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ragsto:
Actually, in the case of a class action lawsuit, shorts hold the price of shares lower than it would otherwise be, which effect is increased artificially by naked shorting where non existent shares are sold. Damages in a class action lawsuit are incurred not by purchasing shares that are being held down artificially, but by the fact that damaged shareholders / class members have paid share prices that were higher because some material, bad news was improperly not disclosed to shareholders. In any event, this would have nothing to do with the responsibility of E & O insurers to provide the agreed coverage to DNDN, much less of the company's responsibility to possibly issue shares or pay damages itself pursuant to any jury award or settlement.
>>If discovery commences would not DNDN have the right to know the true share count during the class action period?<<
No. Only those who actually document out of pocket losses from purchasing shares at improperly inflated values during the class period can make a claim for a proportionate share of any jury award or court approved settlement.
>>Sorry but the real cover up on why Provenge will be protected. And its not the 483 issue.<< It's not? - how would you know that? The FDA confidentiality regulations only apply to matters not disclosed by the applicant. Since discovery virtually opens DNDN's records in a Federal lawsuit, the FDA communications and actions are also discoverable. If the Form 483 issues had little or nothing to do with the FDA not approving Provenge last May, DNDN's attorneys will raise that defense, which they have not chosen to do yet. There has been a lots of speculation, but very few hard facts revealed about the FDA decision. That could change. JMHO.
ocyanblue;
If DNDN loses its Motion to Dismiss and discovery commences in the class action lawsuit, many unpleasant facts may come out. IMO, the probability that croumagnon's belief that the failure of the FDA preapproval inspection and the FDA's assessment of the time that DNDN would require to correct the problems was a major factor in not accepting the Advisory Committee's recommendation for conditional approval and was a major factor in the FDA asking for more Provenge efficacy data from the ongoing IMPACT trial. If DNDN wins its motion, we'll prbably never know whether or not this was true. OTOH, if it is true and the manufacturing issues were serious and hidden from shareholders (as they continue to be), wouldn't you agree that this is something that shareholders deserve to know?
p3analyze:
Assuming, as I will, that your statistics are accurate wrt stopping at 98 deaths in the TAX 327 docetaxel trial yielding a calculated p value of 0.20, IMO, that statement would have stopped Hussein and Scher cold at the Advisory Committee meeting, especially if DNDN would have followed up with a Petrylak type analyis of how powerful the combination of Provenge and docetaxel are. The argument would have gone over to trial numbers then, but your statement regarding what would have been a comparison to the standard of care, IMO, would have made a strong impression.
Unfortunately, as you know, IMO, the failed February preapproval manufacturing inspection would ultimately have produced the same result. The results of DNDN's Motion to Dismiss are still not known in the court case. If DNDN loses, discovery should provide a definitive answer to my belief; if not, no one but some at the FDA and a few insiders will ever know for sure. JMHO.
New JCI Publication: Murine study of GVAX + a hmab in breast cancer supporting John Hopkins Ph2 clinical trial of GVAX + Herceptin in HER2/new breast cancer (which is also targeted by Neuvenge). Discussion at: http://www1.investorvillage.com/smbd.asp?mb=247&mn=403&pt=msg&mid=4541063
The best type of competition: hope for dying cancer patients.
http://biz.yahoo.com/bw/080411/20080411005320.html?.v=1
Alzheimer’s Vaccine: For vaccine aficionados, Barrons has a fascinating article on a discontinued Alzheimer’s vaccine turned into a humanized monoclonal antibody, which triggers a B cell response in vivo, to eliminate the possible side effects of brain swelling due to T cell reactions. http://online.barrons.com/article/SB120735036855791183.html?mod=yahoobarrons&ru=yahoo&page=1
Interesting developments wrt CTLA4 blokers such as the MEDX / BMY ipilimumab (MDX-010) and PFE's tremelimumab. Both of these products are thought to hold great potential as adjuvants to cancer vaccines, but were initially being targeted as standalone therapies in melanoma. CTLA4 decreases the expression of IL-2, a T cell growth stimulant, during the course of an immune attack. IL-2 is preferentially taken up by Tregs, however, so blocking it in a high dose systemic manner in theory, not only exposes cancer cells to attack, but also exposes patients to a widespread autoimmune attack.
PFE has apparently just terminated its tremelimumab development and ipilimumab is in trouble after not meeting its primary endpoint in a recent trial. http://www.pharmatimes.com/WorldNews/article.aspx?id=13203
Dr. Dranoff of Harvard, who was a non voting member of the Provenge AC (and who later spoke positively about Provenge) and is an inventor of GVAX, recently published a study of an early clinical trial of GVAX with low dose ipilimumab in melanoma and ovarian cancer. The trial showed some early signs of efficacy while minimizing ipilimumabs otherwise harsh side effects. Ipilimumab apparently increased the number and avidity of CD8 effector T cells while not impacting Tregs, the opposite of the result that was expected, but positive nontheless. In any event, any CTLA4 blocker, perhaps unfortunately, must effectively make it as a standalone therapy - unfortunate since early results of GVAX and ipilimumab in AIPC look promising. JMHO.
Re: CEGE:
http://investorshub.advfn.com/boards/read_msg.asp?message_id=28121098
http://www1.investorvillage.com/smbd.asp?mb=247&mn=386&pt=msg&mid=4471600
http://www1.investorvillage.com/smbd.asp?mb=247&mn=387&pt=msg&mid=4471617
Nothing like a good race. Let's hope that both Provenge and GVAX make it across the FDA approval finish line.
ocyanblue and iwfal:
Sherwin, the CEGE CEO, has discussed the fact that the subgroup of TAX 327 experimental patients who received the FDA approved dosing and were symptomatic (around 45%) had median survival of 16 months, which data was plugged into the Vital 2 model. The median survival for the same Tax327 subgroup who were asymptomatic was some 22 months. As iwfal just pointed out there were some 367 events in the comparison of the FDA approved Taxotere dose group and the mitoxantrone control group, which yielded a p value of 0.009 for a treatment effect as determined by increased median survival of experimental over control patients of 2.4 months.Using the extremely optimistic numbers for comparable high dose GVAX patients cited from Ph2 would suggest an increase of over 12 months for GVAX patients over asymptomatic Taxotere patients with 400 events required for the Vital 1 final data, projected to occur in 2H09.
