FDA ODAC Meeting Material discussion analysis, page-50

I think what MSB is arguing is they have improved the production process and that TNFR1 levels should be the potency marker but FDA are saying there is no MOA to say that this should be the case and asking if they can disregard previous negative results without this process improvement.

Still think it will be approved with post marketing registry to see what the response rate is like in real world application. MSB is directly citing Jakafi which had a better understood MOA but much worse safety profile which got marketing approval post a single arm trial because there was no other drug available but required a 2nd RCT to be performed. There is no treatment approved still for those 12 yo. and younger and Jakafi was hardly tested in those 18 y.o. and younger. ORR is better than for the Jakafi trials as well

Probably impossible to do a sufficiently powered RCT for paediatric patients, another option could be mandating another RCT for adults with SR GVHD as proof of mechanism. A positive result in the COVID ARDS trial would be proof of immunomodulation as well and could also be why there are so many immuno biomarkers as secondary endpoints in that trial

Optimized Manufacturing Process
In parallel to the clinical studies, quality manufacturing improvements were made throughout
development to optimize and streamline the overall process, which Mesoblast has consistently
carried forward. In 2009, enhancements made in the manufacturing process resulted in an
increase in TNFR1 levels on the surface of remestemcel-L and an increase in ability to inhibit
IL-2RA, a marker of T cell proliferation. Further analyses have demonstrated an association
between the increase in these potency attributes and improved patient survival. All patients in
Protocol 280 received remestemcel-L made using the original process prior to the manufacturing
changes; approximately one-quarter of patients in EAP 275 received product made with the
optimized process; and 51 of the 54 patients in Study GVHD001 received only product made
with the optimized process, and the remaining 3 patients received both.