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Msg  369190 of 485877  at  9/5/2010 3:01:58 AM  by


 In response to msg 369176 by  owlinkfan
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Strong Buy

Re: P-11

Use in Earlier Stage Disease

The FDA label for Provenge calls for its use in men with late-stage prostate cancer. This is a very small percentage of the men who have PC. The sales for Provenge could be huge if Dendreon is able to obtain a label expansion so that it is used in men with earlier stage disease or if doctors on their own decide to use Provenge “off-label” in such men, especially if insurance companies agree to reimburse for such early treatment. My recollection is that Dendreon cannot promote off-label use of Provenge but it sales reps are permitted to provide doctors with medical papers dealing with use of Provenge in earlier stage disease. For example, if there is a medical paper prepared regarding the next data from the P-11 trial, the sales rep could provide that paper to the doctor.

Last January, ocyan dealt with the question as to why Provenge extends survival without reducing the prostate tumors and spoke of Circulating Tumor Cells (“CTC”) and Approval of Provenge in early stage disease (318966):

“The answer lies in how Provenge works. It trains the immune system to first hunt for stray tumor cells on a long term basis so that they cannot spread to other parts of the body and second to attack any existing tumors. The long-term hunt for stray tumor cells is what makes Provenge different from drugs such as Taxotere and Avastin that aim mostly at destroying established tumors on a short-term basis.

The key in the Provenge trials was that enrolled patients must be free of any sign of metastasis to vital organs. The long-term hunt for stray tumor cells prevented the disease from spreading to places that could kill. That's what improved the chance for survival of treated patients over placebo ones.

The same protective mechanism could make Provenge a potentially good treatment to use in the early phase of the disease before it gets out too far from the prostate. Circulating Tumor Cells counting * * * is gaining some acceptance as a predictor for survival and could be accepted as a surrogate endpoint for prostate cancer trials. IMO, it would be easy to test the effectiveness of Provenge in reducing CTCs.

As I posted earlier, perhaps a new trial of Provenge in the Androgen-Dependent PC stage could be started to test for CTCs. That could go fairly quickly and could even be timed to finish at the same time as the P-11 trial for its Time-To-Metastasis endpoint. Then, if P-11 succeeds, a label extension to ADPC can be attempted with the additional data in a few years - perhaps even 2012.”

In a private message commenting on an earlier draft of this memo, ocyan noted:

“The arrival time of the Time-To-Metastasis that I gave for P-11 was based on a calculation that assumed a trigger at 60% of patients reaching the endpoint. That was consistent with IMPACT but it was also possible for that percentage to go up to 70% per common trial design. In that case, the timing will be off by about 2 years.”

Use of Provenge in men with earlier stage prostate cancer and healthier immune systems should be more effective as David Miller writes in the just-cited Minyanville article:

“I believe prostate cancer is the only place where an active immunotherapy is likely to be effective in later stages of the disease when used as a monotherapy. Prostate cancer is unique in its slow growth, though it can get out of hand quickly once metastatic and causing symptoms. Everyone believes the place to use active immunotherapies is in the earliest-stage patients you can afford.

“You can afford?” Odd statement, I know. Small companies have limited cash and are always burning it. We know the only proper clinical trial measure for active immunotherapies is survival. Earlier-stage patients live a long time. That means it takes a long time to get results from a clinical trial in earlier-staged patients. Long time equals more money.”

I doubt that a label expansion is in the cards any time in the next few years. DNDN has a couple of trials ongoing that involve men with earlier stage disease—the P-11 trial and the NeoACT trial. But neither of these trials would be sufficient for a label expansion absent a major change in policy by the FDA. And the results from the P-11 trial will not be available soon. The always reliable, ocyan, posted an interesting personal reflection after Approval and also indicated that the next major data for the P-11 trial would come in late 2011 or early 2012.

To do a clinical trial in men with earlier stage disease and with survival as the endpoint would take many years. In the Chat, Miller seemed to say it would take two years for a survival trial to commence, 2 to 3 years to enroll patients and probably 10 years to follow the enrolled patients. I doubt such a trial would happen unless Dendreon comes up with a Provenge #2 that would have a longer patent life.