The above is the case for optimism and over confidence in the final Ph3 Vital 1 results. OTOH, much more modest results could still result in statistical significance for Vital 1's primary endpoint of survival. Is the likely cut-off point an increase in median survival of GVAX patients compared to Taxotere of 4 months,, 6 months? Who knows? You make your investment decision and you take your chances. JMHO.
Iwfal:
Some 200 events were required for the Vital 1 interim; more than the total number of events in the combined 9901 and 9902a Ph3 trials. GVAX dosing is allowed to continue indefinitely in Vital 1 as long as no alternate therapy is commenced and Vital 2 is probably less than 70% fully enrolled at this point. If it isn't working and patients are dying faster on GVAX, patients should be informed and further dosing stopped. My limited understanding of the O'Brien Fleming method of allocating alphas lead me to believe that it also provides some sort of horizontal funnel plot that can be used to set some outer limits for futility and any stopping test for unexpected overwhelmingly positive results. (BTW, does anyone know if 9902b uses the same Haybittle Peto method of allocating an interim alpha as was used in 9901 and 9902a?)
IMO, GVAX still represents a pretty decent speculative investment.However, having said this, I am well aware of the risks in biotech, including the almost invaraiable hyping of results. Caveat emptor.
The CEGE CEO stated that the interim for the Vital 1 GVAX Ph 3 trial in asymptomatic AIPC interim occurred as modeled and not earlier. With an extremely low allocated alpha for the interim per the O'Brien Fleming method, the chances of Vital 1 making it then were minimal. Actually, the fact that GVAX can hold its own during its ramp up period against a relatively fast acting cytotoxic such as Taxotere dosing in the control arm is a somewhat postive factor for the final look. Vital 1 allows monthly boosters without limitations if a patient and his doc wish unless and until a patient elects alternate treatment, such as subsequent Taxotere, after the initial 6 month GVAX biweekly dosing. This would seem to be an equal or better choice for patients than the limited three Provenge doses allowed in the 9902b trial. 9902b also allows experimental arm patients to take subsequent Taxotere. Dr. Petrylak's analysis, of course, that immunotherapy in AIPC followed by Taxotere might be very effective. In any event, we should all remember that the 3 year survival rate of Provenge in 9901 was 33%, meaning that 67% of patients in the Provenge experimental arm died within three years. The multi institution rapid autopsy program in AIPC found that most men died of undetected tumors and PAP was not among the 5 antigens that pathologists found predominantly expressed in these occult tumors. Wishing, of course, does not make GVAX or any cancer immunotherapy successful. However, Dr. Small and others have written about the critical need for other antigen taqrgets for immunotherapy in AIPC. The GVAX technology approach is to use a patient's own immune system to destroy and use antigens from irradiated metastatic cell lines genetically modified to express GM-CSF. This approach has proven surprising efficacy in a wide variety of different cancers in both preclinical and Ph 1 and Ph2 clinical trials. I doubt whether the many top docs at Harvard and John Hopkins using GVAX in these clinical trials of various cancers chose to do so because of lack of alternative experimental therapies. There are obviously risks in the Ph3 trials of any oncology product. IMHO, however, the FDA will eventually approve both Provenge and GVAX in AIPC. As an investment, CEGE has the advantage of having a much lower market cap, a more advanced and diverse pipeline and a much better reputation among top docs than DNDN. If GVAX in AIPC is successful in either or both Vital 1 and/or Vital 2, CEGE has the potential of being an enormously successful company. All JMHO.
Fair questions:
1. 483 issues. As you state, these issues will eventually be rectified with time and hard work. However, if the Federal Court rules that DNDN had a duty to disclose this material information and intentionally failed to do so in the present DNDN Motion to Dismiss, and implicitly that Gold and two directors took financial advantage of this, there could be two obvious ramifications. The most important is that every investor should realize that Gold and other directors place their own financial self interest above shareholders and patients and that the BOD collectively is too weak to police their own members. The second is that DNDN (and its insurers) will ultimately pay damages, which could be substantial.
2. New events need not be internal. A competitor in AIPC immunotherapy, CEGE has two well powered 600 patient Phase 3 trials expected to report final results next year; one Vital 1 in asymptomatic AIPC, the other, GVAX with concurrent use of Taxotere in symptomatic AIPC. Both are compared to groups where Taxotere, the existing standard of care, is given control patients. Vital 1 recently passed its interim look measured against the extremely conservative O'Brien Fleming alpha allocation and continues toward its final survival endpoint. Some well respected DNDN observers thought that Vital 1 would be stopped for futility, in part, due to the difficulty in early comparisons of any immunotherapy, where a ramp up time is involved, to a relatively fast acting cytotoxic. Such competitive events, external to DNDN, could have far reaching impact, if successful, to DNDN's financial and marketing prospects.
3. As far as we know, the 9902b interim p value or alpha allocation may not have changed at all from last year or the extremely conservative Haybittle Peto method used in 9901 and 9902a. The recent discussion about powering and the number of events could effectively be irrelevant if the required interim p value has been, and remains, so low as to be out of reach at the interim. Some commentators have suggested during the past year that the FDA might be very liberal with DNDN, possibly even allowing a p value of 0.05 at the interim to be sufficient for refiling the amendments to the BLA. DNDN could help clear this issue up by publishing the target interim alpha. However, DNDN has not, and if management puts their own financial interest above those of shareholders, there is no reason to believe that any such full and honest disclosure will ever be forthcoming.
4. I'm glad for you that you were able to do well during last April's run up. IMHO, the question is not so much being "jaded" by management, but not wanting any investment to take on certain aspects of liar's poker. While, IMO, there is potentially a great opportunity in cancer immunotherapies, including Provenge and GVAX, both from a financial as well as patient perspective, there are also a great many risks in any biotech. Management hype and duplicity should not be among them. JMHO.
