Update on Dendreon's Briefing Docs: Provenge Missed All Endpoints

The FDA briefing documents for Dendreon's (DNDN) Provenge review were released Tuesday morning. Here are the conclusions, taken directly from the documents:

Conclusions: Neither study D9901 nor study D9902A met any study objectives A review and analyses of the data submitted, including sensitivity analyses and review of death events, supported the finding of an increase in the median survival reported by the sponsor in APC8015 arm compared with the APC-Placebo in study D9901. However, the lack of a pre-specified primary method for survival analyses renders it difficult to estimate the type I error of this survival analysis. In addition, the six month difference in median survival times between D9901 and D9902A despite similar study design, inclusion criteria, and baseline characteristics, suggest that the eligibility criteria did not define a homogeneous population in these small studies. These observations increase the possibility that the survival difference in D9901 might be attributable to chance.

Safety and tolerability: APC8015 was generally well tolerated; approximately 90% of subjects in the two studies received the 3 infusions specified by the protocol. The most frequently reported adverse events in APC8015 treated subjects were transient chills, fatigue, and pyrexia. However, the increased CVA frequency reported in subjects treated with APC8015 constitutes a potential safety concern.

Let's first address the efficacy. Provenge has failed ALL primary and secondary endpoints in both their trials. Survival was not even an endpoint in the trials. Below is a summary of the secondary endpoints found in the briefing documents:

Note the 0% response rate as well as the complete and utter failure to meet any of these endpoints. And now on to the primary endpoint, time to disease progression. A picture says a thousand words so here is the graph of TTP:

In other words, there is basically no treatment effect on tumor size or tumor progression or even tumor related pain. The only thing positive that ever came out of the 9901 trial was the survival benefit. But as the FDA statistician explains, as the analysis was not pre-specified it makes sense to look at several to see how the data would have come out. Take a look at the table below. In 3 of the 6 models, they actually miss significance, and in one that was a hit, they just barely hit with a p=0.048. Also note that in the test where they saw a p=0.002, there were a whopping 10 datapoints missing. And if these patients were on drug, they tended to have reacted worse to treatment. If they were on placebo they were reacting better. In other words, those 10 missing data points helped the Provenge arm look much better than it was.

Treatment effect on overall survival using Cox model with different set of covariates (total subjects: 127)

*: The sponsor’s analyses and confirmed by the reviewer

~: Reviewer’s analysis

So, in conclusion, Provenge missed all their endpoints and even their survival signal is in question. Now let's move onto safety. People have been arguing that with a survival benefit and a clean safety profile, Provenge should get approved. Apparently, it might not be so safe. There appears to be an increase in the number of cerebrovascular accidents, with 5 people dying in the Provenge arm compared to 0 in placebo. The key conclusion here is "although these differences did not reach statistical significance, the increased CVA frequency is a potential safety signal."

With these briefing documents in hand I am definitely looking forward to the actual panel meeting and vote on Provenge.

Disclosure: Author has a short position in DNDN

Comments

[Dan Gseekin...:]

Maxim, did we read the SAME briefing documents? It took you 24 hours to post this MISLEADING "analysis" report so I am sure that you read the entire package very carefully. So let's examine your conclusion:

"appears to be an increase in the number of cerebrovascular accidents, with 5 people dying in the Provenge arm compared to 0 in placebo. "

-->> This is a LIE. Please check #2 in www.fda.gov/ohrms/dock... ... quote:
"Page 3, safety results, 1st paragraph, replace the phrase “compared to none in APC-Placebo treated subjects” with: “compared to 2.6% (2 out of 78) in APC-Placebo treated subjects.”

Hmmm... how come you missed this "LITTLE" correction? This minor correction makes this entire CVA thing a NON-ISSUE (and it is worthy a lengthy discussion, but perhaps you should first explain your readers why you've misrepresented the facts ONCE AGAIN - as all documents were posted at the same time.)


Now let's proceed to the meat of the report and let's jump right to the CONCLUSIONS of the biostats reviewer:

"Conclusions

· Based on the results of the statistical analyses of the efficacy data presented by the sponsor and the results of analysis performed by this reviewer, it appears that the two studies provide some evidence in support of using Provenge for the treatment of men with asymptomatic metastatic androgen independent prostate cancer.



