Wall Diver

Dendreon's Provenge Looks Likely to Be Approved in Mid-2010

Man, what an utterly clueless comment. What subset are you talking about? The previous pivotal trial was p=0.01 for survival over the entire intent to treat population. There was no subset submittal for the main dataset. DNDN was asked by the FDA in 1999, before the trial was initiated, to track the survival of every patient, even if it wasn't the primary endpoint. So how is that a retrospective analysis? There is no way you're a regulatory "expert," Mr. Clueless Newbie who's stuck in an untenable short position.

Is Dendreon a $360 Stock - Or Is That Too Low?

Michael, please check some of the dates in your article. You imply that DNDN filed the Provenge Biologic License Application (BLA) for Provenge in 1996/1997, when it was actually late 2006. It's possible that you're confusing the BLA with the Investigational New Drug (IND) application, which is what you file when you're ready to advance your product out of the clinic and test it on humans.

You also might be interested to know that DNDN has already virtually completed a Phase 3 trial (PROTECT, aka P-11) in an earlier stage of prostate cancer (ADPC), whereby patients in the experimental arm get three infusions of Provenge after they complete a course of Lupron that has lowered their testosterone level to zero. Then, approximately 18 months later, they get a booster dose of Provenge. The control arm received Lupron and sham Provenge (saline solution). The primary endpoint was the time it takes one's PSA count to double, and the secondary endpoint was the time it takes to develop distant metastases. Both endpoints looked good, with the primary a little better than p=0.05, but because of the length of time this stage of the disease usually takes, the dataset was incomplete for the secondary endpoint when they announced preliminary results back in 2006. Only 16% of the total of the patients in the trial had developed metastases on their bone scans, but the hazard ratio (HR) measurement showed that the patients in the Provenge arm were 27% less likely to have developed bone metastases (HR=0.73).

The hormone sensitive market treated in the PROTECT trial is probably four or five times greater than that of the hormone refractory market treated in the recently announced IMPACT trial. So, there is huge potential here.

Dendreon Troubles Beyond Provenge Test

Hmmm....you're a 60-year old man whose hormone treatments for prostate cancer have stopped working to slow the spread of the cancer, and its metastasizing to your bones...specifically, to your pelvis. You're starting to feel pain. You know that without any treatment, your future is one of severe pain, when the metastases rip your pelvis apart. Your choice is between seven months of Taxotere chemotherapy plus prednisone, or doing nothing. One course of Tax every three weeks for seven months. Your hair and nails will fall out, your white blood cell count will drop, leaving you vulnerable to infection, and you'll probably need anti-nausea medication. There's probably a 50-50 chance Tax's side effects will be so severe that you'll need to be hospitalized. Perhaps a 5-10% chance that Taxotere kills you outright. The Taxotere itself will cost perhaps ~$35K for a full seven-month regimen. Then you have to factor in the cost of the anti-nausea medication, the frequent use of prednisone, and the cost of your hospitalizations. Then, you must factor in the horrible way you're going to feel both during and after the Tax treatment--nausea, exhaustion, and a general feeling of malaise. You decide to decline Taxotere chemotherapy, just as 50% of all men with AIPC do.

Oh wait, now Provenge is approved! Now, you can sit down for an hour in the doctor's office a few times over a four-week period. Your blood gets drawn, and your dendritic cells will be reinfused into your blood, along with the immune booster CM-GSF plus the PAP antigen. Your immune system will be on the alert for any cells with PAP on them, and will be trained by these reinfused elements to be on the lookout for any cells with PAP that are already in your body too (PAP is only found on prostate cancer cells). After the infusions, you'll probably have a low-grade fever and chills for about a day. If you're unlucky, the fever will rise to the 102F range. A couple days after the treatment, you can go play golf. Your urologist has seen the trial results, and he knows that your chance of surviving for three more years after Provenge treatment is about five times higher than if you didn't receive Provenge or Taxotere. Hmmm....what should you do?