IMHO, the next big event that relates to the whole manufacturing issue will be the ruling of the Federal District Court in Seattle on the DNDN Motion to Dismiss the class action lawsuit based on the cause of action related to the non disclosure of the Form 483 issued at the February 2007 FDA preapproval inspection. The judge is very highly respected, the issues have been briefed and there will be an oral argument on 3/27. If DNDN prevails, they are really off the hook, and there will be no need for DNDN to be any more straight with shareholders than they have been. If they lose, discovery will commence and those deep dark secrets (eg, what were the Form 483 violations, etc.)will eventually come out.Perhaps most importantly for DNDN to lose, the Court would have to decide that there was reasonable evidence of "scienter" on DNDN's part, essentially that their failure to disclose material information where there was a duty to disclose was more than simple negilgence.If so, Gold's central role in non disclosure and his sale of $2.7 million in DNDN optioned shares in April will come back to haunt him big time.JMHO.
http://www1.investorvillage.com/smbd.asp?mb=971&mn=187807&pt=msg&mid=4342354
Eagleye:
Gold's use of the word "validation" in relation to the NJ manufacturing plant was just more of the same meaningless spin. The issue was, and is, FDA approval of commercial production as a result of a successful FDA preapproval inspection. Schiffman previously acknowledged at the 3Q07 CC that the FDA will require a reinspection during any new review cycle. There was some suggestion that DNDN had made a new submission to the FDA recently, which may have been a corrective action plan, which has to be approved by the FDA before they will schedule any renspection. For example, DSCO's initial submission of a corrective action plan, reportedly of over 100,000 pages, was not accepted by the FDA.So, getting such a plan submitted for FDA review and hopeful approval is an important first step. The scope of any plan would obviously be a function of the number and nature of the discrepancies listed in the February 2007 Form 483.
It amazes me (finally) that after so many past outright misleading statements and omissions that investors put any faith in what Gold says. With all the discussion about "comparable power", increased events, etc. at the interim, one of the most important aspects is, of course, the allocated alpha. If DNDN stated clearly what that p value is, the many fine stat experts both here and on IV would be able to give a far better reading of the probabilities of success at the interim. Can anyone offer a reason why shareholders should not be given this info.
I truly hope that the FDA finally approves Provenge, but if and when that happens, it seems increasingly likely it would be in spite of Gold. JMHO.
The FDA Priority Review rules provide a target of 6 months, the "PDUFA clock" or review cycle from the time an applicant submits a complete BLA. If you assume that the FDA accepts DNDN's corrective action plan for its manufacturing problems and appropriate stat results, a preapproval reinspection would occur during that 6 month period. CEGE's timing for a GVAX filing would also have to include the time required to prepare the BLA itself, which is no small job. DNDN's BLA was impacted by the requirement that the planned commercial production facility be ready for inspection when the BLA is filed. In DNDN's case the NJ facility was only in planning at the time of the pre-BLA meeting. CEGE apparantely completed their California production facility in 2004 at a cost "north of $50 MM" (according to their CEO). The State of California required that it be inspected each year per the same cGMP standards that the FDA uses, while NJ does not. If you assume that neither company will face further manufacturing inspection problems, a reasonable assumption might be that it might take DNDN 2 months to file an amendment to its BLA, while it could take CEGE 9 months to complete and file a BLA.Thus, DNDN could have a lead of some 7 months or so assuming equivalent clinical and manufacturing results and timing.
While not directly responsive to your question, capacity might also be a consideration wrt Provenge. Past PR's indicate that only 25% of the plant was equipped with modular clean rooms, labs and offices and 12 out of a planned 96 workstations. Gold once indicated that at capacity, the NJ facility would be capable of producing Provenge yielding $1 billion in sales. At an estimated $35,000 per patient for three doses, this would equate roughly to 30,000 patients and 90,000 doses. Obviously, DNDN would have to expand present capacity rapidly. The batch processing nature of GVAX makes it easier, cheaper and faster for CEGE to expand output.CEGE's CEO has stated, however, that their plant has ample capacity to launch commercial production. All JMHO.
>>Statistical question: If DNDN has in fact used the Haybittle-Peto method to allocate an interim aplha in 9902b, and the resultant required P value to beat is 0.001, this might be a great question that David Miller or some other analyst to ask at the next quarterly CC.<<
I guess that no one wanted to ask this question.Who wants to be stonewalled? Please correct me if I'm wrong, but some very smart posters on statistics may have been thrown off by a diversion. The number of events, power etc.suggest that, assuming a certain treatment effect, some educated guesses can be offered as to what a p value might be, but those changes do not reveal what the allocated alpha for the interim might be. Assuming that it is the same method that was used for 9901 and 9902a, Haybittle-Peto,the interim would still be unlikely to better a p value of 0.001, perhaps explaining the FDA's OK to change other parameters.
DNDN is unfortunately not the only biotech that prefers word games to clear explanations. As another example, Gold said that the NJ manufacturing facility was "validated", not that it was reinspected by the FDA and passed, which Schiffman previously stated can only be done after refiling an amended BLA. DNDN can still ship clinical quantities of Provenge from NJ, as they could previously from their Seattle pilot plant, but the preapproval inspection deals extensively with the control and self policing aspects of a production cGMP facility, which involves an order of magnitude increased difficilty, over the requirenments for shipping lab level quantities for smallish clinical trials. Was the term "validated" meant to enlighten or confuse?
Gold seems the perfect foil to turn an optimist into a cynic in the great tradition of Bill Clinton's when is "is" is?
From the errata of the Advisory Committee Briefing Materials:
"Page 6, Section 1.2 Analysis plan, 1st paragraph, line 6: change the text “an O.Brien-Fleming adjusting” to be “the Haybittle-Peto method” according to the corrections the sponsor provided for their original submission."http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_03b.htm
From what I remember reading, both of these approaches for allocating alpha are quite conservative. Since the alpha for the interim would have been set when the 9902b protocol was changed, a conservative allocation might have remained for the interim. This might have made the interim a real reach even if the number of events was relatively high (say 240 interim, 360 final), The real issue might then be a realization that given a small chance of making it on the interim, everything will ride on making it on the final.
This further suggests that rumors about the FDA accepting a p value of 0.05 at the interim were wishful thinking by DNDN and some analysts, obviously serving to support the market cap and ability to raise funds given the recurring optimism of so many biotech investors.
The other very real factor is the CEGE projection that its final look at the results of their 625 patient Vital 1 trial in asymptomatic AIPC is projected to occur in 2H09, and possibly the 600 patient Vital 2 trial in symptomatic AIPC as well. If either is successful, CEGE would probably still require an additional 6 months to prepare a BLA, which DNDN has already largely done with 9902b amendments to follow. The bottom line is that there could be real competition from the get go, although there would technically be nothing except possible reimbursement issues, to preclude a patient from usung both Provenge and GVAX if the FDA approves both. DNDN cannot, however, risk seeing CEGE's GVAX enter the market first, especially if they sign up a strong marketing partner. This could be a very prudent time for DNDN to also revisit the partnership issue. JMHO.
