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Currently, six CAR-T cell therapy products have reached the market within the U.S. and others have received international approvals. Kymriah (Tisagenlecleucel), developed by Novartis, became the first CAR-T cell therapy ever to receive FDA approval in August 2017. This landmark approval was to treat patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL). On May 1, 2018, the FDA approved Kymriah for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) and high grade B-cell and DLBCL arising from follicular lymphoma. Since that time, Kymriah has been approved in other global markets as well, including the EU and Japan. Kymriah is available in 25 countries and 240 treatment centers around the world.
Kymriah carries a U.S. price tag of $475,000 for ALL and $373,000 for DLBCL. Novartis is manufacturing its Kymriah at its Morris Plains facility in New Jersey and has a signed a contract manufacturing agreement with CELLforCURE. Kymriah earned just $76 million in 2018 and $278 million in 2019. Its total sales in 2020 were $141 million and $587 million in 2021. In 2022, Kymriah achieved sales of $536 million, down by 9% relative to the previous year.
The second CAR-T cell therapy to receive the FDA-approval was Yescarta (Axicabtagene ciloleucel) from Kite/Gilead on October 18, 2017. It was approved for DLBCL patients including primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and diffuse large B-cell lymphoma arising from follicular lymphoma, after two or more systemic therapies. The therapy received marketing authorization in E.U. on August 23, 2018 for the same indications. Yescarta carries a U.S. price tag of $373,000.
Kite is offering treatment using Yescarta in 16 countries and 90 qualified treatment centers. Gilead’s Amsterdam facility can produce enough Yescarta to treat 4,000 patients per year in 15 European countries and Israel. Already, Gilead is manufacturing Yescarta in a plant near Los Angeles and is building a new plant on a 20 acre site near Frederick County, Maryland. Yescarta generated sales revenues of $264 million in 2018, $456 million in 2019, $563 million in 2020, $695 million in 2021, 1.16 billion in 2022, and a staggering $1.50 billion in 2023, up 29 percent from the year before. Thus, Yescarta has edged ahead of Kymriah in the CAR-T race from a commercial perspective.
Tecartus (Brexucabtagene autoleucel) developed by Kite/Gilead was approved on July 24, 2020 by the FDA for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL). The therapy is available at a list price of $373,000. Tecartus is being manufactured in Kite’s commercial manufacturing facility located in El Segundo, California. In the ZUMA-2 trial, Kite demonstrated a 96% manufacturing success rate and a median manufacturing turnaround time of 15 days from leukapheresis to product delivery. Tecartus generated revenues of $44 million in 2020 and $176 million in 2021 from the U.S. and European markets. In 2023, Tecartus produced $370 million in sales, up 24 percent from $299 million in 2022.
Breyanzi was the fourth CAR-T to be approved by the U.S. FDA after Novartis’ Kymriah and two Gilead/Kite therapies: Yescarta and Tecartus. Like its predecessors, Breyanzi targets CD19, but supporters believe that Breyanzi could potentially be superior based on showing similar efficacy but appearing to have a better safety profile than Kymriah and Yescarta. However, Breyanzi has been cleared with a similar black box warning on its label for neurotoxicity and cytokine release syndrome (CRS) as Novartis and Gilead/Kite’s therapies. Bristol Myers Squibb has set a list price of $410,300 for Breyanzi, a little higher than the launch prices of Yescarta and Kymriah. Breyanzi earned $87 million in 2021 and spiked to $182 million in revenue in 2022. Bristol Myers reported global Breyanzi revenue of $263 million for the first nine months of 2023, so 2023 total earnings will probably be in the range of $350 million.
The fifth FDA approved CAR-T therapy product, Abecma, was developed by Bluebird bio and Bristol Myers Squibb, which acquired rights through its buyout of Celgene in 2019. Abecma is the first of the new multiple myeloma therapies emerging from clinical testing that could greatly expand the number of options available for people with the persistent and deadly blood cancer. It joins an already wide array of drugs granted approval since the early 2010s that have extended patient survival and given doctors more armaments to drive multiple myeloma into remission. The list price of Abecma is $419,500. Abecma had earned $158 million in 2021 and it is anticipated to earn $190 – $220 million in 2022.
The sixth FDA approved CAR-T therapy product was CARVYKTI® (Ciltacabtagene autoleucel), which was approved in February 2022 for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy. Shortly thereafter in May 2022, it received a conditional marketing authorization in the EU. Currently, Carvykti is priced a $465,000 for a one-time infusion.
Global CAR-T Approvals
Of course CAR-T therapies have reached commercialization in other regions as well, such as Relma-cel’s (Relmacabtagene) and Yikaida’s (Axicabtagene ciloleucel) approval from the NMPA in China, Ebvallo’s (tabelecleucel) approval from the European Commission, Actaly-cel’s (Actalycabtagene autoleucel) in India, and Fucaso’s (Equecabtagene autoleucel) approval in China, for example.
Of course, this list is not exhaustive and CAR-T approvals are accelerating on a global scale.
Commercialization of CAR-T Cell Therapies
In recent years, the CAR-T therapy products have been viewed as potential blockbusters. However, the sales of these products have not risen to this status. Only Yescarta has broken $1 billion in sales per year. This slow growth can likely be attributed to two reasons: a relatively small number of patient population and the hefty price tags carried by these products.
To date, the CAR-T products have been approved to treat only a small subset of hematological malignancies and hematological cancers account for only 10% of the total cancer patient population. Additionally, CAR-T drugs are only recommended to a small fraction of patients who happen to fail in all other treatment options. It doesn’t help that these therapies are sold with a list price ranging from $373,000 to $475,000 for the one-time treatment. When other hospital expenses are included, the total bill can be $1 million or more to treat a single patient.
In general, patients prefer treatments that are approved by regulating agencies over experimental drugs that are being tested in clinical trials. Nonetheless, the prohibitive pricing of CAR-T therapy has forced many U.S. patients to choose the experimental treatments being tested in the clinical trials over the approved drugs. For example, the University of Alabama’s O’Neal Comprehensive Cancer Center is now referring nearly 25% of its lymphoma patients to clinical trials. While it is authorized to administer Yescarta, it has not used it for a paying patient for lack of insurance coverage.
The one-time curative potential of CAR-T cell therapy is promising, but these factors are affecting the commercialization rate of the CAR-T therapies.
Thankfully, there is a tremendous amount of promising research that is now underway. Currently, hundreds of preclinical and clinical studies using advanced technologies, such as CRISPR, are active in developing CAR-T therapies that are targeting a wide range of both liquid and solid tumors. The development of allogeneic CAR-T therapies is also a very real and near-term possibility.
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