EU P&MA implications for developments

The EU P&MA implications for recent regulatory development in the CAR T-cell therapy sphere



While the world is currently consumed by the COVID-19 crisis, several pharmaceutical companies have been busy in bringing new cutting-edge CAR T-cell (chimeric antigen receptor T cells) therapies to the fore in the treatment of blood cancer. Kite Pharma’s Yescarta (axicabtagene ciloleucel) and Novartis’ Kymriah (tisagenlecleucel) are currently the only licensed CAR T-cell therapies (both indicated for large B-cell lymphomas). However, Kite Pharma and Bristol Myers Squibb (BMS) are both looking for approval of new CAR T-cell therapies in two variations of lymphoma, and BMS/bluebird in multiple myeloma. This article will look at these CAR T-cell therapies and speculate the pricing and market access implications for the lymphoma and multiple myeloma therapy areas.

Drug summaries

Over the last few months, Kite Pharma’s KTE-X19 and BMS’ lisocabtagene maraleucel (liso-cel) have begun the US Food and Drug Administration’s (FDA) 6-month ‘Priority Review‘ for the treatment of two different forms of lymphoma. BMS/bluebird’s idecabtagene vicleucel (ide-cel) was submitted to the FDA at the end of March 2020. Additionally, the evaluation of KTE-X19 by the European Medicines Agency (EMA) began at the end of January 2020. A brief summary of these therapies is below.

It is not currently clear how the COVID-19 crisis will affect the ability of the EMA or FDA to approve these therapies. However, if these regulatory processes are unaffected, it would not be unrealistic to expect European health technology assessment (HTA) agencies to be assessing these therapies and announcing decisions throughout 2021. It can be difficult to predict how long these processes can take: NICE (National Institute for Care and Health Excellence) issued a decision regarding Kymriah within just 10 days of receiving market authorisation.

Effect on lymphoma market

Mantle cell lymphoma (MCL) is a form of B-cell non-Hodgkin lymphoma with poor prognosis rates, and low 10-year survival rate of between 5-10%. Currently, no CAR T-cell therapy is available for the treatment of MCL. KTE-X19 will likely face similar challenges that existing CAR T-cell therapies faced in achieving European market access.

HTA bodies across Europe had concerns over the evidence base of Kymriah and Yescarta at launch. These concerns revolved around both clinical uncertainty (e.g. treatment response, long-term survival and relative efficacy/side-effects against a comparator) and cost-effectiveness uncertainty as a result of submitting immature survival data from single-arm, open-label studies. Despite these uncertainties, the HTA agencies recognised the potential benefits of such treatments. As a result, many EU HTA bodies granted reimbursement with on-going evidence development. For example, Yescarta was awarded an SMR rating of ‘important’ and an ASMR III (moderate improvement against standard of care) despite HAS requesting real world evidence (RWE) and further data from the JULIET study and post-authorisation efficacy studies. We expect a similar situation for KTE-X19. Alternatively, KTE-X19 could be tied to an outcomes-based deals, as seen in Germany for Kymriah and Yescarta, in order to gather the evidence to match the price given.

The entry of liso-cel into the DLBCL indication will be interesting to follow, as this in an indication in which two CAR T-cell therapies are already approved. It is possible that liso-cel will come up against unique barriers in the HTA process that Kymriah and Yescarta did not face.

A likely consequence of liso-cel entering the market is a reduction in price of the other CAR T-cell therapies in the same indication. Payers typically like to see competition in the marketplace as it helps lower overall drug costs, as seen in other therapy areas such as hepatitis C.

Unless the HTA agencies deem that liso-cel’s trial results to be so game-changing that it is considered a more effective option outright, there is a less of an unmet need in the therapy area. As a result, the evidence requirements for access may be more stringent as there are existing treatments available (and less patient, clinician and political demand for these therapies), or at least undergo the same process of reimbursement with further evidence development steps.

A specific criticism that CAR T-cell therapies have faced is their lack of long-term safety and efficacy data. Now that Yescarta and Kymriah have been on the market long enough to collect and analyse real world evidence, liso-cel could be at a disadvantage when compared indirectly against these two treatments. Additionally, in some markets that prioritise clinical differentiation (e.g. France, Germany), an argument may be made by the HTA agencies that comparator data should be presented against Yescarta or Kymriah.

Effect on the multiple myeloma market

As a patient becomes unresponsive or refractory to their multiple myeloma treatment, they are moved onto a new drug with a different mechanism of action. As there is no cure for multiple myeloma, it is common for patients to be exposed to four or five lines of treatment. It is for these heavily treated patients that BMS/bluebird are hoping that ide-cel will be an effective treatment. Specifically, the indication is for those who have received ≥3 prior therapies that include a proteasome inhibitor, an immunomodulator and an anti-CD38 monoclonal antibody.

As a therapy area with no licenced CAR T-cell therapy, the introduction of ide-cel is likely to have a significant impact. The multiple myeloma market is notoriously crowded, with many therapeutic options available at each stage. Remap Consulting’s experience with payers and key opinion leaders has previously shown us that the introduction of therapies with a new mechanism is highly valued in multiple myeloma. A therapy with a new mechanism action, accompanied by strong supporting clinical evidence, could be perceived as a significant by clinicians (but since it is not curative, not truly game-changing).

While multiple myeloma experts will be keen to use ide-cel in earlier lines of treatment, this may not be possible if BMS/bluebird pursue a typical ‘CAR T-cell therapy-like’ price point. Similarly, at a CAR T-cell therapy price, it is unlikely to expand its indication (like other drugs approved for multiple myeloma have done e.g. daratumumab) to earlier lines of treatment without a significant price reduction. Although there is an argument that CAR T-cell therapies should reduce in cost as the technology becomes more mainstream and more integrated into healthcare systems, healthcare authorities might still restrict ide-cel beyond its label to keep it as the last-line of therapy or for a specific sub-set of heavily treated patients

In conclusion, while these therapies may be 1-2 years away from the market access stage, it will be crucial for these companies to understand the value of their therapies in a world that is now more familiar with CAR T-cell therapies. The most likely implication is that evidence requirements will be more stringent for these therapies than for Kymriah and Yescarta, creating a tougher route to reimbursement. Discussions at the recent EyeForPharma virtual conference highlighted that, in some respects, the entrance of CAR T-cell therapies has caused a shift in the industry paradigm in that value has been awarded without the necessary evidence available at launch. These new CAR T-cell therapies may still have this opportunity for therapy areas where there is an existing unmet need.

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