Regretably, the primary reason may be, as countless oncologists have said: "Metastases kill". Is a quiescent tumor shedding cells that will "extravasate" through the wall of blood vessels and begin new tumor forming colonies elsewhere? Has that process already started prior to first diagnosis and treatment? Was the cancer initiated in respone to environmental or genetic predisposition factors; if so, do those same factors remain active and relevant? The great promise of immunotherapy when appropriately assisted by the blocking of immunosuppressive factors by chemotherapy is that it theoretically can be both equisitively sensitive and specific in locating and destroying target cells, even after cancer metastacises. Hopefully, there may be better measures of "Progression Free Survival" coming in diagnostics to judge whether the survival is, in fact, progression free. One example may be IMMC's circulating tumor cell technology that presently can give a real time assessment of metastases and changes in its rate, and soon may be able to permit genetic analysis of the cancer cells to inform better therapy choices. See: http://biz.yahoo.com/bw/080227/20080227006321.html?.v=1
DNDN is not claiming that CD54 upregulations is a "surrogate" marker, but rather proof of manufacturing potency. A surrogate marker is some specific clinical observation that can reasonably predict a meaningful clinical benefit in a life threatening diseases(eg, tumor shrinkage) that has been prospectively validated and that allows for FDA Accelerated Approval if a clinical trial demonstrates statistical significance of the surrogate marker. The standards for FDA approval of a biologic are potency, purity, safety and efficacy. Potency esssentially means that there is some measurement made upon completion of the manufacturing process that indicates that the biologic has been properly processed for its intended purpose.
eagleeye:
Since the method of allocating an interim alpha is apparently locked into a trial protocol long before an interim for both DNDN and its only realistic "competitor", CEGE (whose low O'Brien Fleming allocated alpha for Vital 1's interim has now been passed with the final look in 2H09), "competitive concerns" seem like thin gruel. At the risk of being overly naive, one would think that a CEO / MD would realize that that there is plenty of room in the AIPC "market" for both Provenge and GVAX, which also could be somewhat complementary in terms of patient benefit. A cynic might, of course, note that Gold withheld disclosing the fact that the FDA issued a Form 483 in its preapproval inspection while he sold $2.7 million in DNDN shares in April and any revelation of a conservative interim alpha might impact optimism while raising money, issuing management options, etc. Gold, of course, expressed surprise when the FDA issued a Complete Response Letter in May, before noting that DNDN had little contact with the FDA after the Provenge Advisory Committee meeting when FDA Guidance states that that period is the time that labeling discussions would be held. Caveat Emptor. JMHO.
Statistical question: If DNDN has in fact used the Haybittle-Peto method to allocate an interim aplha in 9902b, and the resultant required P value to beat is 0.001, this might be a great question that David Miller or some other analyst to ask at the next quarterly CC. If the expected: "We're not releasing that information" comes up, a follow-up question might be: "Why shouldn't every shareholder / owner be entitled to an answer?" After the entire FDA Form 483 non disclosure fiasco, DNDN's management could use some practice in the trnsparency area.
eagleeye:
The CEGE YMB stated Feuerstein referenced the following article in his comments:
http://www.slate.com/id/2181789
I posted some comments after reading the reference:
1. Most cancer studies don't have a reliable nomogram such as the Halabi nomogram with which to compare actual to projected results as in AIPC.
2. Sometimes Ph 3 results surprise for the better. Witness the fact that DNDN's Provenge didn't achieve the same delay in progression that was achieved in Ph2, but did far better in survival, which was not measured in Ph2.
3.Unless you follow Soviet consumer theory, reducing a patient's choices of experimental clinical trials in cancer will not increase enrollment by requiring larger, longer and more expensive randomized Ph2 clinical trials beyond the 5% participating now and may very well reduce it. The FDA's adoptive clinical trial process goes the other way. If modern genetic and proteomic diagnostics are used as a trial proceeds, the trial can advance faster if such diagnostics can target patients who are getting the most benefit from a trial in progress.
4. Vital 1 began enrollment in July 2004 and just passed it interim point where it would have been stopped if the Taxotere control arm, which uses a faster acting cytotoxic than the delayed ramp up of an immunotherapy, had significantly better survival than GVAX. OTOH, data analyzing the use of Taxotere after either GVAX or Provenge has been shown in the last two years to significantly enhance survival. Since the subsequent use of Taxotere in the Vital 1 experimental arm is permitted, Vital 1 docs have the opportunity of applying this knowledge rapidly for the benefit of patients.
5. IMO at best, the article's rationale might be applied where a similar approach is tweaked to try for a marginal improvement, such as varying cytotoxic chems. Fuerstein should look at the remarkable consistency in the results of immunotherapies followed by Taxotere in AIPC. The one third of the 147 Provenge patients in the DNDN 9901 and 9902a Ph 3 trials who had the Provenge followed by Taxotere combination saw median survival increase by 14 months to 34 months over patients taking Taxotere alone. These results are consistent with the 35 high dose GVAX ph 2 Patients showing a median survival of 34.9/ 35 months, 30% of whom received a subsequent taxane.
The truth of the matter is that there are few areas of research and development in modern science where generalizations such as are reached in this article produce meaningful results in the most efficient way. JMHO.
ocyanblue:
>>you still run into the issue that the subgroups that took Taxotere were self-selecting << All patients were asymptomatic at randomization. I know that the theory is that only healthier patients choose to take Taxotere, but the TAX327 study also proved that Taxotere was superior to mitoxantrone and prednisone for palliation of pain and QOL. IMO, the difference in results is so dramatic between the Povenge only results and the combination results that it will be reaffirned in 9902b. Petrylak also used the Halabi nomogram to minimize the impact of bias. The long term survival data also suggests that the Provenge 9902b experimental arm will have an easier control group treatment to contend with than the CEGE Vital 1 Taxotere control arm. All just semi-educated guesses, the data will tell.
BTW, in looking at the AC Briefing Material data again, I noted the followingin statisical errata: "Page 6, Section 1.2 Analysis plan, 1st paragraph, line 6: change the text “an O.Brien-Fleming adjusting” to be “the Haybittle-Peto method” according to the corrections the sponsor provided for their original submission." Google then produced this discussion of interim allocation methods: http://mrw.interscience.wiley.com/emrw/9780471462422/wect/article/eoct030/current/html
This states in part: "Both the Haybittle-Peto boundaries and the O'Brien-Fleming boundaries are very conservative at the interim analyses; therefore, using these boundaries, a low chance of very early stopping exists because of a chance dramatic difference in outcomes. The conservatism of the Haybittle-Peto boundaries at the interim analyses came from applying a uniformly stringent criterion, with a nominal P-value of 0.001, at all interim analyses."
