Insight: New doubts about prostate-cancer vaccine Provenge

[[email protected]]

http://www.reuters.com/article/2012/...82T07420120330

Insight: New doubts about prostate-cancer vaccine Provenge

By Sharon Begley

NEW YORK | Fri Mar 30, 2012 9:29am EDT

NEW YORK (Reuters) - Prostate cancer vaccine Provenge has long incited
passions unlike any other cancer therapy.

Doctors who raised doubts about it received death threats. Health
regulators and lawmakers faced loud protests at their offices. A
physician at the American Cancer Society was so intimidated by
Provenge partisans that he yanked a skeptical discussion of it from
his blog.

The vitriol dissipated in April 2010, when the U.S. Food and Drug
Administration approved Provenge for advanced prostate cancer,
satisfying investors in manufacturer Dendreon and patients who for
years had demanded it be put on the market.

But the bell on Round Two sounded when Marie Huber, a trained
scientist and former hedge-fund analyst, made it her mission in the
last year to analyze what she believes are deadly flaws in the studies
that led to the approval of Provenge by the FDA.

She argues that the main reason Provenge seemed to extend survival - a
crucial factor in the FDA's decision - was that older men in the study
who did not receive Provenge died months sooner than similar patients
in other studies.

She raises the possibility the "placebo" they received was actually
harmful and made Provenge, known scientifically as sipuleucel-T, look
better by comparison.

As Huber gains traction, most notably with a February paper in the
prestigious Journal of the National Cancer Institute, she, too, is
receiving threats. One post on an investors' message board last month
suggested that "somebody smack her with a rubber hose." An email said
"don't think you will be unscathed in this battle you waged on
Provenge."

Provenge is Dendreon's only product and the company's stature with
investors has waned with disappointing sales. In 2011, product
revenues totaled $213.5 million, far from the $400 million Dendreon
initially projected.

The company insists Huber's analysis is flawed and that Provenge has
helped thousands of men with prostate cancer.

"I'm looking forward to getting this to patients around the world,"
said President and Chief Executive John Johnson.

FIRST CANCER VACCINE

Since it won FDA approval two years ago, Provenge has been Exhibit A
for the idea that a patient's immune system can control or cure
cancer. The first therapeutic cancer vaccine to reach the market,
Provenge tries to engineer white blood cells, part of the immune
system, to vanquish prostate cancer, which killed an estimated 33,720
men in the United States last year.

Its path to approval has all the features of a heavyweight healthcare
fight - desperate patients demanding access to a promising therapy, a
very expensive drug that extends life only a few months and efficacy
data open to interpretation.

The FDA declined to approve the drug in 2007, when a clinical trial
failed to show it slowed tumor growth. That incited protests, lawsuits
and death threats against physicians on the FDA advisory panel who did
not recommend approval, breaking with the 13-4 majority in favor.

"Provenge came along when we didn't have much to offer for prostate
cancer," said Dr. Len Lichtenfeld of the ACS. "The advocacy community
was bursting at the seams for something that worked. When you have
that situation, it inflames passions and that can overtake the
science."

In the pivotal trial called IMPACT, published in July 2010, but shared
with the FDA months earlier, Provenge extended median survival by 4.1
months to 25.8 months from 21.7 months. That was sufficient for FDA
approval. The vaccine costs $93,000 and patients also incur physician
and other charges. Medicare agreed to cover Provenge last year, as
have private insurers, but doctors initially balked at a long wait for
reimbursement.

Huber had long been "utterly intrigued" by Provenge and its "huge
promise of harnessing the immune system to battle cancer," she said in
an interview.

In documents JNCI requires authors to sign, she declared no financial
conflicts of interest. Neither she nor her former firm nor anyone else
she is connected to stands to benefit financially from her analysis,
she said.

Instead, she says she is motivated to help "vulnerable and desperate
patients" - so much so that she gave up her job, salary and health
insurance. Arguing that Provenge is harming these men, she called "the
whole thing utterly horrific. The company got away with hiding data
and doctors making $7,000 per prescription won't even engage in
discussion" about whether it helps their patients.

After receiving degrees in biochemistry and bioscience enterprise from
Cambridge University, Huber began working as an analyst for a hedge
fund in 2007. A Thomson Reuters analysis of securities filings
confirmed her former firm has not held any positions in Dendreon.

LACK OF EVIDENCE

Each dose of Provenge is custom-made. A nurse or technician withdraws
white blood cells from a man's arm in a three-to-four hour procedure
called leukapheresis.

