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ODAC Member Raises Concerns About Dendreon's Provenge

From: 10 MD's, 4 Phd's and a research advisor

As a group of medical doctors and scientists we are writing to express our concern with the contents of a letter reportedly sent by Howard Scher, M.D. of the Memorial Sloan-Kettering Cancer Center, to the FDA, and published in Volume 33, No. 14 of The Cancer Letter, on April 13, 2007. Dr. Scher reportedly warned the FDA about flaws in the Provenge (Sipuleucel-T) trial data (Sponsor, Dendreon Corporation). The FDA decision about Provenge approval is presently pending. As Dr. Scher acknowledged, he served as a member of the Cellular, Tissue and Gene Therapy Advisory Committee on March 29, 2007, which voted positively on the FDA questions placed before it. The Advisory Committee efficacy vote was 13-4 in favor of Sipuleucel-T; Dr. Scher was among the four Committee members who voted in disapproval on that point though the transcript reveals that he voted Yes to the question of “substantial evidence” and No to “established efficacy” but changed his vote in an unclear manner (EXHIBIT-1).

The Advisory Committee safety vote was a unanimous 17-0.
In Dr. Scher’ s letter, there were a number of questionable, or debatable,
assertions, and a number of seeming logical flaws. This response to his
letter is an attempt to address some of those items.

Dr. Scher opens by stating his concerns on a Committee recommendation for approval based on: (a) data that fall far short of regulatory requirements; (b) “an inadequate statistical construct to determine definitive benefit”; (c)
incomplete data on product safety; and, (d) “what appears to be different
criteria for approval by two Advisory Committees to the Agency” Dr. Scher
acknowledges that all but the latter were discussed at the open meeting, but
warrant further consideration given the outcome”.

To begin with, one must ask why an expert invited by the FDA as a “special Federal employee” with expert knowledge in the given field, given a waiver of Conflict of Interest requirements (we are delighted that the outdated conflict of interest waiver guidelines under which Dr. Scher’s waiver was issued are currently being revised by the FDA) to participate in an Advisory Committee (EXHIBIT-2) with respect to “a particular matter”, and given access to Briefing Materials, the opportunity to comment, question and vote, chooses to question the outcome of the Committee’s recommendation, including his own vote on Safety, after the fact. Absent new material information, Committee members, if no one else, should respect the fairness of the process and the final vote of the Committee.

In addressing his efficacy concerns, Dr. Scher 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.”

The FDA has allowed increases in overall survival to be statistically tested for significance where it was not a primary endpoint and has approved a supplementary NDA, where the primary endpoint of survival was not statistically significant. The pre-specified primary endpoints in both the 9901 and the supporting 9902a trial were the time to disease progression (TTP). While not reaching statistical significance, a probability of 0.052 was undeniably close. It is understood that the positive Advisory Committee (AC) vote was primarily on the basis of the survival benefit subsequently discovered (and agreed by the FDA for the proper endpoint for filing of the Provenge BLA). The FDA has, in the past, considered an increase in overall survival in a life threatening disease, as a “gold standard” worthy of its own “alpha” of 0.05. See: www.ncbi.nlm.nih.gov/e...;db=PubMed&lis... In addition, the FDA has given Accelerated Approval to a supplementary NDA in NSCLC to Alimta, which failed to reach its primary endpoint of survival with a p value=0.93.: The Oncologist, Vol. 10, No. 6, 363-368, June 2005: FDA Drug Approval Summary: Pemetrexed for Injection (Alimta®) for the Treatment of Non-Small Cell Lung Cancer. theoncologist.alphamed...


The FDA, NCI and academic experts from around the world have agreed on a new Clinical Trial Paradigm for cancer vaccines which, if applied to the Provenge 9901 clinical trial would have made the increase in Time to Progression (TTP) statistically significant. See: “A Clinical Development Paradigm for Cancer Vaccines and Related Biologics”
www.sabin.org/files/PD...
T.2007.pdf.
Specifically, “Other Time-to-event End Points” on page 6 of the Clinical Development Paradigm stated: “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, Drs. Paul B. Chapman, M.D. and James Allison, M.D. Memorial Sloan- Kettering, where Dr. Scher also practices medicine, participated in this development effort. There was further discussion of this Paradigm during the second day of the FDA / NCI Workshop on “Bringing Therapeutic Cancer Vaccines and Immunotherapies through Development to Licensure”
The agenda for the Workshop is accessible at: https://cms.palladianp... and a video webcast of the Conference is accessible at:
videocast.nih.gov/Past...