If the Haybittle-Peto method is used in 9902b as well, would this reduce your assessment that the interim might be successful?
ocyanblue:
1. The following references are relevant: (a) The analysis by Dr. Daniel Petrylak in the GU presentations at: http://www.chemotherapyfoundationsymposium.org/meeting_archives/meetingarchives_tcf2006_main.html
(b) DNDN’s PR at: http://investor.dendreon.com/ReleaseDeta
© the list of the 20 covariates used in the Provenge 9901 trial in Slides 19 and 20 at: http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb
61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=31910
(d) the Provenge Advisory Committee statistical Briefing Materials at:http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1-00-index.htm
(e) the NEJM published TAX 327 Taxotere pivotal trial data at: Volume 351:1502-1512 October 7 Number 15 (2004) http://content.nejm.org/cgi/content/abstract/351/15/1502
(f) Updated Survival in the TAX327 Study at: Journal of Clinical Oncology, Vol 26, No 2 (January 10), 2008: pp. 242-245 http://jco.ascopubs.org/cgi/content/abstract/26/2/242
2. The citation that you take from page 72of DNDN’s Briefing Materials (d) says so little that as a standalone statement it appears meaningless. First,as you know, a Cox proportional hazards model adjusts for factors present at the time of randomization. Thus, a Cox proportional hazards model could not adjust for docetaxel (Taxotere) use after Provenge, nor does the citation make such claim. I believe statisticians refer to such after occurring factors as “instrumental variables”. The Briefing Materials also point out that the dosing and duration of subsequent docetaxel was not recorded, only the type of chemo and the date of initiation. See Section 2.3.6 of the Statistical Briefing Materials (d). “This analysis revealed that there was not a statistically significant imbalance in the administration of chemotherapies between treatment groups” . This suggests that any adjustment for the treatment effect adjusted only for simple percentage of use comparisons between the two arms as previously presented by Dr, Small for 9901 at the 2005 ASCO.
3. As the DNDN PR (b) states: "The median survival observed in the PROVENGE treated patients who subsequently received docetaxel was 34.5 months compared to 25.4 months for patients randomized to receive placebo who went on to receive docetaxel, a difference of 9.1 months (HR = 1.90; p-value = 0.023). Approximately 68 percent of the patients randomized to receive placebo also subsequently participated in a cross-over salvage protocol that allowed them to receive active cellular immunotherapy with APC8015F, a version of PROVENGE generated from cryopreserved cells. The median survival was 25.7 months for patients who received APC8015F followed by docetaxel. In contrast, the median survival was 20.2 months for patients who received placebo only and subsequent treatment with docetaxel, a 14.3 month difference compared to 34.5 month median survival seen in the patients who received initial treatment with PROVENGE followed by docetaxel." In other words, an unstated net percentage of the 68% of control patients receiving the 2/3 dosing (compared to the experimental arm) of Frovenge processed from cryopreserved cells subsequently received docetaxel and those patients had a median survival of 25.7 months compared to 34.5 months for the experimental arm patients who received docetaxel, a difference of 8.8 months. Dosing, of course, does make a difference as both the Total Nucleated Cell data and the recently published CD54 Provenge data points out. There should be little surprise that any simple adjustment for treatment effect between experimental and control arms that ignores dosing of Provenge and the net use of the combination therapy and its net impact means little.
4. Dr. Petrylak’s presentation (a) of the Provenge data analyzed how median survival was increased by the combination therapy use in the 147 patent experimental arms of its two Phase 3 9901 and 9902a trials using the Halabi nomogram.. He reported that the experimental arm patients receiving subsequent docetaxel had a actual survival of 34.6 months vs, that predicted by the Halabi nomogram of 20.9 months, a difference of 13.6 months. The crossover control patients who subsequently received doceataxel had an actual median survival of 25.4 months vs. a predicted 19.9 months for a 5.5 month difference. The median survival in 9901, the more successful of the two trials in AIPC, of the Provenge experimental arm was compared to that projected using the Halabi nomogram and bettered it by 5.8 months (reported by Dr. Small in a 10/06 presentation). If that median survival was conservatively extrapolated to all experimental arm patients in both trials, the total projected increase in median survival would be some 853 patient months over that predicted by the Halabi nomogram (147 X 5.8). According to Dr. Petrylak’s analysis, the 51 patients receiving the Provenge + Taxotere combination would represent a projected 694 patient months of that increase over what the Halabi would predict (51 patients X 13. 6 month increase in survival) , which suggests that the 96 patient (147-51) who received Provenge alone would account for an overall increase in projected median survival of 159 patient months over that predicted by the Halabi nomogram, or about 1.7 months each ((853-694)/96). Taxotere showed an increase in median survival as a monotherapy in AIPC of 2.4 months in its TAX 327 pivotal trial (e), where 45% of the enrollees were symptomatic.
5. The 36 month survival rate for the 333 patients in the Taxotere TAX327 pivotal Phase 3 trial who took the FDA approved dosing every three weeks was recently reported to be 18.6%.(f), again where almost half of the patients were symptomatic. If the 51 patients out of the 147 in the 9901 and 9902a experimental arms who received the Provenge + Taxotere combination had median survival of 34.5 months, it is a reasonable assumption that some 24 or 25 of this subgroup were alive at 36 months post randomization, a month and a half later. 33% of the 147 experimental arm patients or 49 patients in the integrated experimental arms survived 36 months. That would mean that 24 or 25 of the 96 integrated experimental arm patients who did not receive subsequent Taxotere, or about 26%, survived 36 months. This is better than the 19.3% 3 year survival of Taxotere treated TAX 27 patients, even allowing for some upward adjustment for more advanced symptomatic patients, but is obviously far lower than 9901 and 9902a experimental arm patients who received the combination therapy.
