% | $
Quotes you view appear here for quick access.

Dendreon Anonim Ortaklik Message Board

  • tooskookum4u tooskookum4u Feb 27, 2003 9:00 PM Flag


    Furthermore, the Maxim Pharma situation was much different than we have here.

    In Maxim's case, there wasn't just a problem with the subgroup analysis. The problem the FDA had was with the subgroup analysis AND a strong indication the sickest patients were "randomized" into the control group. I would argue most of the skepticism of the Maxim results came from the randomization problem. Many -- even those outside of Maxim management -- felt the FDA might have been willing to at least give fair consideration to Maxamine in patients with liver mets if it weren't for the hinky randomization.

    If anything, the opposite happened in the 9901 trial. Not only were the patients in the 9901 trial much sicker than your average HRPC patient, the group in the placebo group was healthier than the group given Provenge.

    I agree retrospective subgroup analysis can be taken to extremes by desparate management teams. But let's compare apples to apples here. The situation with Provenge and Gleason < 8 patients is far different than the Maxim situation.

    SortNewest  |  Oldest  |  Most Replied Expand all replies
    • good post

    • technkl99 & others --

      Anyone catch the JCO article (a few months back) and accompanying editorials on prescreening for targets prior to admitting patients to a clinical trial. One of the letters to the JCO editor used the Herceptin example. Herceptin was saved when the developers made the decision to prescreen for the presence of HER2-neu. It baffles me why companies with non-pervasive targets test targeted drugs in an all-comers situation.

      One of the reasons I liked Dendreon to the exclusion of all the other dendritic therapy companies (other than the 48-hour turnaround) was even though PAP was theorized to be pervasive, they screened for it anyway. We learned along the way 95% of men are PAP+, but it was worth doing.

    • First and foremost, everyone wants to cure cancer and help patients. And, many times discussions on stock BB's that aren't one-sided are denigrated as being "mean," so I appreciate your comment. That said, there is a downside to undue optimism, and anyone following biotech has seen it - hopes dashed, treatements altered to enter trials for "breakthroughs" that simply don't prove out in the end. Nobody has a clue whether Provenge will ultimately be the next Gleevec or one of a host of failed immunotherapies, but there is a tenuous balance supporting biotech now IMHO - too much disappointment will squelch funding and innovation, but the same will be true for too much caution.

    • This discussion is wonderful. It is meaningful and informative.
      Almost five years ago I was diagnosed with Prostate Cancer. I had a low PSA and a Gleason of 3+3. When I surveyed my treatment options I was dismayed. Controversy surrounded all options to a varying degree, including conflicting statistics, and self serving statements by practioners. Eventualy, I opted for seeds and external radiation mainly out of morbidity concerns. I am doing very well (PSA <0.1). At that time, I wondered out loud that there has to be a better way. Since then the protocols have changed to a degree by combining treatment options, but nothing new has been added. Provenge offers the opportunity for advancement. Anyone who denigrates the phase III results, because it worked for subset is missing the big picture. This is a major step forward. It opens a whole new avenue for potential treatment, but it will be incremental. Fotunatly, there are orginizations like CapCure who will maintain the pressure for change and minimize the controversy when a new tretment is introduced.

    • Ok - we've closed the gap. Some points of disagreement but nothing worth debating. Now we wait for more data to dissect!

    • Autologous vaccines won't work in the clinic and aren't likely to be approved by the FDA. No oncologist is going to tell a just-diagnosed cancer patient to wait 45 days before the drug is ready. The FDA halted several autologous trials to get more information on the characterization and repeatable doses so there is a real concern there. Large scale manufacturing of autologous vaccines has never been tried and isn't likely to work.

      As far as auto-immunity is concerned, that is much more likely in autologous vaccines than Dendreon's products because of the way they select and engineer the antigen in the cassette. Provenge, of course, is supposed to create immunity to prostate tissue because the patients have had their prostate removed. Anything left over should be attacked.

      Polyvalent vaccines are a great idea, but most who have tried have failed simply because they've made some truly stupid HLA choices and assumptions. There is likely much value in a polyvalent approach, but good (i.e. conserved) antigen targets are hard to find. I'm more comfortable with monovalent drugs like Provenge and APC8024 -- baby steps in the infancy of a new treatment modality is often the safer bet.

      As far as the rest, I understand you would like to see some evidence of activity in all patients to increase the size of the safety blanket. This is the first double-blind, placebo-controlled Phase III trial for immunotherapies. I would not be surprised we learn seeing activity into the sickest patients is going to be the exception rather than the rule for all the reasons I've discussed.

      Furthermore, the de-differentiation of the cancer cells and the down-regulation of the PAP target in those cells may well help them escape immunosuppression. This does not lessen the chance of "true activity" except in those cells at the outer boundaries of de-differentiation (i.e. those cancer cells that have mutated a long way away from recognizable prostate tissue). You apparently see this as a reson Provenge will fail the upcoming trial. I see is as the logical reason why Provenge doesn't work in the high Gleason ranges.

      And finally, there is much debate as to whether it is ethical to limit efficacy tests on the new immunotherapies (and even Mab technologies) on the sickest patients. I don't debate the need to have good late-stage treatments, but I believe it is foolish to presume that a drug with marginal efficacy in late stage patients won't work in earlier stage patients.

      Cancer treatment these days sucks. It's painful, too often requires radical surgeries, and involves terrible, terrible side-effects. 50 years from now we'll look back on irradiation and chemotherapy of cancer patients much like we look back upon blood-letting and electro-shock therapy. We'll shake our heads and wonder why we took so long to clue in.

      Chemo and radiation are the best we've got for many cancers so we're forced to use them. It would be a shame to filter the development of new drugs through the hazy looking glass of what worked for these old drugs.

