Dendreon Holds Its Breath, Big Provenge Clinical Trial Result Coming In October

7/31/08Follow @xconomy

Dendreon’s David Urdal never fails to give off the impression that he’s a ballast for the company, at least in the dozens of times I’ve interviewed him in the past seven years. The even-keeled chief scientific officer has lived through all the ups and downs since he joined the Seattle biotech company back in its early days in 1995.

Now Urdal, 58, is gearing up for another turning point in October. It’s from a clinical trial of 500 prostate cancer patients, known as Impact. The company (NASDAQ: DNDN) will find out if that trial can crank out the kind of evidence needed to convince the FDA it truly has a drug that can help prostate cancer patients live longer. If it does, the company will sprint to bring that drug, Provenge, to the market as the first treatment of its kind to stimulate the immune system to fight cancer cells. But if the early peek at the data—an interim analysis—shows results that could even possibly be due to chance, then everyone will have to wait in suspense one more year for a final verdict.

“I think people here now can feel the moment coming,” Urdal says. “We’re within a couple of months of knowing new information, and there’s a high level of anticipation and excitement about it.”

Provenge has captivated the imaginations of doctors, patients, and investors (and journalists) for years. The treatment, called an immunotherapy, or a cancer vaccine, doesn’t work like a traditional cancer drug. Blood is drawn from a patient, and some white blood cells vital to the immune system, called dendritic cells, are separated in a lab. The cells are shipped to the company and incubated with a genetically engineered protein found on prostate cancer cells, called PAP. The white blood cells are supposed to recognize the protein as an invader and recruit the immune system’s arsenal to attack tumor cells that contain it. The revved-up white blood cells are shipped back and re-infused into the patient.

Without going too long on the history—that’s a book-length project—Dendreon thought it had done enough to get Provenge approved by the FDA a year ago. It asked the agency to clear the product for the sale mainly on a study of 127 men that showed it could extend patients’ lives by a median time of 4.5 months, with minimal side effects, like fever and chills. An FDA advisory panel agreed in March 2007 that the drug was safe and “substantially effective.” The next day, Dendreon became the heaviest traded stock on the entire Nasdaq exchange, rocketing from $5.22 a share to briefly more than $20 after the panel vote, as investors were betting that the FDA would follow the panel’s advice and approve the drug, as it usually does.

The operative word in that last sentence is “briefly.” Dendreon crashed back to earth in May of last year. That’s when the FDA chose not to approve the drug, preferring to wait for more evidence from the ongoing 500-patient Impact trial. Almost $1 billion of stock market value evaporated in a heartbeat.

So Dendreon knows about ups and downs. Now it could be in for some more.

The Impact study itself has been through a circuitous history. It was started in June 2003, and originally aimed to enroll patients with terminal prostate cancer who have moderate -to-less aggressive tumor types, as measured by a standardized “Gleason” scoring system. It was designed that way because earlier trials had suggested that Provenge didn’t work for patients with the most aggressive Gleason-rated tumors, so weeding them out would give the drug a better shot, Urdal says. The study also was primarily designed to see whether Provenge could slow down the spread of tumors, instead of waiting a longer time for data on whether it helped men live longer—the gold standard for cancer drugs.

Then in 2005, more data rolled in from the previous clinical trials suggesting that Provenge actually did extend lives, for all kinds of patients, regardless of Gleason score. So in November of that year, Dendreon agreed to an overhaul of the Impact trial, at the request of the FDA, Urdal says.

The changes were big. The new protocol called for Dendreon to enroll patients with all types of Gleason tumor scores. It switched the main goal of the study from the squishier and more debatable point of slowing tumor progression, to the more definitive measurement of survival time. It boosted total enrollment to 500 patients. And, it started allowing a slightly sicker kind of patient with bone pain into the study.

This October, then, the trial is designed to take an interim look after a certain number of deaths among the 500 men have occurred, which Dendreon hasn’t disclosed. Since it’s an early peek based on a small set of data, the analysis has to show Provenge patients are living longer than those on placebo, and demonstrate it with a higher degree of statistical certainty than normal to assure regulators that it isn’t a result of chance. If the interim analysis doesn’t clear that bar, then Dendreon expects it will have to wait for 304 patients in the trial to die, so it can do the final survival analysis.