6. Thus, whether considering the median survival point or the 3 year survival point, IMHO, the DNDN / Petrylak supplied data conclusively demonstrates the significant advantage that the combination Provenge plus Taxotere therapy provides over either Provenge or Taxotere alone. Dr, Petrylak’s presentation suggests why this may be so from a clinical MoA standpoint. IMHO, the increased efficacy of using Taxotere after an immunotherapy demonstrated in the Provenge clinical trials will also be demonstrated in CEGE’s Vital 1 trial where GVAX patients taking subsequent Taxotere will also demonstrate substantially increased efficacy over both the Taxotere only control arm and those only using GVAX in the experimental arm.
p3analyze:
Thank you for a very thoughtful response.
IMO, the CEGE discussion on the antibody response to GVAX in AIPC could be as best described as exploratory. I can fully understatnd that given your demonstrated knowledge in statistics, the data borders on meaningless in that context. The two antibody responses found in a subset of some 30 out of 65 patients were trolled from a total of 400 antibody responses found in those patients.
Dr. Sherwin went on the say that as additional antibody response correlations to survival potentially emerge from background noise with ongoing GVAX diagnostic screening, a group of such antigens could form the basis of a diagnostic assay. Even this provokes a "So what?" response. Other studies have found that the expression of some 239 genes changes substantially as PC cells transition from ADPC to AIPC, so just on that score one would expect that the resultant proteins would produce a plathora of newly developed antigens in AIPC cells. However, from a clinician's standpoint, IMO, the issue would always be "How then should I modify my patient's therapy to maximize benefit?" At this point in time, there is no way to boost an individual's specific antibody response to a particular antigen, although I suppose that in the distant future a humanized monoclonal antibody could be developed to supplement a clearly beneficial antibody response.
There is also a certain confounding aspect to the antibody data since CEGE reported that it was independent of dosing. Yet, overall, both Ph2 studies reported that patients who received the highest dosing that is now being used in Ph3 had significantly improved survival over patients receiving a mid or low dose. John Hopkins has recently started a new Ph 2 trial on the use of GVAX in pancreatic cancer in part based on a Ph2 report that suggests that significant survival benefits dissipated over time after monthly GVAX boosters ceased. The Provenge P11 data indicated that even though response to PA2024 declined somewhat over 21 months, it remained remarkably robust and could be improved substantially with boosters. Unrelated hmab data also suggests a fall-off in benefit after dosing ceases. Perhaps the dose independent characteristic was merely a short term phenomena.
I brought up the use of subsequent Taxotere issue since this is the other way that therapy can be modified in Vital 1. Dr. Sherwin appeared reluctant to discuss any possible benefits for patients and impact on Vital 1 results that would result from the GVAX plus Taxotere combination in Vital 1. Considering that Drs. Small, Higano and Petrylak were all involved in some aspects of both Provenge and GVAX clinical trials, I seriously doubt whether the potential synergistic benefits of subsequent Taxotere after an immunotherapy in AIPC are lost on them.
IMHO, Dr. Petrylak's analysis raises substantial questions on whether Provenge would have been statistically significant for survival absent the synergistic impact of subsequent Taxotere, especially if compared to Taxotere in the control arms rather tha lower dose and deferred Provenge processed from a control patient's frozen then thawed immune cells. My guess is that if Vital 1 is successful in asymptomatic AIPC, it will also be due to the experimental GVAX arm patients receiving subsequent Taxotere as their AIPC advances.
There are two striking aspects to GVAX at this point. The first is that there appears to be no serious autoimmune side effects found to date (excluding its use with high dose MDX-010) while dosing over 700 patients in both AIPC and a range of other cancers. The second is that the docs at John Hopkins and Harvard have reported encouraging clinical data when using the appropriate starting cell lines, that GVAX shows patient benefit in prostate, pancreatic, breast, and ovarian cancers as well as in melanoma and leukemia. That is a powerful signal even at this early stage of cancer immunotherapy. JMHO.
Oops, those typos. You're right, Sam.
p3analyze:
Unfortunately, it seems that what many biotech execs fail to tell their shareholders winds up being the most important things. D Miller may be a nice guy and a decent analyst, but if anything, rather than interrogating Gold as to why DNDN failed to disclose their preapproval inspection failure to shareholders when it occurred in mid February, he seems to offer excuses for it, in spite of the fact that even he doesn't know what those deficiencies were. He might also have asked why DNDN was surprised to receive the Complete Response Letter for Provenge in May despite those known manufacturing problems and the absence of labeling discussions in April while Gold and two directors were selling millions in DNDN shares. Then again, he needn't bother now since those issues may be resolved by a Federal Court in Seattle within the next two months.
IMO, the FDA will eventually approve both Provenge and GVAX for use in AIPC, but there is obviously some very useful information that DNDN and CEGE are keeping close to their vests that they don't necessarily have a legal duty to disclose. Statistically, for example, CEGE recently indicated that the Vital 1 trial passed its interim look and will continue to its final look when 400 events have occurred, now projected to occur in 2H09. When CEGE reached their Vital 1 interim point in January, they also disclosed that Vital 1 used the very conservative O'Brien Fleming method of allocating its alpha at the interim, which was estimated to be a p value as low as 0.003. The number of interim events in Vital 1 was said to be 200. Prior knowledge of those constraints especially when comparing a relatively fast acting cytotoxic against a delayed action immunotherapy would have set the Vital 1 interim up as a non event in advance, except perhaps to assure that the GVAX treated patients weren’t dying faster than the Taxotere treated patients.
WRT DNDN, estimates as to what the allocated alpha might be in 9902b needed to supply the FDA with the required additional efficacy data and restart the Provenge PDUFA clock vary widely, as do estimates as to the number of events required for the interim look (180?, 240?), which DNDN projects will occur in mid 2H09. All DNDN has said is that the number of events will be more than the 164 recorded at the 3 year mark in 9901 and 9902a. Success or failure at the 9902b interim will have an enormous impact on the market cap of DNDN and any ability to have a significant lead over CEGE’s GVAX in introducing the first FDA approved immunotherapy in AIPC. It’s safe to say that a very conservative interim allocated alpha combined with a low number of events would substantially reduce the probability of success at the interim as compared to a high alpha and larger number of events. DNDN should know these numbers, but has not disclosed them.
