On July 12, Novartis’ CAR-T therapy, CTL019 (tisagenlecleucel), received a unanimous recommendation for approval from the reviewing U.S. Food and Drug Administration’s advisory panel for use in the treatment of children and young adults with advanced acute lymphoblastic leukemia (ALL). The FDA is now expected to make its final decision by October 3.
CTL019 is a customized autologous treatment made by harvesting the patient’s white blood cells, shipping them to a facility where they are engineered to home in on tumor cells, and then sending them back to the treatment center for infusion back into the patient.
Novartis studied CTL019 in 68 patients with ALL that persisted despite prior therapy. In the trial supporting its approval, 83% of CTL019-treated patients were cancer-free after three months, and three quarters of those remained cancer-free at six months post-therapy. As a result, the advisory panel had few questions about the treatment’s effectiveness, which was hailed as major advance for patients with few other options. Instead, the panel focused heavily on safety issues — both well-known and speculative.
CAR-T therapies — while highly effective for some patients — are associated with major side effects as a result of cytokine release syndrome (CRS), a severe immunologic reaction that can leave a patient with high fever, dangerously low blood pressure, and send patients to the intensive care unit. In the pivotal study reviewed by the panel, about half of the treated patients experienced high-grade CRS, although none died from it. Given the severity and frequency of such reactions, Novartis plans to limit the availability of CTL019 treatment to about 30 approved sites that are well equipped to deal with this side effect, and where personnel will be trained in the multi-step process of harvesting the cells, as well as their shipping and handling.
The panel also brought up potential risks that might arise from injecting genetically modified cells into patients, including the potential for deadly viral infections, brain toxicity, and the growth of new tumors caused by the CAR-T cells years after treatment. Novartis has pledged to follow treated patients for up to 15 years, as part of its risk mitigation plan.
And so, everyone expects to see CTL019 gain approval sometime in the next several months. The FDA is also reviewing Kite Pharma’s CAR-T therapeutic for the treatment of adults with advanced and aggressive lymphoma, with a decision expected in late November. In addition, Novartis is studying CTL019 for lymphoma, and Juno is still in the running with their CAR-T treatment as well.
But as we’ve learned from the history of Dendreon (among others), FDA approval does not necessarily mean commercial success. In this case, there are several important factors to consider that could present challenges for Novartis and/or the companies following in its footsteps.
A big one is manufacturing. The process of creating an autologous CAR-T therapy like CTL019 is complex and time-consuming, requiring a 14-21 day turn-around time between cell harvesting and treatment. The complexity, timing and multiple shipments required for such procedures have reportedly resulted in occasional manufacturing problems. Moreover, the turn-around time means that some patients who might otherwise qualify for treatment will be too sick to wait that long, further limiting the already small population of ALL patients — just a few hundred each year — who might be eligible for CTL019 therapy. This manufacturing complexity could provide a real advantage to the next-generation of CAR-T therapies, which are focused on the development of allogeneic, “off-the-shelf” therapies that would eliminate the wait and extra expense associated with cell processing and shipment. The current leader here is France’s Cellectis, which recently entered the clinic with an allogeneic CAR-T treatment for acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN).
A second issue is the question of whether differentiation is possible between CTL019 and the other autologous CAR-T therapies that reach the market later. Once physicians and hospital personnel gain experience with CLT019, they may be reluctant to change to another therapy without a truly compelling reason. And how far will the first approval for CTL019 go for Novartis towards gaining market acceptance for its product in other indications? Could Kite or Juno yet take the leading position, despite a later approval?
Finally, there is the increasingly frequent issue of pricing. Like gene therapy, CAR-T may be a one-time treatment. Or it may have a more limited duration in its effects. It’s too early to know. And so, it’s also too early to know whether the currently estimated $300,000 – 500,000 price for treatment will be supportable. Moreover, given the high risk of CRS and the high cost of managing affected patients, how much will such severe side effects add to the cost of therapy? Who can afford it? And who will pay?