Dr. Scher debates whether there was a “Delayed Effect” observed in the Provenge 9901 trial, but strangely goes on to implicitly suggest that more modern methods of measuring progression could have made Provenge’s TTP statistically significant without the need for a “Delayed Effect” adjustment. Dr. Scher disputes the existence of a Delayed Effect in the 9901 trial since: “serial imaging to assess disease were not performed once a patient was considered to have “progressed” and taken off study. As a result, individual sites were no longer being monitored so that no statements could be made regarding a possible “delayed effect” of the product on disease status”. Please refer to the Provenge 9901 plot (Slide 7) and the ITT and control group separation of curves at approximately 12 weeks accessible at: investor.dendreon.com/...
Dr. Scher comments that: “the Prostate Cancer Working Group 2 has advised that an apparent progression on bone scan at a three month assessment, be confirmed by documenting further progression on a subsequent scan six or
more weeks later before considering a patient to have failed the treatment.” (ASCO Multidisciplinary Prostate Cancer Symposium, (ASCO Abstract #221) February 22-24, 2007, Orlando FL, 2007). With respect to the Provenge trial : “the eight week interval between disease assessments was too short to observe clinically significant changes by bone scan, and that in many cases apparent progressions eight weeks after the start of a therapy are more a reflection of disease worsening that lead to trial entry, and not a failure of the treatment (CCR1 3: 1488, 2007)”. Thus, the Provenge Phase 3 protocol adopted in 2001 used a method of measuring progression that needlessly penalized treatment effects during the early months by actually documenting as progression, metastases that existed at randomization. So long as the measurement protocol was consistent between ITT and control groups during the entire time that Time to Progression was assessed, this logic suggests that eventual separation of curves could be expected and the actual Provenge TTP p value was much better than the p value of 0.052 reported. Thus, consideration of the recommended Delayed Effect for immunotherapies would have been unnecessary.

If Provenge’s 9901 trial’s TTP, its pre-specified primary end point, was statistically significant due either to a “Delayed Effect” or a methodology that, in effect censured early progression events due to metastases present at the time of randomization, then statistical analysis of overall survival to confirm that TTP is a surrogate for a meaningful clinical benefit is required.
The Kaplan-Meir log rank p value for increased overall survival was 0.01 for the 127 patient 9901 trial and 0.011 for the integrated 225 patient database of the 990l/9902a trials. Dr. Scher should be particularly sensitive to the desired use of overall survival in AIPC/ HRPC since he participated in the Oncology Drugs Advisory Committee (ODAC) meeting on March 3, 2004 when ODAC unanimously recommended that overall survival should be the primary endpoint in all AIPC / HRPC clinical trials. The 3/3/05 ODAC afternoon transcript discussing endpoints in ADPC and AIPC, and mentioning the importance of control crossover in the FDA approval of Mitoxantrone is accessible (starting at page 204) www.fda.gov/ohrms/dock... The Power Point Slides prepared for the meeting are available at: www.fda.gov/ohrms/dock...

The transcript and slides of the March 3, 2005 ODAC meeting further reveal conflicting inconsistencies with Dr. Scher’s letter. Dr. Scher writes; “Concerns about the validity of the findings were reinforced by the absence of other signals of an antitumor effect. Specifically there were no data provided of a favorable effect on PSA, regression or stabilization of soft-tissue or boney disease radiographically, health related quality of life, or that administration of the product delayed the development of pain. Even the time to the administration of chemotherapy, an indication to the treating Physicians that the clinical course had worsened, was similar between the two groups. Reinforcing the uncertainty was the fact that in response to a direct question at the meeting, none of the Physicians representing the Sponsor could articulate how treatment with the product had “helped” any individual patient.” Is it really necessary for one physician to tell another physician that increased survival “helps” a patient? Slide 15 of Dr. Small’s presentation at 2005 ASCO shows that, although not statistically significant, there was a positive trend in the delay of onset of Time To Disease Related Pain (TTDP) in the Provenge 9901 Phase 3 trial: www.asco.org/portal/si...;vmview=abst_detail_vi...