The cells are shipped to a Dendreon manufacturing facility, where for
two days they are incubated with a "fusion protein:" One protein that
stimulates the cells' growth and maturation and another called PAP, or
prostatic acid phosphatase. PAP is an antigen that studs prostate
cancer cells like antennae, pieces of it sticking out of the cells'
surfaces.

Dendreon says the patients' white blood cells take up the antigen and
within hours their surfaces bristle with fragments of the telltale
molecule. The cells are then shipped back to the physician and infused
into the patient. A full treatment includes three such procedures, two
weeks apart.

Back inside the body, Dendreon claims the modified cells trigger the
immune system to produce T cells that kill any cell sporting the PAP
antigen — namely, prostate cancer cells.

In principle, that should eliminate the cancer, but Provenge does not
shrink either the primary tumor or metastases.

Steven Rosenberg of the National Cancer Institute, a leading tumor
immunologist, says that raises doubts over whether Provenge helps
patients live longer, as the IMPACT trial reported.

"We have a lot of data that supports the idea that the product works
the way it was designed to," said Dr. Mark Frohlich, Dendreon's chief
medical officer. "We're seeing evidence of immune-system activation.
The only question is whether the T cells are killing the tumor."

The FDA acknowledges that data supporting Provenge's approval did not
show the drug shrank tumors, but says the overall survival benefit was
enough to bring it to market. Spokeswoman Rita Chapelle, citing data
submitted by Dendreon, said there is a "lack of evidence of anti-tumor
activity," the reason for which "is unclear."

SUSPICIONS OVER SURVIVAL BENEFIT

Huber's analysis comes from data showing that men who received the
placebo had very different survival times based on their age. Men
older than 65 lived 17.3 months on placebo and 23 months with
Provenge. Men younger than 65 lived 28 months after receiving placebo
and 29 months after Provenge.

Other studies have shown that age generally does not affect how long a
man survives with this form of prostate cancer, says Peter Iversen, a
urologist and prostate-cancer surgeon at the University of Copenhagen
and co-author of the paper with Huber.

Combining these findings led to the new paper's conclusion: The
four-month edge in median survival from Provenge for all patients was
due to longer survival among older men who got the vaccine.

"There is no efficacy in the younger patients, the primary group where
you would expect it," said Huber.

Since the immune system weakens with age, an immune-based therapy
should work better in younger men.

Some experts agree.

"If it was really a vaccine, you'd think younger men would show more
response, since they are more immunocompetent," said NCI's Rosenberg.

On that basis, Huber and her co-authors, including two prostate-cancer
specialists, argue the placebo used in the trial may have harmed the
older men, cutting months off their lives and inadvertently making
Provenge seem beneficial.

One way that could have occurred was through leukapheresis. That
process removed about 90 percent of certain kinds of circulating white
blood cells, according to calculations by immunologist Laura Haynes of
the Trudeau Institute, a co-author of the JNCI paper.

The Provenge men got back about 32 percent of those cells, which had
been stored at body temperature. The placebo men got back 12 percent,
which had been incubated at near-freezing temperatures. Cold storage
has been reported to kill "most, if not all, of those cells," notes
the JNCI paper. Moreover, said Haynes, "if you return dead and dying
cells to older men you are likely to cause inflammation," which can
stoke the growth of cancerous cells.

Younger men were better able to replace the lost white blood cells,
argued Iversen. Older men could not, resulting in early death.

"These cells are very specialized and there is research suggesting
that removing them can harm older men," he said.

Earlier this month, DynaMed, an online database used by physicians,
added to its Provenge entry a note on the JNCI paper, but calls the
concern "not substantiated." ACS's Lichtenfeld says the analysis
"might inhibit some patients and doctors from going ahead with a very
expensive drug."

Huber says she plans to approach European regulators as they consider
Dendreon's application to approve Provenge.

Investor message boards have lit up in response to the new paper. In
February, an anonymous commentator on InvestorVillage.com warned that
Huber's work was about to be published "a few days before our
earnings. Her agenda is obvious."

IFFY STATISTICS

Critics of the new analysis argue the number of cells removed is too
small to suppress the immune system. Charles Drake, an oncologist and
immunologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer
Center, said there is no evidence the placebo men in IMPACT suffered
more infections or other effects of a depleted immune system than the
Provenge men.

The scientist who led IMPACT, oncologist Philip Kantoff of Dana Farber
Cancer Center, said colleagues in immunology "dismissed as nonsense
the idea that leukapheresis could hurt individuals."

