Today’s early US approval for Novartis’s CTL019 – a month before the FDA’s action date – sweeps away most of the remaining doubts that might still have existed about regulatory caution on cell therapies.
Many of those doubts must of course have dissipated two days ago when Gilead shelled out $11.9bn to buy Novartis’s CAR-T competitor Kite Pharma. Now the battle turns to the complexity of commercial manufacturing, pricing and reimbursement; how much the world’s first ever CAR-T therapy will cost has also been announced: $475,000 per patient, which seems lower than some had feared.
However, already Novartis has dropped a major hint that the real cost of CTL019 – now trademarked Kymriah – will be lower. Today’s statement said the company was setting up a collaboration with the US Centers for Medicare and Medicaid Services “to include indication-based pricing ... [and payments] based on the clinical outcomes achieved”.
What has yet to be determined in the case of CAR-T, of course, is how long a response counts as a clinical outcome, though Novartis is proposing just one month, which seems an extremely low bar. While remissions in some patients have been durable, many others relapse within six months of infusion of the modified T cells.
On a press call Novartis's chief executive, Joe Jimenez, was clear: "There is no charge for this therapy if the patient does not respond by the end of the first month after treatment."
Bruno Strigini, who heads up the Swiss group's oncology division, said several factors had been considered, and it was determined that a price of up to $750,000 would have been cost effective to healthcare systems in ALL: "Recognising our responsibility ... we set the price below that level, at $475,000."
That said, today’s approval was never really in doubt. It follows July’s hugely optimistic and largely benign advisory panel for CTL019 in its first indication, paediatric acute lymphoblastic leukaemia.
Further signs of regulatory confidence came on August 8 when Kite revealed that the FDA had decided against convening an adcom for its KTE-C19 project, the likely next CAR-T entrant. It is possible that this signal gave Gilead the confidence to sign on the dotted line (For Gilead Kite is no Pharmasset, August 29, 2017).
As for manufacturing, it is already known that Novartis thinks it can meet US and even global demand via its Morris Plains plant; it had included a contract manufacturer, the Fraunhofer Institute in Germany, in its pivotal Eliana trial, but commercially this at present represents only a back-up.
For its part Kite reckons it can meet global supply for KTE-C19, also known as axicabtagene ciloleucel, in aggressive lymphoma – a potentially bigger use than the relapsed/refractory paediatric ALL studied in Eliana for which CTL019 has just been approved – through its El Segundo plant next to Los Angeles airport.
Among other issues is the use of cryopreservation of initial apheresis material in manufacturing. Novartis has played up the scheduling flexibility that this allows, but it is also partly a necessary step due to the complexity of manufacturing, which in studies has opened up a time gap and allowed some of the severest patients to progress.
In an example of joined-up thinking the FDA today also extended the approval of Roche’s rheumatoid arthritis drug Actemra to treat CAR-T cell-induced cytokine release syndrome (CRS), though interestingly it had not been studied specifically in this setting, and the approval was based on restrospective analyses of CAR-T trials.
CRS is a known toxicity with efficacious cell therapies, and largely consists of release of IL-6. It was the use of Actemra – an anti-IL-6 MAb – that largely enabled this side effect to be controlled, and gave the recent adcom confidence (Novartis’s CAR speeds towards approval with panel nod, July 13, 2017).
The stance of regulators across the Atlantic is still unknown, but this too will soon be tested, as Novartis has said it plans to submit CTL019 to EU regulators late this year. In this market it was beaten to the punch by Kite, which filed KTE-C19 in July.
Gilead rose 7% on news of Kymriah's green light, as confidence grew over the approvability of KTE-C19. Still, it is worth considering whether Novartis just set a ceiling on the price of CAR-T; moreover the cost economics in paediatric ALL are far more advantageous than in lymphoma, which occurs in older people, potentially constraining the cost of KTE-C19.
As soon as the Kite deal closes these details will be down to Gilead to sort out.
This story has been updated to reflect Novartis's additional comments about pricing.