Dendreon: Provenge's Shortcomings Have the Shorts Coming

Mr. Kapur...the two experts you mentioned, Dr. Maha Hussain and Dr. Howard Scher, already had their chance on March 29 at the advisory panel meeting...they were 2 of the 4 No votes on the "Does the product demonstrate substantial evidence of efficacy" question. Unfortunately for their position, there were 13 Yes votes. In addition, Drs. Hussain and Scher both voted Yes on the safety question, which Provenge passed by a 17-0 vote. Before you decide to take a short position, you should know that well over 90% of the time in the past ten years, the FDA has confirmed approval after a positive advisory panel vote. When the FDA does reverse an advisory panel recommendation, it almost always is a reversal of a negative panel vote. Do Gemzar and ovarian cancer ring a bell?
findarticles.com/p/art...

By the way, there were four other oncologists on the Provenge advisory panel, and they all voted Yes on the efficacy question. You should also know that Drs. Hussain and Scher were chosen to sit on the panel by the CDER (drugs) division of the FDA, along with another oncologist, Dr. Alexander, who voted Yes. These were the only three advisory panel members chosen by CDER to sit on the panel. The other 14 members were chosen by the CBER division (biologics), and they voted Yes by a 12-2 margin. You should know that it will be CBER, not CDER, who makes the final decision on approval.

Anyway, even with all this info, I do hope you short the stock before the FDA makes the decision. We longs can always use a little more fuel for the price rise when the FDA inevitably approves.

Dendreon: An Even Better Risk vs. Reward Scenario

I see a lot of articles in the press that discuss the 4.5-month median survival benefit in the Provenge D9901 trial and then elaborate on how the treatment only gives you an extra 4.5 months to live. This is the MEDIAN, people! It compares the length of survival of the person at the 50th percentile in the treatment arm vs the length of survival of the person at the 50th percentile in the control arm. Because so many of the people in the Provenge arm of D9901 survived at least three years when compared to the control arm (34% vs 11%, p=0.0046), the AVERAGE survival benefit for Provenge in this trial is probably closer to 10-12 months. From the briefing documents published on the FDA website, it's entirely possible that close to 25% of the Provenge arm patients in that trial are still alive, 5 1/2 to 7 YEARS after they received Provenge. The typical life expectancy of a hormone-refractory prostate cancer patient is in the 14 to 20 month range, although Taxotere chemotherapy somewhat improves that outcome.

Dendreon: Revisiting the Risk/Reward Scenario

While many on Wall Street still believe that the FDA won't approve Provenge on the current dataset, don't forget the recent survey of positive overall committee votes and subsequent FDA approvals. The positive panel votes were reaffirmed by the FDA approximately 97% of the time in that survey, although the survey didn't include ODAC, VRBAC, or CTGTAC, the latter being the committee that voted on Provenge. I would imagine that the percentage would stay close to 97% or even improve on that figure if these committees were included.

Also, don't forget that the CTGTAC chairman Dr. Mule was the one who asked for clarification on the efficacy question, and the head of CBER (the division which decides on whether or not to approve therapeutic and prophylactic vaccines) and the head of the Office of CTGT were the two people who changed the efficacy question to make it conform with the FDA's own guidelines for drug approvals.

ODAC Member Raises Concerns About Dendreon's Provenge

In Dr. Scher’s letter, there were a number of questionable, or debatable, assertions, and a number of seeming logical flaws and contradictions, to the extent that it seems possible that he was not the actual author of this letter. However, for the sake of discussion, the authorship attribution by The Cancer Letter is considered to be factual. This response to Dr. Scher’s letter is an attempt to address some of those items, both to clarify the issues, and to encourage debate about them.

In addressing his efficacy concerns, Dr. Scher reportedly stated:
“My vote was based on the fact that neither of the two trials presented met their primary endpoint, which renders the significance of results from any subsequent analyses as “exploratory” and “hypothesis generating.” As such, the results do not constitute “proof” of benefit or justify a conclusion that they are “reasonably likely” to predict benefit.”