He takes issue, too, with the statistics. Dividing the men by whether
they are older or younger than 65, he said, is "arbitrary" and to pick
apart data retrospectively is a statistical no-no.

Dendreon's Frohlich also criticizes the statistics: "If you do enough
of these (post-hoc analyses) then by chance alone you'd expect to get
one positive finding."

In other words, it is almost always possible to find a subset of
patients who do better than others.

When Dendreon divided the men by whether they were older or younger
than about 71, he added, they found no red flags.

The FDA agrees that such post-hoc statistical analyses "are
exploratory" and their results "must be interpreted with caution, as
acknowledged by the authors." Yet a paid consultant to Dendreon before
the IMPACT trial agreed with many of Huber's concerns.

"The control vaccine used in IMPACT and in the predecessor trial had
never been used anywhere for anything and may well have been
detrimental to patients," said Donald Berry of MD Anderson Cancer
Center, a leading biostatistician. "Here's a great way to get your
drug approved: Kill the control patients."

Despite the heated rhetoric, Provenge may go out with a whimper more
than a bang. Promising new agents for advanced prostate cancer include
an oral drug from Medivation Inc called enzalutamide, in the final
phase of clinical trials, and Zytiga from Johnson & Johnson, which won
FDA approval in 2011. A vaccine that targets PSA, from Bavarian Nordic
Immunotherapy, is in late-stage trials.

Dendreon does not disclose how many patients have been prescribed
Provenge. CEO Johnson said that about 70 percent of its Provenge
revenue comes from sales to community hospitals and doctors and 30
percent from academic medical centers. Some of the latter decline to
use Provenge, deterred by lingering concerns over whether it provides
a meaningful benefit.

Three such facilities in the Midwest, contacted at random by Reuters,
confirmed they do not recommend Provenge. All asked not to be named
for fear of receiving threats.

"It is my policy not to make public comments about this drug," said
one oncologist. Patients who ask for it "are referred to another
facility."

(Editing by Michele Gershberg, Ed Tobin and Andre Grenon)

[bertxavier]

