Sometimes the answer is in plain view. CBER probably believed at the time of the first CRL , there was a risk that sub potent cells were being used in the earlier Prochymal trials and wanted an explanation to ensure it could not happen again . I believe the reason for higher batch variabilty was most likely CMC related, NOT the individual cells, nor the underlying process up to the point of harvesting …because this did not occur in the Phase 3 trial GVHD001 conducted by Lonza Singapore . If it was an ongoing problem, how could MSB have passed its manufacturing inspection ? In his presentation today , Silviu stressed batch variability formed a key part of that manufacturing inspection. Even though Mesoblast was not responsible for the Osiris trials, the data formed part of the BLA submission and they inherited the problem. As CBER already had a file on suspect batch variability using another manufacturing site in the US…Mesoblast are now keen to stress that Prochymal was an “earlier generation” product. I would suggest that the “new” potency assay is able to calibrate, to some degree, the extent of damage to cells used by Osiris during the manufacturing process to prevent any future issues with reproducibility and potency. If the FDA are persuaded by the new clinical data , that they have a perfectly good explanation for the Osiris cock up, it would be ridiculous to deny Ryoncil approval as it is the only known technical issue outstanding post the second CRL. Whilst, I am a little concerned that CBER might not want to lose face, because Mesoblast appear to be vindicated by the new data (or it would not have been submitted) I can in retrospect appreciate from the FDA’s standpoint that an answer needed to be found for the batch variability anomaly. The point is that Mesoblasts process had
always worked. If the new assay is accepted by CBER for the adult trial, Mesoblast could rightly claim there is no legal basis to withhold paediatric approval and move straight away to resubmit their BLA for approval.
Regarding the minutes for the FDA meeting on CHF. Silviu’s comment that he had a “very encouraging” meeting with the FDA, sounds as though Mesoblast might have requested to use a trial protocol for CHF with a surrogate endpoint in a pivotal Phase 3 trial , like 12 months ejection fraction. If this trial is allowed to treat a wide CHF patient population (like the large ischemic sub population where it proved so efficacious in the Phase 3) Mesoblast would potentially have a blockbuster . Pharma partners looking for one of the greatest causes of mortality in the US, should be frothing at the bit to get a chunk of the IP. A short term primary endpoint will reduce costs dramatically. Mesoblast still needs to raise additional capital but the next few months of key inflexion points is likely to make this a very binary outcome. The market opportunity must be in the tens of billions for back and heart and the market cap is peanuts.
(20min delay)