in existing facilities, it is a big deal for a new autologous biologic since the basic product characterization issue has sunk previous therapeutic vaccines, and the potency, purity and stability issues that DNDN's quality assurance protocols must have addressed may have been unique and the first of their kind to be inspected by the FDA.I'm assuming, of coutse, that no show stoppers were present.
2. The second issue concerns whether any FDA Provenge approval was going to be held up until the 9902b clinical trial was fully enrolled, and would become a Phase 4 post marketing approval trial. The 9902b figures presented as part of Dr. Provost's 2/9/06 presentation to the CBER CTGT Advisory Committee suggested that 9902b enrollment may have only been at the 20% or lower level at that point. IMO, completion of 9902b enrollment, described initially as being expanded for compassionate purposes, has declined in importance. If the March Advisory Committee is largely selected by CBER, as I believe that it will be, a highly likely and strong recommendation for FDA approval, FDA approval in May may be virtually assured. Recent comments by Dr. Daniel Petrylak on studying optimal sequencing of Provenge and Taxotere suggests that he may believe that Provenge booster dosing and less than full courses of Taxotere may provide equal or better results than the one year increases in median survival that Taxotere following Provenge achieved in the 9901/9902a trials. The FDA and DNDN likely realize this, as will an Advisory Committee, which in many ways, suggests that different clinical protocols could rapidly obsolete the 9902b trial protocol and further improve upon 9901/9902a efficacy. JMHO.
Good luck to all DNDN longs.
Glaxo's Tykerb appears to be a bigger competitive threat (and potential benefit for breast cancer patients) to both DNA's Herceptin and DNDN's Neuvenge. See:http://yahoo.reuters.com/news/articlehybrid.aspx?storyID=urn:newsml:reuters.com:20061214:MTFH96037_2...
1. The median survival for both the Cumulative CD54 Cell Counts above median and for Cumulative CD54 Upregulation both appear to be approximately 30 months, but the Cell Count 36 month survival rate appears to be about 35% vs. the Upregulation survival rate of 45%.
2. The median stimulation index (T cell proliferation) when challenged by the PA2024 fusion antigen in the P11 trial measured 21 months post Provenge therapy and prior to a booster shot was 93.7 and when measured 13 weeks after the booster was 221.8. It's intriguing to consider the possible effect of such Provenge booster shots in further improving survival in AIPC.
3. For those of you into heavy duty science lectures and interested as to where all of these CD54 mature dendritic cells processed from peripheral blood monocytes go after infusion, the following lecture (with the assistance of pen, paper and the rewind key) is fascinating:
Migratory Properties and Immunological Consequences of Dendritic Cell Migration
Wednesday, October 25, 2006
Uli Von Andrian
Total Running Time: 01:03:39
http://videocast.nih.gov/PastEvents.asp?c=28
4. View this in the context that the NCI/Therion Phase 2 report on the PROSTVAC fowlpox based vaccine targeting PSA had a median stimulation index of 3.3, and that Dr. Rosenberg of the NCI was required to genetically engineer T cells used in adoptive cell therapy against melanoma to overexpress IL-2 and IL-15 in order for them to persist in vivo for more than 48 hours.
5. Dr. Von Adrian's data suggests that dendritic antigen presenting cells derived from blood monocytes accumulating in bone marrow, cannot enter the thymus, and are thus not subject to deletion/negative selection there, and are a source of long term memory T cells. The P11 data clearly suggests that monitoring a patient's T cell proliferation data as a function of time and boosting as it declines may be quite beneficial. Thus, the source of the progenitor cells as well as their CD54 expression characteristics might be of fundamental importance. For example, skin derived dendritic cells recruited at injection sites by the Therion, CEGE's GVAX and Onyxax's prostate cancer vaccines may be unable to stimulate such robust T cell proliferation and to maintain it over such long periods.
6. At the end of the Von Adrian lecture, he shows a real time video of fluorescently tagged cells (using B cells expressing a target antigen) to show how regulatory T cells prevent CD8 effector T cells from staying attached to target cells long enough to empty their destructive compounds into the target cell. This reduces their killing effect by a factor of 7. This impressive demonstration suggests the importance of controlling T regs, possibly with antibodies against CTLA4, PD1, LAG3, or ONTAK and Treg depletion strategies. The synergistic effect of Taxotere might also be related to its possible preferential destruction of Tregs.
