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Replies to post #243148 on NorthWest Biotherapeutics Inc (NWBO)
09/08/19 8:34 AM
09/08/19 5:50 PM
The JUNO/KITE trials were registrational quality and proved safety/efficacy.
Although some degree of immune stimulation and inflammation was expected with T cell activation after ACT, severe cytokine release syndrome (CRS) has been observed with CD19-specific, BCMA-specific, and CD22-specific CAR-T cells. Unexpected neurologic complications ranging in severity from mild to life-threatening have also been reported across different clinical studies with CD19- and BCMA-specific CAR-T cells. The neurologic toxicities described with CD19-specific CAR-T cells have been largely reversible4. In 2016 patients died in a clinical trial testing a CAR-T therapy from Juno Therapeutics, known as JCAR015. After the patient deaths in July 2016, when the FDA halted testing, the Agency soon allowed the clinical trial to resume under a revised protocol. But two more patients died later that year, and Juno pivoted to other products in its pipeline. The Juno trial deaths represented a serious setback for the CAR-T field at the time10. Overall, 34 deaths were reported from the time of informed consent to the data cut-off for the YESCARTA study (January 27, 2017). Thirty patients died of progressive disease and four deaths were attributed to the product as per FDA analysis. Three deaths occurred within 30 days of YESCARTA infusion. Fatal cases of CRS and neurologic toxicity have occurred after receiving YESCARTA15. Overall, 29 deaths have been reported from time of informed consent to the data cut-off of the KYMRIAH study (November 23, 2016) as submitted for the BLA. Six patients died in the failed screened population, 12 pre-infusion, awaiting manufacture of KYMRIAH (six from ALL, five from infection, and one respiratory failure), and 11 patients died post-infusion. Of the 29 deaths, two were attributable to the product and were considered by the FDA as related to CRS13. The severity of CRS seems to be proportional to the tumor burden. Although CRS is an adverse effect of CAR-T cell therapy, there may be a correlation between the development of CRS and response to therapy. Patients who are not developing CRS may be less likely to benefit from CAR-T cells, whereas those who are developing CRS often respond to the therapy. Even if there may be some correlation between developing CRS and efficacy, there does not appear to be a strong correlation between the degree of CRS and response to therapy21.
However, not only clinical challenges but also issues in development, manufacturing, and commercialization must be overcome in order to further enhance this technology. Compared with other product classes where issues are, in the majority of cases, in the clinical part of the dossier, ATMPs show shortcomings in all parts of the dossier, from product quality to the non-clinical program up to the clinical program and data. This leads to a high number of objections, including major objections during the evaluation of the Marketing Authorization Application. In order to respond to regulators’ questions and to address major objections, long clock stops are often needed during the evaluation procedure. For some products and programs, the issues are so severe that they cannot be sufficiently addressed during the procedure. As a consequence, applicants either withdraw their application or regulators issue a negative opinion11. An overview on the existing Food and Drug Administration (FDA) regulatory pathways and tools including the strategic use thereof is presented in Figure 3.
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