Having gotten over the hurdle of FDA approval with the market's first therapeutic cancer vaccine, Dendreon now faces the challenge of getting Provenge to the market. Already the company is also signaling that supply is unlikely to match demand in the near term.

Provenge (sipuleucel-T), an autologous cellular immunotherapy, was approved April 29 for treating asymptomatic or minimally symptomatic prostate cancer that is metastatic resistant to standard hormone treatment. Approval was widely expected, based in part on results from the pivotal Phase III IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial, which showed a four-month benefit in survival (Also see "PDUFA Cliffhanger: Will FDA End The Provenge Regulatory Saga?" - Pink Sheet, 23 April, 2010.).

Dendreon's stock price soared by 26 percent to $50.18 in late afternoon trading that day, having already been on the rise as the May 1 PDUFA date neared.

However, now that approval is out of the way, one of the biggest challenges will be meeting demand. Holding true to previous declarations of readiness for launch, during an April 29 investors' call executives said that they will be treating the first patient within a week.

Options for men with castrate-resistant prostate cancer are very limited and patient groups had been fighting in favor of approval. Without treatment, patients will die within a year and a half - unmet need and demand for new options to extend survival are high, said Mitchell Gold, Dendreon's president and CEO.

"We expect demand will exceed supply. That is the challenge early on in the process," he said.

Dendreon has already hired about 70 sales reps to manage the product. It has three manufacturing facilities; one is in Morris Plains, New Jersey and is now running at 25 percent of capacity. The other two facilities are in Atlanta, Georgia and Orange County.

All three sites will be fully operational by mid-2011, the company confirmed, but initially the New Jersey facility will be the sole source of product. The aim is to serve 2,000 patients within the next 12 months.

Dendreon has been preparing for the difficulty of transitioning to commercial production of a unique drug with unique manufacturing and supply chain issues.

Manufacturing is a big challenge for the immunotherapy, as each dose is produced specifically for a particular patient using the patient's own cells. With Provenge, a patient's own immune cells are altered in a process called leukapheresis to boost their ability to fight prostate cancer. Then the activated immune cells are delivered back intravenously to the patient.

Following discussions with leading physicians, the company decided to limit its initial launch to patients at 50 oncology and urology centers nationwide, all of which were approved trial sites. That should soften the transition, as those sites are familiar with use of the product.

Pricing Details Revealed: $90,000 Per Patient

During the call, executives also unveiled plans for product pricing. Each course of treatment includes three infusions given within a month. Pricing has been set at about $31,000 per infusion, or a total of about $93,000.

This price is significantly higher than what some analysts had expected. For example, in a note issued prior to the investors' call on April 29, J.P. Morgan analyst Cory Kasimov had made a conservative estimate of $65,000 per patient.

The $93,000 price tag was set based on the value of the product, particularly the improvement in median survival, said Hans Bishop, executive VP and chief operating officer.

In the IMPACT study of 512 patients, median survival for those receiving Provenge was 25.8 months, compared to 21.7 months for the control group of non-activated autologous peripheral blood mononuclear cells. Results were released in April 2009 (Also see "Provenge Scores In Phase III; Will Dendreon Need To Confirm The IMPACT?" - Pink Sheet, 4 May, 2009.).

Bishop explained that Dendreon used that survival benefit as the basis of the price, and that the price is comparable to other late-stage oncology treatments, such as Sanofi Aventis' Taxotere , the standard of care, based on the 4.1 month benefit. Taxotere costs about $60,000 per patient but offers only a 2.9 month survival benefit.

Dendreon also pointed out that unlike other cancer treatments, additional costs for supportive treatment are minimal with Provenge compared to other oncology treatments.

Going forward, reimbursement is another challenge. About three-quarters of the target population are Medicare-eligible. The company will initially be using a temporary J-code for billing and plans to meet with Centers for Medicare and Medicaid officials the first week of May. Prior to approval, executives have been meeting with payers to pave the way for reimbursement.

Dendreon has created a patient assistance program for those who have trouble making copayments plus a telephone number staffed by dedicated social workers in oncology to help navigate the reimbursement process.

FDA Release Notes High Rate Of Mild To Moderate Side Effects

Provenge's approval followed a number of regulatory setbacks. FDA's Cellular, Tissue and Gene Therapies Advisory Committee reviewed the drug in 2007 and voted in favor of approval, but the product nevertheless received a "complete response" letter from FDA.

In a Q&A about the Provenge approval, the agency noted the factors that initially worked against clearance. Deficiencies in the application included "the absence of sufficient information to determine that the product would be safe and effective, as well as sufficient information to determine that the facility in which the product is manufactured, processed, packed or held would ensure the continued safety, purity, and potency of the product."

Results from the IMPACT study, released in April 2009, helped shore up the application. FDA said based on these and other information submitted by the company, it has now determined that the product is safe and effective.

However, labeling - FDA's official expression of its determination of the product characteristics - is limited on the efficacy demonstration. The clinical trials section notes that the primary endpoint of time to disease progression was not statistically significant. The label notes survival findings were consistent across subgroups, and it presents the data only in graphs. Overall survival was statistically significant only in the smaller, second study submitted later. [Editor's note: this story was updated May 3 to correct information on the clinical trials section of labeling.]

Though FDA's press release on the approval notes a high rate of side effects, and higher rate of cerebrovascular events for the Provenge group, labeling on the drug's risks is relatively brief.

"Almost all of the patients who received Provenge had some type of adverse reaction," the release states, most of which were mild to moderate. "Common adverse reactions reported included chills, fatigue, fever, back pain, nausea, joint ache and headache."

Serious adverse reactions, reported in approximately one quarter of the patients receiving Provenge, included some acute infusion reactions and stroke. Cerebrovascular events, including hemorrhagic and ischemic strokes, were observed in 3.5 percent of patients in the Provenge group compared with 2.6 percent of patients in the control group.

FDA is requiring that Dendreon study cerebrovascular events in a registry of about 1,500 patients as a mandatory post-marketing commitment.

Though those side effects were noted in the press release, they were not elevated to the level of warnings/precautions. The only real warning in the label is about acute infusion reactions, which covers the high rate of reactions (71 percent), and seems to cover the common reactions (chill, fatigue, etc).

The adverse reactions section notes that almost all patients - 98.3 percent of those treated with Provenge and 96.0 percent in control patients - reported an adverse event, but most of those were mild or moderate and there were few differences between the arms in terms of severe events.

- Emily Hayes ( e.hayes@elsevier.com )

Dendreon Set To Ship Provenge Within A Week

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