This is, of course, in reference to the time to disease progression (TTP) (11.7 weeks Provenge vs. 10.0 weeks placebo) endpoint pre-specified in the primary trial (D9901). Depending on the 2002 unblinding or the 2003 unblinding of the TTP data, the p value was either 0.085 (91.5% chance that the 1.7-week benefit was due to Provenge), or it is 0.052 (94.8% chance that the benefit was due to Provenge). In other words, Dr. Scher's argument is that because the probability of the 1.7-week benefit being due to Provenge treatment was not 95.0% (p=0.050), then the reported survival benefit of p=0.01 (99.0% probability that survival benefit was due to Provenge) must be disregarded as an "exploratory" statistic. Provenge supporters contend that the correlation between time to progression (91.5%-94.8%) and survival (99.0%) is so strong that the FDA should approve Provenge as soon as possible, especially considering its much milder side effect profile when compared to the treatment alternatives.

It should be noted that the TTP endpoint is only a surrogate endpoint for survival, often used because it could be measured faster than survival. It is somewhat disheartening to see Dr. Scher make the above argument. He is undoubtedly familiar with "A Clinical Development Paradigm for Cancer Vaccines and Related Biologics", to which the reader is referred, www.sabin.org/files/PD... Dr. Scher is surely aware of the new guideline on "Other Time-to-event Endpoints" on page 6 of the Clinical Development Paradigm (“Therapeutic cancer vaccines pose the possibility of a delayed onset of activity….based on the time required to mount an effective immune response and the time for that response to be translated into an observable clinical effect”, with discussion of TTP measurement issues) developed after extensive debate among the FDA, the NCI and outside experts, including Paul B. Chapman, M.D. and James Allison, M.D. from his own institution, Sloan-Kettering. There were no objections to the presentation of this paradigm during the second day of the FDA/NCI Workshop on Bringing Therapeutic Cancer Vaccines and Immunotherapies through Development to Licensure (February, 2007) and during the panel discussion on the second day, at which the FDA was represented by two physicians. A videocast may be seen at: videocast.nih.gov/Past...

Also, see Slide 7 of the following link, a copy of which was also shown at the Advisory Meeting, investor.dendreon.com/...
A cursory view of Slide 7 of Dr. Small's presentation of Provenge data would indicate that, using this new experience driven change in the way immunotherapies impact TTP and allowing for a three-month ramp up of the immune response, TTP would clearly achieve statistical significance. Of course, if TTP is accepted as significant, it would provide support to the survival benefit finding which, as noted, achieved p-value of .01, highly statistically significant.

Dr. Scher stated, “Another concern is that the requirements for regulatory approval appear to differ between the ODAC and CBER Advisory Committee.”

His discussion of the work at ODAC on clinical trial endpoints is somewhat stunning in regard to omission, especially with respect to the ODAC meeting on the afternoon of March 3, 2005 which he attended, when that Committee unanimously recommended that survival should be the only endpoint in AIPC / HRPC trials. It is incongruous that Dr. Scher now dismisses the survival finding in the D9901 trial just because the trial slightly missed the TTP endpoint which the FDA, NCI, and experts from around the world decided was inapplicable to immunotherapies.

As an aside, regarding Provenge survival data, the reader is referred to the presentation of Dr. Daniel Petrylak at the Chemotherapy Foundation in New York in November 2006, neglected by Dr. Scher, but accessible at: chemotherapyfoundation...
Although this presentation was indeed a retrospective analysis of 9901/9902a Provenge data, Dr. Petrylak reported that patients who received Taxotere 4 to 6 months after Provenge, when compared to that predicted by the Halabi nomogram (with which Dr. Scher is familiar), showed an astonishing increase in median survival of some 14 months (as compared to the 2.4 month increase demonstrated in the Taxotere TAX327 pivotal trial and the 4.5 months increase of Provenge as a standalone therapy). Dr. Petrylak’s presentation anticipated follow-up clinical trials in which the sequencing of Provenge, followed by some Taxotere, followed by a Provenge booster can be explored to further extend survival, perhaps in the absence of any prolonged chemotherapy. Surely, Dr. Scher and every oncologist hope that this will be the beginning of unprecedented management of this deadly disease. This further supports the comments of NCI’s Dr. Niederhuber at the outset of the second day of the FDA / NCI Workshop, that chemotherapies may be the first combinations used and approved to further improve cancer vaccines. The FDA will look forward to receiving the confirmatory data and analysis from Provenge’s third 9902b trial in 2010. Until then, Dr. Petrylak’s future Provenge sequencing trials of Provenge followed by a taxane and perhaps followed by a Provenge booster present reason for real, enduring hope by prostate cancer patients. Such additional studies will, of course, be greatly facilitated by FDA approval of Provenge.

