Dendreon unlikely to develop diagnostic despite potential to allay reimbursement fears

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Dendreon’s (NASDAQ:DNDN) prostate cancer vaccine Provenge will continue to see underwhelming uptake due to the lack of a predictive test, oncologists told Biopharm Insight.

There is a low likelihood that researchers in the field will focus their efforts on developing an assay, due to the entrance of newer prostate cancer drugs on the market such as Johnson & Johnson’s (NYSE:JNJ) Zytiga, experts said. Zytiga costs approximately USD 5000 per month for a median treatment cycle of 8 months.

In contrast, the annual cost of Provenge therapy is USD 93,000 per patient. Approved in April 2010, Provenge is an active cellular immunotherapy vaccine for men with advanced stage prostate cancer.

Dendreon recently reported gross sales of approximately USD 19m, which was below anticipated growth, President and CEO Mitch Gold said on a Q211 earnings call. The number represents a shift in the launch trajectory with a more gradual adoption of Provenge, he noted. Company shares fell 67% after 2Q earnings as the company lowered annual revenue guidance for its cancer vaccine therapy to between USD 500m and USD 1.2bn. On the call, Gold said the company identified key issues with uptake, including reimbursement, identification of patients eligible for Provenge, and the need for clinicians to adapt to use of an immunotherapy.

A spokesperson for Dendreon said the market research the company has conducted does not indicate that slower than expected physician uptake is caused by uncertainty related to whether patients are actually responding.

No measurable markers of efficacy

Provenge has no measurable markers of efficacy such as changes in tumor size as visible through X-rays or pain improvement, said Dr Thomas Hutson, a medical oncologist at Texas Oncology. The pivotal Phase III IMPACT study met the primary endpoint of improving overall survival, he added. It not clear which patients benefit from Provenge, added Dr Martin Sanda, director of the Prostate Care Center at Beth Israel Deaconess Medical Center. There is no information to guide treatment other than it is intended for use in patients who have failed hormonal therapy or chemotherapy -- but it is unlikely that all these men will benefit, he said.

Sanda noted that the overall benefit showed in the study was modest.

Provenge extended a patient’s life by an average of 4.1 months compared to patients in the control group (25.8 months vs. 21.7 months).

Another issue, according to Sanda, is the lack of an assay to show that a Provenge-treated patient is responding to therapy or that a patient would respond well once on therapy.

It is unclear if there is an effort to develop such an assay by Dendreon or by the National Institutes of Health (NIH), Sanda added. Both NIH and National Cancer Institute funds are dwindling in this field, he said.

Dr Scott Fields, a professor of uro-oncology at the Hofstra School of Medicine in partnership with North Shore-LIJ Health, said a predictive assay would be useful but does not seem to be in development. Work is being done by researchers in the field to determine which Provenge-treated patients have a prolonged response versus those who have a weaker immune response, he said. He noted that these patients would have already received all infusions of Provenge.

Dr Philip Kantoff, chief of the Division of Solid Tumor Oncology and director of the Lank Center for Genitourinary Oncology at the Dana Farber Cancer Institute, said that the determination in advance of which patient will respond to therapy is a critical issue in oncology in general and is not unique to this therapy. Provenge, like other therapies, does not provide an immediate benefit for patients, he added. The field has tried to develop assays that correlate or predict response for years, yet not enough is known about the immune system, in contrast to genetic based therapies, Kantoff noted.

Dr Celestia Higano, professor, Medicine and Urology at the University of Washington noted that Dendreon has some interesting data showing that there may be ways of determining who is going to benefit from Provenge in terms of survival based on how the immune system responded to Provenge during and after the fact, which was presented at a meeting of the Society for Immunotherapy of Cancer in September 2010.

Provenge does provide benefit to patients, yet determining which individuals stand to benefit is a work in progress that could take several years, he added. Additionally, clinicians are working on the scientific and clinical challenges concerning how to best combine the drug with other therapies such as Zytiga, he said.