The analogy I used in my conversation with Urdal, which he agreed is a good way to think about it, is that an interim analysis is like taking a look at the standings half way through the football season, seeing an undefeated team, and saying it looks like they will win the Super Bowl. The final analysis is confirmation that they can hoist the Vince Lombardi trophy.

Right now, Dendreon’s contract research organization is in the middle of its season. It’s double-checking patient records to make sure no mistakes are made. By October, it will have collected the data and sent it to an independent monitoring committee. That group of experts will then make a recommendation to Dendreon on whether it should declare victory now and ship off a fresh new application to the FDA, or whether it should wait for the full analysis before it sends in its application.

Urdal doesn’t sound like he’s sweating the interim analysis. If the statistics don’t show the survival benefit the company needs right away, “then we’ll just have to wait another year.”

Of course, Dendreon is naturally working on a fallback plan in case the interim analysis fails to show a clear enough survival advantage. It is developing Provenge for earlier stages of prostate cancer, and it has other drugs on the back burner designed to use the same technique for breast, kidney, and colon cancers. Another drug discovered internally, trp-p8, is being prepared to enter clinical trials, Urdal says.

So is the interim analysis really a make-or-break moment for Dendreon? Not really, says David Miller, president of Biotech Stock Research, a Seattle-based equity research firm that covers the company. “It’s clear that (CFO) Greg Schiffman has financially positioned them in a way that they won’t get in financial trouble if the interim analysis doesn’t pan out,” Miller says.

Either way, Dendreon bulls and bears are certainly going to rev up their engines between now and October in hopes they can ride the shares up past $20 again, or short them down to something a whole lot lower than its closing price yesterday of $5.69.