Among his efficacy objections, Dr. Scher found, “Imbalances in disease aggressiveness and disease extent were noted between the Sipuleucel-T and “control” groups including a higher proportion with Gleason 6 disease or less at diagnosis (26.8% vs. 15.6%), and a lower proportion with both bone and soft tissue disease (52% vs. 69%) at the time therapy was started. Both factors favored the Sipuleucel-T arm, predicting a longer survival for the “treated” patients independent of therapy.”

None of the cited imbalances was statistically significant. However, Dr. Scher did not mention the most important imbalance, the number of bone metastases (BM) > 10, which heavily favored the placebo arm: 40.2% treatment with #BM>10 compared to 26.7% placebo. This prognostic factor was highly predictive of survival in both D9901 and D9902a trials. It also makes clinical sense, as advanced prostate cancer has a tendency to metastasize to bone, the higher the number of bone metastases, the more severe the disease. AC members thoroughly reviewed issues of imbalances between experimental and control arms.

Dr. Scher also stated, “Specifically there were no data provided of a favorable effect on PSA…”
However, this observation seems disingenuous, and surprising in light of Dr. Scher’s own Slide Presentation at the 3/3/05 ODAC meeting, where a slide was entitled: "Post Therapy Based Outcomes and Survival" states at item 3, “May not apply to non-cytotoxic agents or drugs directed at different aspects of the metastatic process." Later, under "The Association Between Time Dependent PSA Levels and Relative Risk of Death is Modest", he indicated that "A large part of the treatment effect is not explained by PSA" www.fda.gov/ohrms/dock... At page 285 of the Transcript of that meeting, Dr. Scher is quoted as, "So, where does this leave us in terms of PSA change and survival? Trial 9916 showed that there was an association of PSA decline and the treatment effect was eliminated when adjusting for the intermediate, did not see the same effect in both arms of the TAX-327 study. The Q3 week arm was the only arm to show a survival difference.” And, at page 289, "The regulations for accelerated approval are very clear. They require substantial evidence from well-controlled trials regarding a surrogate endpoint."

It is perhaps only slightly gratuitous to note Dr. Scher’s 3/3/05 reference to the term, "substantial evidence", as opposed to the term, "establish.” This has been the subject of some controversy both during and after the 3/29/07 Advisory Committee meeting. In his letter, Dr. Scher complained,

“Finally, the original question posed by the Agency to the Advisory Committee at the meeting was: “Does the submitted data establish the efficacy of Sipuleucel- T (APC-8015) in the intended population?” The first 4 respondees on the Committee voted “no.” The question was then changed to: Do the data show “substantial evidence?” A series of “yes” votes followed.”

Apart from the irony of his own previous statement suggesting general endorsement of the term “substantial evidence” (albeit in regard to accelerated approval), as an Advisory Committee member, Dr. Scher should well understand that this term is specifically cited in the May 1998 FDA Guidance for Industry publication regarding evidence for effectiveness of drugs and biological products, regulation, www.fda.gov/CDER/GUIDA... The regulatory requirement is that the treatment must find “substantial evidence of efficacy”. There is no deviation between Advisory Committees as long as they conform to clearly articulated regulatory requirements. It is not known why the original wording of the question to AC members was altered from the standard regulatory language, but this alteration created conceptual difficulty, and it was properly corrected.

Despite himself having voted in favor of the Provenge AC safety question, Dr. Scher averred in his letter, “The first question the Agency posed to the Committee was whether the product was “reasonably safe” for the intended population. While the vote was yes, the issue of cerebrovascular events as a potential safety signal was raised….Deaths due to CVA’s were recorded in 1.5% of Sipuleucel-T patients and 0.9% of those receiving “placebo.”

