Dendreon Corp fka DNDNQ

[rancherho]

Dosing and Docetaxel: If you read the Phase 2 report of GVAX in HRPC by Dr. Small et al at http://clincancerres.aacrjournals.org/cgi/content/abstract/13/13/3883 which analyzes the smaller (32 patients) of the two Phase 2 studies, the strong inference is that the efficacy of this immunotherapy depends on both the highest available dosing and subsequent therapy with docetaxel.

Does this observation have any applicability to Provenge? We know from many sources, including the Briefing Materials for the Provenge Advisory Committee that the placebo / crossover patients in the 9901 and 9902a Provenge trials received one third less Provenge dosing than the ITT patients since the first on the three apherisis products was sent back to the placebo patients without processing in order to maintain blinding, while the remaining two apherisis products were frozen for later processing should a placebo patient chose to receive Provenge on the crossover protocol upon disease progression. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1-00-index.htm

We also know from the same source that both the ITT and crossover placebo patients who chose docetaxel therapy after Provenge commenced it at about the same point in time after randomization (debunking a spurious theory put forth by Jonathan Ashcroft that the ITT patients received docetaxel earlier). We also know from Dr. Petrylak’s presentation in November 2006 to the Chemotherapy Foundation that the interval between completion of Provenge therapy and starting docetaxel generally ranged between 4 and 6 months. See: his presentation under GU listing at: http://chemotherapyfoundation.org/professional_education/meetingarchives_tcf2006_main.html

Dr. Petrylak reported that the 51 of 147 ITT patients who commenced docetaxel therapy after Provenge had an increase in median survival of 13.6 months over that predicted for the same patients using the Halabi nomogram. The Halabi nomogram is based on a study of 1100 HRPC patients using 7 weighted diagnostic factors prognostic for survival during the period 1991 to 2001 when there were no FDA approved therapies extending survival. 31 of the placebo crossover patients also received docetaxel after their 2/3 dosing of Provenge. The increase in their actual survival over that predicted by the Halabi nomogram was 5.5 months or about 40% of that of the ITT Provenge plus docetaxel group.

Going back to the AC Briefing Materials, the statistical section stated that there was a correlation between increasing CD 54 cell count (a dosing potency marker) in the 9901 trial and improved Hazard Ratio and survival, although it did not reach statistical significance - further lending credence to the importance of the dosing amount of Provenge given a patient. In addition, the analysis pointed out that the 9901 survival curves begin to separate at 8 months post randomization, which schedule-wise ties into the early post Provenge use of docetaxel. The Briefing Materials also stated that 15% more of the 9901 placebo group received subsequent docetaxel than its ITT group (the percentages for the 9902a ITT and control groups were about the same). This statement as a standalone conclusion is somewhat misleading if it is meant to convey the impression that the use of docetaxel subsequent to Provenge was not a significant confounding factor since controls received a higher percentage than the ITT group. When dosing is factored in per the Petrylak analysis, all of the placebo group would have to crossover to Provenge and then their percentage using docetaxel would have to be 2.5 times that of the ITT group in order for the subsequent use of docetaxel not to be a confounding factor. This may have important ramification for the interim 9902b survival results; it is extremely unlikely that any overwhelming preponderance of both 100% crossover Provenge and subsequent docetaxel use favoring the control group will occur, thus maintaining a strong treatment bias in favor of the 9902b Provenge ITT group.

All of this further ties into one of the Dr. Small’s conclusions as the the Implications for Clinical Practice in one of his last Provenge presentation in October 2006 that Provenge “should not be viewed as replacement for chemotherapy, but as another treatment option." http://investor.dendreon.com/medialist.cfm

It is somewhat surprising that the Petrylak analysis, which was formerly presented on 11/10/06 prior to the 11/15/06 submission of the final BLA, or some summation of the Petrylak data, was not included in the AC Briefing Materials and was not discussed at all in the Advisory Committee meeting. While it may be true that it would be based on a retrospective subgroup analysis that may have lead to less than favorable survival plots of the ITT and placebo groups not receiving subsequent docetaxel , the data is so overwhelmingly positive for the combination therapy of Provenge plus docetaxel and would be viewed as a supplement to the existing standard of care, docetaxel, that even Drs. Scher and Hussein and Provenge’s unknown skeptics within the FDA might have been convinced of the wisdom of conditionally approving Provenge and docetaxel as a combination therapy. Some of the likely unrealistic luster as Provenge being the first immunotherapy to banish chemotherapies might have been lost, but the benefit to patients from earlier access to the combination therapy would have gained. JMHO