Consider Dr. Scher’s issue of “ a favorable effect on PSA”. Dr. Scher’s Slide Presentation at the same 3/3/05 ODAC meeting included a slide titled: "Post Therapy Based Outcomes and Survival", which 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" Dr. Scher shows that "A large part of the treatment effect is not explained by PSA" At page 285 of the Transcript: "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."

Dr. Scher’s letter states: “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.” Dr. Scher fails to point out that the question was changed by the FDA to conform with Federal law and FDA published guidelines. The FDA Guidance points out that: “ Congress adopted the 1962 Drug Amendments, which included a provision requiring manufacturers of drug products to establish a drug’s effectiveness by "substantial evidence." Substantial evidence was defined in section 505(d) of the Act as “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.” See: www.fda.gov/cber/gdlns...
More surprising is the fact that Dr. Scher clearly knew what the proper standard was and not only failed to suggest clarification at the meeting but now objects to its use. Dr. Scher noted at page 289 of the Transcript of the 3/3/05 ODAC meeting: "The regulations for accelerated approval are very clear. They require substantial evidence from well-controlled trials regarding a surrogate endpoint." Thus, "Substantial evidence", not "establish" were the correct operative words. Dr. Scher went on the say at that same ODAC meeting at page 294: " One could certainly consider an accelerated approval based on an interim evaluation assuming the trial endpoint was met, with the proviso that the trial accrual and monitoring continue until accrual was complete, the analysis complete, to assess the primary endpoint, which in this case would be survival." Thus, if the 9901 Provenge trial TTP was corrected for a Delayed Effect or realizing that early progression is often misleading and followed by a delayed increase in time to progression, the 9901 TTP would have been significant, and FDA approval could have been granted in 2002, with trial accrual, monitoring, and analysis for survival to follow in a confirmatory trial. This is exactly what the Committee recommended on March 29, that the accrual, monitoring and analysis of the 500-patient Provenge 9902b trial be continued, but that FDA Approval be given now. It is also in accord with the FDA’s comments of November 11, 2005 that the FDA has the authority to require that Sponsor conduct a Phase 4, post Regular Marketing Approval Phase 4 confirmatory trial, and to withdraw or modify its Regular Approval should such trial fail to confirm the efficacy or safety of the therapy. See: (pages 59 to 65) at www.fda.gov/ohrms/dock...

Dr. Scher raises questions about trial size, but a prior FDA approval of Mitoxantrone in AIPC /HRPC and the use of the “Halabi nomogram” as a check on the heterogeneity of the control group suggests that this concern is not justified. : Dr. Scher states: “The 2: 1 randomization increased the power of the experimental arm, but it may have inadvertently made the small 43 patient control group more heterogenous and less representative of the global population for whom the indication was proposed”. At that same March 3, 2005 ODAC meeting, much was made of the few – four – number of FDA approvals in AIPC /HRPC. One of these was a 1996 FDA approval of Mitoxantrone for quality of life (QOL) / palliation of pain; The Mitoxantrone pivotal Phase 3 trial enrolled 160 patients. That trial had a high crossover rate (approximately 62%) which negatively impacted a potentially more significant p value by effectively making the treatment given to the Intent to Treat (ITT) group ultimately be measured against itself when the control group receives the treatment upon crossover. Mitoxantrone’s p value for palliation of pain was 0.01. The crossover rate in the Provenge trials was higher ( over 70%) than the crossover rate in the Mitoxantrone trial, the number of enrollees in the integrated 9901/9902a trials (225) higher in the Provenge trial, and the Provenge p value for overall survival of 0.011 remarkably similar to the Mitoxantrone’s p value for palliation of pain of 0.01. See: www.jco.org/cgi/reprin...