7. IMHO, looking at the larger picture that this immunology data suggests, the ex vivo processing and maturation of blood monocytes creates a uniquely powerful T cell reaction, likely only modulated by Tregs. If so, with Treg control therapies advancing through various clinical trials, the potential for combining such adjuvants with DNDN vaccines appears extremely promising. JMHO.
Good luck to all DNDN longs.
1. All of us, myself included, are trying to interpret the Cumulative CD54 Upregulation vs. Survival data in the absence of enough information and analysis. DNDN has yet to post the data and analysis presented by Dr. Urdal on its website. The P11 trial in ADPC commenced after Provenge's Ph2 data in AIPC was known, but before any Ph 3 data in AIPC was unblinded, and yet, provides for booster dosing. It might be a great idea if some analyst asked Gold during the Q&A after Wednesday's CC to address some of these issues: (a) Expand on Drs. Urdal and Provost's CD54 upregulation presentations (eg. the exact meaning of "Cumulative" CD54 upregulation - Would an additional dose increase the "Cumulative" value as that word is used?); (b) Does DNDN believe that additional doses in AIPC beyond 3 would be beneficial? (c) If not, why not? (d) if so, why didn't DNDN change 9902b's protocol to provide for additional doses?
Good luck to all DNDN longs.
PGS:
1. It would be interesting to hear your description of the biologic method of action to explain how 2 trials that fixed doses to 3 in the first month of a trial followed for 3 years on the basis of Ph1/Ph2 T cell proliferation data measured in the first few months, which ultimately ultimately was not stat significant for survival, now depends on patient specific CD54 upregulation measured ex vivo before infusion on an individual dose related basis as opposed to the Cumulative CD54 upregulation vs. Survival that DNDN has actually plotted, rules out the simple expedient of increasing the number of doses over time to increase the cumulative treatment effect in terms of numbers of antigen primed CD8 effector T cells and their resulting in vivo persistence.
2. Drs. Urdal and Provost reported that Cumulative CD54 Upregulation was stsistically significant for increasing survival with a Kaplan Meier log rank p value of 0.01, the same p value as the 9901 trial, which increased to the p value of 0.002 when deaths were limited to AIPC specific mortality, and when the 225 patients in the integrated 9901/9902a database were analyzed using a Cox regresion analysis, the p value dropped further to 0.006. Please explain how and why you would further modify the 9902b trial to satisfy your statistical curiousity, while many AIPC patients would have shortened lives while awaiting its outcome.
3. My reference to "profound truth" was, indeed, a spoof, but if you have some of the real stuff, please enlighten us.
Good luck to all DNDN longs.
b
Deleted. Just my deleted reply to your deleted erroneous reply to my posted recap of profound truth.
io_io:
1.p3analyze responded to my intial question in Ivillage about a Cox regression analysis being the primary statistical anaysis method in 9902b rather than Kaplan Meier, and the impact on his projection regarding the number of events required to reach a p value on the basis of Cox regression analysis results equivalent to that of the combined 9901/9902a integrated as follows:
Re: 9902b event target and timing
Thank Rancherho - yes - the Cox regression adjusted hazard ratio is 1.8, ie 80% prolongation of median OS, or close to 50% reduction in risk of death, powering the study at 90% would only require 1definitely will require only 122 events (scary thought - I have to go back to my event curve to find where they are at - I wouldn't be surprised that can be reached at in early 2007).
But for practical consideration, the more events, the higher the likelihood of success. If I were designing the trial, I would probably stick with 1.5 to be conservative. But one efficacy interim anlaysis at the end of accrual should have a good chance of success, if one could assume a hazard ratio of 1.8. Prod me more, so I could think more. Thanks.
His comment signing off on IHub today that DNDN seems to have positioned itself well with 9902b seems right on. The Provenge BLA skeptics including UBS's Maged Shenouda and a couple of notable IHub posters believe that statistically significant efficacy results of 9902b will be required for FDA Regular approval of Provenge and that the FDA will only issue an approvable letter on the the present BLA. UBS's further assumption was that 9902b results would not be mature until 2009 justifying its $3 target. Earlier this year, Gold projected that 9902b enrollment would be completed by the projected FDA approval in 1H07, and that based on unblinding upon reaching its projected number of events, it would be unblinded in 1H08. It would seem that if statistical significance using the Cox regression analysis is likely to be achieved in 9902b in 1H07, and the FDA was actually considering only issuing an approvable letter, they would allow DNDN to unblind 9902b upon full enrollment, and if it achieved statistical significance, grant immediate Regular approval. Therefore, the implicit assumption for those believing that only an approvable letter will be issued in response to the submission of the BLA, would seem to be that the Cox regression results of the integrated 225 patient 9901/9902a database are bogus since the smaller 127 patient size of the 9901 trial alone or concerns about TTP being the initial 9901 trial primary endpoint would be irrelevant.JMHO.
