NorthWest Biotherapeutics Inc (NWBO)

[Lykiri]

Gary,

IMO,it's a good thing that the improved L has been incorporated into the trial.(NOTE: I believe the Germans) If not, you could have difficulties in transforming a complex, individualized treatment into a commercial product.

Example : Kymriah (Novartis) and postmarketing requirements (PMR) by the FDA.

As with all drugs, there's a checklist of attributes the engineered cell dose must meet in order for Novartis to release the product for use in patients.

One has proved problematic for Novartis. When Kymriah was approved, the FDA set out a requirement that Kymriah product must consist of at least 80% "viable" T cells, meaning they're alive and active. That was a change from clinical testing when Novartis aimed to clear a 70% viability threshold, and is higher than in the other countries in which Kymriah is approved.

In the real-world data at ASH, 29 of 102 lymphoma patients treated commercially and evaluated for the study received an out-of-specification dose with less than 80% viable cells. Among leukemia patients included in a second analysis, 14 of 92 received a dose below 80% viability.

Importantly, there was no evidence that those receiving doses between 60% and 80% viability fared worse. All 14 of the leukemia patients achieved a complete response, according to the study abstract. And a similar number of lymphoma patients given out-of-specification product responded to treatment as those receiving in-specification Kymriah.

When it approved the cell therapy, the FDA identified non-viable cells as a "potential clinical safety issue." The new results suggest that may not be the case.

"Now we have more and more evidence that above and below 80% has the same safety and efficacy, that also will strengthen our dialogue with the FDA," said Hendricks.

Stephan Grupp, an oncologist at Children's Hospital of Philadelphia and a lead investigator of one of Novartis' Kymriah studies, told BioPharma Dive the difference between 70% viability and 80% viability had not worried him previously. Grupp was lead author on the real-world analysis of commercial Kymriah use in leukemia patients.

"We did [the analysis] not because there was a concern, but more to show there wasn't," said Samantha Jaglowski, an oncologist at The Ohio State University Comprehensive Cancer Center, in an interview. Jaglowski was lead author on the other analysis of Kymriah use in lymphoma patients.

Part of the reason the percentage of viable cells may not matter as much is due to another product release specification that lays out the minimum absolute number of viable T cells expressing the chimeric antigen receptor, or CAR.

Novartis' Hendricks said the company is both working to ensure all of its commercial doses of Kymriah meet the 80% threshold, as well as discussing with the FDA whether the requirement in the drug's label could be lowered.

https://www.biopharmadive.com/news/novartis-kymriah-car-t-manufacturing-difficulties-cell-viability/568830/

The major risks of KYMRIAH include:

• Cytokine release syndrome, which occurred in 79% of the patients and can be fatal or lifethreatening
• Transient neurologic toxicity which occurred in 65% of the patients
• Febrile neutropenia which occurred in 38% of the patients
• Cytopenias not resolved by day 28 which occurred in 53% of the patients
• Infections which occurred in 59% of the patients

https://www.fda.gov/media/107962/download