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The U.S. has recently witnessed a new era in medicine with the approval of the first treatment produced using gene therapy: Kymriah® (Tisagenlecleucel). Kymriah is the first of the chimeric antigen receptor T-cell (CAR-T) products approved, with Novartis ending a multi-year race to be first-to-market among the CAR-T products. Three months later, coming in a close second in this race is Yescarta® (Axicabtagene Ciloleucel), developed by Kite (who was recently acquired by Gilead).

These treatments are provocative given the scientific elegance and remarkable efficacy, offset by significant safety concerns and an enormous price tag – US$475,000 for Kymriah and US$373,000 for Yescarta. Here we draw on available information about Kymriah and Yescarta, along with our own operational experience with CAR-T therapies to debate one question: are they worth the hype?

CAR-T Therapy

Each dose of a CAR-T treatment is entirely unique, and specific to the patient receiving it. The treatment is custom manufactured per patient, starting by harvesting some of the patient’s own cells. These cells are shipped to a manufacturing facility, and over an approximate three-week manufacturing process, they are sorted, genetically modified, and grown to a predefined volume or dose. The genetic modification uses a viral-based gene therapy process where a new protein is inserted into the patient’s T-cells to allow those cells to recognize the “CD19” protein on the surface of the leukemic B-cells in the patient’s body.

The genetically modified living cells are infused back into the patient, and since T-cells are killer immune cells, and all B-cells (including those in B-cell leukemia) express the CD19 protein, the treatment trains the patient’s own cells to kill the leukemia. Though both Kymriah and Yescarta are CD19 CAR-T products, they have subtle differences, and other CAR-T products are being developed to different immune targets. Scientifically, this is exhilarating.

Kymriah Efficacy and Safety

On July 12, 2017, the U.S. Food and Drug Administration (FDA) convened a panel of experts to debate the clinical risk and benefit of Kymriah. The briefing materials discussed 63 children with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) – the sickest population of childhood leukemia. There are treatments available, but this disease is mostly incurable and many patients relapse. Yet 52 of the 63 kids (82.5 percent) treated in the clinical trial responded to Kymriah, and for a long time. The data from these trials are statistically and clinically amazing. But, if this isn’t enough, the efficacy was summarized in the FDA’s own briefing documents by stating, “The overall effectiveness of this product is not the primary issue for consideration by this Committee.”

The issues for debate were 1) how to safely manufacture a living product, and 2) how to manage the significant toxicity. The manufacturing process uses a virus, and there exists a theoretical risk that the virus could incorporate into the patient and cause unintended infections. And from a safety standpoint, of the kids treated, 47 percent of them have severe or life-threatening Cytokine Release Syndrome (CRS) reactions to the treatment, similar to a severe allergic reaction. The committee ultimately voted unanimously to approve the treatment, paving the way for the formal FDA Approval on Aug. 30, 2017. Approval decisions in other regions have not been publicized.

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Yescarta Efficacy and Safety

Yescarta was approved by FDA on Oct. 18, 2017 based on treatment of 101 patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the ZUMA-1 trial. Seventy-two percent of these patients responded to treatment, including 51 percent who had no detectable cancer remaining. Similar to Kymriah, these data are exciting and compelling. But these patients likewise had CRS, with 13 percent of the patients experiencing severe or life-threatening CRS. Approval decisions in other regions have not been publicized.

Manufacturing and Operational Considerations

There is no bulk manufacturing of pills or vials to dispense to hospitals. This is a highly specialized patient-specific “vein-to-vein” treatment.  The patients need to present to a hospital and be considered for the therapy before manufacturing can begin. The patient must undergo lymphodepletion through high doses of chemotherapy to make room in the body for the new genetically modified cells. (Of note, the costs mentioned above do not include the cost of this chemotherapy, or the patient’s stay in the intensive care unit – which could push the total cost of treatment over US$1,000,000.) The chain of custody is paramount: there can be no risk that two patient’s cells will be mixed up, as this would certainly be lethal. Time is of the essence given the patient’s illness, lymphodepletion process, and the time the manufacturing process takes, so cells must not be lost in transit. Furthermore, to prevent cell death, these live cells must be kept at extremely cold temperatures during shipping.

Collectively, we have been involved in clinical trial operations for over a dozen cell and gene therapies, and the significance of these operational considerations cannot be understated. We’ve witnessed first-hand the work that goes into managing this supply chain, and we’ve developed many best practices along the way to apply to future trials. Novartis and Kite should be applauded for their success in this area. But commercializing this treatment will be an even greater challenge, a task that Novartis will mitigate by assignment of a Novartis employee to each hospital before that hospital is certified to prescribe Kymriah. Kite has a similar process for assuring hospital suitability for prescribing Yescarta, as currently only 16 trained program centers can prescribe the treatment. Certainly, these steps are a testament to the complexity of the manufacturing, operations, and treatment.

Of note, Kymriah and Yescarta both treat hematologic malignancies, or liquid tumors, rather than solid tumors. To-date, the activity of CAR-T in solid tumors has been limited, with lower response rates than seen in hematologic malignancies. The gene therapy approach used in CAR-T has been applied to a related technology, T-cell Receptor (TCR) therapy, and these treatments have shown exciting results in solid tumors, with several companies advancing these products in clinical trials, though nothing is approved.

Worth the Hype?

We are approaching a defining moment in time for biotechnology. CAR-T represents the potential of advanced science, including genetic engineering and personalized medicine, to transform the way doctors treat human illness and the ability of patients to survive life threatening diseases. Mastering the logistics of the CAR-T therapy manufacturing process, and carefully monitoring all patients that receive CAR-T therapy in order to appropriately manage toxicity, will be paramount to future success.

Ultimately, a combination of health authorities, physicians, and patients / caregivers will decide whether or not CAR-T therapy is worth the hype. These approvals, and the ongoing race for approval of additional CAR-T treatment options, including therapies to treat adults and other types of cancer, certainly indicate that it is. CAR-T pioneer Dr. Carl June recently commented, “There are at least 40 companies right now making CAR T-cells … and they are incentivized to make it more cheaply,” he says. “The rate of innovation is so fast, patent life is going to be irrelevant for T-cells because it will be like your phone. Every two or three years, you buy a new phone because it’s better even though the patent hasn’t gone out.”

These treatments are scientifically exciting and offer a tremendous treatment option for some patients – though at a hefty price. Are we ready to move into this new paradigm? Are the challenges of CAR-T therapy worth the potential benefit? We think so – but would welcome your comments below.



Brandon, Greg, Giovanna, Cassandra, and Stephanie are involved in clinical development. Between them they have played key roles in development strategy, operations, medical monitoring, and oversight of many different cell and gene therapies, including autologous CAR-T, gene therapy, TCR therapy, and allogeneic cell therapy.