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  • Dan

    The Unreachable Availability of Provenge

    Terminal patients are those who are not expected to live due to usually illness such as advanced cancer. If the patient has 6 months or less to live, those patients are considered terminally ill. Regardless, if a patient is terminal, they are without a cure or a tolerable treatment for their illness. Since such patients will likely die in a short period of time, treatment options, even if unproven, are often desired by such patients. This is understandable, because at such a severe stage of illness, such as prostate cancer, possible extension of their lives with comfort is worth it to them, regardless of lack of evidence of proof of whatever treatment that may be advantageous to them regarding these issues. The FDA, however, claims authority on the treatment options of such patients, although that administration has proven itself over the years to be rather inadequate with its frequent drug recalls and black box warnings, and they do these things only under pressure from the public, usually. So, the FDA may not be an ideal judge regarding such issues as treatment options for very sick patients.
    Prostate cancer is rather frequent, with between 10 to 20 percent of men predicted to acquire the disease during their lifespan, resulting in about 30,000 deaths a year from this disease. It is the third most common cancer one can acquire, and the United States has the most cases diagnosed n the world, which usually strikes men past the age of fifty. One million do have prostate cancer in the United States, and about thirty thousand will die from the disease each year. Furthermore, there are different stages of prostate cancer, and the more severe the prostate cancer cases are, the higher of what are called Gleason Scores will be, and the severe cases are the most difficult to treat, of course.
    Yet innovation still exists in medicine. A few years ago, a small Biotechnology company called Dendreon was working on a conceptually new treatment for the worst prostate cancer patients, and this treatment therapy created by Dendreon was named Provenge. Provenge is the first immunotherapy biologic treatment for the progressed prostate cancer patients. Usually, these patients are unresponsive to usual treatment methods for prostate cancer, and are left with chemotherapy, specifically a hazardous drug called Taxotere, as their only treatment option at such a traumatic stage of prostate cancer. Understandably, most patients at this stage refuse treatment entirely, largely due to the brutal side effects of such chemotherapy treatments as Taxodere, which include cytotoxic side effects and haematological adverse events. The immunotherapy method developed by Dendreon requires the removal of white blood cells of the diseased patient and, after altered, are re-injected into this patient now designed to attack within the diseased body what is called PAP, which is on prostate cancer cells only. This treatment requires only three such injections in a period of six weeks. This results in life extension twice that of Taxodere, and Provenge is free of the discomfort of the only other treatment of Taxotere. The medical community and survivors of prostate cancer were elated and waited with great anticipation for access to this treatment method.
    Fortunately, as the years passed, Provenge, by 2007, had convinced others of its safety and efficacy in its benefit for severe prostate cancer patients. This caused great joy to such patients and their families. Perhaps greater elation was experienced by the caregivers and specialists of such a disease, such as Urologists and other caregivers who treat such patients. While Provenge was on fast track status at this time at the FDA, as they at the time agreed with the benefits of this new therapy, the FDA panel recommended with clarity the approval of Provenge based on its proven and superior efficacy and safety that was demonstrated in its trials, as they announced in March of 2007. Lifespan extension of severe prostate cancer patients was twice as long with Provenge versus Taxotere, which is the only other treatment indicated for this stage of prostate cancer that had only superficial efficacy, and is free of the toxic effects of this chemotherapy agent.
    Now for the bad news: With great shock and surprise, the FDA agency rejected the approval of this great treatment for very sick patients due to, they said, ‘lack of data’ in May of 2007. This contradicts their favorable opinion of Provenge weeks before delivering this terrible news. Especially when one considers the FDA Commissioner is a prostate cancer survival himself! Many found this ruling completely unbelievable.
    Soon after this judgment was passed by the FDA, conflicts of interest were discovered by others. For example, a member of the FDA agency who was evaluating Provenge, Dr. Scher, was found to have a financial commitment to a future competitor of Provenge that was being produced by a company called Novacea, and this company had signed a co-promotion agreement with Schering to provide support for this similar prostate cancer drug treatment being developed by this company. Dr. Scher never disclosed this conflict during the approval process of Provenge. As it turns out, this anticipated prostate cancer drug made by Novacea was discovered to have serious flaws, and Schering pulled out of the agreement with Novacea. In addition to this incident and before May of 2007, baseless letters were anonymously delivered to the FDA stating negative qualities about Provenge that were without Merit and speculative claims about the treatment were fabricated in these letters, it is believed Oncologists were speculated to lobby and pressure the FDA not to approve Provenge due to anticipated revenue loss. Yet overall, the disapproval by the FDA of Provenge angered and saddened many, and a newly formed advocacy group called Care to Live filed a lawsuit against the FDA for their clear lack of etiology for not approving Provenge, as they should have, according to the data about the therapy last year.
    Terminal patients, I surmise, desire comfort during their progressive disease that has placed them in the last chapter of their lives, and certainly should have a right to choose any treatment that possibly could benefit them. Clearly, because of their lack of desirable and beneficial treatment options, most are willing to assume any risks of unapproved, yet potentially and likely beneficial treatments such as Provenge. Because they have a terminal illness, these benefits provided by Provenge take priority over any possible safety issues of unapproved treatments for them. The controversy could be concluded by a terminal patient signing a waiver of some sort, perhaps, stating that they are responsible for the consequences of an unapproved treatment regimen such as Provenge. Yet the FDA, with reckless disregard and with deliberate intent, denied what likely was a great treatment therapy for these very ill patients. Several have concluded that the FDA ultimately harmed others more by not approving Provenge, or offering any valid explanations explaining their action. Thier action was irrational, as one considers the agreement of the FDA and others regarding the need of the benefits provided by Provenge for the sickest of the sick with advanced prostate cancer.
    The FDA does in fact presently have the ability to grant what is called conditional approval for such treatment methods as Provenge at this time, and why they have not remains completely unknown. What is known is that they are accelerating and worsening the illness, an illness the FDA pledged to protect so long ago. So now the FDA appears to be a bought, corrupt, and incompetent administration without loyalty and dedication to the public and its health, but with what appears to be overt collusion with venture capitalists and corporations. This needs to be corrected in any way possible for the lives of others- regardless of their own present health state today. Because of the FDA’s flaws in the past regarding drugs taken off the market along with increasing black box warnings of other drugs, which happens often with both, the individual should be the deciding factor in such matters of deciding thier treatment course presently, along with their health care provider, due to this unreliable administration called the FDA.
    “Facts do not cease to exist because they are ignored.” — Aldous Huxley
    Dan Abshear

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  • patty halperin

    my husband has advanced prostate cancer he is 56 he already went throuth taxotere he brezzed through it no problem but after 3 and half months it didn,t work any more he,s in pain his doc promised another drug called alberteron atrail study but said no more patients allowed inthe study we will try anything, anything at all please help. I will try my congressman we have nothing to lose but our beloved husband,father, brother and son he also works two jobs threw this ugly diseace thankyou patty

  • sally landrette

    My husband is 64 four years old and has gone thru taxotere treatments twice for advanced prostate cancer. We are also trying to get him in to clinical trials but we have had no luck in the abiraterone trials and provenge is taking to long. What do we do next??? This is so unfair someone has to be able to help???
    sally