    • I wasn't being "fancy" just precise for your benefit, as you have professed expertise. However, you have not characterized my thinking accurately.

      More simply, then, if the situation is that advanced cells no longer express the target, and that expression is therefore mutable, then that increases the likelihood that "stressed" cells are more likely to down-regulate expression. This makes escape from suppression and tachyphylaxis more likely, lessening the chances of true activity.

      This explains:

      1. Why mechanistic/immunogic activity often does not translate into clinical activity very often
      2. Why polyvalent vaccines and autologous vaccines are used in lieu of monovalent approaches
      3. Why monovalent approaches targeting normally expressed antigens that are expressed in neoplastic cells have NOT been successful (let alone issues of auto-immunity that may arise targeting "normally" expressed antigens)
      4. And yes, why it is indisputable that CLINICAL activity (e.g. regression even if not >50%) in later-stage disease is considered a critical measure of activity.

      In addition, the statistical noise in better prognostic CA groups is well recognized, and that is why activity in later-stage disease is so important. My comments here are simply meant to inject some realism into the enthusiastic discussion, though I see that the level of promotionalism has devolved some of the discussion into insults. That said, the Biotech universe has seen many monovalent approaches falter. No matter how you slice it, it would have been better if the drug showed activity, not necessarily improvement, across the board.

    • Yes, the issue is exactly what I said earlier without using the fancy terms. I restate it again for those without medical backgrounds -- hopefully in a more thorough fashion this time.

      For Provenge, the situation is a little different. PAP is an enzyme found in normal prostate tissue. When cancer cells grow, it is well known the longer they grow unchecked they more likely they are to morph away from characteristics common to the original tissue. this makes it less likely PAP is expressed -- and less likely Provenge will work.

      Gleason scores are a measure of how different the biopsied cells are from base cancer cells. The higher the score from 2-10, the farther away they are from normal Prostate cells and the less likely they are to express PAP.

      This is one reason why it makes sense for Provenge to work in patients with smaller Gleason scores -- those tumors are more likely to express the target antigen/enzyme.

      This phenomenon is well-known in oncology immunotherapeutics. It is why companies have strayed down the path of using whole bits of the actual tumor to produce the immune system fighters.

      What is only now being understood is the lag time involved in cancer immunotherapy. Well, we actually learned this with the failed T-cell in vitro training programs of the 80's and 90's, but presumed the newer methods of training dendritic cells would cancel it out. It appread to have shortened the lag time somewhat, but not enough to remove it as a factor. In Provenge -- the first double-blind, randomized Phase III cancer immunotherapy trial -- it's pretty clear it takes about 10-12 weeks for things to get started. This is also why Dendreon's 48-hour turnaround is such a competitive advantage compared to other companies with 20 or 45-day turnarounds. The earlier you can dose, the more likely you are to avoid having the tumor growth outpace the ability of the therapy to be effective.

      This gets us to the other important part of the Gleason score, its ability to predict survival. Peedoc is right in that men who initially present with high Gleason scores can live for years -- meaning Gleason is not perfectly predictive for survival. However, this is not usually the case when the men are hormone refractory (androgen independent). In Provenge's population, the men have failed hormone therapy, like all prostate cancer patients eventually do. Their PSA is rising and their tumors are spreading. At this point, Gleason scores become more clearly predictive of survival.

      The highest Gleason scores predict a pretty rapid decline in the patients due to a high growth rate for the tumor. It is logical a cancer could grow fast enought to outpace an immunotherapy drug that takes 10-12 weeks. High Gleason scores are an excellent predictor for bone pain, which is a symptom of tumor growth (it splits the bones from the inside).

      When you combine the fast growth of the cancer cells in high Gleason patients with the fact these cells are less likely to express PAP, it is perfectly clear and logical why Provenge would work in lower Gleason scores and not higher Gleason scores.

    • I'll be a bit more specific. For Provenge to work, you need to believe that there are shared rejection antigens that are inevitably expressed and do not display significant plasticity. If you believe as you state that part of the anaplastic process of dedifferentiation removes the target from later stage cells, you've got your answer and understand the problem I'm referring to. Given your innuendo regarding my immunologic knowledge, I assume you are aware of this issue.

    • I'm not sure you can claim there was inactivity in later patients, only that there was a lack of efficacy.

      Histology and clinical practice shows, as mouton pointed out, the higher the Gleason score the more likely the tumor is to grow rapidly. This is especially true in hormone refractory patients.

      It takes 10-12 weeks for Provenge to get going. While this is happening, the prostate cancer is advancing. It is advancing slowly in those with low Gleasons scroes. It is advancing quickly (or at least more likely to advance quickly) in patients with high Gleason scores. If you know anything about immunotherapy, it makes sense that a fast growing cancer would outstrip the healing effects of an immune response. It makes even more sense when you consider Gleason 8+ cells are very differentiated -- meaning they look a lot less like prostate cells than they used to (a nod here to the poster who corrected me, but since PAP is found on normal prostate tissue, more differentiation means less likely the antigen exists). The more differentiated, the more likely a given cell no longer has the PAP marker necessary.

      Let's bring it back to the 10,000-foot level for a moment, though. The 9901 group was clearly sicker than the average prostate cancer patient who was just diagnosed as HR. More bone tumors, higher PSAs, higher Gleasons. The group with Gleason 8+ was like 36% of the population (correct me if I'm wrong here, I'm not looking at my Biotech Monthly reports for the facts) whereas they are only 25% of the normal population.

      If 9901 was representative of a real-world HRPC population, there is a decent chance it would have been able to reach statistical significance for the entire population. It nearly did, despite the sicker population and the small sample size (125-ish).

    • View More Messages
0.130.00(0.00%)Nov 18 4:00 PMEST