Dr. Scher coauthored and published in 2002 a study based on a 409 patient reference group of AIPC / HRPC patients detailing a nomogram which predicted survival based on certain diagnostic and functional patient characteristics. . See: jco.ascopubs.org/cgi/c... A year later, Dr. Susan Halabi and several distinguished coauthors, including Dr. Eric Small, the lead investigator of the Provenge 9901 clinical trial, published a similar study and nomogram. See: jco.ascopubs.org/cgi/c... The “Halabi nomogram” has since become a standard reference tool in comparing the survival it predicts for any group of AIPC / HRPC patients with the actual survival of the same group of patients treated with a new therapy. Since none of the Halabi reference group of 1100 patients benefited from any therapy extending survival in the period from 1991 to 2001, when no such therapies were available, the nomogram is based on a truly untreated group of patients where the confounding effects of a crossover trial protocol would not be a factor and the large number would assure heterogeneity. Dr. Small tested the Provenge 9901 ITT group against the Halabi nomogram and reported that median survival increased from 4.5 months to 5.8 months. See Slide 14 accessible at: investor.dendreon.com/...

While the FDA does not accept a nomogram in place of a control group in a randomized clinical trial there is no question that an appropriate nomogram serves as an invaluable check on the heterogeneity of both the intent to treat and control groups in a clinical trial.

Dr. Scher makes no reference to, or indication that he is aware of, a November 2006 presentation by Dr. Daniel Petrylak, a lead investigator of the Taxotere SWOG 9916 Phase 3 trial, at the Chemotherapy Foundation in New York that reported a remarkable increase in survival of AIPC /HRPC patients who received Taxotere after Provenge when compared to their survival predicted by the Halabi nomogram. See: (a) Dendreon’s November Press Release at investor.dendreon.com/...;Header=News
and (b) Dr. Petrylak’s presentation at: chemotherapyfoundation...

Although this presentation was indeed a retrospective analysis of 9901/ 9902a Provenge data, it was also supported by some very strong immunology
data reported by Dendreon in November, 2006 regarding the potential
efficacy of a Provenge booster infusion with a follow-up presentation at the annual AACR meeting on March 16, 2007, See: investor.dendreon.com/...;Header=News and www.abstractsonline.co...={34D88016-D025-4791-B...
Dr. Petrylak reported that 81 AIPC /HRPC patients in the 9901 and 9902a Provenge trials who received Taxotere 4 to 6 months after Provenge, showed an astonishing increase in median survival of some 14 months as compared to the 2.4 month increase in median survival reported in the Taxotere TAX327 pivotal trial, and the 4.5 month increase in median survival reported in the Provenge 9901 trial when compared to that predicted by the Halabi nomogram. This analysis was per the 9901 and 9902a trial protocols, which did not allow any booster dose of Provenge after the initial three dose therapy. The Dendreon P11 immunology trial data, where a single booster is given per its protocol in Androgen Dependent Prostate Cancer (ADPC), reported that Provenge primed long lasting, highly avid T cells against the PAP antigen (strongly supporting the conclusion that these are “memory” T cells), but also that the avidity of these T cells could be substantially increased with a single booster. Dr. Petrylak’s presentation anticipated follow-up clinical trials in which the sequencing of Provenge, followed by some Taxotere, followed by a Provenge booster may be explored to further increase patient survival, perhaps in the absence of any prolonged chemotherapy. These findings further supports the NCI’s Dr. Niederhuber’s comments at the outset of the second day of the February FDA / NCI Workshop that chemotherapies may be the first combinations used and approved to further improve cancer vaccines.