Good luck to all DNDN longs.
Re: 9902b event target and timing
p3analyze:
1. You have abundantly demonstrated your knowledge of biostatistics in the past (the musing about the 4 Prentice criteria for surrogacy being a great example), and I am defintely no statistician, so what follows is a question regarding your analysis.
2. The statistical significance of 9902b is to be determined by the Cox regression analysis where we know the pooled 225 patients 9901/9902a p value was 0.0006 vs. the Kaplan Meier p value of 0.011, in spite of a placebo crossover rate somewhat in excess of 70% It would seem to me that if one assumes the same treatment effect and event rate for 9902b as for the pooled 9901 and 9902a enrollees, the target p value threshold of 0.05 would be reached with substantially fewer events than if a Kaplan Meier derived p value was needed. Would this be true?
3. Although not exactly on point for 9902b since any trial unblinding will likely only be precipitated by reaching a prespecified number of events event, the following citation points to a somewhat comparable case where trials were stopped short of full planned enrollment due to unexpectedly high treatment effects, a caveat being that statistical data can have spikes during the trial period and stopping a trial short of full enrollment could be precipitated by such a spike.Randomized Trials Stopped Early for Benefit A Systematic Review http://jama.ama-assn.org/cgi/content/full/294/17/2203
4. A Cox regression analysis corrects, of course, for certain prespecified variables that its calculations determine to be statistically signficant at a set rate (p=0.05 in 9901/9902a, p=0.010 in the Taxotere TAX327 trial). In the 9901/9902a trials, treatment effect was the most statistically significant. If one assumes that the placebo crossover for 9902b might increase from somewhat over 70% to 80% in 9902b due to an enlargement of the acceptable patient enrollment criteria, there could be 100 true placebos in the final 9902b trial. Both ITT and crossover placebo patients would receive Provenge, and thus have data to calculate their cumulative CD54 cell counts and cumulative CD54 upregulation. There should be some analysis that could be done, admittedly retrospective, that would censor non AIPC deaths, include the crossover patients in the ITT group and then calculate and plot a sensitivity analysis of the impact of the spectrum of the new ITT group's cumulative CD54 cell count and cumulative CD54 upregulation on survival vs. true placebos where the underlying Cox regression analysis has preumably corrected for the relative health of all enrollees. It seems to me that this would suggest where increasing initial Provenge dosing might be appropriate. Subsequent booster dosing probably would require some ongoing immunity monitoring, including T cell proliferation, memory T cell and Treg levels.
Just a thought.
Good luck to you and to all DNDN longs.
Wall:
1. You were right the first time. If a Provenge dose for an ITT patient did not meet the minimum CD54 potency standards, and an additional leukapherisis was required, the trial enrollee and his doc would likely consider that the patient was in the ITT arm. DNDN could, of course, cover their tracks by asking for some extra leukapherisis from placebo patients, but that might be frowned upon ethically. My impression from Dr. Provost's transcript comments was that this is a rare occurrence and likely was not considered material in clinical practice.
2. When I inquired about 8015F given to placebo patients on crossover, I was told that the blood white cell product of each of their 3 leukapherisis was frozen, and then upon crossover, each was thawed and then processed individually as needed for each of the three crossover doses.
Good luck to you and all DNDN longs.
Composition of the FDA’s CBER Cellular, Tissue, and Gene Therapy (CTGT) Advisory Committee
1. DNDN’s Dr. Provost made a presentation on DNDN’s CD54 potency QA release marker to the presently constituted CTGT Advisory Committee on 2/9/06, which a review of the Transcript seemed very well received.See: FDA link to 2/9/06 presentation of DNDN’s Dr. Nicole Provost to CBER’s Cellular, Tissue and Gene Therapies Advisory Committee (Transcript and Slides)http://www.fda.gov/ohrms/dockets/ac/cber06.html#BloodProducts
2. In 9/05 post the FDA / DNDN pre-BLA meeting, Gold mentioned the possibility of a hybrid Advisory Panel. Considering that Provenge will be the first therapeutic cancer vaccine coming before an Advisory Panel, IMO, the likelihood of a hybrid Advisory Panel where oncologists and possible immunologists would replace the members of the Advisory Committee who really are not experts in the relevant specialties is great.
