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Dendreon Makes History: FDA Approves First Active Immune-Booster to Fight Cancer

Xconomy Seattle — 

[Updated: 11:05 am Pacific] Scientists have been dreaming for a century about therapies that actively harness the power of the body’s immune system to kill cancer cells like an invading virus or bacteria. Today, Seattle-based Dendreon has made history by winning the first-ever FDA approval for this kind of cancer-fighter. Shares climbed 15 percent to $45.50 after the news broke.

The good news for Dendreon (NASDAQ: DNDN) came today when it received clearance from the FDA to start selling sipuleucel-T (Provenge) to men in the U.S. with terminal prostate cancer that has spread, even after prior rounds of standard hormone-deprivation therapy, according to a statement on the FDA website. The agency gave the green light after Dendreon showed in a trial of 512 men that patients lived a median time of 25.8 months if they got Provenge, compared to 21.7 months for those on a placebo. Patients on the drug had minimal side effects of fever and chills that lasted a couple days.

The FDA’s decision will have far-reaching impact for years. The drug is the first marketed product for Dendreon, which has piled up a deficit of more than $700 million in its 18-year development quest. The product is forecasted by analysts to exceed $1 billion in U.S. sales after a couple years on the market. Dendreon could morph into the regional anchor Seattle’s biotech community has lacked since Immunex was acquired by Amgen in 2002. For the 27,000 men in the U.S. who die each year from prostate cancer, the drug represents some hope for a longer life, and a higher quality of life alternative to chemotherapy. And for researchers, it offers new possibilities for a mode of treatment beyond surgery, chemotherapy, radiation, and targeted biotech pills and antibodies that must be taken chronically.

“This is a huge advance,” said Dr. John Corman, a urologist at Virginia Mason Medical Center in Seattle, and an investigator in Provenge clinical trials for eight years. “This is the first immunotherapy agent that’s been shown to provide a survival benefit for prostate cancer patients. And it’s a completely new class of therapy that provides remarkable opportunities for R&D.”

[Update with company statement.] Dendreon said the drug will be made available initially at about 50 medical centers in the U.S. The company didn’t say in its statement today how much it will charge for the drug, although it plans to hold a conference call with analysts and investors at 2:30 pm Eastern/11:30 am Pacific.

“The approval of Provenge is a significant step towards realizing our mission of transforming the lives of patients with cancer, and it also marks Dendreon’s transformation into a commercial enterprise,” CEO Mitchell Gold said in the statement.

While today’s FDA approval is groundbreaking, it’s worth being precise about what this means, and what it doesn’t. Treatments like Dendreon’s are most accurately referred to as “active immunotherapies,” although scientists sometimes loosely call them “cancer vaccines” in the media. Just to be clear, Dendreon’s product is a treatment that people get after they’ve already been diagnosed with prostate cancer, so it isn’t a vaccine in the traditional sense that prevents people from getting a disease. Because Dendreon’s treatment “teaches” the immune system to recognize certain cancer cells and fight them on its own, for months or even years, it’s considered an “active” immunotherapy. That’s also different from what researchers sometimes call “passive” immunotherapy. It’s fair to consider an intravenous-delivered antibody drug, like Roche’s rituximab (Rituxan), a “passive” immunotherapy because it works in part by stimulating the immune system to fight cancer cells, at least while the drug is active in the blood. It’s also fair to call Merck’s human papillomavirus vaccine (Gardasil) a cancer vaccine, because it prevents women from getting infected with a virus known to cause cervical cancer.

Whatever you choose to call Provenge, the anticipation of today’s FDA approval has already transformed Dendreon. A few weeks before the defining clinical trial data arrived in April 2009, the company’s stock was trading around $2, cash was running low, and it had about 200 employees. After the data arrived and was presented at a urology meeting in Chicago, Dendreon raised $630 million from investors, announced plans to grow to 600 employees, added two more drug factories, and saw its stock climb to more than $40 a share.

Plenty of questions remain about how well Dendreon will be able to seize this new opportunity. It doesn’t have enough manufacturing capacity to meet all the anticipated demand from prostate cancer patients on Day 1, and it has to strike a delicate balancing act on pricing the product so as to maximize profits without alienating doctors and patients. Since the product involves incubating patient’s own white blood cells with a complex engineered protein, the manufacturing and shipping logistics are more complicated than they would be for a usual pill in a bottle. Any slip-ups could lead to shortages of a potential life-saving product, which is the kind of the PR nightmare all biotech companies fear (see: Cambridge, MA-based Genzyme).