Provenge is an active immunotherapy, not a cytotoxic drug. Dr. Scher should look to reported successes in immnotherapy to inform the proper analysis of its likely method of action. Dr. Steven Rosenberg and his NCI colleagues are making startling advances with immunotherapy in end stage melanoma. See his presentation during the first day of the FDA.NCI Workshop at : videocast.nih.gov/Past... To briefly summarize the method that Dr. Rosenberg uses in his adoptive immunotherapy, it is the infusion of (a) large numbers of (b) long lasting T cells, (c) primed against a single melanoma antigen, into (d) patients who have been preconditioned with chemotherapies to deplete regulatory T cells. Provenge can be described as an active immunotherpy, which infuses (a)large numbers of dendritic antigen presenting cells, which in vivo prime even larger numbers of (b) long lived memory T cells against (c) an AIPC/HRPC antigen, Prostatic Acid Phosphatase (PAP). Instead of preconditioning patients to deplete regulatory T cells, which could also deplete the available pool of naïve T cells for Provenge’s dendritic antigen presenting cells to prime, the Taxotere (docetaxel) post Provenge analysis suggests that docetaxel, which preferentially targets rapidly proliferating regulatory T cells and cancer cells expressing bcl-2, (d) “post-conditions” and depletes the regulatory T cells in an established tumor and its microenvironment, potentiating a patient’s powerful immune response against cancer. See, for example, the fundamental research coming out of the laboratories of Professor Hans Schreiber at the University of Chicago at: www.jem.org/cgi/conten... and the presentation at the NIH of Professor Ulrich non Andrian of Harvard explaining how the ex vivo maturation of dendritic antigen presenting cells leads to the priming of long lived memory T cells upon their infusion. See: Migratory Properties and Immunological Consequences of Dendritic Cell Migration Wednesday, October 25, 2006 Uli Von Andrian Total Running Time: 01:03:39 videocast.nih.gov/Past...;s=11 The Provenge trials excluded men who had known metastases to visceral organs. It is just such metastases, frequently undetected, that ultimately cause death in AIPC/HRPC. Androgen-Independent Prostate Cancer Is a Heterogeneous Group of Diseases Lessons from a Rapid Autopsy Program Cancer Research 64, 9209-9216, December 15, 2004 cancerres.aacrjournals... A logical hypothesis to explain how an immunotherapy such as Provenge, can fail to cause the regression of an established tumor, and yet increase overall survival is that it may slow or stop cancer metastases by destroying targeted cancer cells in the bloodstream that are shed by an established tumor and are relatively unprotected by regulatory T cells. When Taxotere or some other post-conditioning agent depletes regulatory T cells, some tumor regression should result until and unless too much or too long administration of Taxotere also depletes attacking CD8 effectors T cells. At that point a Provenge booster may be given to initiate a further sequence of tumor destruction. While only a logical hypothesis, this would explain Provenge’s method of action far more plausibly than proposed methods of action, or absence thereof, for many drugs on the market today.

Dr. Scher raises question concerning the safety of Provenge and of his own Committee meeting vote on safety by making irrelevant and somewhat absurd comparisons to the cardiovascular side effects of chemotherapies while not addressing Dendreon’s direct statements regarding Provenge safety. The safety issue is not the cardiovascular side effects of Taxotere or of DN-101, which Dr, Scher discusses, but the safety of Provenge. At the Committee meeting, Dendreon’s Dr. Frohlich responded to the safety question by pointing out that there were no CVA’s in the ADPC Provenge treated patients (P16, 9906 and P11), there were no CVA’s in the 3 months following Provenge dosing for men who experienced CVA’s, and that reference to a large database of men with similar advanced cancer indicated that there was nothing extraordinary about the Provenge CVA rate. Dr. Frohlich then described the proposed FDA / DNDN 3,000 patient monitoring plan for CVA’s in men treated with Provenge. That obviously satisfied the Committee on the safety issue leading to a 17 to 0 vote, If Dr. Scher has problems with any of the Sponsor’s comments, he should discuss those comments as they deal with Provenge safety and not digress to safety issues in two unrelated chemotherapy trials.

