Dendreon's release of positive Phase III results for immunotherapeutic Provenge - including a four-month overall survival benefit compared to placebo - begs the question of whether FDA will now approve the prostate cancer vaccine without a confirmatory trial.

In the double-blind, Phase III IMPACT (9902B) special protocol assessment trial of 512 men with metastatic, androgen-independent prostate cancer, Provenge (sipuleucel-T) was shown to yield a survival benefit of 4.1 months over placebo, and to boost three-year survival by 38 percent. Results were presented at the American Urological Association meeting in Chicago April 28 (¹ Also see "Provenge Wins In Phase III; Will Dendreon Need to Confirm The IMPACT?" - Pink Sheet, 28 April, 2009.).

The company's stock price fluctuated wildly around the time of the release, with a mysterious major sell-off just prior, and heavy trading after, doubling the share's value. The early slide has not yet been explained - and has prompted a NASDAQ investigation - but some observers are considering it a "mere blip." By the time analyst reports came out, most were listing Dendreon as a "buy."

The reason for the rating and rebound is the level of efficacy shown in IMPACT, which exceeded expectation enough that it's put pressure on FDA to clear the cancer vaccine and renewed the hopes in a class that many had written off. As Rodman & Renshaw analyst Reni Benjamin wrote in an April 29 note, "These results support the marketing approval of Provenge and highlight a new paradigm in the treatment of prostate cancer."

On top of the efficacy results, the safety profile was very clean, with adverse events in the Provenge arm including mainly low-grade chills, fever, and headache.

Provenge consists of peripheral blood mononuclear cells taken from a patient and activated in vitro with a recombinant fusion protein. The product is infused intravenously into the patient to stimulate his or her immune system to fight cancer.

With its ambitious goal of introducing the first therapeutic cancer vaccine in the U.S., Seattle-based Dendreon has faced intense scrutiny and high stakes. But the firm may in the end persevere, helped along as the understanding of how the cancer vaccines may work has evolved, enabling them to refine clinical trial design and better assess efficacy.

The company originally submitted a BLA for Provenge in 2007, but the application was supported by two trials (D9901 and D9902A) with missed primary endpoints, though retrospective pooled analyses of the two trials showed survival benefit. After a "complete response" letter from FDA, Dendreon set out to bolster the efficacy case by showing an overall survival benefit in IMPACT - a trial that was designed in consultation with FDA (² Also see "Dendreon’s Therapeutic Vaccine Provenge Gets “Complete Response” From FDA" - Pink Sheet, 9 May, 2007.).

In an April 28 investor call, Dendreon CEO Mitchell Gold reaffirmed plans to file the results as an amendment to its BLA in the fourth quarter of 2009. "In addition, we are preparing our manufacturing, sales and marketing operations to ensure we are able to launch Provenge successfully in the United States," Gold said.

Believers Vs. Skeptics

The IMPACT results have been eagerly awaited in many quarters. "For a long time, the question of whether immunotherapy will work has been a matter of belief - some accepted it on faith alone as opposed to data. Now, we see the skeptics are more or less becoming convinced," said Charles Ryan, urologic cancer specialist at the University of California San Francisco, a Provenge test site.

But the more persistent skeptics are taking a wait-and-see approach in a space littered with past failures. Even in the face of strong results and media fanfare, they wonder if some design flaw will come to light.

As Merriman Curhan Ford analyst Joseph Pantginis put it in a note before the results were aired, "the cards were stacked against a positive final outcome," because the study included patients with Gleason scores 8 and above, as well as patients who have become symptomatic for bone pain.

"We believe that enrolling patients with more severe disease is counter to what is now clearly known in the cancer immunotherapy space that more severe patients do not respond as well to this form of therapeutic approach," the analyst wrote in a March 13 note.

Among other issues under question is IMPACT's crossover trial design. In the treatment arm, patients showing disease progression were given the option of moving on to chemotherapy with Sanofi-Aventis' Taxotere (docetaxel).