· However, the key efficacy evidence (difference between the two arms in overall survival) is based on post-hoc analyses. Although it is impossible to precisely estimate the false positive rate due to the nature of the analyses, it is certain that the level of falsely claiming effectiveness for this product is substantially higher than the one in a conventional setting.



· It may be important to weigh the following points while considering the unfavorable strength of statistical evidence: 1) showing statistically significant difference in overall survival in Study 9901 and showing a trend toward improvement in overall survival in the second study; 2) showing a trend in favor of APC8015 arm in all comparisons for other important endpoints; 3) the safety profile of the product; 4) other existing effective treatments for the targeting patient population.



Let me post again the third and final conclusion as written by the FDA (stat) reviewer:

It may be important to weigh the following points while considering the unfavorable strength of statistical evidence: 1) showing statistically significant difference in overall survival in Study 9901 and showing a trend toward improvement in overall survival in the second study; 2) showing a trend in favor of APC8015 arm in all comparisons for other important endpoints; 3) the safety profile of the product; 4) other existing effective treatments for the targeting patient population.




Maxim, one more interesting point that is worth a lengthy discussion is about the recent ILLEGAL "printing/issuing" of phantom shares (aka "naked shorts") by the shorts. Your comment about this ILLEGAL activity will be very interesting ...

2007 Mar 28 06:11 AM

[Maxim Jacobs:]

Dan,

"It took you 24 hours to post this MISLEADING "analysis" report "

I think Seeking Alpha has simply become so popular that the editors are swamped with posts to look at. 2 months ago when I submitted a post on AGIX it took about 2-3 hours to post. The last couple have taken much longer. I submitted this before noon yesterday, just about 3 hours after the briefing docs were released.

"This is a LIE. Please check #2 in www.fda.gov/ohrms/dock... ... quote:
"Page 3, safety results, 1st paragraph, replace the phrase “compared to none in APC-Placebo treated subjects” with: “compared to 2.6% (2 out of 78) in APC-Placebo treated subjects.”"


We are referring to two different statistics. I am referring to deaths due to CVA while you, and the correction, refer to CVA events (that did and didn't result in death). Check out www.fda.gov/ohrms/dock... Table 25, and you will see the statistic that I am quoting. Given the number of CVA deaths in such a small trial, I wouldn't call it a non-issue. It is at least one that needs to be explored further. Or would you rather give someone a drug of questionable efficacy that could kill them of stroke?

I think the opinion of the clinical reviewer trumps anything from the statistician (and by the way, he wasnt exactly pro-Provenge given all the discrepancies he found).

"Maxim, one more interesting point that is worth a lengthy discussion is about the recent ILLEGAL "printing/issuing" of phantom shares (aka "naked shorts") by the shorts. Your comment about this ILLEGAL activity will be very interesting ..."

I'm not quite sure what you are referring to. I remember some stock a few years ago were listed on the Berlin Bremen exchange without their knowledge and you could naked short them there but I dont see how this naked shorting can be done on the US market, especially not en-masse (sometimes brokers print your tickets but end up taking forever to deliver your shares, but those incidents are always isolated). Everyone I know is complaining that they have no borrow even though this recent pop in DNDN is creating a wonderful shorting opportunity.

2007 Mar 28 09:15 AM

[Echo To All:]

maxim, your twist on the safety data is wrong.

u simply show that patients unfortunately died w/ CVA from the provenge arm and not placebo, but Dan rightfully pointed out that in the placebo arm a few patients experienced CVA also.

all that can be said for the CVA issue is that it was experienced in both areas, but no one from the placebo arm died.

it is something to look into, obviously, but as per the results from the placebo arm, the CVA does not deserve much negative focus.