Readers may recall that the subjects in this trial were elderly men, who, independently of prostate cancer, had an age-associated, elevated risk of cerebrovascular accidents (CVAs). The risk of CVAs of U.S. men older than 65 is anecdotally estimated to be 2-3% per year. For the 147 patients in the 9901/9902A treated group, there were 8 CVAs. If one estimates that the average survival of this group for the three-year study period was ~26 months (median was 23.2 months), this data would be consistent with the expected risk of CVAs.

Dr. Scher further stated, “To place the frequency of the neurologic events in perspective, no cerebrovascular events were observed in TAX-327, a 997 patient three arm randomized trial that evaluated two different dose schedules of docetaxel in comparison to mitoxantrone,(NEJM 351:1052, 2004) or ASCENT1, a 251 patient randomized comparison of docetaxel weekly with or without high dose calcitriol (DN-101)(JCO 25:669, 2007).”

If true, this absence of CVAs in the TAX-327 trial group would be rather amazing, as these 997, primarily older patients were followed for some 18 months! Instead, it may be that specific CVAs were not reported; e.g. the FDA documents on the trial report only TEAE (Treatment Emergent Adverse Events). How Dr. Scher could confuse the absence of a specific item report with non-occurrence, given generally known incidence, is not readily apparent. Despite being the lead investigator for the ASCENT trial, he seems to not have recalled that, in the 125-patient Taxotere arm, there were 10 (8%) thromboembolic events, of which 2 were CVAs, 1 Myocardial infarction, and 1 arterial thrombosis. The first link below is the table from the JCO article on the ASCENT trial, the second is the abstract.
meeting.jco.org/cgi/co...
meeting.jco.org/cgi/co...

In addition, from five earlier Taxotere studies, 15/149 patients experienced thromboembolic events, including 3 CVAs and 2 arterial embolisms. For example, in this 2003 Docetaxel citation, www.pubmedcentral.nih...., it is stated,

“In the Columbia Presbyterian Phase II trial of docetaxel and estramustine, the occurrence of vascular events, including grade 4 and 5 cerebrovascular accidents (6%) and grade 3 deep vein thrombosis (5%), prompted the initiation of prophylactic anticoagulation.”

The above phase II trial tested Taxotere+Estramustine, the same regime tested in the Southwest Oncology Group's phase III counterpart to the TAX-327 phase III trial that Dr. Scher quoted, and 6% of treated patients had CVAs. This data suggests that TAX-327, for whatever reason, simply did not report CVAs. Dr. Scher’s suggestion that this proves their absence, and that, in contrast, Provenge is unsafe, seems to represent remarkably flawed reasoning.

The Provenge AC voted unanimously positive on the safety question, a vote which occurred after AC discussion of the CVA issue and members being informed that the FDA and Dendreon have planned to subsequently monitor 3000 Provenge patients for CVAs and any other identified safety issues. Provenge is generally considered to have very minimal side effects, in stark contrast to chemotherapy treatments.

Dr. Scher also suggested that the frozen version of Provenge given to placebo crossovers may have harmed them, “More important, and perhaps underappreciated during the discussion, is the recognition that the “placebo” used in this trial, a portion of the leukopheresis product that is cultured without the immunizing antigen and reinfused, may not be inert and in itself contributed to a relative worsening of survival for the control group in this trial.”

However, he did not identify any physiological process to support the assertion, and failed to represent the Dendreon clinical trial evidence that contradicts this assertion. According to the briefing documents posted by Dendreon and FDA, each subject in the Provenge trial underwent aphresis to collect peripheral blood mononuclear cells (PBMC) in certified hemodialysis centers. Subjects in the APC placebo arm underwent the same apheresis procedure as those in APC 8015 arm to harvest PBMCs. One-third of the total PBMCs were freshly administered to subjects and the other two third were frozen. If a subject in the placebo arm had disease progression, these frozen cells would be thawed and loaded with the therapeutic vaccine- PA2024 (APC8015F) and infused.

