FDA approves Novartis’ CAR-T therapy for leukemia, ushering in the gene therapy era


First gene therapy product in US; approval expedited by evidence of high cure rates

Following a highly favorable review committee vote in July, FDA has granted approval of Novartis’ tisagenlecleucel therapy, now to be known as Kymriah. It’s an important milestone in the commercialization of CAR-T (chimeric antigen receptor T cell) technology, as well as for gene therapies generally. And while the therapy is highly complex and expected to be very expensive, raising question on how the demand for it will be met, FDA’s initial approval targets a limited subset of leukemia patients: children and young adults (up to 25 years) with B-cell acute lymphoblastic leukemia (ALL), and who have failed standard therapy. FDA, citing National Cancer Institute data, says that some 3,100 children and adults to age 20 are diagnosed each year, and 15-20% of those fail initial treatment. Those 600 or so patients will be the first to receive the therapy; however, CAR-T is expected to be applicable to a variety of other blood-based cancers.

“At Novartis, we have a long history of being at the forefront of transformative cancer treatment,” said Joseph Jimenez, CEO of Novartis. “Five years ago, we began collaborating with the University of Pennsylvania and invested in further developing and bringing what we believed would be a paradigm-changing immunocellular therapy to cancer patients in dire need. With the approval of Kymriah, we are once again delivering on our commitment to change the course of cancer care.”

Kymriah comes to the market with a strong tailwind: the trial that excited the FDA review panel in July showed that 83% of the patients taking the tisagenlecleucel therapy were in remission, with 79% remaining so after one year. Partly for that reason, Kymriah has been granted Fast Track review, and Priority Review, and Breakthrough Therapy designations—each of which is designed to expedite review through the FDA approval process. FDA has set up an Oncology Center of Excellence for these designations; approval was coordinated with the Center for Biologics Evaluation and Research (CBER).

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” said FDA Commissioner Scott Gottlieb, in the announcement. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”

There is a risk with CAR-T therapies: A condition called cytokine release syndrome (CRS), causing high fever, neurological effects, and threats to a variety of organs can occur; and the CAR-T lymphocytes also attack normal B-cells (which protect the body against infection). Thus, FDA has expanded the approval of another drug, Genentech’s Actemra (tocilizumab), which addresses CRS. FDA is also issuing the Kymriah approval with a REMS with ETASU (Risk Evaluation and Mitigation Strategy, with Elements to Ensure Safe Use). REMS requires training of practitioners using a drug therapy, and follow-up safety studies.

The REMS requirement is not likely to be an obstacle to Kymriah’s commercialization, in part because the therapy is so complex to administer. Kymriah (and other CAR-T therapies) involves extracting patients’ T cells (via an apheresis step), conveying the cells to a manufacturing facility where the cells receive the genetic makeover, and then conveying back to the patient for infusion. Novartis is in the process of setting up a group of hospitals and cancer centers where the treatment will be carried out; at least initially, it won’t be available outside those facilities. This limited availability is both to control the patient care closely (thus, the ability to address REMS concerns) as well as the fact that the manufacturing process at Novartis’ Morris Plains, NJ facility is constrained. On the bright side, in earlier announcements Novartis had said that it was able to reduce the turnaround time for the CAR-T makeover from months to 22 days. In its announcement following the Kymriah approval, Novartis noted that this facility has produced “a reproducible product” for over 250 patients, and across a variety of indications.

Novartis says that it is also pursuing approval for adult forms of ALL. Meanwhile, it has announced a “novel collaboration” with CMS to provide an indication-based pricing for Kymriah, “based on the clinical outcomes achieved, which would eliminate inefficiencies from the healthcare system.” Translation: Novartis will get paid more for patients who are cured, and less (or nothing) for patients who are not, for what Novartis has priced at $475,000 for a one-time treatment. "Novartis has been at the forefront of outcomes-based pricing and is very pleased to work with CMS on this first-of-its-kind collaboration with a technology that has the potential to transform cancer care,” said Jimenez. “We look forward to continuing to work with CMS to potentially expand this approach to other products and disease states.”

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