(Repeats story from earlier on Friday, March 30)
* Paper criticizes study that led to approval
* Manufacturer Dendreon defends drug
* Critic is target of online attacks
By Sharon Begley
NEW YORK, March 30 (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."
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)