Provenge And The Immunodepletion Theory: The Facts

| About: Dendreon Corporation (DNDN)

Recently, Reuters published an article titled Insight: New doubts about prostate-cancer vaccine Provenge that focused on a so-called 'immunodepletion theory' described in a Commentary published in the Journal of the National Cancer Institute, or JNCI, by Huber et al. (Note: the JNCI has no relationship whatsoever with the United States National Cancer Institute. In fact, the JNCI is published by Oxford University Press, a department of the University of Oxford, Oxford, UK.) The theory, according to Reuters' author Sharon Begley, raises questions about the pivotal Phase 3 trials that Dendreon (DNDN) conducted as part of its effort to obtain FDA approval for company's lead product Provenge (here and here), an immunotherapeutic treatment for asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

In the wake of the Reuters' article, several authors on Internet forums and in other venues published articles related to the Reuters' article and the Huber et al. JNCI Commentary, many lacking in veracity. Some -- including the Reuters' article -- contained errors and misrepresented facts, in some cases by omission. Others cited 'facts' without reference to the literature, popular of otherwise, as if 'proof by strong assertion' was sufficient. As a scientist with more than 45 years of experience with industry and academia, this is not how I was trained to present information or defend a scientific hypothesis. Positions, pro or con, are developed on the basis of demonstrable facts, using yours or the credible works of others to methodically develop and present a logical and sustainable proof.

I have no problem discussing the facts in the matter of Provenge's efficacy, but discussing highly controversial theories in the absence of objective data and honest discourse is a whole different matter. And so, it bothers me greatly to see what are purported to be 'insights' and 'analyses' related to Dendreon and Provenge published on Seeking Alpha and elsewhere that contain factual errors, half-truths, and mis/disinformation. For that reason, Seeking Alpha has provided me the opportunity to respond to those who, I believe, have misstated or distorted the facts in this case.

The so-called theory of 'immunodepletion' as it allegedly pertains to the discussion of Provenge and the pivotal trials of that treatment conducted by Dendreon in preparation for seeking FDA approval was initially (as far I as I can determine) espoused by Dr. Bart Classen in an anonymous paper submitted to CMS, subsequently acknowledged as written by him, and then discussed by him at the CMS Medicare Evidence Development & Coverage Advisory Committee, or MEDCAC, meeting held on November 10, 2010 (transcript here) to review Provenge. The theory was summarized in his own words (minutes, p. 128 of 135) as follows [Note: the FDA transcript shows an incorrect spelling of Classen: 'Clausen']:

7 DR. CLAUSEN: My name is Bart Clausen, I'm an
8 M.D., a physician, I'm an immunologist. For 20 years I
9 have been publishing on vaccine trial designs and clinical
10 safety. I also, besides that, researched trials for Wall
11 Street trial design, work for some other research
12 partners. I have spent a lot of time reviewing this data.
13 The biggest question I have is that you have a
14 trial design from the most recent Phase III trial, the
15 IMPACT trial, and the issue is, did you show that you've
16 improved survival or did you reduce survival in your
17 control group because you removed white blood cells and
18 discarded most of them? We know that removing white blood
19 cells will decrease your survival rate. Look at AIDS, for
20 example.
21 Now, specific white cells are there, so in a
22 situation where you had no impact on disease progression,
23 the opposite thing was that removing the white blood cells
24 actually decreased survival in your control group.
25 DR. GOODMAN: Doctor, we got your point, thank
00266
1 you very much. Yes, Dr. Gulley

The response to Dr. Classen was swift and dismissive. Here is what Dr. James Gulley, Director of Clinical Trials at the National Cancer Institute, said:

2 DR. GULLEY: I would just like to respond to
3 that one comment.
4 DR. GOODMAN: Please keep it brief.
5 DR. GULLEY: I will. The number of white blood
6 cells that were, the proportion of white blood cells that
7 are removed in terms of the total body white blood cell
8 count is around two percent, so it is not a clinically
9 meaningful amount.

Thus debunked, the 'theory' lay dormant until recently when, for reasons unknown, it was resurrected in a paper published by Huber et al., as noted above, in the JNCI. The work was published as a JNCI 'Commentary' in the March 21, 2012 edition with a note indicating it had first been published online on January 9, 2012. It appears to have been peer reviewed.

Curiously, the Commentary, which was entitled Interdisciplinary Critique of Sipuleucel-T as Immunotherapy in Castration-Resistant Prostate Cancer, was presented as an original work by the authors without acknowledgement to Dr. Classen's earlier efforts.

The authors of the Huber et al. paper are Marie Huber, who the author of the Reuters article described as "a trained scientist and former hedge-fund analyst;" Laura Haynes, PhD, Trudeau Institute, Saranac Lake, NY (LH); Chris Parker, MD, Academic Urology Unit, The Royal Marsden NHS Foundation Trust, UK (CP); and Peter Iversen, MD, Department of Urology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark (NASDAQ:PI). According to her resume, Ms. Huber has a BA in Biochemistry and an "MPhil in BioScience Enterprise (part MSc, part MBA with entrepreneurship emphasis)."