Patients in the placebo arm had the option of enrolling in a salvage protocol that involved administration of a version of Provenge manufactured from cells cryopreserved at the time of placebo generation, prior to chemotherapy.

Earlier exposure to chemotherapy theoretically could have given an advantage to those in the treatment arm, critics have asserted. However, the company has adjusted the results to account for time to chemotherapy and found no evidence that chemotherapy use following the investigational therapy interfered with the results, Chief Medical Officer Mark Frohlich said in an interview.

Can Dendreon Get Around Another Trial?

The regulators remain a wild card. A particularly hot topic is whether FDA will accept one major, positive Phase III trial for approval, when typically it asks for two adequate and well-controlled studies, especially when there is conflicting evidence from other trials. But given the fervor surrounding the pressure, especially with the favorable results, it will be politically difficult for FDA to deny approval.

The fact that the IMPACT survival benefits are in line with the other two Phase III studies from the original application could work in Provenge's favor, if the FDA reviewers are inclined to be lenient and are convinced in the underlying scientific rationale of the product. Having an SPA should also help. And lack of impact on time-to-progression won't tarnish the vaccine, given that it is thought to have a delayed treatment effect.

The safety profile also looks clear for Provenge and patients are in need, with Taxotere as the only FDA-approved drug to treat late-stage prostate cancer.

However, the agency may take a more conservative view, particularly for such a pioneering treatment. Although the overall survival benefit appears to be solid in IMPACT, the p-value of 0.032 was acceptable but not a knockout. Some question whether a single positive, but small, Phase III trial will be enough.

It's possible that FDA will opt to grant an accelerated approval, with the condition that a confirmatory trial be done post-marketing, especially since FDA would be able to require whatever trial design it wants.

There are economic factors to consider as well, as treatment is likely to be priced at about $50,000 per year. Though 30,000 men might be initially eligible, analysts expect much wider off-label use - a high cost for society.

For example, it could potentially help after surgery for men with no overt metastases but who are at risk for developing them, said Peter Carroll, co-director of urologic cancer at the UCSF Helen Diller Family Comprehensive Cancer Center. Some day Provenge could rival similarly-priced chemotherapy earlier on in treatment, improving the cost-effectiveness profile, investigators say. "The next question is to try this head-to-head against chemo," Carroll said. But that gets ahead of the game. UCSF investigators are now studying how the vaccine actually works.

Rocky Regulatory History

Provenge's regulatory review has been criticized as too slow by some and too flimsy by others. After cancer drug reviews were organized under the Office of Oncology in 2004, biologics and chemo-preventative drugs fell under the Center for Drug Evaluation & Research's Office of Oncology, but vaccines remained under the Center for Biologic Evaluation & Research division.

Thus Provenge landed on the table of the CBER's Tissue and Gene Therapies Advisory Committee in a controversial review. The panel ultimately voted 14-3 that there was enough efficacy data and unanimously that the vaccine was reasonably safe, but they amended the efficacy question to reflect a less stringent standard (if there was substantial evidence of efficacy instead of whether efficacy was definitely demonstrated). Many have viewed that panel as mismanaged, and contended that the vote was motivated more by desire that the vaccine would work than a calculated assessment of the available data.

The data, however, were inadequate to sway reviewers in CDER's office of oncology drug products, particularly Richard Pazdur, director of the cancer office, and some dissenting panel members vociferously complained about the process (³ Also see "The Provenge Precedent" - Pink Sheet, 1 May, 2007. May 2007). Subsequently, FDA fended off lawsuits from nonprofit groups. Pressure to approve Provenge could continue to prove intense, as an April 19 editorial in the Wall Street Journal attests.

It's unclear what if any involvement CDER and/or its officials will have from now on in the Provenge review. A CBER spokesman declined to comment.

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

Provenge Scores In Phase III; Will Dendreon Need To Confirm The IMPACT?

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