FDA Approval of Provenge in castration-resistant prostate cancer represents the first therapeutic cancer vaccine to reach the market. While a significant step forward in the treatment of cancer, it remains to be seen how frequently Provenge is used. The current standard of care is Taxotere-based chemotherapy, which is comparatively easier to manufacture and administer, but is associated with significant toxicity.
The FDA has approved Provenge (sipuleucel-T; Dendreon) for the treatment of asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer (CRPC). This approval marks a significant step forward in oncology, representing the first ever therapeutic cancer vaccine to reach the market.
Provenge 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 2 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 4-week period, in order to provide three vaccinations to each patient.
Approval of Provenge comes following 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 high levels of controversy from the public, with Care to Live, a prostate cancer patients group, filing a lawsuit against the FDA, demanding that approval be granted to Provenge.
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.
Despite this approval, it remains to be seen how frequently Provenge will be used in CRPC. At present, these 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. Taxotere costs under $3,000 per cycle of therapy, with an average of 6 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. 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.
The number of healthcare-focused licensing deals entered into by the top 10 pharmaceutical companies in 2009 rose by 12% over the previous year. With the pharmaceutical industry seeking to reshape its development pipeline amid widespread cost-cutting and restructuring of internal R&D activities, deal numbers are expected to continue growing.
Martin Adams, senior healthcare analyst at Datamonitor, comments: “The annual increase in in-licensing deal activity confirms that Big Pharma is actively seeking acquisitions and licensing agreements as a more cost-effective means of gaining access to novel products than carrying out extensive in-house R&D.”
However, as companies compete to secure late stage deals that offer a short to mid-term solution to the pending patent cliff of 2011, the cost of acquisitions is inevitably rising.
Martin adds: “Companies of all sizes have to be far more creative and flexible in their approach to securing the best deal terms if they want to maintain healthy returns on investment (ROI) and, as a result, relationships between Big Pharma and its partners are becoming increasingly dynamic. Traditional licensing deals, for example, continue to be replaced by option arrangements or heavily back-ended deal structures.”
Another consequence is that as competition for the most attractive candidates intensifies, would-be licensees are being forced to look at either less commercially attractive late-stage drugs, or earlier-stage licensing opportunities. In 2008-09, 57% of all product in-licensing deals involved drug candidates at the earliest stages of development (pre-clinical).
“The structure of these early-stage deals is evolving with licensees becoming more risk-averse and placing increasing emphasis on commercial milestone payments (back-loading) supporting smaller upfront fee,” adds Martin.
Datamonitor also expects out-licensing deals, which have been relatively sparse historically, to rise over the coming years as Big Pharma seeks local marketing expertise to increase the regional commercial prospects of marketed products and free up resources and cash that can be put to other uses.
Date: April 30, 2010