Dr. Carl A. Olsson of New York, New York, writing in the March 2012 issue of AUA News (p.42; sign-in required), penned a negative review of the JNCI paper. He concluded his overview with this:

'The authors missed the report by Hall et al. that "there was no evidence that leukapheresis led to immunodepletion," citing literature proving that each apheresis removed less than 1% of the total body pool of 1012 lymphocytes and reporting a normal measured cell count after the third apheresis in all men.'

Huber et al. stated they developed the immunodepletion theory to debunk Provenge efficacy because of a particular subgroup analysis presented in the FDA Clinical Review, or CR, of the Provenge Biological License Application, or BLA. According to the authors, this analysis showed the experimental data supporting the clinical benefit of Provenge was mainly derived from the subgroup of patients older than 65 years old while younger patients saw no benefit. (The age of 65 years most likely was selected because it is the age cutoff for Medicare coverage.) This would be a contradiction to the putative mechanism of action of Provenge because younger patients should have better immune systems. In fact, the authors further asserted that Provenge was nothing more than a placebo, so the efficacy seen in the subgroup of patients older than 65 years must be because those placebo patients were harmed by their treatment as a result of lost blood.

So, the first question to ask is: was the above subgroup analysis in the FDA Clinical Review of sufficient concern that it would require some complex explanation such as that embodied within the immunodepletion theory proposed by Huber et al.?

The FDA did, as it always does with any anomalous statistical data point, perform various analyses to address the problem. Below are the agency's comments, as codified in Table 13 (see page 38 of the Clinical Review), for the data shown in Table 14 in the CR:

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"The exploratory pooled analyses in Table 14 were conducted across multiple studies to analyze the effect of age on the primary endpoint, overall survival. The above analyses of the data from all three studies (D9901, D9902A, and D9902B) support the hypothesis that the subgroup of subjects who were less than 65 years of age also benefit from treatment with sipuleucel-T. The hazard ratio in the subgroup of Study D9902B subjects who were less than 65 years of age most likely resulted from chance, related to the multiplicity of comparisons in 49 different subgroups."

What that means is: the anomalous subgroup analysis was simply statistical noise caused by imbalances between the two arms of the trial when restricted to the subgroup. That is, the problem with which Huber et al were concerned was not considered a real problem upon closer examination by FDA statisticians.

The FDA Clinical Review also presented a sensitivity analysis performed for the data on patients on the placebo arm of the IMPACT trial who crossed over to take a weaker form of Provenge (Frovenge) made from their frozen blood salvaged from the original three placebo infusions after disease progression. Of the 171 placebo patients in the IMPACT trial, 109 crossed over to take Frovenge. The median time from randomization to take Frovenge was 5.7 months (range 2.2 months to 31.3 months). The median survival time for these patients was 23.8 months.

Now, let us return to the hypothesis found within the paper published by Huber et al.

The hypothesis, simply put, is that Provenge itself had no beneficial effect-that is, the treatment is effectively a placebo and the efficacy finding in the IMPACT trial was the result of placebo patients older than 65 being harmed by not getting a sufficient amount of their immune cells back. It is well-known that circulating white blood cells, or WBCs, are replaced in the body daily. So, the fact that Frovenge was administered a median of 5.7 months after randomization means that it had no effect on reversing any lost blood at the start of the treatment.

Next, if Provenge were just a placebo as Huber et al. claim, then Frovenge must be the same or worse.

But this assertion now must be reconciled with the fact that the Frovenge patients had nearly the same median survival time as the 25.8 months seen for patients treated with Provenge while the median for entire placebo arm was far lower at 21.7 months. Although this high median value of the Frovenge population was likely subjected to selection bias, Frovenge most certainly benefitted patients. This conclusion was supported by a recent analysis using the well-known statistical technique of Rank Preserving Structural Failure Time, or RPSFT, to correct for the effect of crossing over to Frovenge. RPSFT used the entire dataset, so it was not subjected to any biases that may lurk in a subgroup analysis. The result of the analysis showed a median difference of about 7.8 months between patients treated with Provenge and those treated with 'theoretically pure' placebos, nearly doubling the 4.1 months seen in a straightforward comparison of the two trial arms. (See figure below, reproduced with the permission of Dr. L. G. Gomella, personal communication, February 17, 2012), which was presented in General Poster Session B of 2012 GU by Chadi Nabhan, MD, director of the division of haematology and medical oncology at Advocate Lutheran General Hospital in Park Ridge, Illinois; here is the poster. (The authors of the poster are: Chadi Nabhan, Leonard G. Gomella, Todd DeVries, James Boyd Whitmore, Mark Walter Frohlich, Daniel J. George; Advocate Lutheran General Hospital and Oncology Specialists, S.C., Park Ridge, IL; The Kimmel Cancer Center at Jefferson, Philadelphia, PA; Dendreon Corporation, Seattle, WA; Duke Cancer Institute, Durham, NC.) A more complete discussion of these data can be found here.)

