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Kymriah 14-month data should be ‘significant’ for physicians, though still early days for CAR-T – Novartis

Country : U.S.

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by Natalie Morrison
LONDON, 22 June (APM) - Novartis’ longer-term data for its CAR-T therapy Kymriah should be significant for prescribers who are still getting to grips with the new treatment paradigm, the firm’s global head of cell and gene therapy Pascal Touchon told APM.
However, it is still early days for prescribing physicians dealing with the two CAR-Ts (chimeric antigen receptor T-cells) now approved, he said, noting doctors will be assessing safety and efficacy when deciding which to use.
Kymriah was the first ever therapy of its kind to be approved - a CAR-T therapy made up from the patients’ own cells to be given as a once-only dose. Its U.S. approval in August last year was for the largely paediatric and adolescent indication acute lymphoblastic leukaemia (ALL) (APMHE 54476). Gilead/Kite Pharma won the second CAR-T approval for Yescarta (axicabtagene ciloleucel) in relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in October (APMHE 55223).
The long-term Kymriah data released over the weekend from the JULIET study was for its second approved indication - the same DLBCL indication as for Yescarta, which was approved in the U.S. this May (APMHE 57935).
It showed that 14 months after treatment the overall response rate was 52%, a complete response rate was achieved in 40% of patients and 12% had a partial response. Of the patients who achieved a complete response at month three, 83% remained in complete response at month 12 and the median duration of response was not reached, “indicating sustainability of response”.
Touchon spoke to APM on a Thursday phone call about the results, which he said are “very important for patients and physicians in the sense they show what we were hoping for in developing CAR-T for diseases that are progressing rapidly, and are severe in terms of outcome”.
He stressed the fact the median duration of response and overall survival rate was not reached for complete response patients shows that “clearly we have a long duration of response”.
The study is in line with long-term data from the original University of Pennsylvania developers of Kymriah, showing the CD-19 antigen targeting CAR-T had a 40% complete response rate in DLBCL which was maintained at 29 months. Touchon noted that those who have achieved a response at six months are the ones still responding at 29 months.
Though the JULIET study has less “maturity” than the 29-month follow up from UPenn, it shows similar results, he said.

Real-world use

It is still early days for the institutions and physicians using CAR-T therapies, he said, but noted the data presented in JULIET are important.
“Overall survival is very important, that’s what we aim at in terms of bringing transformative therapies to patients, we want them to live longer in good conditions and enjoy a good quality of life,” he said.
Analysts have previously told APM that as doctors do not yet know whether CAR-Ts will be fully curative because these treatments are still so new, they may look to use CAR-T as a sort of “bridge” to condition patients for treatment with other options which are proven in the long-term setting, namely stem cell transplants (APMHE 55298).
This could make collecting long-term data in a real-world setting difficult, they said.
APM asked whether this is a phenomenon Novartis has so far experienced with its CAR-T and whether the company envisages any issues collecting long-term real-world data as a result.
Touchon replied that both Kymriah’s approvals were based on data in the third-line setting, where patients were relapsing a second time after two lines of systemic therapy or after stem cell transplant. It also included patients who were not eligible for stem cell transplant. Kymriah is therefore not challenging the current indication for stem cell therapy, he said.
“At this stage, stem cell transplant has more long-term data because it started many years ago, but at this stage our indication is not to replace transplant - it is complementary for doctors to use transplant in the limited number of patients (who are eligible) and it is also possible to be effective after transplant when patients relapse,” he said.
“I’m not so sure we will have difficulties getting long-term follow up,” he added, noting Novartis is just at the beginning of commercial use for Kymriah, and that it has agreed on patient follow-ups with the U.S. Food and Drug Administration.
“We also have follow-up in the long term with studies like JULIET, today we have 14 months data and progressively we will be able to update this.”

Kymriah vs Yescarta

APM raised the argument that Yescarta may have ‘first-comer’ advantage for the DLBCL indication since it was approved back in October (APMHE 58025), but questioned whether differences in long-term data could help give Novartis a competitive advantage.
According to the longer term data for Yescarta in the ZUMA 1 study 42% of patients remained in response with Yescarta after 15.4 months. Novartis used an overall response rate measurement for Kymriah, which it said was 52%.
“We have seen differences in terms of efficacy and safety profile,” he said, although he declined to discuss any data for therapies not within Novartis’ portfolio.
Touchon added that the two CAR-Ts are “very different therapies”, marking significant differences in manufacturing process and chimeric antigen construct.
He added that Novartis has a “very well characterised safety profile” for Kymriah, with studies showing the cytokine release syndrome side-effect which is commonly associated with CAR-T therapy at a grade three or four level occurred in 22% of patients. The safety profile has allowed for 27% patients in the JULIET study to be treated as outpatients, he said.
“We are the only one having approval in two indications, that is really because we were able to show to the FDA a clear benefit-risk ratio for these therapies and long-term durability of response and now with 14 months data we can evidence that further,” he said.
On the point of Yescarta’s first-comer advantage, he said: “We were the first to the U.S. market because we had the first approval in ALL. We were the first to experience a launch of these transformative therapies and to be able to prepare and certify sites for launch.”
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