Dendreon Corp fka DNDNQ

[rancherho]

Ocyanblue:

1. Dr. Small and his coauthors of the Phase 2 report in the 12/2000 JCO also discussed the choice of CD54 and the other CD markers that were used to characterize a dose of Provenge. http://www.jco.org/cgi/content/full/18/23/3894 CD54 was known as a maturation marker for immature dendritic cells and peripheral blood monocytes, indicating that these cells had taken up the fusion antigen and become antigen presenting cells. My guess is that Dr. Prevost’s remark about being “lucky” had more to do with the strong correlation of CD54 upregulation with long term survival than wrt any blind guess as to its use as a potency marker. I would also imagine that every panelist on the CBER Advisory Committee would have been well aware of the enormous amount of effort that DNDN would have expended to advance Provenge as far as it had come.

2. In retrospect, there is little doubt that both analysts and DNDN itself was pleasantly surprised by the results of DNDN’s interim look at 9901’s median survival in late 2003, and DNDN’s look at the final 36 month 9901 survival results in October 2004, especially after terminating 9902a early in 2002, and commencing a 9902b trial limited to Gleasons 7 and below AIPC patients. Could DNDN have been too hasty in writing off TTP as a valid surrogate marker for overall survival and therefore as a basis for FDA Accelerated Approval? That question was seemingly answered in January 2005 when DNDN reported that an analysis of 9902a’s TTP showed that it was not statistically significant, overall or for any subgroup (eg, GS=<7). It did not take some analysts and major institutions long to surmise that TTP in the slow enrolling 9902b trial would ultimately fail to show statistical significance for TTP, with devastating consequences at the time for DNDN’s pps. Interestingly, as an aside, Dr. Kantoff’s ASCO 2006 video presentation on the randomized, blinded 125 patient Ph2 trials of the Therion / NCI prostate cancer vaccine in AIPC, which ultimately failed to show statistical significance in either TTP or overall survival, also mentioned that enrollment in their trial was limited to GS=<7 due to the Provenge 9901 TTP results. Given these twists and turns in Provenge’s clinical trial history, it’s not a stretch to describe the unexpected, and to a certain extent, unplanned statistically significant 9901 survival results as “lucky”.

3. At the risk of sounding like a broken record, the NCI’s spoken and published observations / questions as to how any vaccine that fails to kill sufficient cancer cells to cause significant numbers of objective tumor responses or complete remissions early on can increase long term survival is more than theoretically relevant. If Provenge’s method of action explains that apparent inconsistency, it also destroys the significance of TTP as a surrogate for survival and as a primary endpoint in Provenge’s clinical trials, no matter what statisticians may argue. This would not only provide obvious benefits in the regulatory process by reducing any lingering uncertainty about Provenge's impact on long term survival rates, but suggest ways that Provenge efficacy might be further improved.

4. A working hypothesis is that high levels of regulatory T cells blunts the initial Provenge effector phase immune attack, but that CD54/ICAM-1 expressing dAPC’s preferentially create memory T cells primed against the PAP antigen in secondary lymphoid tissues. When these memory T cells are challenged by AIPC cells metastasizing to visceral organs, not protected by high regulatory T cell levels, the resulting activation and proliferation of memory CD8 T cells destroy the metastatic AIPC cells. There are several immune diagnostic tools available to test, and validate or not, this hypothesis. Whether this hypothesis or another explains Provenge’s method of action, one would expect the very capable Dr. Urdal to provide some data, analysis and discussion as to how Provenge’s cumulative CD54 cell count infused and/or CD54 upregulation can impact its method of action and correlate to long term survival in AIPC in the absence of demonstrated short term cytotoxicity against AIPC. In any event, its all to the better if luck accompanies DNDN’s choices and hard work.

Good luck to all DNDN longs.