Biovest doesn’t anticipate that its cellular immunotherapy, BiovaxID, will face the same market hurdles as Dendreon’s Provenge. [© Sebastian Kaulitzki - Fotolia.com]
Some have questioned whether issues with the launch of Dendreon’s prostate cancer vaccine, Provenge (sipuleucel-T), in 2010 will impact the market for other immunotherapies. Clearance of Provenge for asymptomatic or minimally symptomatic hormone-refractory metastatic prostate cancer marked the first for a therapeutic cancer vaccine.
A likely next-up cancer vaccine is BioVest’s BiovaxID® for some types of non-Hodgkin lymphoma. Like Provenge, BiovaxID is also an autologous vaccine. Biovest reported in October that it is initiating the process to conduct clinical meetings with various regulatory agencies including Health Canada, FDA, and EMA to discuss next steps required for marketing approval in follicular lymphoma.
Results from an eight-year, randomized, multicenter, double-blind, controlled Phase III trial showed that patients who received BiovaxID experienced a median disease-free survival of 44.2 months compared to 30.6 months for those who received a control vaccine. In the study, which had a median follow-up of 4.7 years, patients receiving BiovaxID experienced a 38% lower risk of disease recurrence compared to the control group.
GEN asked Howard Liang, Ph.D., Leerink Swann managing director, whether Dendreon’s issues would impact the market’s support of autologous cell-based therapies. “Before Provenge made it to market, the question was whether autologous cell-based manufacturing was commercially viable and scalable. Dendreon proved that it can be done, and while people may still ask the production question, the issue is now about reimbursement and driven by the nature of the market.”
Justifying High Costs
Provenge and BiovaxID, in contrast to chemotherapeutics, are individually manufactured for each patient. Provenge consists of a patient’s own antigen-presenting cells that have been cultured with a recombinant antigen PAP-GM-CSF. Biovax ID consists of the cancer-specific idiotype linked to KLH (idiotype-KLH conjugate) injected under the skin with GM-CSF.
The Provenge manufacturing process requires that cells are removed from the patient, treated in the laboratory, and then returned to the patient. For BiovaxID, hybridoma cells are used to express the lymphoma patient’s individual tumor idiotype, a protein fragment expressed only on a particular individual’s cancerous B lymphocytes.
As compared to other prostate cancer drugs, Provenge at $93,000 per patient, seems relatively expensive. Thomas, Schwabb, M.D., Ph.D., assistant professor in the departments of urology and immunology at Rosewell Park Institute, pointed out, “any cellular therapy or immunotherapy dealing with taking cells out of the human body, culturing them, manipulating them, and putting them back into the body requires a certain degree of labor, which means a big component of the cost is simply labor.
“The cost of a treatment course of docetaxel is actually in the same ballpark,” he told HemOnc Today. “Docetaxel, given in 10 cycles, costs $30,000 to $50,000 and confers a survival benefit of two months, whereas sipuleucel-T is associated with a survival benefit of four months.”
In commenting on cancer therapy costs, Biovest’s president, Samuel S. Duffey, told GEN, “The elephant in the room for cancer therapy has always been the indirect cost of dealing with toxicities created by therapies. A nontoxic and nonimmunosuppressive therapy like ours immediately shifts the cost to benefit ratio not just in terms of survival and patient safety but also in terms of reducing the risk of long-term indirect cost potentially associated with highly toxic or profoundly immunosuppressive therapies.”
While Biovest hasn’t announced pricing for BiovaxID, Duffey said, “we are committed to being in tune with the market place that exists today for medical therapies, particularly in oncology.”
While Provenge has been approved for payment by most insurance carriers including Medicare, the reimbursement reality has proven to be a major hurdle. Dendreon abandoned its original sales forecasts for Provenge, saying that, in part, slow product uptake was attributable to uncertainty among physicians about whether they would be reimbursed.
Physicians must acquire the drugs and charge an insurer—the so-called ‘buy and bill’ reimbursement method—instead of simply writing a prescription. This means that an individual practice, if treating 10 patients simultaneously, would have to cough up about $930,000 up front, without being entirely sure that the reimbursement will happen.
Dr. Liang of Leerrink Swann added, “Urologists who provide care for prostate cancer patients are less familiar than oncologists with the ‘buy and bill’ model.” He also pointed out that urologists may not be as accustomed to IV therapies as oncologists. Additionally, prostate cancer patients who are asymptomatic may not require immediate treatment, “so, while I am not minimizing the medical need, physicians might wait for a couple of months before paying for the drug and initiating treatment,” according to Dr. Liang.
Duffey noted that BiovaxID is a different situation where the product will follow an approximately six-month induction therapy cycle. “We believe the nature of our consolidate therapy will allow ample time for reimbursement determinations.”
Some analysts have questioned whether reimbursement issues account for Dendreon’s entire problem. “Management’s reason is addressable reimbursement issues, whereas there are many reasons to believe this is, at least in part, also a permanent demand issue,” Goldman Sachs analyst Sapna Srivastava said in a note to clients, as reported by The Wall Street Journal.
In September, Dendreon withdrew its guidance calling for Provenge sales in the range of $350 million to $400 million during this year, saying only that the company expected “modest” growth during the third and fourth quarters.
Signaling potential supply problems, Dendreon terminated its 2010 contract with GlaxoSmithKline, which covered the supply of antigens intended for the manufacture of Provenge. Dendreon said in securities filings that the decision was based on “unforeseen delays and implementation difficulties.” The company also announced in September other cutbacks including the elimination of 500 jobs.
With regard to autologous manufacturing, Duffey pointed out that, “while the process of producing our vaccine might be more involved than a one-size-fits-all therapy, the indolent nature of follicular lymphoma is such that the time frames are not as limited as Dendreon’s. The logistics associated with our vaccine manufacturing allows Biovest to focus on only one manufacturing facility and operation.”
He also said that due to the nature of how BiovaxID is administered, “Biovest will have some luxury with regard to manufacturing time because it is being developed as a consolidation therapy to extend remissions that have been induced with chemotherapy, monoclonal antibodies, or both.”
While Provenge is administered in three injections, two weeks apart, for a treatment course lasting six or seven weeks versus the 30 weeks needed for 10 cycles of docetaxel, BiovaxID, if approved, will be given as a monthly subcutaneous injection after the rest period following induction therapy in months 1, 2, 3, and 4, and a fifth booster injection will be given in month 6.
“We manufacture our vaccine during the approximately six-month period while patients receive induction therapy,” Duffeey explained. “The unique nature of Dendreon’s product and process impose severe constraints on production and their therapy has to be administered quickly. That quick cycle impacts their billing and reimbursement situation.”
Should all Biovest’s development programs for BiovaxID pan out, the company anticipates a potential $1 billion market opportunity in the U.S. and Europe. Besides follicular lymphoma, the company is developing BiovaxID for mantle cell lymphoma and this October received Orphan Drug Designation for the treatment of Waldenstrom macroglobulinemia, a rare subtype of non-Hodgkin lymphoma.
There is no doubt that autologous immunotherapies are progressing through clinical trials. Their potential benefits of less toxicity, enhanced efficacy, and relatively shorter courses of administration may eclipse purely financial considerations.
Cancer vaccines may also, ultimately, lessen the cost of cancer treatment by reducing or eliminating the need for the management of side effects. All these factors should translate to commercial success, but reimbursement and physician acceptance of a new therapeutic approach also need to start trending positively.
Will Biovest’s immunotherapy for follicular lymphoma, if approved, gain acceptance more quickly than Dendreon’s vaccine for prostate cancer?