Scher’s letter concludes with a warning regarding the far reaching implications of any FDA approval of Provengen: “For one, it provides the Agency’s endorsement of Sipuleucel-T as a “standard of care” treatment for asymptomatic androgen independent (castration resistant) disease that represents upwards of 45,000 men in the US. The second is that by extension its elevates Sipuleucel-T to a position of being the new “control” arm for future randomized Phase 3 trials that are being designed for the regulatory approval of any new experimental agent or approach. It also opens the door to the premature approval of drugs based on inconclusive data”.
“The “standard of care” designation comes with ethical and possible legal implications for doctors. Marketing data makes it clear that far fewer AIPC / HRPC patients choose to take the only standard of care presently FDA approved that extends survival, Taxotere, than its is indicated for, reportedly due to the side effects patients experience over its 7 month course of therapy. Taxotere’s pivotal Phase 3 TAX327 trial showed only a 2.4-month increase in median survival. If the FDA approves Provenge doctors would be expected to fully discuss treatment options to this dying AIPC/HRPC patient population with explanations of what clinical trials for various FDA approved therapies demonstrated, may have demonstrated, and did not demonstrate, and even, perhaps, to ask for signed acknowledgments that they were given this information before making a therapy choice. What a revolutionary idea! Doctors would actually give a dying man the best available information about his disease, and allow him to make his own informed decision after consulting, if he chooses, with one or more doctors. How would most asymptomatic AIPC / HRPC patients respond to a question as to whether or not they would consider a three dose course of Provenge, if: (a) the side effects were much like 3 flu shots and were generally resolved within a couple of days; (b) the chances of being alive three years hence would double or triple, (c) there was a possibility, however, that the risk of stroke might increase by about 1% over that period of time, and, (d) if Provenge is chosen, a later choice to take some Taxotere, or other taxane, and a possible Provenge booster might further increase survival substantially?

The FDA can make decisions with sponsors of new trials of experimental drugs or therapies in AIPC / HRPC, as to whether the use of Provenge treated patients in a control arm would be appropriate pending completion and analysis of the 9902b Provenge Phase 3 confirmatory trial. Sponsors of future trials may have reason to be concerned and potentially have a high bar to overcome if, when, and subsequent to, Dr. Petrylak introducing the sequencing of Provenge, then limited Taxotere or other taxane, then a Provenge booster into a FDA Phase 3 pivotal trial. AIPC / HRPC patients and their families may benefit enormously, but competitive therapies may indeed suffer.

The March 3, 2005 ODAC meeting dealt with the issue of clinical trial endpoints in prostate cancer, in part, because there have been so few that have received FDA approval in a cancer where there is a significant unmet need. A slide presentation to ODAC listed four therapies approved by the FDA: (a) Taxotere (docetaxel) approved in 2004 for increased survival; (b) Zoledronic Acid approved in 2003 for QOL; (c) Mitoxantrone approved in 1996 for QOL; and (d) Estramustine approved in 1981 under the “Old Rules”. It is disheartening to think that so few therapies have been tested in clinical trials and approved by the FDA for such a large population of critically ill men. ODAC gave a recommendation to the FDA during its March 3, 2005 meeting that survival should be the primary end point in all AIPC /HRPC trials. It is disheartening to see an oncologist, as distinguished as Dr. Scher, use a scientifically outdated analysis of Time to Progression, a proposed surrogate for survival to argue against an intelligent analysis of survival, and then failing that, to criticize the Provenge trials as too small, when comparison of the Provenge trials to the FDA approval of Mitoxantrone in AIPC /and HRPC, and the actual survival of Provenge treated patients compared to that predicted by an 1100 patient reference control group in the Halabi study strongly support the finding of substantial evidence of efficacy.

In retrospect, with what we now know about the measurement and analysis of increased Time to Progression in therapeutic cancer vaccines, Provenge theoretically could have filed its BLA and received FDA Accelerated Approval in 2002, and continued with the data collection and analysis of 36 month survival data to receive Regular Approval. Time has long since passed when this valuable new tool in the treatment of prostate cancer should be made available to all AIPC/ HRPC patients.

For all of the above reasons, but most of all for the benefit of all present and future prostate cancer patients and their families, we urge the FDA to approve the Biologics License Application submitted by Dendreon Corporation for Provenge (Sipuleucel-T).

Very truly yours,




Exhibit 1.—Text of Dr. Scher’s vote on efficacy

The following discussion took place after a round of voting on safety of Provenge (unanimous Yes) took place. The discussion below and reference to two questions are regarding efficacy, the original question was regarding the efficacy was established. The question was revised into a second question of “substantial evidence”. Due to quality of audio transmission the text below is deemed “complete and accurate to better than 95% of the transcript” by the transcriber.

Dr. Mulé - Dr. Scher?

Dr. Scher -
I think is complete and accurate to better than 95% of the transcript of Scher's vote on efficacy.

