Friday, May 07, 2010

Dendreon: landmark cancer vaccine approval but high costs may hinder uptake

Having been approved by the FDA in castration-resistant prostate cancer (press release), Dendreon's Provenge represents the first therapeutic cancer vaccine to reach the market (click here for related reports). This is a significant step forward: the current standard of care is Taxotere-based chemotherapy, which is associated with significant toxicity. However, it remains to be seen how frequently Provenge is used.

Provenge (sipuleucel-T; Dendreon) is composed of autologous peripheral blood mononuclear cells, including antigen-presenting cells that have been activated during culture with a recombinant human protein, PAP-GM-CSF. PAP-GM-CSF consists of prostatic acid phosphatase (PAP), an antigen expressed on approximately 95% of prostate tumor cells, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. Upon administration, the PAP-activated cells cause activation of T-cells and other immune system components to recognize the target antigen and destroy prostate tumor cells.

Manufacture of Provenge requires collection of antigen-presenting cells from individual patients, via leukapheresis, a blood collection process used to isolate white blood cells. The cells are then transported to the Dendreon manufacturing facility, presumably in cold storage, where co-culture with a PAP-containing recombinant fusion protein occurs. Manufacture of Provenge takes approximately two days, after which the vaccine is delivered to the physician's office for infusion into the patient. This entire process is carried out three times over the course of a four-week period, in order to provide three vaccinations to each patient.

Provenge has had a troubled development history to date. Dendreon initially filed a Biologics License Application (BLA) in January 2007 on the basis of Phase III D9901 study results, which showed an improvement in overall survival but failed to meet its primary endpoint of time to progression. The FDA issued an approvable letter in May 2007, requesting additional clinical data. This was met with controversy from the public; indeed, prostate cancer patient group Care to Live filed a lawsuit against the FDA, demanding that Provenge be approved.

Following this, the FDA stated that it would accept interim or final data from the ongoing Phase III IMPACT study to amend Provenge's BLA. Positive results were announced in April 2009, showing that Provenge conferred a 4.1 month survival benefit over placebo in asymptomatic or minimally symptomatic metastatic CRPC, thus meeting the study's primary endpoint. This made Provenge the first therapeutic cancer vaccine to demonstrate an improvement in overall survival for metastatic CRPC.xx Despite now having received FDA approval in asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer (CRPC), it remains to be seen how frequently Provenge will be used in the treatment of this disease. At present, patients are typically treated with standard Taxotere (docetaxel; Sanofi-Aventis)-based chemotherapy. Taxotere is relatively simple in terms of manufacture and use, capable of immediate, 'off the shelf' administration. In comparison, an autologous vaccine like Provenge requires a costly and labor-intensive manufacturing process.

Dendreon has indicated that Provenge will be priced at $31,000 per dose, equating to $93,000 per complete course of treatment. In comparison, Taxotere costs under $3,000 per cycle of therapy, with an average of six cycles of treatment therefore costing around $18,000. Dendreon has stated that Provenge is more cost effective due to the lack of required premedication and supportive care costs compared to Taxotere.

Furthermore, Provenge's favorable toxicity profile may influence physician preference in comparison to Taxotere's adverse side effects, particularly in patients who are asymptomatic. Taxotere is associated with significant toxicity, while Provenge causes only mild grade 1/2 side effects. Provenge is therefore likely to be used in those patients precluded from Taxotere therapy.

Provenge's approval in asymptomatic or minimally asymptomatic patients indicates that the vaccine may be used before Taxotere. Presumably once patients progress and become symptomatic after Provenge, Taxotere will still be required. Given that healthcare systems are becoming increasingly cost-conservative, the high cost of Provenge may hinder its uptake in some patient groups, particularly those that do not qualify for the patient access plan that Dendreon has set up in light of the approval.

See also our editorial: Advaxis lights up the future for cervical cancer and maybe some head and neck cancers

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