But today’s FDA approval is a vindication for a company that has persevered through some fascinating twists and turns over the years, which I summarized in an in-depth feature story for Xconomy in April 2009. The dream of getting an FDA-approved cancer immunotherapy has eluded dozens of biotechs over the past two decades, including notables like Cell Genesys, Antigenics, Genitope, and Favrille. In Seattle, Xcyte Therapies failed to get its immune-booster through the FDA, and now Oncothyreon’s partner, Merck KGaA has been tripped up by an unexpected side effect seen in a clinical trial.

Here’s some of the Dendreon history that can be useful for people trying to understand the context around why today’s news is a big deal.

Dendreon’s treatment doesn’t work like a traditional chemotherapy or even a targeted antibody drug that’s supposed to seek out cancer cells and spare healthy ones. Instead, the Dendreon treatment is designed to trigger the body’s natural immune defenses to recognize cancer cells as foreign invaders, like a virus, and kill them.

Here’s how this works: Dendreon’s approach requires blood to be drawn from a patient, and some white blood cells vital to the immune system, called dendritic cells, to be separated in a lab. The cells are shipped to the company’s factory in New Jersey, and incubated with a genetically engineered protein found on prostate cancer cells, called PAP. This process is supposed to “teach” the immune system to recognize cells with this marker as foreign and fight them, and is sort of like waving a red flag to get the attention of a bull. The newly revved-up white blood cells are shipped back in cold storage from the Dendreon factory to the clinic, and re-infused into the patient, giving them new ability to fight off the cancer. The patient gets three of these infusions at the clinic over a one-month period, and then he’s done.

Much of the theory and practice of boosting patient’s own blood cells was worked out at Dendreon in the 1990s, and the company thought it had seen enough promising anti-tumor activity to take Provenge into the third and final stage of clinical trials, back in 1999. The gold standard measurement of effectiveness then, and now, for all cancer drugs would be a clinical trial that randomly assigns people to either the experimental drug or a placebo. Researchers would then follow patients for years to see if those on the drug live longer, with acceptable side effects in the eyes of the FDA.

Dendreon, like many biotech companies, couldn’t afford to wait around for the years it would take to show a survival advantage for patients with slow-growing tumors like those of the prostate. It might take years to enroll all the patients, and since men with late-stage forms of prostate cancer have a life expectancy of 18 to 20 months, there would have been a lot of waiting. So the company came up with a primary goal that would provide a quicker answer. They looked at how long patients on the drug are able to keep their tumors from spreading-a goal that’s long been thought to be a reasonably accurate predictor of improved survival time.

That first trial, of 127 men, failed to show that Provenge could slow down the spread of tumors with the required statistical confidence. For many biostatisticians, that was the end of the story. The treatment had failed on its primary goal. Investors left the company for dead in 2002, driving the stock below $2. But Dendreon, again, in a desperate situation, fished around in the data for something positive to hang onto. For a while, it tried to convince investors there was a benefit for patients with slower-growing forms of tumors, just not for the most aggressive cases.

Many investors—and biotech industry peers—scoffed at this notion and figured the company was toast. But the story kept investors interested for a while, and it kept Dendreon in the game long enough so it could flip over an ace it had in the hole.

From the beginning of that trial, the FDA required the company to keep track of whether these patients were alive or dead for a full three years. It took time for this data to roll in, but the final analysis in 2005 showed that patients on Provenge ended up living a median time of 4.5 months longer than men who got a placebo. About one-third of the men on Provenge were alive after three years of follow-up, about triple the three-year survival rate of men in the control group. Side effects were minimal.

Dendreon hypothesized that the vaccine just took a while to kick in, a so-called “delayed effect” that might explain why tumors would spread shortly after treatment, but the treatment would end up helping patients live longer after all.

Patient advocacy groups cheered on Dendreon from the sidelines, saying they needed alternatives to the existing treatments-chemotherapy and chemical castration therapy-that have nasty side effects. Many scientists considered the Dendreon data intriguing, but the sort of thing that would need to be verified in another, larger trial.

While all of this was going on, Dendreon had another trial ongoing called Impact, and this time it had enrolled enough patients fast enough to produce a definite answer on survival. In consultation with the FDA, Dendreon agreed in November 2005 to expand the Impact trial to enroll 500 men with a broader range of tumor-aggressiveness scores, and make survival the main goal. After all of these meetings with the FDA to talk about next steps, and before the definitive results from Impact were ready, Dendreon decided to go for it anyway. It completed an application to the FDA in November 2006, asking it to approve the drug primarily on the basis of the survival benefit shown in the earlier study of 127 men.

This gambit was controversial. Many in the scientific and medical community wanted to see Dendreon hit the primary goal of a clinical trial designed to show it could help patients live longer. Many investors were skeptical that Dendreon could win approval on its thinner set of existing data. Short-sellers, who intend to profit on a falling stock price, placed huge bets with millions of shares that said Dendreon was bound to fail.