David Miller has held out hope that one of the competing prostate cancer trials, Abiraterone discussed infra, would validate Circulating Tumor Cell technology as a surrogate that the FDA would accept in lieu of survival data; that would shorten the necessary trial periods substantially.

I am very optimistic that, with all of the publicity that Provenge has received recently and over the last three years, many patients will be pushing their doctors for early use. I also would not be surprised to see many wealthy PROSTATE CANCER patients in the Rest of the World fly here for the one-month Provenge treatment if Provenge will not be available in their home country for quite some time (see 350219).

Dr. Charles Drake, who works on prostate cancer at Johns Hopkins University, was recently quoted about earlier use of Provenge in the Voice of America News:

"I think we'll start to have the kind of clinical benefits that you alluded to, you know, more than four months. We want long-term survival, frankly. Maybe a cure," said Dr. Drake. (Emphasis added).

Dr. Corman of Virginia Mason is quoted in the Seattle Times article referenced earlier with these great quotes from the article:

"Patients and their families have been asking about the drug and tracking its roller-coaster ride through the regulatory process for years," Corman said. "I must talk about this with 10 patients a day.’"

"Though Provenge was approved specifically for advanced prostate cancer, it may prove even more powerful in men with earlier stages of the disease whose immune systems haven't been hammered by radiation and chemotherapy," said Corman, who is involved in studies to answer that question.

Doctors are allowed to prescribe drugs ‘off-label,’ and Corman said he's already getting requests from recently diagnosed men.

It's not clear yet whether insurance companies will restrict coverage to only patients with advanced cancer.

David Miller lost his father to prostate cancer and has a family history of PC. In post 34809, he says that, if he were diagnosed with PROSTATE CANCER and chose a prostatectomy, he would “mortgage the house to take Provenge as soon as I am healed after the surgery.”

In the Chat, Miller doubted that there would be much off-label use until late 2011 or 2012 when the backlog of late-stage PROSTATE CANCER patients with the conditions in the label has been satisfied. However, Dendreon itself has said that it will leave it up to the doctors at the 50 trial centers to choose the patients who will receive Provenge in this initial supply-constrained period. Possibly some doctors would choose to treat earlier stage patients in order to see how it works. However, Dendreon may well be limiting the number of treatments at each center—Dr. Higano said that each of the 50 sites around the country would have slots for only two patients per month. Since that would only add up to 1,200 in the first 12 months, not the 2,000 the company has mentioned, presumably the 2-per-site figure is for the initial phase and would be increased when the rest of the New Jersey facility is completed early in 2011. Doctors will probably find themselves in the difficult position of choosing which patients receive Provenge out of a much larger group of men that want Provenge.

In curious timing, the FDA on May 3rd issued a New Release warning about the side effects of Lupron and other hormone drugs that suppress testosterone due to concerns about “a small increased risk for diabetes, heart attack, stroke, and sudden death.”

The late-stage PROSTATE CANCER patients eligible to take Provenge per the label have become resistant to the effects of these hormone drugs. If doctors become worried about the side effects of the hormone drugs, they may push patients to take Provenge off-label at an earlier stage and skip the hormones. In fact, many men will be pushing their doctors to do Provenge and skip the hormones entirely due to the side effects of hormone therapy, the main ones of which include:

• Constipation or diarrhea
• Nausea
• Loss of or decrease in appetite
• Dizziness or headache
• Swelling of or tenderness in the breasts
• Trouble sleeping
• Impotence or decrease in sex drive
• A bloated feeling accompanied by gas or indigestion
• Confusion
• Drowsiness
• Dryness of mouth
• Flu-like symptoms

David Miller in commenting on an earlier version of this memorandum said that he thought it unlikely that doctors would abandon hormones. He also said that the FDA’s warning is about 4 years late: all urologists are aware of the side effects of hormones and almost all do not keep their patients on constant hormone therapy.

I note that there is always the risk of the unknown when something new is tried. Could Provenge possibly trigger too much immune response in men with strong immune systems so that the immune system started attacking healthy tissue or did something else that was unexpected and bad? The fact that no such strong adverse reactions has occurred in the smaller earlier stage disease trials that Dendreon has done is encouraging on this point (see ocyan’s 349995).


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Msg # Subject Author Recs Date Posted
369214 Re: P-11 ralphla54 13 9/5/2010 9:47:17 PM

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