Less anxiety with prescribing Zytiga

Effective 1 July 2011, the Centers for Medicare and Medicaid Services (CMS) granted Provenge a temporary, product-specific HCPCS Q-Code. This new code may facilitate the filing of Provenge claims and payment of those claims by third-party payers, according to the company sponsored website.

Physicians may have reservations about the use of Provenge because they are sensitive to the limitations of funds available to cover the cost of prostate cancer in general, said Sanda. The drug requires special authorization by insurers, explained Hutson. While prior authorization is common for new cancer therapies, physicians may be anxious to prescribe due to the initial high drug payout, he added.

Patients and doctors are “not thrilled” with the cost-benefit of treatment with Provenge, said Dr Howard West, medical oncologist at the Swedish Cancer Institute. While Zytiga costs USD 5000 a month, there is an option of going off the treatment if it is not working, he noted. Yet with Provenge there is a USD 93,000 commitment without being able to monitor therapy effectiveness.

There is demand for Provenge and it is easy to administer, but Dendreon must financially de-risk it as it is difficult for an individual practitioner to take on without guaranteed reimbursement, said Kantoff. If even one patient is not reimbursed, the loss to the practitioner is great. Medicare has done a good job with reimbursement, but all other insurers have not done the same and there is a lot of fear, he said.

The spokesperson added, “we have seen strong physician interest in Provenge as evidenced by the number of sites who are now Provenge infusers which exceeds what we had guided at the end of Q2 – indicating physicians do believe in Provenge as a treatment option.” The primary concern of physicians as been reimbursement over the brief period of administration with Provenge, they said.

“We are committing USD 93,000 to a treatment where you cannot see tumor shrinkage or PSA (prostate-specific antigen) going down,” agreed West. PSA, a protein produced by cells of the prostate gland, is often measured after treatment to ensure it has worked.

The company spokesperson said it will take time to educate urologists on the importance of identifying asymptomatic or minimally symptomatic patients who may potentially benefit from Provenge. While the long-term cost-benefit advantage of Provenge is clear, the financial risks associated with administering the therapy in the absence of clear reimbursement signals had a dampening effect on sales. Dendreon believes that the CMS decision in June, coupled with the issuance of a ‘Q-code’ to speed reimbursement paperwork, will remove that obstacle.

Fields said an advantage of Zytiga is that a PSA response is seen quickly upon treatment.

Zytiga is indicated for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. West noted that Zytiga’s label requires the patient to be on chemotherapy, while Provenge is given a few weeks before or after chemotherapy. Hutson noted that the two drugs can be used in combination.

Higano noted that Provenge must be given at least three to six months prior to Zytiga due to its impact on the immune system. Combination with Medivation’s (NASDAQ:MDVN) MDV3100 and Bayer (PINK:BAYRY) and Algeta’s (OSL:ALGETA) Alpharadin are also of interest.

Zytiga is also being evaluated in a Phase III trial with patients who have yet to receive chemotherapy, with results likely next year, said Hutson.

Zytiga is relatively well-covered by payers, but there have been some reimbursement issues with it as well, said Hutson. In the first one or two years a drug is on the market, there is always a lot of ‘tweeking’ of reimbursement that occurs, he added. The void in an assay to assess response as with Provenge is being addressed with other immunological or vaccine approaches in drug pipelines, as well as alternative hormonal treatments, Sanda said.

Bavarian Nordic’s (CPH:BAVA) Prostvac is in late stage-development. Sanda also noted that off-the-shelf vaccines like Prostvac would not require Provenge’s laborious cellular processing.

Still, while a predictive assay for Provenge and the way in which it will be integrated into the treatment armamentarium remain valid scientific issues, these are secondary to the hurdles of reimbursement, said Kantoff. The spokesperson concluded that Dendreon believes that the overall market opportunity for Provenge is significant and are educating physicians to identify patients who may benefit from treatment.

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