Provenge-Maker Sued for Fraud, Lays Off 500 Staff

MDs Balking at Cost, Logistics?

Nick Mulcahy

September 29, 2011

September 29, 2011 — A series of media reports in the past few weeks have detailed mounting problems at Dendreon, the Seattle, Washington–based maker of the immunotherapy sipuleucel-T (Provenge), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

The latest troubles involve the company's chief executive officer, Mitchell Gold, and other company executives; they are being sued for stock fraud. Members of the management team sold $87 million of stock in the months before reporting disappointing Provenge sales figures, according a report from BNET, the CBS Interactive Business Network.

The report of slow sales and the related shortfall of revenue have caused the company to lay off 500 workers, cancel a supply contract with a major vendor, and experience a 60% drop in its stock value, according to the industry news Web site PharmaLive.

At the root of all these problems is the disappointing clinical uptake of the Provenge. Clinicians are reportedly concerned about being reimbursed by Medicare for the treatment, which costs $93,000 per patient.

Medical practices are required to pay for the treatment upfront and get reimbursed later. But doctors might be balking at the arrangement, suggested a clinician, in light of the fact that the immunotherapy is made uniquely for each patient at an offsite facility with his or her own white blood cells.

"Provenge is very exciting because it is the first immunotherapy for prostate cancer, but it is fraught with logistical issues," said Elizabeth Plimack, MD, from the Fox Chase Cancer Center in Philadelphia, Pennsylvania, in a Reuters story. "Centers are nervous to take on the cost in case reimbursement doesn't come through," she said.

The recent problems with Provenge are the latest chapter in the history of struggles for this prostate cancer treatment, which include regulatory setbacks, questions about the quality of clinical trial data, and competing products in the treatment of mCRPC.

In 2007, the US Food and Drug Administration (FDA) deferred a decision on Provenge and requested more data because a phase 3 study (J Clin Oncol. 2006;24:3089-3094) failed to meet its primary end point — a significant increase in time to disease progression in men with asymptomatic mCRPC.

When the vaccine was finally approved by the FDA in 2010, clinical trial data demonstrated that the drug statistically significantly improved overall survival.

With a median follow-up of 36.5 months, men treated with Provenge (n = 341) had a median survival of 25.8 months, compared with men treated with placebo (n = 171), who had a median survival of 21.7 months.

This showed a 4.1-month median survival advantage for Provenge and a 24.1% reduction in the risk for death (hazard ratio, 0.759; P = .017).

However, the survival data were potentially confounded by the trial design, according to a federally sponsored independent report that accompanied the Centers for Medicare and Medicaid Services (CMS) review of the drug.

The report called into question the exact length of the survival benefit seen with Provenge, because the therapy was tested in conjunction with postprogression chemotherapy.

"The current existing analyses are insufficient to know to what degree sipuleucel-T is effective in the absence of chemotherapy, or [to what degree it] depends on chemotherapy to demonstrate improvement in survival," the report notes. The report was commissioned by the Agency for Health Research and Quality as part of the CMS review of Provenge, and was compiled by the Blue Cross and Blue Shield Association, Technology Evaluation Center evidence-based practice center in Chicago, Illinois.

Furthermore, Provenge was "not a home run," according to an expert who noted that its 4.1-month survival benefit is not largely different from that seen with the standard chemotherapy used in this setting, docetaxel (Taxotere, Sanofi-Aventis).

Docetaxel and prednisone demonstrated a 2.4-month survival advantage on average, compared with mitoxantrone and prednisone, in men with mCRPC (N Engl J Med. 2004;351:1502-1512).

At the time Provenge was approved, docetaxel was the only other approved treatment for men with mCRPC.

However, after its groundbreaking approval in 2010 — Provenge was the first immunotherapy approved by the FDA — a number of other therapies were approved in advanced prostate cancer, creating competition where little had existed previously.

Cabazitaxel (Jevtana, Sanofi-Aventis) was approved by the FDA in June 2010; the approval of abiraterone (Zytiga, Johnson & Johnson) followed in April 2011. Both demonstrated a prolongation of survival in randomized clinical trials for patients with castration-resistant prostate cancer.

Media Coverage Galore

Many of these triumphs and tribulations have been well chronicled in the press. Provenge has received an extraordinary amount of media coverage, in part because the FDA approval and subsequent CMS coverage decision for the costly treatment came at a time of growing financial problems in the United States and concerns about related healthcare costs.

A media circus has ensued at various points.

For instance, when the CMS conducted its inquiry into the efficacy findings on Provenge, media interest was so intense that 40 journalists were unable to listen into a presscast of the review committee because CMS phone lines were at full capacity.

Additionally, Provenge became a target for health-policy experts in discussions about needed reform of CMS coverage, which does not allow price negotiations with manufacturers in Medicare Part B. This might have been unfair, given the fact that other cancer treatments have similar costs and provide even less survival benefit, but it occurred nonetheless.

In an essay in the New England Journal of Medicine (2011;364:1687-1689), a pair of editorialists even went so far as to say that the CMS review of Provenge would eventually be a "turning point" in CMS reform.

The case of Provenge highlighted the "inflexibility of existing payment rules" that allow the CMS "little leeway to contest or otherwise address manufacturers' stated prices," wrote the editorialists, a pair of health economists from Tufts Medical Center in Boston, Massachusetts.

On the positive side of media coverage, Provenge has been enthusiastically welcomed along the way by prominent urologists, who expressed hope that the treatment would help patients who were out of treatment options.

For instance, when it was reported at the 2009 American Urological Association (AUA) annual meeting that Provenge had finally shown a statistically significant improvement in survival in men with mCRPC, J. Brantley Thrasher, MD, chair of the Department of Urology at the University of Kansas Medical Center in Kansas City, and an AUA spokesperson, said that "this will cause a big splash."

"We don't have anything for patients with hormone-refractory disease, which is very aggressive.... Improved survival with T cell immunotherapy is really very significant," he said at the time.

Lawsuit and Other Problems

Details of some of the goings-on in the company have been detailed in a report from BNET, which recently chronicled the story of a lawsuit brought by one of Dendreon's investors, Michael Wendt.

According to that report, CEO Mitchell Gold sold $34 million of his stock in the company prior to announcing in August that Dendreon would not meet revenue projections for the year, which was followed by a devaluation of the stock by 67%.

Investors had previously been told that Dendreon would have revenues of up to $400 million in 2011, with an expected 2000 patients treated with Provenge.

In August, Dendreon reportedly said it expected only "modest" 2011 sales.

In the 9 months before that disappointing announcement, Mr. Gold and other company executives sold $87 million of stock, the suit reportedly says.

Meanwhile, the company announced on September 8 that it would be laying off 500 employees.

In the same announcement, Mr. Gold said that Dendreon would continue in the prostate cancer treatment marketplace and, among things, educate physicians.

"We believe that the improved reimbursement landscape and our comprehensive plan to educate physicians, coupled with the meaningful clinical benefit that Provenge provides to patients, creates a strong market opportunity," he said.