2007 Mar 28 09:45 AM

[hpski:]

Well, when non-clinicians comment on complex biological issues on financial sites, it's almost always about the money influencing their analysis. Echo toall is on the right track, however, since all solid organ neoplasms result in an increased state of coagulation, which oncologists, often via a hematology consult, carefully try to manage. Activation of coagulation and predisposition to thrombosis, associated with most cancers, is more common in prostatic carcinoma. As early as 1967, a large study of patients with advanced prostatic carcinoma showed that the incidence of thromboembolic disease was 2 to 3% in early-stage disease and 8 to 9% in more advanced forms. This hypercoagulability, or “disseminated intravascular coagulation” (DIC) results from several factors. Firstly, there are specific tumor properties including direct or indirect induction of thrombin generation either by cytokines or by tumor cell procoagulants (tissue factor (TF) and cancer procoagulant (CP)). Secondly, there are nonspecific factors, such as inflammatory state, tissue damage from tumor burden or necrosis leading to the activation of systemic coagulation. Chemotherapy, as well as hormone treatment is also associated with DIC, so there is a complex multifactorial hypercoagulation process that may or may not result in a CVA. No biological marker is truly sufficient for predicting thromboembolic accidents and identifying patients who may benefit from (low-molecular-weight heparin) prophylaxis. Conclusion? FDA knows that in cancer, CVA’s, “come with the territory”, it is a risk in cancer patients with or without chemo or any other anti-neoplastic therapy. Only an unqualified, albeit financially manipulative, “player”, would publish such a knee jerk over-reaction to a drug’s toxicity profile on the cusp of an FDA decision.

2007 Apr 01 01:35 AM

[Dan Gseekin...:]

Max pain --- My GAIN!!!

:-)))))))))))

2007 Mar 29 04:15 PM

[gearle0521:]

I guess you're going to be hot water Friday.

2007 Mar 29 04:42 PM

[gearle0521:]

Hmmm... NO posts today????

2007 Mar 29 06:54 PM

[i_m_jones:]

Maxim, I think you put too much weight on the stroke factor...whether or not they had more strokes on the drug, or the strokes had a higher fatality rate- this drug is for dying patients..so why would the FDA, or the patients care if they had a 5% chance of having a fatal stroke? They are going to die anyway.

Hence- the unanimous approval from the panel.

2007 Mar 29 08:13 PM

[Justin Moy:]

>

Ouch! Stock may open anywhere between 13 and 20 tomorrow. Hope you have enough funds to cover the loss.

2007 Mar 29 08:53 PM

[Dan Gseekin...:]

thousands of new retail investors, institutions (only 30% of the float is held by institutions) and a handfull of crooked hedge-funds (short interest - around 35,000,000) will all run after a float of 82 million shares most of which is held in VERY strong hands of retail investors that weathered the psychological war of the shorts and know the real value of DNDN.

Provenge's (sexy, if I may say) story is so amazing that it will reach the cover of many magazines in a matter of days.

HUGE DEMAND
VERY LITTLE SUPPLY


-->> PERFECT STORM

2007 Mar 30 03:52 AM

[Dan Gseekin...:]

It is time to call the money-moving truck fleet as this is wealth re-distribution time --- from the HF crooks to the retail investors!!!

MAXim, oh poor Max, MAX PAIN is DNDN's shareholders GAIN!!!

|^^^^^^^^^^^^^|||___
| $ $ DNDN $ $ _||||__\,__
| "Screw the shorts" __|_] ]
(@)'(@);;''''(@)*(@)**...


|^^^^^^^^^^^^^^^^|
| DNDN LINES | . |"""\.., ____
|_..._...______===|= |__|...,....]]
"(@ )'(@ )""""*|(@ )(@)***(@)


|^^^^^^^^^^^^^^^|||___
| $$$$ DNDN $$$$ ||||__\,__
| PROVENGE ____|__] ] ]
(@)'(@);;''''(@)*(@)**...


It could even be a good opportunity to squeeeeze Edeleman's Perceptive Biotech Fund a little more (before it goes belly up) by shorting some IDEV... hmmm....

2007 Mar 30 03:57 AM

[Al Lackey:]

it is kinda scary trying to figure out when to buy in. Anyone have an idea of a date and/or a price to load up? I think on Friday it hit 18 but then closed around 13. The 18 buyers are sorry -will the 13 buyers be sorry also??
They say not to ride a shooting star or catch a falling knife.

2007 Mar 31 02:13 AM

[i_m_jones:]

an article last week mentioned if the drug was approved, sales would be worth an estimated 1 billion, and so he valued the shares around $27. If thats the case, then 18 or 13 would both be a great deal.

2007 Mar 31 08:17 PM