An unusually high degree of public attention was focused on an FDA review panel on July 12, as Novartis presented results from a Phase II trial of its investigational drug, tisgenlecleucel. The panel voted 10-0 to approve the drug, to target relapsed B-cell acute lymphoblastic leukemia (ALL), the most common form of US childhood cancer. The treatment is the first approved employing CAR-T, chimeric antigen receptor T-cell therapy; at least four other companies are pursuing similar applications of CAR-T.
CAR-T is a form of autologous cellular therapy: T cells are removed from a patient’s blood by apheresis, brought to a lab where they are genetically engineered to recognize cancer cells, then re-infused in the patient. There are challenges at each step in the process, when looked at from a commercial perspective: medical centers need to conduct the apheresis correctly; the cells (which are refrigerated or frozen) must be conveyed safely to and from the central facility, and the genetic engineering carried out correctly. The process used to take months, but Novartis says that it has reduced the process to 22 days. The genetic engineering is a highly manual, complex process; in time it might be automated to a large degree, but it will retain aspects of a laboratory research project rather than a bioprocessing production line.
According to press reports, 83% of patients in the Novartis trial (who had previously undergone traditional chemotherapy but relapsed) showed remission; after one year, 79% were still in that state. Conventionally, patients who relapse after initial chemotherapy have a 16-30% chance of survival. There can be severe side effects, including a condition called cytokine release syndrome, which in turn causes fevers and organ stress, but the patients were successfully treated for those side effects.
Figures for the cost of treatment range from $300,000 to $500,000 or more; on the plus side, only one treatment is expected to be employed.
There is a cautionary tale to mention: in 2010, a company called Dendreon won approval for Provenge (sipuleucel-T), a similar T-cell treatment (but one not involving genetic manipulation), for a form of prostate cancer. As detailed in a newly published paper from AmerisourceBergen on the overall cellular therapy movement, market access issues cropped up after Provenge was approved. Dendreon had difficulty in winning over physicians (in part because the remission rates were only marginally better) and also had initial difficulty in getting the proper coding for reimbursement. A costly plan to build regional processing centers (in part to minimize transit times for the cell extraction and re-infusion), combined with disappointed stockholders, led to the company’s bankruptcy; it was purchased by Valeant Pharma in 2015.
With Novartis’ tisgenlecleucel, FDA reviewers expressed a concern that the treatment could cause new malignancies eventually, but only longer term longitudinal studies will reveal that. For now, the excitement is that a truly new mechanism of action has reached potential commercialization. FDA is to act on an approval decision sometime in September.