I think we are really poised at the beginning of what will be hopefully an outstanding era of immunotherapy. I think there is sufficient evidence demonstrated which justifies the definitive study, and I would say there are investors in that who concur. But I think it does not meet the … umm … as the question was phrased, to establish the efficacy, I think this is still an open question.

M - So I take I you’re saying “yes” with these provisos?

S. You have two questions, I would say yes to one, no to the second.

Pausing, murmuring laughter and confusion in the room.

S - If the question is posed as “establish”, I say “no”.

M - No, its, uh, “substantial evidence”.

S - No.

M - No.



Exhibit 2.—Extract from Dr. Scher’s Conflict of Interest Waver

DATE: February 7, 2007

FROM: William Freas, Ph.D., Director, Division of Scientific Advisors and Consultants, CBER

SUBJECT: 208(b)(3) Conflict of Interest Waiver for Howard I. Scher, M.D.

TO: Randall Lutter, Ph.D., Associate Commissioner for Policy and Planning

Through: Vince Tolino, Director, Ethics and Integrity Staff, Division of Management Programs, OM




Dr. Scher advised the GDA that he has a financial interest related to the above topic that could potentially be affected by his participation in the matter at issue. Dr. Scher reported that he has joint stock in (DELETED) at a current value of (DELETED). Additionally he reported that his institution has a grant from (DELETED) (competing firm). The grant is current and his institution receives (DELETED) per year from 2006-07. Dr. Scher receives no salary from the grant. The grant is to study a licensed, approved drug (DELETED) in prostate cancer trials. (DELETED) is a licensed drug currently used in other cancer therapies. Dr. Scher also reported that his institution has a grant from (DELETED) (competing firm). The grant is current and his institution receives (DELETED) per year from 2006-2008. Dr. Scher receives no salary from the grant. The grant is to study an investigational drug (DELETED) that is also being studied in several types of cancer. It is unlikely that Dr. Scher's participation in the discussions on March 29 of a cellular therapy for prostate cancer will have a direct and predictable effect on his financial interest.

The Short Case on Dendreon Corporation

"I would still want to do a good job, whether or not I had a financial interest. If I believed in the FDA mandate to approve drugs that have the data proving efficacy, there is no way I would approve this drug. "

Get real. whether or not. sure. you do have a financial interest in seeing Provenge fail and seeing cancer patients die and it was you and other shorts' efforts that contributed to shelving of other cancer drugs (e.g. for breast cancer) because the company could not raise as much money as it wanted through its offerings. Now shorts are selling shares that don't even exist. This is dirty business if you ask me.

But my issue with you is bigger than this. You are misrepresenting the company. I wonder why these shorts, and their crooked analysts keep misrepresenting things. You owe the company and the public a retraction of your original message and a correction of items which you misrepresented. I'll let you do it on your own and correct your false misrepresented and defamatory statements and I hope you do it voluntarily because all options are on the table for us and we will take action against crooked activities no matter how big you think you are.

Dendreon: Thinking Strategically Ahead of the FDA Review

“Whether Provenge is approved or not is very speculative. Results of a Phase 3 study published in The Journal of Clinical Oncology last July showed that the difference in time to progression of the disease was statistically the same as a placebo, which is not encouraging. However, patients taking the drug lived, a statistically significant, 20% longer (3-5 months) than those receiving the placebo. So, I’m mildly bullish that this drug will be approved.”

Don’t forget that the FDA agreed to Survival as the appropriate endpoint for filing of the BLA (and as the Gold Standard for cancer drugs).

“It should be mentioned that DNDN’s technicals are not favorable, and that short interest on this stock is 25%.”

So if lots of crooks gang up on a company that makes the technicals unfavorable. I see a very favorable technical picture with a triple bottom and a major rebound from the $3’s blowing through moving averages.

“Clinically, Dendreon has nothing else going for it.”

False. See the company’s pipeline on Dendreon.com. Thanks again to the shorts who helped shelf the company’s breast cancer drug but I think we will learn more about that pipeline soon given the company’s hiring frenzy that seems for research (pipeline) as well as launch (Provenge).