You have all by now heard that Dendreon has filed for bankruptcy protection. If you’re a regular reader of Signals, you may have first heard the news here. While the company has successfully reached agreements on a financial restructuring with a majority of its senior debt holders, its fate remains unclear and could include a recapitalization of the company (when you restructure a company’s debt and equity mixture to make it more stable), an outright sale of the company, or the sale of the company’s primary assets.
Dendreon’s product, PROVENGE®, has been riddled with adoption issues since its launch in April 2010. This has prevented it from reaching the sales necessary to repay the enormous amount of debt ($620 million) on its balance sheet, which matures in 2016. As the cell-based immunotherapy industry grows apace, now is the time to reflect on Dendreon’s unfortunate state of affairs and what can be learned from the marketing of its lead product.
- Reimbursement does not guarantee adoption.
PROVENGE is a patient-specific dendritic cell (DC)-based immunotherapy that was approved by the FDA for the treatment of advanced prostate cancer. Its health benefit, a median 4.1 months extension on survival, comes at a cost of $93,000 to the system. Despite coverage by Medicare, doctors have not broadly adopted the therapy. There are a few reasons for this. First, some physicians failed to see the value-proposition, many believing the incremental health it offered simply did not warrant the price tag. Second, the product has a high cost density. PROVENGE® is administered as three doses spread two weeks apart, which requires doctors to commit to a large cash outflow in a short period of time. Finally, the reimbursement process was, simply, too slow.
- Frameworks for reimbursement of cell therapies are in their infancy.
The cost density of PROVENGE would not have been such a dilemma for Dendreon if physicians’ claims were being processed in a timely manner. Due to the novelty of the product, payers were slow to the mark and doctors, apparently, grew tired of waiting for reimbursement.
Many, if not all, cell-based immunotherapies will have similar issues given their high cost and the nature of their administration to patients. So, efficient frameworks for the reimbursement of advanced cellular products will be required in the future if we are to expect physicians to prescribe these treatments.
Xtandi and Zytiga, two small molecule drugs for castration-resistant prostate cancer, were approved not long after PROVENGE, the timing of which could not have been worse for Dendreon. Given the choice, doctors took the more convenient route, and one they had confidence in from a reimbursement perspective.
- Priming of dendritic cells against cancer targets may require multiple biomarkers.
PROVENGE utilizes a single recombinant fusion protein composed of PAP, an enzyme overexpressed by prostate cancer cells, and GM-CSF, a protein that stimulates white blood cells, to prime DCs. However, a more recent trend in the development of DC-based vaccines is to prime DCs against a cassette of cancer antigens, as opposed to a single antigen.
Cancer cells evade attack by the immune system via a number of mechanisms. One of these is to evolve around immune targeting of specific biomarkers. So-called “escape variants” are able to sustain malignancy. In light of this information, therapies should optimally involve not one, not two, but multiple biomarkers, limiting the ability of cancer cells to persist and repopulate. The efficacy of PROVENGE is moderate, but there is a possibility it could be enhanced if multiple antigens are used in its preparation.
- Personalization may be the key to addressing heterogeneity.
Every individual with the “same” type of cancer has a unique profile. In fact, deep sequencing of individuals within the same indication has revealed that, on a granular level, every patient has an orphan disease. One patient may express a specific target, while that target is absent in another. Perhaps a target is present, but only temporally.
To address these issues, the DC-priming step during preparation of a cell-based immunotherapy can be personalized by mixing DCs with the patient’s own tumour cells acquired through biopsy. Clinical evidence suggests this approach will increase the percentage of patients that respond to treatment. As an example, Northwest Biotherapeutics is seeing response in 80 percent of patients receiving its DC-Vax technology for glioblastoma multiforme.
Dendreon was a pioneer in the field of cell-based immunotherapy. Its platform is a bet placed on one approach, but given new advances in the field, it may not have been the right approach. Of course, every thing is 20/20 in hindsight. These are the trials and tribulations of commercialization. Despite the failure of PROVENGE to become the cell therapy blockbuster we had all hoped for, its commercialization has been a needed, and I would contend, valuable, learning lesson for all companies in industry pursuing cell-based immunotherapies for cancer.