On Apr 6, 4:54*pm, candl...@fastmail.us wrote:
> http://www.reuters.com/article/2012/...dUSBRE82T07420...
>
> Insight: New doubts about prostate-cancer vaccine Provenge
>
> By Sharon Begley
>
> NEW YORK | Fri Mar 30, 2012 9:29am EDT
>
> NEW YORK (Reuters) - Prostate cancer vaccine Provenge has long incited
> passions unlike any other cancer therapy.
>
> Doctors who raised doubts about it received death threats. Health
> regulators and lawmakers faced loud protests at their offices. A
> physician at the American Cancer Society was so intimidated by
> Provenge partisans that he yanked a skeptical discussion of it from
> his blog.
>
> The vitriol dissipated in April 2010, when the U.S. Food and Drug
> Administration approved Provenge for advanced prostate cancer,
> satisfying investors in manufacturer Dendreon and patients who for
> years had demanded it be put on the market.
>
> But the bell on Round Two sounded when Marie Huber, a trained
> scientist and former hedge-fund analyst, made it her mission in the
> last year to analyze what she believes are deadly flaws in the studies
> that led to the approval of Provenge by the FDA.
>
> She argues that the main reason Provenge seemed to extend survival - a
> crucial factor in the FDA's decision - was that older men in the study
> who did not receive Provenge died months sooner than similar patients
> in other studies.
>
> She raises the possibility the "placebo" they received was actually
> harmful and made Provenge, known scientifically as sipuleucel-T, look
> better by comparison.
>
> As Huber gains traction, most notably with a February paper in the
> prestigious Journal of the National Cancer Institute, she, too, is
> receiving threats. One post on an investors' message board last month
> suggested that "somebody smack her with a rubber hose." An email said
> "don't think you will be unscathed in this battle you waged on
> Provenge."
>
> Provenge is Dendreon's only product and the company's stature with
> investors has waned with disappointing sales. In 2011, product
> revenues totaled $213.5 million, far from the $400 million Dendreon
> initially projected.
>
> The company insists Huber's analysis is flawed and that Provenge has
> helped thousands of men with prostate cancer.
>
> "I'm looking forward to getting this to patients around the world,"
> said President and Chief Executive John Johnson.
>
> FIRST CANCER VACCINE
>
> Since it won FDA approval two years ago, Provenge has been Exhibit A
> for the idea that a patient's immune system can control or cure
> cancer. The first therapeutic cancer vaccine to reach the market,
> Provenge tries to engineer white blood cells, part of the immune
> system, to vanquish prostate cancer, which killed an estimated 33,720
> men in the United States last year.
>
> Its path to approval has all the features of a heavyweight healthcare
> fight - desperate patients demanding access to a promising therapy, a
> very expensive drug that extends life only a few months and efficacy
> data open to interpretation.
>
> The FDA declined to approve the drug in 2007, when a clinical trial
> failed to show it slowed tumor growth. That incited protests, lawsuits
> and death threats against physicians on the FDA advisory panel who did
> not recommend approval, breaking with the 13-4 majority in favor.
>
> "Provenge came along when we didn't have much to offer for prostate
> cancer," said Dr. Len Lichtenfeld of the ACS. "The advocacy community
> was bursting at the seams for something that worked. When you have
> that situation, it inflames passions and that can overtake the
> science."
>
> In the pivotal trial called IMPACT, published in July 2010, but shared
> with the FDA months earlier, Provenge extended median survival by 4.1
> months to 25.8 months from 21.7 months. That was sufficient for FDA
> approval. The vaccine costs $93,000 and patients also incur physician
> and other charges. Medicare agreed to cover Provenge last year, as
> have private insurers, but doctors initially balked at a long wait for
> reimbursement.
>
> Huber had long been "utterly intrigued" by Provenge and its "huge
> promise of harnessing the immune system to battle cancer," she said in
> an interview.
>
> In documents JNCI requires authors to sign, she declared no financial
> conflicts of interest. Neither she nor her former firm nor anyone else
> she is connected to stands to benefit financially from her analysis,
> she said.
>
> Instead, she says she is motivated to help "vulnerable and desperate
> patients" - so much so that she gave up her job, salary and health
> insurance. Arguing that Provenge is harming these men, she called "the
> whole thing utterly horrific. The company got away with hiding data
> and doctors making $7,000 per prescription won't even engage in
> discussion" about whether it helps their patients.
>
> After receiving degrees in biochemistry and bioscience enterprise from
> Cambridge University, Huber began working as an analyst for a hedge
> fund in 2007. A Thomson Reuters analysis of securities filings
> confirmed her former firm has not held any positions in Dendreon.
>
> LACK OF EVIDENCE
>
> Each dose of Provenge is custom-made. A nurse or technician withdraws
> white blood cells from a man's arm in a three-to-four hour procedure
> called leukapheresis.
>
> The cells are shipped to a Dendreon manufacturing facility, where for
> two days they are incubated with a "fusion protein:" One protein that
> stimulates the cells' growth and maturation and another called PAP, or
> prostatic acid phosphatase. PAP is an antigen that studs prostate
> cancer cells like antennae, pieces of it sticking out of the cells'
> surfaces.
>
> Dendreon says the patients' white blood cells take up the antigen and
> within hours their surfaces bristle with fragments of the telltale
> molecule. The cells are then shipped back to the physician and infused
> into the patient. A full treatment includes three such procedures, two
> weeks apart.
>
> Back inside the body, Dendreon claims the modified cells trigger the
> immune system to produce T cells that kill any cell sporting the PAP
> antigen — namely, prostate cancer cells.
>
> In principle, that should eliminate the cancer, but Provenge does not
> shrink either the primary tumor or metastases.
>
> Steven Rosenberg of the National Cancer Institute, a leading tumor
> immunologist, says that raises doubts over whether Provenge helps
> patients live longer, as the IMPACT trial reported.
>
> "We have a lot of data that supports the idea that the product works