The conclusion must be, then, that Provenge showed a significant survival benefit, Frovenge not quite as good, and the placebo . . . well, it was a placebo. This is a logical contradiction to the assumption of a Provenge placebo by Huber et al.

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Another statistical anomaly can be found when we look at the data for African Americans. Note that only fifty-two (52) African American subjects (5.8%) enrolled in the Provenge trials. As seen in the table below from the FDA BLA Statistical Review and Evaluation, African Americans had a 45.3-month survival with Provenge, which by any measure is dramatic. Yet, Huber et al. offer no explanation for this aberration, perhaps because it was in opposition to their theory. The explanation for this result, of course, is the same as that which should be applied to the 65-year-old subset analysis: small numbers and an imbalance of control-versus-treated patients leads to erroneous conclusions.

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The authors of the FDA Statistical Review and Evaluation concluded with the following statement (section 4.2):

"The large randomized, double-blind, well-controlled Phase III study (D9902B) demonstrated that patients with metastatic AIPC who received Sipuleucel-T had improvement in overall survival, compared with those who received placebo. The finding was also supported by the other two small randomized trials (D9901, D9902A). Sipuleucel-T appeared to be generally safe and well tolerated by patients with metastatic AIPC.

"The efficacy results from the three randomized trials support the claim of using Sipuleucel-T for the treatment of men with asymptomatic or minimally symptomatic metastatic AIPC."

In preparing this response for Seeking Alpha, I received the following personal communication from a physician with more than 30 years oncology experience whose practice administers Provenge.

"The statistics show one thing but they still do not address the issue as to whether or not immunosuppression and white blood cell, or WBC, loss cause increased deaths in patients suffering from prostate cancer.

"In that regard, theoretically, according to the arguments set forth by Huber et al., immunosuppression can affect survival by either increasing the number of deaths from immune-related deficiencies such as infection or by allowing the rapid progression of the cancer.

"First and foremost, however, the randomized trial data show no increased rate of infectious complications resulting in death.

"Second, there is no evidence that immunosuppression affects the development or progression of prostate cancer. Not only is prostate cancer the most common malignancy by far found in men, but the incidence is still underestimated. Thirty percent of men in their 50s and more than 80% of men over the age of the age of 80 years have prostate cancer (confirmed by autopsies). Patients who suffer WBC loss as a result of (1) blood loss through trauma or surgery, immunosuppression from treatment for (2) organ transplant, (3) Crohn's disease, (4) ulcerative colitis, (5) rheumatoid arthritis or other autoimmune disorders, or (6) persons receiving immunosuppressive radiation or chemotherapy have no increased development of, or death from, progression of prostate cancer." (Personal Communication, R. Rostock, MD, April 8, 2012)

As an addendum to the above note, I would add that the FDA performed a sensitivity analysis of the data based on prostate-cancer-specific deaths by censoring out death events classified by causes other than prostate cancer. This analysis also met statistical significance. That is, there was little question that Provenge had an efficacious effect on altering the course of the disease. There is little question that FDA personnel were more than thorough in their examination of the clinical trial data supporting the approval of the Provenge marketing license.

Finally, Dendreon released this statement to Pharmalot in the wake of the plethora of mis/disinformation surrounding the so-called immunodepletion theory:

"The FDA approval was based on a significant improvement in overall survival shown in three well-designed, randomized, double-blind, controlled clinical trials - including the pivotal IMPACT trial - with remarkably consistent results shown across the trials as well as in numerous patient subgroups.

"The Provenge clinical data have undergone a rigorous scientific review process that included [an] FDA review process, a Center for Medicare and Medicaid Services national coverage determination, a Technology Assessment and the peer review of multiple publications. As evidenced by the FDA approval, CMS national coverage decision, and NCCN treatment guidelines, the PROVENGE data clearly demonstrated a significant patient survival benefit and support its use as a clinically meaningful treatment option for certain types of advanced prostate cancer."

I doubt the information presented above will end the discussion regarding the 'immunodepletion theory' set forth by Huber et al. But as a learned professor once told a fellow graduate student during a heated argument over certain aspects of Einstein's General Theory of Relativity: "Sir! You are entitled to your own opinion, but you are not entitled to your own facts! Prove your point!" I have endeavored to do that today regarding Provenge and the results of the treatment's pivotal Phase 3 trials.

I thank Seeking Alpha for this opportunity to respond. I also thank Don Sharpe, Founder and Publisher, Oncology Business Review, for his support over the past several days.

Disclosure: I am long DNDN and will not alter my position within 72 hours of the time of publication of this article. Material presented here is for informational purposes only. Consult your financial adviser before making investment decisions. Investing includes risks, including loss of principal.