3. Look at the composition of the Cellular, Tissue and Gene Therapies Advisory Committee at: http://www.fda.gov/cber/advisory/ctgt/ctgtmembers.htm
4. Six members have immunology (IM), oncology (ONC) or biostatistics (STAT) experience relevant to Provenge’s BLA: (a) Dr. Mule’ (IM, ONC). (b) Dr. Kwak (ONC), (c) Dr.Urba (ONC), (d) Dr. Gerson (ONC), (f) Dr. Chappell (STAT), and the non-voting industry rep, Dr.Gunter (Cellular Therapy).
5. 8 members really do not have relevant ONC, IM or Cellular Therapy expertise: (a) Dr. Allen (Veterinary), (b) Dr. Calos (BIO/GENETICS), (c) Dr. Taylor (Cardiovascular), (d) Dr. Guilak (Orthopedics), (e) Dr. Tomford (Orthopedics), (e) Dr. Chamberlain (Gene Therapy), (f) Dr. Woo (Gene Therapy), and (g) Sharon Terry (Genetics) non-voting consumer rep.
6. I still believe that Dr. Raj Puri of CBER, who has been involved with DNDN since the beginning, will probably be the lead FDA doc. The CTGT panel’s Chair, Dr Mule’, an oncologist and immunologist, who, I believe, worked at the FDA at the time of DNDN’s initial Ph 1 trial, will remain and may have a substantial say in the appointment of any temporary members. The FDA may go to Dr. Pazdur of CDER, however, to nominate substitute members. FDA Chief von Eschenbach might also appoint some NCI immunologists / oncologists as temporary members.
7. In any event, the composition of the Advisory Committee members will be quite important given the importance of receiving a strong endorsement prior on any final FDA approval and the resulting effect of such endorsement to DNDN’s ability to raise launch funds at attractive rates. The timing of a Provenge Advisory Committee meeting and the designation of its composition will probably depend on the pre-BLA FDA inspection of the DNDN NJ facility going on now, and completion of the BLA.
8. Does anyone have any inputs on if and how previous temporary hybrid Advisory Panels were handled?
Good luck to all DNDN longs.
Ocyanblue:
1. Dr. Small and his coauthors of the Phase 2 report in the 12/2000 JCO also discussed the choice of CD54 and the other CD markers that were used to characterize a dose of Provenge. http://www.jco.org/cgi/content/full/18/23/3894 CD54 was known as a maturation marker for immature dendritic cells and peripheral blood monocytes, indicating that these cells had taken up the fusion antigen and become antigen presenting cells. My guess is that Dr. Prevost’s remark about being “lucky” had more to do with the strong correlation of CD54 upregulation with long term survival than wrt any blind guess as to its use as a potency marker. I would also imagine that every panelist on the CBER Advisory Committee would have been well aware of the enormous amount of effort that DNDN would have expended to advance Provenge as far as it had come.
2. In retrospect, there is little doubt that both analysts and DNDN itself was pleasantly surprised by the results of DNDN’s interim look at 9901’s median survival in late 2003, and DNDN’s look at the final 36 month 9901 survival results in October 2004, especially after terminating 9902a early in 2002, and commencing a 9902b trial limited to Gleasons 7 and below AIPC patients. Could DNDN have been too hasty in writing off TTP as a valid surrogate marker for overall survival and therefore as a basis for FDA Accelerated Approval? That question was seemingly answered in January 2005 when DNDN reported that an analysis of 9902a’s TTP showed that it was not statistically significant, overall or for any subgroup (eg, GS=<7). It did not take some analysts and major institutions long to surmise that TTP in the slow enrolling 9902b trial would ultimately fail to show statistical significance for TTP, with devastating consequences at the time for DNDN’s pps. Interestingly, as an aside, Dr. Kantoff’s ASCO 2006 video presentation on the randomized, blinded 125 patient Ph2 trials of the Therion / NCI prostate cancer vaccine in AIPC, which ultimately failed to show statistical significance in either TTP or overall survival, also mentioned that enrollment in their trial was limited to GS=<7 due to the Provenge 9901 TTP results. Given these twists and turns in Provenge’s clinical trial history, it’s not a stretch to describe the unexpected, and to a certain extent, unplanned statistically significant 9901 survival results as “lucky”.