By March 2007, the FDA, as it often does with new drugs, sought the advice from an expert panel of cancer physicians, statisticians, and immunologists on whether to approve the drug.

This hearing-which I covered live from a hotel in suburban Washington D.C.—was a riveting drama. After panelists debated the effectiveness of the drug for an afternoon, with analysts on the edge of their seats in suspense, the panel voted 13-4 in Dendreon’s favor that Provenge demonstrated “substantial evidence of effectiveness” and 17-0 that it was safe. One panelist from the National Cancer Institute told me after the meeting that he voted in favor, partly because he was hopeful this would spark a new day in immune therapy research.

Since the FDA almost always follows the advice of its expert panels, investors wagered that Dendreon had actually achieved the impossible. Its stock boomed from $5.22 before the panel to close at $12.93 the day after this vote, as 92 million shares changed hands that day. This little company from Seattle, without a product on the market yet, was the most active stock in the entire NASDAQ that day, with even more activity than Microsoft or Cisco Systems.

But there were even more plot twists to come. The four members of the advisory committee who voted no apparently felt strongly that the panel had made a mistake that could set a dangerous precedent for the FDA, essentially lowering the required standards for approval. Letters from two of these panelists, Maha Hussain of the University of Michigan and Howard Scher of Memorial Sloan-Kettering Cancer Center in New York, were eventually published in The Cancer Letter, a trade publication.

The market essentially blew this off as a minor academic dust-up for a while, as Dendreon shares reached a peak of more than $24 a share, making it briefly worth more than $1 billion in market value. During this extraordinary run-up, many people chose to sell their shares at a high point-including a few Dendreon board members and CEO Mitchell Gold. (The Dendreon CEO sold 202,090 shares on April 2, 2007, at $13.46 apiece, for gross proceeds of $2.7 million, according to this filing with the SEC.)

Nobody seemed to mind much if Gold or the Dendreon directors made some money. After all, so were a lot of other people. I heard stories of low-paid nurses in Seattle-not the usual biotech investors-buzzing to all their friends about how they made a bundle on Dendreon stock.

Then came a bombshell.

Before markets opened on May 9, 2007, Dendreon announced the FDA had turned down its application. Regulators demanded the company produce more evidence from the ongoing clinical trial of 500 men, designed from the outset to answer the question of whether the treatment can prolong lives. This meant Dendreon would have to wait another two years, at least, to achieve its dream of winning FDA approval for Provenge. Dendreon’s release made it sound like it was stunned, as the company needed to seek “clarification” from the FDA about what it really meant.

All that stock wealth was wiped out in a heartbeat. Dendreon stock collapsed from $17.74 the previous day to close at $6.33. Trading volume skyrocketed, again making Dendreon the world’s most active stock that day. Patient advocates were outraged. The inevitable shareholder lawsuits arrived.

The recriminations in the wake of the FDA rejection got ugly at times. Some infuriated individuals went so far as to physically threaten Hussain and Scher before they appeared in public at the American Society of Clinical Oncology (ASCO) meeting the following month, forcing officials there to tighten up security. The Provenge advocates continued their fight, urging members of Congress to hold hearings and investigate the FDA’s decision. No hearings were held.

Dendreon, once a highly visible and promotional company, had little to say at that year’s ASCO meeting and didn’t make much news the rest of the year. It sought to pick up the pieces and find a new way forward. After yet another meeting with the FDA, the two sides agreed on a compromise of sorts that could get the agency the proof it needed to be confident Provenge works in the study of 500 men.

Now that the Dendreon drama is moving further in the past, it has gotten researchers thinking big again about immunotherapy in the future. Dr. Corman, the Virginia Mason urologist, noted that the Impact trial looked at men who are quite sick, who have had their immune systems weakened by their cancer and rounds of radiation therapy. Might Provenge be even more effective if it were given to men with earlier-stage forms of the disease, who still have more robust immune systems that are more likely to respond to the priming from Provenge?

That’s a question Dendreon has had on its mind for years, but it is a difficult one to answer because early-stage prostate cancer is so slow-growing it would take many years to show a definite survival advantage of the drug over the placebo.

“The benefit should be greater in men who are younger, with healthier immune systems,” Corman says.

How much demand will there be from patients? It’s likely to be high because Dendreon’s public saga with investors and the FDA, it already has unusual name recognition already without spending any formal marketing dollars. Provenge had 93 percent brand awareness about a year ago, according to a Dendreon survey of targeted physicians, which CEO Mitchell Gold cited at last year’s annual shareholder meeting.

Corman has found a way to help some of his patients get access to the drug prior to FDA approval through what amounts to a really large clinical trial. He’s expecting the phone to start ringing shortly from patients as news spreads of the FDA approval.

“There will not be 50 patients on our doorstep here on Day 1, but there might be five,” Dr. Corman says.

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