The other topic, which was obviously sensitive for CEGE yesterday, and may be for DNDN, is the permissive use of subsequent Taxotere after GVAX in Vital 1 and after Provenge in 9902b. DNDN finessed this subject in the Briefing Materials for the AC by reporting that a slightly higher percentage of the control group in 9901 had received subsequent Taxotere, suggesting that the overall increase in median survival, therefore, did not disproportionately favor the Provenge experimental arm. CEGE’s CEO stated that there should be sufficient Vital 1 subgroup data to compare those who take GVAX alone vs, those who take the combination. The issue may have more to do with marketing than medicine, however, since the analysis by Dr. Petrylak suggests that the combination of Provenge with subsequent Taxotere is clearly and substantially superior to Provenge alone. However, many more asymptomatic AIPC patients might elect to take Medicare reimbursed Provenge or GVAX with their relatively mild side effects without committing to the rigors of Taxotere if either or both therapies are approved as substantially effective standalone therapies and the disproportionate beneficial contribution of the combination therapy on reported composite survival inclusive of immunotherapy alone is not highlighted in labeling.
IMO, biotech history strongly suggests an inverse relationship between the level of management hype and non disclosure and the problems that any therapy seeking FDA approval encounters. There is also a likely inverse relationship between biotech investor gullibility and investor net worth. The whole FDA approval process, and the patients and investors who depend on the process, could greatly benefit from FDA transparency and public reporting on progress or problems encountered in each application. JMHO.
Immunicon Corporation Announces FDA Clearance of the CellSearch(TM) Circulating Tumor Cell Kit for Monitoring Patients with Metastatic Prostate Cancer
Wednesday February 27, 6:06 pm ET
Diagnostic Test Is Now Cleared for Three of the Four Most Common Cancers
http://biz.yahoo.com/bw/080227/20080227006321.html?.v=1
This may answer a question I had as to why CEGE, John Hopkins or Harvard were not testing GVAX in colon cancer, a seemingly high priority target, when it is in clinical testing for prostate, breast and ovarian cancers, as well as melanoma and leukemia, wth preclinical testing for lung cancer just being completed. As I understand the Onyvax therapy, cancer cells are harvested from each patient processed and then injected interdermally with BCG to stimulate an immune response. BCG is derived from TB and is presently FDA approved for use in bladder cancer. Not elegant or inexpensive, but if it works...
CEGE is supposed to report on an early bladder cancer trial this year using its oncolytic virus therapy, which they picked up from Novartis.
I'm not aware that the covariates for IMPACT have been published. However, the covariates from 9901 can be accessed as follows:
http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb
61a7010VgnVCM100000ed730ad1RCRD&vmview=abst_detail_view&confID=34&abstractID=31910
New genetic markers of prostate cancer:
http://www.nature.com/ng/journal/v40/n3/full/ng0308-257.html
iwfal:
>>To my knowledge **ALL** active immunotherapies show a strong correlation between some measure of immune responsiveness to vaccine and survival.<<
Don't have time to provide referemces, but in fact there has been a frustratingly large disconnect between immune responses and statistical increases in survival. In fact, one of the mysteries with Provenge is that it is difficult to measure a T cell stimulation response against human PAP, its putative target antigen. As a result, T cell response to the PA2024 fusion protein, which is not found in nature is used. The excitement about Provenge CD54 cell count, CD54 upregulation and Total Nucleated Cell count relationship to survival is due in part because there is such a poor relationship between human PAP expression and results.
All of this is not surprising, however, since antibody responses or T cell stimulation when testing serum deals with the "offense" of an adaptice immune attack rather than the "defense" of regulatory T cells as well as other immunosuppressive factors in the microenvironment surrounding a tumor. As my last Ihub post concerning the NIH video webcast of STAT3 expression detailed, STAT 3 expression has the ability not only to stimulate angiogenesis in the tumor microenvironment, but also to turn immune cells attacking cancer into defenders. The significant independent post randomization variable, that both DNDN's analysis and CEGE's analysis fail to account for, is the subsequent use of Taxotere that not only depletes rapidly proloferating regulatory T cells in the tumor microenvironment, but also activates macrophages, which are the primary weapon of choice that the B cell arm of the adaptive immune system uses to destroy antibody marked cancer cells. Without such breaking of tolerance, IMO, neither Provenge nor GVAX alone would be statistically significant for increased survival.
With due respect to your healthy and well deserved skepticism about biotech hype and obvious statistical expertise, I stand by my opinion that the identification of two antigens derived from metastatic AIPC cell lines that GVAX produces a strong antibody response to increased survival, with the adjuvant effects of Taxotere in long surviving Phase 2 GVAX patients, makes a strong case for scientific validation of the technology. Unfortunately, any statistically significant validation of that opinion must await the final Vital 1 results now projected to occur in 2H09.
Cell Genesys Reports Association Between Immune Response and Patient Survival in Phase 2 Trial of GVAX Immunotherapy for Prostate Cancer
http://biz.yahoo.com/prnews/080215/aqf043.html?.v=32
This is strong scientific validation for GVAX Phase 2 results. CEGE has also stated that they are archiving blood samples from all its Vital 1 and Vital 2 experimental arms (totalling 600 patients) for ongoing immunological testing. The results reported today suggests that immunological diagnostics from those samples might be a true biomarker during the therapy itself as to whether or not it is working wrt individual patients. This is potentially wonderful news for all cancer patients where the GVAX technology is being used.
More on hmab / GM-CSF secreting GVAX irradiated metastatic cancer cell lines. Anyone interested in reading the full article can access the link to Springer at Pubmed with the following link. The cost is $32. For anyone with some knowledge of the science, this is an absolutely creative and fascinating study. When, not if, the technology is brought forward into human trials and shows any similar success, it has the potential to become the dominant method of cancer immunotherapy since it combines the sensitivity, specificity and power of combining T cell and B cell antibody based immunotherapy in doses effective in the tumor microenvironment without higher systemic levels of antibodies necessary to break tolerance. The methodology also appears adaptible to causing similar expression in vivo of other useful anti-cancer hmabs. It also appears scalable in an allogenic vaccine, eliminating the enormous expenses of producing the hmabs ex vivo. IMO, this is truly world class science.
http://www.ncbi.nlm.nih.gov/sites/entrez
Breaking Tumor Tolerance to GVAX Immunotherapy without Systemic Chemotherapy?
Title Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity.
Author(s) Simmons AD, Moskalenko M, Creson J, Fang J, Yi S, Vanroey MJ, Allison JP, Jooss K
Institution Cell Genesys, Inc., 500 Forbes Blvd, South San Francisco, CA, 94080, USA, andrew.simmons@cellgenesys.com.
Source Cancer Immunol Immunother 2008 Jan 31.