3. At the risk of sounding like a broken record, the NCI’s spoken and published observations / questions as to how any vaccine that fails to kill sufficient cancer cells to cause significant numbers of objective tumor responses or complete remissions early on can increase long term survival is more than theoretically relevant. If Provenge’s method of action explains that apparent inconsistency, it also destroys the significance of TTP as a surrogate for survival and as a primary endpoint in Provenge’s clinical trials, no matter what statisticians may argue. This would not only provide obvious benefits in the regulatory process by reducing any lingering uncertainty about Provenge's impact on long term survival rates, but suggest ways that Provenge efficacy might be further improved.
4. A working hypothesis is that high levels of regulatory T cells blunts the initial Provenge effector phase immune attack, but that CD54/ICAM-1 expressing dAPC’s preferentially create memory T cells primed against the PAP antigen in secondary lymphoid tissues. When these memory T cells are challenged by AIPC cells metastasizing to visceral organs, not protected by high regulatory T cell levels, the resulting activation and proliferation of memory CD8 T cells destroy the metastatic AIPC cells. There are several immune diagnostic tools available to test, and validate or not, this hypothesis. Whether this hypothesis or another explains Provenge’s method of action, one would expect the very capable Dr. Urdal to provide some data, analysis and discussion as to how Provenge’s cumulative CD54 cell count infused and/or CD54 upregulation can impact its method of action and correlate to long term survival in AIPC in the absence of demonstrated short term cytotoxicity against AIPC. In any event, its all to the better if luck accompanies DNDN’s choices and hard work.
Good luck to all DNDN longs.
Wall:
No. Just looked at the ASCO videos yesterday. According to an I village post, DNDN's Dave Urdal is scheduled to make a presentation on Provenge's potency marker in January 07. Hopefully, in the 11 months elapsed at that time since Dr. Provost's presentation, there will a lot of additional data and analyses done.
Good luck to all DNDN longs.
Walldiver:
1. I certainly don't want to take anyone's nose away from their chosen grindstones to consider the future, but there are several points covered by the ASCO videos that touch on issues that are relevant now.
2. Therion's conducted a blinded, randomized Ph2 trial of about the same size (125 vs. 127 enrollees)as the 9901 Provenge trial, with the same 2:1 ITT to control ratio. Their trial used a vaccine targeting PSA with a TRICOM adjuvant (CD54/ICAM-1, LFA and B7) that was in development in conjunction with the NCI for over a decade. Dr. Kantoff can criticize 9901 as being a small trial, but in spite of all Therion's perceived advantages, it failed to achieve statistical significance for either TTP or survival.
3. While the use of allogenic vaccines such as CEGE's GVAX may ultimately provide clinical benefits, they represent, to some extent, a roll of the antigen dice since there is little, if any, control over the antigens taken up by the dendritic cells recruited at their injection sites. The use of MDX-010 with them and the greatly increased immune DTH reactions at the injection sites emphasize that point.
4. The comments of Dr. Charles Drake of John Hopkins, IMO, are particularly noteworthy. They are the first that I've heard or read discussing the issue that the level of regulatory T cells in prostate tissue in AIPC, capable of rendering attacking CD8 T cells anergic, is 3 times the level in normal tissue. That would go a long way towards answering the NCI's oft repeated critique of all therapeutic cancer vaccines as applied to Provenge in AIPC: "If there are no objective tumor responses or complete remissions early on following therapy that would indicate cytotoxicity, how can a vaccine that doesn't kill cancer cells extend survival?". IMO, the primary reason lies in the ability of memory T cells primed by CD54 expressing dAPC's to home to secondary lymphoid tissues, blocking metastases to visceral organs and killing cancer cells unprotected by elevated levels of regulatory T cells. When asked by the CBER Advisory Committee in February why CD54 was chosen as a potency marker for Provenge and why it should be correlated with long term survival, DNDN's Dr. Provost replied in a self deprecating manner that perhaps DNDN was just lucky. The next time that question is asked, there should be more thought, supporting data and analysis offered in response. JMHO.
Good luck to all DNDN longs.