Transfusion of leukopheresis product is a safe and widely used clinical option; therefore there is no reason to believe that fresh PBMCs from patients’ body would be harmful. On the contrary, data supports that some placebo patients may have benefited from receiving the frozen vaccine. In study 9901, the median overall survival was 21.4 months, contrasted to 19.9 months as predicted by the widely used and validated Halabi nomogram. The 1.5-month benefit showed a trend of some benefit due to frozen Provenge. In addition, placebo patients that received frozen vaccine survived longer than those who did not. Furthermore, among the placebo patients who received second-line docetaxel therapy, the median survival was 25.7 and 20.2 months for those who received frozen vaccine and those who did, respectively. In addition, preliminary survival data from the D9901 from an interim unblinding in September 2003, two years after the last patient enrolled, showed a laddered improvement in median survival (MS) from the placebo patients who did not receive salvage Provenge (19.3 months), to the placebo patients who crossed over to receive salvage Provenge after their cancer progressed (23.9 months), to the Provenge trial arm itself (26.3 months). This two-year data strongly indicates that the exact opposite of Dr. Scher’s suggestion occurred.

In addition to expressing reservation on efficacy and safety despite votes of majority and unanimity, Dr. Scher was concerned “that the requirements for regulatory approval appear to differ between the ODAC and CBER Advisory Committees. As an example, ASCENT1 was a prospective randomized phase 2 trial of weekly docetaxel with or without high dose calcitriol (DN-101)... A total of 250 patients, 125 per arm were enrolled and followed. The 9% difference in the PSA response rate observed at six months was not statistically significant (P

Dendreon: Don't Forget About Risk vs. Reward

I should have added in my comment above that the placebo patients in 9902B (as well as the first two Phase III trials) have the option to cross over and receive salvage Provenge after their cancer progresses. This is a requirement of the FDA for placebo-controlled trials, and Dendreon's are no different from Onyx's trials or those of other oncology biotech companies.

Dendreon: Don't Forget About Risk vs. Reward

Instead of wondering why the FDA reworded the original question, Lets Be Reasonable should ask why the question read "Does the submitted data ESTABLISH efficacy" in the first place. The FDA's own guidelines for drug approvals are phrased along the lines of "Does the product demonstrate substantial evidence of efficacy?" As the first three panel members all interpreted "establish" to mean "100% conclusiveness," it was understandable that the committee chairman Dr. James Mule asked the FDA officials present at the meeting if the question could be reworded. When it was reworded to conform with the FDA's own guidelines for drug approvals, Provenge passed the efficacy question with ease.

I do agree with Let's Be Reasonable that one ethical question remains, and that is the question of what to do about the remaining ~33 placebo arm patients yet to enroll in the ongoing Phase III trial, 9902B. If the FDA approves Provenge by May 15, what's to prevent these patients from remaining in the placebo arm of the trial?

Does the FDA deny the approval of Provenge in order to get a more accurate reading of 9902B? Or should the FDA withold this safe and more effective treatment from ~100,000 men over the next few years until the 9902B survival data matures? I firmly believe that the agency and the company can hash out a workable solution, such as establishing a cutoff date for US enrollment, filling the remaining spots in the trial with patients from countries where Provenge won't be approved for several years (Canada, NW Europe, Australia), and approving the treatment for marketing. There is clearly an overwhelming demand in the prostate cancer community for an effective treatment like Provenge that does not have the severe side effect profile characterized by Taxotere chemotherapy.

The Short Case on Dendreon Corporation

Thank you for your civil reply.

- "First, it's not an inaccuracy if I don't mention the p-value. They missed plain and simple. The fact that it was close matters to bulls, not to the FDA. Also, even if they hit and it was 0.04 I would question it. Think about it, with a p-value of 0.04 there is still a significant chance that this data is a fake. Coupled with the fact that 9901 was never meant to be a registration trial and it was very small and I just don't see how anyone at the FDA can have confidence that Provenge is definitely a real drug. They will simply make them run another trial, as one is ongoing already. And I wouldnt expect patient groups to be up in arms about Provenge if it is delayed. And as you mention the 9902A trial, I've never seen the TTP data for that one, was it ever disclosed? I'm thinking it will be disclosed tomorrow in the briefing docs and the DNDN bulls may be in for a shock."