Abstract Promising anti-tumor responses have been observed in the clinic using monoclonal antibodies (mAbs) that block immune checkpoints. One concern with these therapeutic agents remains the potential induction of immune breakthrough events (IBEs) resulting from the disruption of T cell homeostasis or the breaking of tolerance to self antigens. As an approach to maintaining anti-tumor responses but decreasing the likelihood of these events, the local expression of a mAb in combination with a GM-CSF-secreting cancer immunotherapy was evaluated. Using anti-cytotoxic T lymphocyte antigen (CTLA)-4 as a model antibody to test this hypothesis, tumor cell lines were generated that expressed the full-length mAb in addition to GM-CSF. Evaluation of these cell lines in two therapeutic tumor models revealed that local, cell-mediated delivery of anti-CTLA-4 from a GM-CSF-secreting tumor cell immunotherapy activated potent anti-tumor responses and prolonged overall survival at significantly lower serum mAb levels in the host. Furthermore, lowering the systemic exposure of the host to the immune modulatory mAb correlated with reduced evidence of systemic autoimmunity. This approach has broad utility for the delivery of mAbs or proteins locally from cellular immunotherapies to minimize IBEs while retaining the potent therapeutic effects of such combination treatments.
Language ENG
Pub Type(s) JOURNAL ARTICLE
PubMed ID 18236040
http://www.unboundmedicine.com/medline/ebm/record/18236040/full_citation/Local_secretion_of_anti_CTLA_4_enhances_the_therapeutic_efficacy_of_a_cancer_immunotherapy_with_reduced_evidence_of_systemic_autoimmunity_
There seems to be a constant stream of new research linking unexpected pathways in the immune system with the initiation, growth and metastases of cancer. A recent video presentation by Drew Pardoll of John Hopkins concerning the overexpression of the STAT 3 gene continues this trend. Organization and Manipulation of the Immune Microenvironment of Cancer
Wednesday, January 16, 2008
Drew Pardoll, M.D., Ph.D., Johns Hopkins University School of Medicine
Total Running Time: 01:16:56
http://videocast.nih.gov/PastEvents.asp?c=28
Pardoll was one of the first to recognize the importance of GM-CSF in the recruitment of dentritic antigen presenting cells, which eventually lead to its use in both DNDN's Provenge and CEGE's GVAX. His latest work confirms among other things: (1) that immune cells are both constituent parts of tumors and active in its microenvironment, (2) the STAT3 gene is overexpressed in various immune cells in almost all cancers, (3) the overexpression of STAT 3 causes immune cells to be cancer promoters rather than suppressors in the microenvironment of tumors even if the immune system remains unchanged elsewhere; (4) STAT 3 overexpression also increases the expression of various angiogenic promoters. Pardoll attributes the failures of the numerous immunotherapies over the last decade to a past lack of understanding that many immunotherapies that were thought previously to cause immune attacks on tumors might actually have assisted in the growth and spread of cancers. Oe of the examples is that the overexpression of STAT 3 in th1 helper cells can lead to their evolution into CD4CD25FoxP3 regulatory T cells. This is a complex but fascinating view of a cutting edge developments in cancer immunotherapy.
An interesting new diagnostic that might be particularly useful in seeing whether an immunotherapy alone or Taxotere following Provenge or GVAX, as compared to Taxotere alone, can be evaluated early on as to its efficacy in slowing or stopping metastases and extending survival:
“Immunicon announced that it had successfully met the primary endpoint associated with its pivotal clinical trial in metastatic androgen-independent prostate cancer in January 2007. The primary endpoint required demonstrating that circulating tumor cells (CTC) levels three-to-five weeks after the initiation of chemotherapy predict overall survival.”
http://biz.yahoo.com/bw/071203/20071203005357.html?.v=1
>>My guess is that they did it because they wanted to end the trial early if it repeated the ph ii results you were talking about earlier.<<
History may suugest that the first part of that statement may be true, but the second part less so. The Vital 1 trial protocol opting for an interim look and setting the alpha for it would have been proposed in the Spring of 2004 for a trial that commenced in July 2004. In May of 2004, the FDA approved Taxotere for use in AIPC on the basis of its TAX327 pivotal trial where survival was the primary endpoint and the total number of patients in the approved dosing every three weeks arm and the mitoxantrone control arm was about 670 patients. Almost assuredly as a result, the FDA would have required the control arm to be Taxotere treated patients, and Vital 1 experimental arm patients could not ethically be prohibited from crossing over to Taxotere. This latter point may explain why Vital 1 would not be an non inferiority trial since an assumption might have been that if GVAX provided no benefit early on, every pattient might elect to start Taxotere. If you subtract 3 years from the Ph2 GVAX data subitted for publication in April 2007 by Dr. Small et al, there would have essentially been no meaningful Ph 2 survival data, and little additional knowledge, except that high dose GVAX was feasible and safe.
http://clincancerres.aacrjournals.org/cgi/content/abstract/13/13/3883
The 1H04 perceived chances of a delayed response demonstratating statistically significant superiority to a cytotoxic in a trial that history suggested would be back end loaded would likely have been remote. OTOH, the eventual Ph2 results for the smaller subgroup that received high dose GVAX and the even smaller subgroup that subsequently received a taxane are provocative at the minimum. If the early interim data, however, showed even a trend suggesting that the GVAX event rate was higher than the Taxotere control arm event rate, the IDMB would almost assuredly stop the trial and recommend against the allowed continuing dosing with GVAX boosters and all Vital 1 patients could decide whether to start Taxotere. As discussed in a previous post, Vital 1 is likely now more a trial of GVAX + Taxotere (rather than GVAX alone) vs. Taxotere in asymptomatic AIPC.
CEGE's CEO announced that he was invited to make a podium presentation at the ASCO GU symposium in San Francisco on February 14 when CEGE will release additional data from their Ph2 trials, which, per ASCO rules, cannot be discussed before then. Stay tuned. JMHO.
iwfal:
epistemology - The branch of philosophy that studies the nature of knowledge, its presuppositions and foundations, and its extent and validity. Have to admit, I had to look that one up.
Thanks for the info. Given the fact, that the CEGE CEO conceded that Vital-1's enrollment pattern was like many other oncology survival trial, a "hockey stick", and that it is rare to get early statistically significant data, especially with the cumulative and delayed ramp up of immunotherapies, it seems there would be little point to having any interim look at all with such a low allocated alpha to it.