> the way it was designed to," said Dr. Mark Frohlich, Dendreon's chief
> medical officer. "We're seeing evidence of immune-system activation.
> The only question is whether the T cells are killing the tumor."
>
> The FDA acknowledges that data supporting Provenge's approval did not
> show the drug shrank tumors, but says the overall survival benefit was
> enough to bring it to market. Spokeswoman Rita Chapelle, citing data
> submitted by Dendreon, said there is a "lack of evidence of anti-tumor
> activity," the reason for which "is unclear."
>
> SUSPICIONS OVER SURVIVAL BENEFIT
>
> Huber's analysis comes from data showing that men who received the
> placebo had very different survival times based on their age. Men
> older than 65 lived 17.3 months on placebo and 23 months with
> Provenge. Men younger than 65 lived 28 months after receiving placebo
> and 29 months after Provenge.
>
> Other studies have shown that age generally does not affect how long a
> man survives with this form of prostate cancer, says Peter Iversen, a
> urologist and prostate-cancer surgeon at the University of Copenhagen
> and co-author of the paper with Huber.
>
> Combining these findings led to the new paper's conclusion: The
> four-month edge in median survival from Provenge for all patients was
> due to longer survival among older men who got the vaccine.
>
> "There is no efficacy in the younger patients, the primary group where
> you would expect it," said Huber.
>
> Since the immune system weakens with age, an immune-based therapy
> should work better in younger men.
>
> Some experts agree.
>
> "If it was really a vaccine, you'd think younger men would show more
> response, since they are more immunocompetent," said NCI's Rosenberg.
>
> On that basis, Huber and her co-authors, including two prostate-cancer
> specialists, argue the placebo used in the trial may have harmed the
> older men, cutting months off their lives and inadvertently making
> Provenge seem beneficial.
>
> One way that could have occurred was through leukapheresis. That
> process removed about 90 percent of certain kinds of circulating white
> blood cells, according to calculations by immunologist Laura Haynes of
> the Trudeau Institute, a co-author of the JNCI paper.
>
> The Provenge men got back about 32 percent of those cells, which had
> been stored at body temperature. The placebo men got back 12 percent,
> which had been incubated at near-freezing temperatures. Cold storage
> has been reported to kill "most, if not all, of those cells," notes
> the JNCI paper. Moreover, said Haynes, "if you return dead and dying
> cells to older men you are likely to cause inflammation," which can
> stoke the growth of cancerous cells.
>
> Younger men were better able to replace the lost white blood cells,
> argued Iversen. Older men could not, resulting in early death.
>
> "These cells are very specialized and there is research suggesting
> that removing them can harm older men," he said.
>
> Earlier this month, DynaMed, an online database used by physicians,
> added to its Provenge entry a note on the JNCI paper, but calls the
> concern "not substantiated." ACS's Lichtenfeld says the analysis
> "might inhibit some patients and doctors from going ahead with a very
> expensive drug."
>
> Huber says she plans to approach European regulators as they consider
> Dendreon's application to approve Provenge.
>
> Investor message boards have lit up in response to the new paper. In
> February, an anonymous commentator on InvestorVillage.com warned that
> Huber's work was about to be published "a few days before our
> earnings. Her agenda is obvious."
>
> IFFY STATISTICS
>
> Critics of the new analysis argue the number of cells removed is too
> small to suppress the immune system. Charles Drake, an oncologist and
> immunologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer
> Center, said there is no evidence the placebo men in IMPACT suffered
> more infections or other effects of a depleted immune system than the
> Provenge men.
>
> The scientist who led IMPACT, oncologist Philip Kantoff of Dana Farber
> Cancer Center, said colleagues in immunology "dismissed as nonsense
> the idea that leukapheresis could hurt individuals."
>
> He takes issue, too, with the statistics. Dividing the men by whether
> they are older or younger than 65, he said, is "arbitrary" and to pick
> apart data retrospectively is a statistical no-no.
>
> Dendreon's Frohlich also criticizes the statistics: "If you do enough
> of these (post-hoc analyses) then by chance alone you'd expect to get
> one positive finding."
>
> In other words, it is almost always possible to find a subset of
> patients who do better than others.
>
> When Dendreon divided the men by whether they were older or younger
> than about 71, he added, they found no red flags.
>
> The FDA agrees that such post-hoc statistical analyses "are
> exploratory" and their results "must be interpreted with caution, as
> acknowledged by the authors." Yet a paid consultant to Dendreon before
> the IMPACT trial agreed with many of Huber's concerns.
>
> "The control vaccine used in IMPACT and in the predecessor trial had
> never been used anywhere for anything and may well have been
> detrimental to patients," said Donald Berry of MD Anderson Cancer
> Center, a leading biostatistician. "Here's a great way to get your
> drug approved: Kill the control patients."
>
> Despite the heated rhetoric, Provenge may go out with a whimper more
> than a bang. Promising new agents for advanced prostate cancer include
> an oral drug from Medivation Inc called enzalutamide, in the final
> phase of clinical trials, and Zytiga from Johnson & Johnson, which won
> FDA approval in 2011. A vaccine that targets PSA, from Bavarian Nordic
> Immunotherapy, is in late-stage trials.
>
> Dendreon does not disclose how many patients have been prescribed
> Provenge. CEO Johnson said that about 70 percent of its Provenge
> revenue comes from sales to community hospitals and doctors and 30
> percent from academic medical centers. Some of the latter decline to
> use Provenge, deterred by lingering concerns over whether it provides
> a meaningful benefit.
>
> Three such facilities in the Midwest, contacted at random by Reuters,
> confirmed they do not recommend Provenge. All asked not to be named
> for fear of receiving threats.
>
> "It is my policy not to make public comments about this drug," said
> one oncologist. Patients who ask for it "are referred to another
> facility."
>
> (Editing by Michele Gershberg, Ed Tobin and Andre Grenon)

