27-Apr-09 08:05 Dendreon Provenge’s complicated manufacturing could stain positive efficacy data, sources say
Story * Even though IMPACT was a positive study full data-set is needed to validate early stage results
* Making Provenge will entail several steps and voluminous amounts of paperwork
* The FDA may reject Provenge due to lack of evidence regarding consistent dosing, an FDA expert said
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Dendreon Provenge’s complicated manufacturing could stain positive efficacy data, according to several sources interviewed by this news service.
Provenge (sipuleucel-T) is in late-stage development for the treatment of patients with metastatic, androgen-independent form of prostate cancer where the cancer no longer responds to hormone therapy.
To manufacture Provenge, antigen presenting cells (APC’s) are extracted from a patient using a procedure called standard leukapheresis, a blood collection procedure which isolates a patient’s white blood cells. The patient’s APC’s are then transported to a facility where they are co-cultured alongside a recombinant fusion protein. Then the antigen-loaded, activated APC’s are delivered to a physicians office for administration.
Producing a cellular based vaccine such as Provenge is fraught with several significant hurdles, said the executive of a biotechnology company developing an anticancer vaccine. To manufacture an immunotherapeutic like Provenge, antigen presenting tumor cells need to be withdrawn from patients, and then sent to a lab to produce the vaccine before the final product is injected into the patient, the CEO explained. Dendreon and other companies developing cancer vaccines will encounter issues because the manufacturing process is so complicated, he speculated.
The process will need to be accompanied by a paper trail of safety and legal documents, and the cost will be quite high – not prohibitive - but may place Provenge at a competitive disadvantage, the executive noted. He further cautioned that although the trial was positive, and met its survival endpoint, physicians would like to see the complete dataset before drawing a definitive conclusion about the vaccine.
More data will be unveiled at the American Urological Association Annual Meeting on 28 April.
The agency wants to be really confident that the product can be manufactured and the data is robust, said Edward John Allera, chairman of law firm Buchanan Ingersoll & Rooney's FDA and biotechnology section. Obtaining consistent doses for vaccines is very difficult, and if the FDA wanted to reject Provenge, they can just say there is no evidence that the product used in patients was consistently the same, he speculated.
But the beauty of these vaccines is that they seem to be very safe, Allera noted.
A second cancer vaccine expert agreed that manufacturing biological agents, in general, is littered with complications, and producing a personalized cancer vaccine is likely to be challenging. The overall production process is long, with many complicated steps along the way, he said. “The agent has to be pushed to a site and you have to gain patient consent prior to surgery,” explained the source, who admitted that he is a traditional non-believer in cancer vaccines.
Furthermore, the efficacy of these vaccines is dubious, and many have stalled in development, he said. Cancer vaccines which are currently approved by regulatory agencies around the world, the HPV vaccines Cervarix and Gardasil, have been heavily criticized for their lack of efficacy, he added.
Smaller biotechnology companies which are currently in the process of manufacturing cancer vaccines lack sufficient quality control when making these vaccines, noted a clinical trialist for oncology agents in development. Companies such as Argos Therapeutics were scrutinized for the quality of measures used to asses their cancer vaccine, he said. While Argos was capable of evaluating the appropriate tumor antigen load, there are still questions whether or not the right amount of protein was extracted, regarding the assays used to measure their quantity, he noted.
Argos Arcelis is an immunotherapy in development for cancer which takes dendritic cells from a patient which are later matured for an immunotherapy, according to the company’s website.
“There are many, many issues manufacturing cancer vaccines and this is something that has emerged time and again,” noted a spokesperson for a company with a cancer vaccine in development. The manufacturing problem is inconceivable and there are large problems with product characterization, the spokesperson said.
When cancer vaccines are personalized, such as Provenge, it needs to express the tumor epitope which the vaccine is being directed at and this may vary from person to person, according to an executive at a cancer vaccine company. Also, another problem in the recent past with cancer vaccines has been that they were lacking an appropriate linker molecule and they were degraded before they actually made it to the endoplasmic reticulum and the golgi apparatus, where they need to be metabolized, the president said. The vaccines were not cleaved appropriately, so they did not show the same type of response, he said. However, this problem was observed mainly in vaccines using a viral based vector for delivery.
“So this aspect of taking things out and personalizing it to each and every individual, this is a real challenge in the field,” the source said. “This is a specific drug, and this is relevant to only a certain percentage of patients,” he added.
An investigator involved in cancer vaccine trials said there has not been a single setting in therapeutic oncology where vaccines have been shown to be efficacious. “The vaccines don’t work and the tumors are too aggressive,” he said.
Dendreon could not be reached for comment.
However, a second industry executive at a cancer vaccine company noted that although vaccine studies are generating greater success, these agents are not yet approvable by the FDA. “It is similar to where monoclonal antibodies were 15 years ago, and there is a strong belief that the various cell mediated immune technologies can work, and we are learning more with every trial,” he noted.
Cancer vaccines are on the threshold of becoming significant additions to the therapeutic armamentarium, and Provenge may be the first one to be approved, the same industry executive said. “While Dendreon’s technology may require the FDA to amend their rules, or perhaps create new ones, this is the natural evolution of regulatory science.”
By Kimberly Ha and Klara Czobor
Source Pharmawire
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