Not sure what your point is...even if the p value was 0.04, that's a 96% chance that the results were not random. Such a tiny miss of 0.002 in TTP is not going to be lightly discarded by FDA biostatisticians. I don't buy the argument that the 95% cutoff point is completely arbitrary, and 94.8% means nothing. In addition, there have been a fair amount of oncology approvals on trials of this size, plus some that weren't randomized and were approved on surrogate endpoints. As for 9902A TTP, the p value was in the 0.7 range, as I recall from the ECCO 2005 presentation. Most of the bulls know this already. Obviously not close, but the story ever since 2004 has been all about survival, especially after the FDA did away with time to progression as a valid endpoint for hormone-refractory prostate cancer patients.

-"The Taxotere statistical analysis is very questionable. First, it was not an analysis that was planned on being done before the trial and therefore is akin to data mining. Second, the problem with subsets is that the baselines may be even less balanced than in the trial as a whole. We are talking about only around 80 patients among the two trials after all, so there can be a lot of statistical hand waving going on."

The docetaxel analysis was released over 18 months after the bears first argued that 9901's survival benefit was due to more patients in the Provenge arm receiving Taxotere, in addition to receiving earlier Taxotere. This analysis successfully refutes that bear argument. The common statistically significant prognostic factors for each trial in overall survival were baseline PSA and number of bone metastases, with disease localization being a stat sig prog factor in 9901 and extremely close to stat sig in 9902A. Gleason score was not a stat sig prog factor in either trial. We haven't even discussed cause-specific survival for the entire intent-to-treat group in 9901. Basically, 13 patients in the provenge arm died of causes unrelated to their prostate cancer, while only 4 patients in the placebo arm did. This improved the p value from 0.01 to 0.002.

-"What I would have really liked to see is the TTP and survival for every Gleason Score integer in the trial. Theyre bundling of so many Gleasons together I think makes the data confusing."

They did that for the three-year survival data in 9901. Obviously, since there are so few HRPC patients with Gleason scores of less than 6, you can count that cohort as Gleason less than or equal to 6.

So, here is that data:
GS less than or equal to 6 Provenge arm: 41% or 9/22 survived for 3 yrs after randomization
GS less than or equal to 6 placebo arm: 28.6% or 2/7 survived
----------------------...
GS equal to 7 Provenge arm: 32.1% or 9/28
GS equal to 7 placebo arm: 11.1% or 2/18
----------------------...
GS equal to 8 Provenge arm: 40% or 4/10
GS equal to 8 placebo arm: 12.5% or 1/8
----------------------...
GS equal to 9 or 10 Provenge arm: 27.3% or 6/22
GS equal to 9 or 10 placebo arm: 0% or 0/12
----------------------...
All GS Provenge arm: 34% or 28/82
All GS placebo arm: 11% or 5/45)
P = 0.0046

I should add that the Cox regression analysis showed that there was an imbalance favoring the placebo arm in the trial...the Provenge patients were sicker on average.

The Short Case on Dendreon Corporation

"If the TTP of If the TTP of patients with Gleason scores (GS) of 6 and 7 or less were so important, one would think that these patients would have progressed slower than those with Gleason scores of 8 to 10. However, the median TTP for the GS 7 or less patients was 9.0 weeks, while the median TTP for the entire placebo arm was 10.0 weeks. This just goes to illustrate the fact that the FDA considers TTP a not so reliable surrogate endpoint, judging from the ODAC meeting a couple years ago on surrogate endpoints for advanced prostate cancer trials. Survival is the true gold standard.

The Short Case on Dendreon Corporation

My initial post was cut off. The final line that begins with, "If the TTP of patients with Gleason scores (GS) of 6 and 7 or less were so important, one would think that these patients would have progressed slower than those with Gleason scores of 8 to 10. However, the median TTP for the GS..."

should be completed with, "...GS

The Short Case on Dendreon Corporation

Forgot to disclose in my above post that I'm long Dendreon

The Short Case on Dendreon Corporation

Hmm....a number of factual inaccuracies in this article. Time to document them, with the comments from Maxim Jacobs in quotes.
----------------------...
"First, Provenge has never hit a primary endpoint, a big no-no for the FDA as the primary endpoint is what the trial is designed to test."