It looks like the original skeptics may have been right.

[Steve Kramer]

Hi, Bert!

It's been a long, long time since you updated us on your circumstances.
December 2007 you had a 2-3 month PSAD and then nothing since.

How are you doing?



PSA OCT 2000 @ 46
Biopsy NOV 2000 3+4=7, T2c
RRP DEC 2000 3+4=7), T3cN0M0, SVI, Neg margins
PSA <.1 <.1 <.1 .27 .37 .75 PSAD 0.19 years
EBRT MAY - JULY 2002 @ 47
PSA .34 .22 .15 .21 .32 PSAD 0.56 years
Lupron started JULY 2003 @ 48
PSA .07 .05 .06 .09 .08 .132 .145 PSAD 1.40 years
Casodex added JUL 2006 @ 51
Last PSA <0.05 Next draw AUG 2012 @ 57
Illegitimati non carborundum




"bertxavier" wrote in message
news:[email protected]...

On Apr 6, 4:54 pm, candl...@fastmail.us wrote:
> http://www.reuters.com/article/2012/...dUSBRE82T07420...
>
> Insight: New doubts about prostate-cancer vaccine Provenge
>
> By Sharon Begley
>
> NEW YORK | Fri Mar 30, 2012 9:29am EDT
>
> NEW YORK (Reuters) - Prostate cancer vaccine Provenge has long incited
> passions unlike any other cancer therapy.
>
> Doctors who raised doubts about it received death threats. Health
> regulators and lawmakers faced loud protests at their offices. A
> physician at the American Cancer Society was so intimidated by
> Provenge partisans that he yanked a skeptical discussion of it from
> his blog.
>
> The vitriol dissipated in April 2010, when the U.S. Food and Drug
> Administration approved Provenge for advanced prostate cancer,
> satisfying investors in manufacturer Dendreon and patients who for
> years had demanded it be put on the market.
>
> But the bell on Round Two sounded when Marie Huber, a trained
> scientist and former hedge-fund analyst, made it her mission in the
> last year to analyze what she believes are deadly flaws in the studies
> that led to the approval of Provenge by the FDA.
>
> She argues that the main reason Provenge seemed to extend survival - a
> crucial factor in the FDA's decision - was that older men in the study
> who did not receive Provenge died months sooner than similar patients
> in other studies.
>
> She raises the possibility the "placebo" they received was actually
> harmful and made Provenge, known scientifically as sipuleucel-T, look
> better by comparison.
>
> As Huber gains traction, most notably with a February paper in the
> prestigious Journal of the National Cancer Institute, she, too, is
> receiving threats. One post on an investors' message board last month
> suggested that "somebody smack her with a rubber hose." An email said
> "don't think you will be unscathed in this battle you waged on
> Provenge."
>
> Provenge is Dendreon's only product and the company's stature with
> investors has waned with disappointing sales. In 2011, product
> revenues totaled $213.5 million, far from the $400 million Dendreon
> initially projected.
>
> The company insists Huber's analysis is flawed and that Provenge has
> helped thousands of men with prostate cancer.
>
> "I'm looking forward to getting this to patients around the world,"
> said President and Chief Executive John Johnson.
>
> FIRST CANCER VACCINE
>
> Since it won FDA approval two years ago, Provenge has been Exhibit A
> for the idea that a patient's immune system can control or cure
> cancer. The first therapeutic cancer vaccine to reach the market,
> Provenge tries to engineer white blood cells, part of the immune
> system, to vanquish prostate cancer, which killed an estimated 33,720
> men in the United States last year.
>
> Its path to approval has all the features of a heavyweight healthcare
> fight - desperate patients demanding access to a promising therapy, a
> very expensive drug that extends life only a few months and efficacy
> data open to interpretation.
>
> The FDA declined to approve the drug in 2007, when a clinical trial
> failed to show it slowed tumor growth. That incited protests, lawsuits
> and death threats against physicians on the FDA advisory panel who did
> not recommend approval, breaking with the 13-4 majority in favor.
>
> "Provenge came along when we didn't have much to offer for prostate
> cancer," said Dr. Len Lichtenfeld of the ACS. "The advocacy community
> was bursting at the seams for something that worked. When you have
> that situation, it inflames passions and that can overtake the
> science."
>
> In the pivotal trial called IMPACT, published in July 2010, but shared
> with the FDA months earlier, Provenge extended median survival by 4.1
> months to 25.8 months from 21.7 months. That was sufficient for FDA
> approval. The vaccine costs $93,000 and patients also incur physician
> and other charges. Medicare agreed to cover Provenge last year, as
