CAR T-cell gene therapies enter the U.S. market

Ground-breaking anti-cancer immunotherapy

Novartis and the University of Pennsylvania’s anti-cancer chimeric antigen receptor (CAR) T-cell therapy Kymriah has become the first ever gene-modified therapy approved in the U.S. The therapy takes the patient’s own T cells, engineers them to express a receptor that binds to the B-cell blood cancer marker CD19, and then re-infuses them back into the patient to recognize and bind the tumor antigen, triggering T-cell mediated destruction of the cancer cells. Kymriah was approved in August in patients aged up to 25 years for acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Although this patient pool is small – approximately 600 patients per year – there is the potential for market expansion with filings in diffuse large B-cell lymphoma (DLBCL) expected later in 2017. The eligible patient pool in DLBCL is 33,000 for second-line therapy and 16,000 for third or later-line.


Novel pricing paradigm

Kymriah’s pricing paradigm is an interesting one, and its price tag of $475,000, not including T-cell collection and re-administration-associated hospital expenses, is certainly hefty. However, the drug is intended to be curative with a single dose, making the cost a one-off expense. Furthermore, Novartis and the U.S. Centers for Medicare and Medicaid Services (CMS) have agreed a novel outcomes-based pricing plan, under which payment is only required if the patient responds to treatment within one month. Although Novartis has received criticism of the agent’s price from some quarters, others have suggested that it could actually be considered low given the cost of manufacture and small patient pool. At just under $300 million a year possible in ALL sales (assuming 100% uptake from 600 patients), the break-even point for the drug will be heavily influenced by when, and whether, the drug is approved in additional patient populations. The price of the drug is also likely to be different in these other populations due to the planned use of indication-based pricing, which adds further complication to predicting the revenue potential of Kymriah. Cortellis Consensus sales forecasts (source Thomson Reuters I/B/E/S) for the therapy rise from $106 million in 2018 to $889 million in 2023, although this latter figure represents individual forecasts that range from $399 million to $1.900 billion.


High price backed by solid data

Novartis will hope to command such a high price through demonstration of commensurately high-value efficacy. Approval of Kymriah was based on data from the phase II ELIANA trial in children and young adults with relapsed or refractory (r/r) ALL – a patient population with historical survival rates of just 16% to 30%. ELIANA showed that the remission rate to Kymriah within three months of infusion was 83%, comprising 63% in complete remission and 19% in complete remission with incomplete blood count recovery. At 12 months, the survival probability was an impressive 79%.


Efficacy at a cost?

The excellent anti-cancer efficacy of activated T cell therapies such as Kymriah comes at the cost of serious side effects such as cytokine release syndrome (CRS) – an immune/inflammatory response manifesting as fever, hypotension, breathing difficulties, hepatic/renal/cardiac dysfunction and coagulopathy. In ELIANA, 79% of patients experienced any-grade CRS, with 49% graded as severe or life threatening. The agent’s label carries a black-box warning regarding CRS, and the drug is only available via a restricted access program. Also mentioned in the black box warning is the risk of severe or life-threatening neurological toxicities, which were seen in 18% of ELIANA patients (65% any-grade neurological toxicities).


Neurotoxicity issues also affect other drugs in this class. One patient death from cerebral edema has been reported for Kite Pharma’s CD19-targeting CAR T-cell therapy KTE-C19, and in March 2017, Juno Therapeutics discontinued development of its CD19 CAR T-cell therapy JCAR-015 following five patient deaths from cerebral edema.


Competitive landscape

While there is a plethora of potential targets for CAR T-cell therapies, development of those targeting CD19 is the most advanced, and the next-approved CAR T-cell agent is expected to be a close competitor to Kymriah. Kite completed a rolling BLA filing for KTE-C19 in March 2017, and a PDUFA date of November 29, 2017, has been set by the FDA, with launch expected in 2018. Kite is seeking a broad label, with indications for r/r aggressive B-cell non-Hodgkin’s lymphoma (NHL) including DLBCL, primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL). In this patient population in the phase II ZUMA-1 trial, KTE-C19 achieved an objective response rate (ORR) of 82% in both the overall NHL population and in the DLBCL subset. ORR at six months was 41% for the overall population and 36% for the DLBCL patients. In comparison, Kymriah achieved an ORR in r/r DLBCL of 45% at three months in the phase II JULIET trial. Cortellis Consensus sales forecasts for KTE-C19 are $117 million in 2018, rising to $851 in 2023 (range: $677 million to $1.025 billion). In August 2017, Gilead confirmed a tender offer for Kite Pharma that valued the company at $11.9 billion; that deal is set to close in 4Q17.


Set to compete with Kymriah in both the DLBCL and ALL space is Juno Therapeutics’ CD19 CAR T-cell therapy JCAR-017. Although at an earlier stage of development, the data so far are promising. In r/r DLBCL patients in the phase I TRANSCEND trial, the three-month ORR rate was an impressive 86%. A pivotal trial is planned, and filing for r/r DLBCL is expected in 2018. In the phase I/II PLAT-02 trial in ALL, the minimal-residual-disease-negative confirmed response rate was 93% within 21 days; overall survival at 12 months was 69.5%. JCAR-017 Consensus sales forecasts are $1.203 billion with little variability between forecasts ($1.170 billion to 1.237 billion).

Kymriah is just one therapy at the forefront of the CAR T-cell therapy revolution, and CD19 just one possible target for this innovative class of agents. For example, the University of Pennsylvania and Novartis are also collaborating in the clinical development of agents such as a multiple myeloma therapy targeting B-cell maturation antigen (CART-BCMA), and a glioma therapy targeting a variant of the epidermal growth factor receptor (CART-EGFRvIII). They also have a next-generation humanized version of Kymriah, CTL-119, that showed a complete response rate at one month of 87% in a phase I pilot trial for ALL. Of note was that the study included 11 patients r/r to Kymriah, for whom CTL-119 provided a 64% complete response rate.



The approval of Kymriah marks the emergence of a potentially game-changing class of therapeutic agents that combine the strengths of the immuno-oncological treatment of cancer with the personalized approach of a gene therapy. The novel pricing paradigm of the first agent in this field should facilitate market access, but with imminent competition from upcoming agents, the area will be a compelling watch in the coming quarters.
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