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CAR-Ts Kymriah and Yescarta step closer to approval in Europe

Final European approval around the corner - but reimbursement and specialist centres among outstanding issues

ema

The European Medicines Agency has recommended approval for Novartis’ Kymriah and Gilead/Kite’s Yescarta, setting them up for what could be more or less simultaneous launches later this year.

Already available in the US, the drugs herald an exciting new era of immunotherapy-based cancer care, but there remain regulatory, reimbursement questions to tackle in Europe before the first small numbers of eligible patients receive them.

Equally important is the setting up of specialist centres to administer and monitor patients on these ‘living medicines,’ which are likely to be priced at around €300,000 or more, though their cost will undoubtedly be subject to much negotiation across Europe.

Unlike in the US, the drugs will go head-to-head straightaway, as Kymriah will be licensed for paediatric and young adult acute lymphoblastic leukaemia (ALL) ALL and adult diffuse large b cell lymphoma (DLBCL), the latter being the key battleground between it and Yescarta.

The drugs are the two pioneering chimeric antigen receptors (CAR) T-cells medicines, with Kymriah having been launched in the US in May 2017 and Yescarta in October.

This is a considerable lag behind the US given the excitement around the drugs, which have been shown to wipe out blood cancers in some of the sickest patients who had failed on all previous therapies.

However the EMA has been working on its own fast-track for the most important new drugs, the PRIority MEdicines (PRIME) scheme, and Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) are the first two to come through the system.

The drugs are classified as ‘advanced therapies’ and were therefore reviewed by the Committee for Advanced Therapies (CAT), who then passed on their recommendation to the EMA’s key decision-makers, The Committee for Medicinal Products for Human Use (CHMP).

Martina

“CAR-T cells transform the fight against serious and often fatal diseases in the EU,” said Dr Martina Schüssler-Lenz, (pictured) chair of the Committee for Advanced Therapies (CAT). “Kymriah and Yescarta offer an innovative approach where patients’ cells are reprogrammed and reinjected to attack the cancer.”

“Innovative treatments such as CAR-T cells have potential to change the outlook for patients with cancer, but they also come with new scientific and regulatory challenges,” commented Dr Tomas Salmonson, Chair of the CHMP.

Salmonson says the EMA has aimed to set up a robust system of data collection for the post-authorisation phase tailored to these medicines.

"We have used a wide range of tools – scientific advice, a specific workshop on patient registries for CAR-T cells, PRIME, to name just a few, to enable us to define the methods to tightly monitor the benefit-risk profile of these medicines and manage their risks once they are on the market, so that patients can benefit from these innovative treatments.”

The main safety concerns related to CAR-T are cytokine release syndrome (CRS), the systemic response causing high fever and flu-like symptoms, and neurologic toxicities.

Both can be life-threatening and in some cases even fatal, although neither of the drugs has produced any worrying safety signals since they were launched in the US.

The EMA has laid out monitoring and mitigation strategies for these side effects, including the use of Roche’s RoActemra to treat CRS. The CHMP says it recommends adding this uses to its licensed indications, as it is would otherwise have to be used off-label, and is also obliging Novartis and Gilead to set up patient registries to monitor long-term safety and efficacy of the treatments.

Reimbursement and new cell therapy infrastructure

The CHMP opinions will now be sent to the European Commission for the final EU-wide marketing authorisations, a process which can take several months, but may be accelerated for these drugs.

Decisions about price and reimbursement will take place in each EU member state, but discussions around payment are already advanced in most of Europe’s biggest markets. Of equal importance is the setting up of new specialist cell therapy treatment centres, as cells need to be harvested from patients, loaded with the CAR-Ts and then reinfused back into the patients by specially trained medical teams.

Novartis plans to restrict the number of centres administering its drug in the US to 30-35 centres, and may elect to have a similar number in Europe. In the UK, NHS England is expected to announce shortly which regional specialist cancer centres will host the cell therapy facilities.

Meanwhile there is much talk about CAR-T prices in Europe, and the possibility of developing novel payment mechanisms. In the US, Kymriah has a list price of around $475,000 and Yescarta is $373,000, although confidential deals mean payers will be receiving discounts on these sums.

European payers are likely to drive a harder bargain, and healthcare systems in countries such as the UK and Italy will want to link payment to outcomes in patients, as there remains a significant minority of patients who do not respond well to the therapies.

Article by
Andrew McConaghie

29th June 2018

From: Regulatory

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