> have private insurers, but doctors initially balked at a long wait for
> reimbursement.
>
> Huber had long been "utterly intrigued" by Provenge and its "huge
> promise of harnessing the immune system to battle cancer," she said in
> an interview.
>
> In documents JNCI requires authors to sign, she declared no financial
> conflicts of interest. Neither she nor her former firm nor anyone else
> she is connected to stands to benefit financially from her analysis,
> she said.
>
> Instead, she says she is motivated to help "vulnerable and desperate
> patients" - so much so that she gave up her job, salary and health
> insurance. Arguing that Provenge is harming these men, she called "the
> whole thing utterly horrific. The company got away with hiding data
> and doctors making $7,000 per prescription won't even engage in
> discussion" about whether it helps their patients.
>
> After receiving degrees in biochemistry and bioscience enterprise from
> Cambridge University, Huber began working as an analyst for a hedge
> fund in 2007. A Thomson Reuters analysis of securities filings
> confirmed her former firm has not held any positions in Dendreon.
>
> LACK OF EVIDENCE
>
> Each dose of Provenge is custom-made. A nurse or technician withdraws
> white blood cells from a man's arm in a three-to-four hour procedure
> called leukapheresis.
>
> The cells are shipped to a Dendreon manufacturing facility, where for
> two days they are incubated with a "fusion protein:" One protein that
> stimulates the cells' growth and maturation and another called PAP, or
> prostatic acid phosphatase. PAP is an antigen that studs prostate
> cancer cells like antennae, pieces of it sticking out of the cells'
> surfaces.
>
> Dendreon says the patients' white blood cells take up the antigen and
> within hours their surfaces bristle with fragments of the telltale
> molecule. The cells are then shipped back to the physician and infused
> into the patient. A full treatment includes three such procedures, two
> weeks apart.
>
> Back inside the body, Dendreon claims the modified cells trigger the
> immune system to produce T cells that kill any cell sporting the PAP
> antigen — namely, prostate cancer cells.
>
> In principle, that should eliminate the cancer, but Provenge does not
> shrink either the primary tumor or metastases.
>
> Steven Rosenberg of the National Cancer Institute, a leading tumor
> immunologist, says that raises doubts over whether Provenge helps
> patients live longer, as the IMPACT trial reported.
>
> "We have a lot of data that supports the idea that the product works
> the way it was designed to," said Dr. Mark Frohlich, Dendreon's chief
> medical officer. "We're seeing evidence of immune-system activation.
> The only question is whether the T cells are killing the tumor."
>
> The FDA acknowledges that data supporting Provenge's approval did not
> show the drug shrank tumors, but says the overall survival benefit was
> enough to bring it to market. Spokeswoman Rita Chapelle, citing data
> submitted by Dendreon, said there is a "lack of evidence of anti-tumor
> activity," the reason for which "is unclear."
>
> SUSPICIONS OVER SURVIVAL BENEFIT
>
> Huber's analysis comes from data showing that men who received the
> placebo had very different survival times based on their age. Men
> older than 65 lived 17.3 months on placebo and 23 months with
> Provenge. Men younger than 65 lived 28 months after receiving placebo
> and 29 months after Provenge.
>
> Other studies have shown that age generally does not affect how long a
> man survives with this form of prostate cancer, says Peter Iversen, a
> urologist and prostate-cancer surgeon at the University of Copenhagen
> and co-author of the paper with Huber.
>
> Combining these findings led to the new paper's conclusion: The
> four-month edge in median survival from Provenge for all patients was
> due to longer survival among older men who got the vaccine.
>
> "There is no efficacy in the younger patients, the primary group where
> you would expect it," said Huber.
>
> Since the immune system weakens with age, an immune-based therapy
> should work better in younger men.
>
> Some experts agree.
>
> "If it was really a vaccine, you'd think younger men would show more
> response, since they are more immunocompetent," said NCI's Rosenberg.
>
> On that basis, Huber and her co-authors, including two prostate-cancer
> specialists, argue the placebo used in the trial may have harmed the
> older men, cutting months off their lives and inadvertently making
> Provenge seem beneficial.
>