The principal trial that DNDN is basing on is the 9901 Phase 3 trial, where the primary endpoint was time to progression (TTP). Hitting the primary endpoint of TTP would mean that the p value equaled or bettered 0.05. The p value for 9901 was 0.052, so it's certainly debatable whether this endpoint was a hit or a miss. Jacobs not mentioning 9901's p value is either true ignorance or categorical dishonesty. While the second Phase 3 trial, 9902A, did not come close to achieving statistical significance in the TTP measurement, the fact remains that Mr. Jacobs saw fit to leave out 9901's actual p value in his article.
----------------------...
"I've heard arguments that survival is the hardest endpoint out there so if they can show a survival benefit, how can the FDA not approve it. For the simple reason that because of the design of the trial, Provenge might have had very little to do with that survival benefit. After disease progression, patients on placebo were given the option of going on Provenge or not. 68% of placebo patients then crossed over and received Provenge but not chemotherapy. If you were on Provenge and progressed, you had the option of receiving chemotherapy right away. This by itself could account for the entire survival benefit seen between the two arms as it is generally better to get chemotherapy sooner rather than later."

There was very little difference between the trial arms in terms of time to first Taxotere treatment. The difference was in the range of 0.5-1.5 weeks, as I recall...and it may have been the opposite of what Mr. Jacobs states..in other words, the placebo patients on average may have received Taxotere earlier than the Provenge arm patients did. DNDN mgmt has stated on more than one occasion that the placebo arm patients averaged more chemotherapy courses than the Provenge arm patients.
----------------------...
"The company has even disclosed data that showed that Provenge patients who subsequently received Taxotere had median survival of 34.5 months compared to 25.4 months for placebo patients (most of whom received Provenge before receiving chemo). Considering Provenge only showed a 4.5 month difference, this 9.1 month difference is pretty important."

This merely indicates that Provenge plus later Taxotere is probably synergistic. If one goes to the link below and scrolls down about halfway to Dr. Petrylak's presentation on Sipuleucel-T (Provenge), the really convincing slide is Slide 18, which compares the median survival of these subgroups:

-placebo arm patients who did not receive salvage Provenge but did receive Taxotere = 20.2 months
-placebo arm patients who, after cancer progressed, received salvage Provenge and Taxotere = 25.7 mo.
-Provenge arm patients who opted for later Taxotere = 34.5 months

Seems pretty convincing to me.
chemotherapyfoundation...
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"Given these confounding factors it seems clear that the survival benefit is in question and will very clearly be questioned in the FDA briefing documents which will be released on March 27th. So let's move on to the more important statistic, the one that was unaffected by patient crossover, time to tumor progression. Here Provenge showed only a 1.7 week difference (11.7 versus 10.0), a difference that was not significant. And given the imbalance in the arms with factors like Gleason score (a higher Gleason represents more aggressive disease and DNDN itself has referred to it as "one of the most important prognostic factors") where Provenge had a major advantage which could easily explain the meager 1.7 week benefit. The Gleason score breakdown was:

-39.0% of Provenge patients and 44.4% of placebo patients had Gleason scores of 8 or higher. These are the patients with the most aggressive disease and worst prognosis.

-34.1% of Provenge patients and 40% of placebo patients had Gleason scores of 7, which is an intermediate type of score.

-26.8% of Provenge patients and 15.6% of placebo patients had Gleason scores of 6 or less.
In other words, the Provenge arm had an 11.2% advantage in patients with the best prognosis. And in a small 127 person trial in only takes imbalances of a few patients here and there to manufacture a benefit."

If the TTP of patients with Gleason scores (GS) of 6 and 7 or less were so important, one would think that these patients would have progressed slower than those with Gleason scores of 8 to 10. However, the median TTP for the GS