> One way that could have occurred was through leukapheresis. That
> process removed about 90 percent of certain kinds of circulating white
> blood cells, according to calculations by immunologist Laura Haynes of
> the Trudeau Institute, a co-author of the JNCI paper.
>
> The Provenge men got back about 32 percent of those cells, which had
> been stored at body temperature. The placebo men got back 12 percent,
> which had been incubated at near-freezing temperatures. Cold storage
> has been reported to kill "most, if not all, of those cells," notes
> the JNCI paper. Moreover, said Haynes, "if you return dead and dying
> cells to older men you are likely to cause inflammation," which can
> stoke the growth of cancerous cells.
>
> Younger men were better able to replace the lost white blood cells,
> argued Iversen. Older men could not, resulting in early death.
>
> "These cells are very specialized and there is research suggesting
> that removing them can harm older men," he said.
>
> Earlier this month, DynaMed, an online database used by physicians,
> added to its Provenge entry a note on the JNCI paper, but calls the
> concern "not substantiated." ACS's Lichtenfeld says the analysis
> "might inhibit some patients and doctors from going ahead with a very
> expensive drug."
>
> Huber says she plans to approach European regulators as they consider
> Dendreon's application to approve Provenge.
>
> Investor message boards have lit up in response to the new paper. In
> February, an anonymous commentator on InvestorVillage.com warned that
> Huber's work was about to be published "a few days before our
> earnings. Her agenda is obvious."
>
> IFFY STATISTICS
>
> Critics of the new analysis argue the number of cells removed is too
> small to suppress the immune system. Charles Drake, an oncologist and
> immunologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer
> Center, said there is no evidence the placebo men in IMPACT suffered
> more infections or other effects of a depleted immune system than the
> Provenge men.
>
> The scientist who led IMPACT, oncologist Philip Kantoff of Dana Farber
> Cancer Center, said colleagues in immunology "dismissed as nonsense
> the idea that leukapheresis could hurt individuals."
>
> He takes issue, too, with the statistics. Dividing the men by whether
> they are older or younger than 65, he said, is "arbitrary" and to pick
> apart data retrospectively is a statistical no-no.
>
> Dendreon's Frohlich also criticizes the statistics: "If you do enough
> of these (post-hoc analyses) then by chance alone you'd expect to get
> one positive finding."
>
> In other words, it is almost always possible to find a subset of
> patients who do better than others.
>
> When Dendreon divided the men by whether they were older or younger
> than about 71, he added, they found no red flags.
>
> The FDA agrees that such post-hoc statistical analyses "are
> exploratory" and their results "must be interpreted with caution, as
> acknowledged by the authors." Yet a paid consultant to Dendreon before
> the IMPACT trial agreed with many of Huber's concerns.
>
> "The control vaccine used in IMPACT and in the predecessor trial had
> never been used anywhere for anything and may well have been
> detrimental to patients," said Donald Berry of MD Anderson Cancer
> Center, a leading biostatistician. "Here's a great way to get your
> drug approved: Kill the control patients."
>
> Despite the heated rhetoric, Provenge may go out with a whimper more
> than a bang. Promising new agents for advanced prostate cancer include
> an oral drug from Medivation Inc called enzalutamide, in the final
> phase of clinical trials, and Zytiga from Johnson & Johnson, which won
> FDA approval in 2011. A vaccine that targets PSA, from Bavarian Nordic
> Immunotherapy, is in late-stage trials.
>
> Dendreon does not disclose how many patients have been prescribed
> Provenge. CEO Johnson said that about 70 percent of its Provenge
> revenue comes from sales to community hospitals and doctors and 30
> percent from academic medical centers. Some of the latter decline to
> use Provenge, deterred by lingering concerns over whether it provides
> a meaningful benefit.
>
> Three such facilities in the Midwest, contacted at random by Reuters,
> confirmed they do not recommend Provenge. All asked not to be named
> for fear of receiving threats.
>
> "It is my policy not to make public comments about this drug," said
> one oncologist. Patients who ask for it "are referred to another
> facility."
>
> (Editing by Michele Gershberg, Ed Tobin and Andre Grenon)

It looks like the original skeptics may have been right.