Ann: MSB Annual Financial Results and Operational Progress, page-193

I think the fact that Mesoblast haven't signalled that they need to run another RCT, suggests that the FDA have conceded on the efficacy front. If the efficacy point in the CRL was the only item raised, I believe the FDA would have already approved Ryoncil after the Type A meeting. However, the potency assay point is something that the FDA have obviously told MSB that they need new data to convince them. Once you introduce new data, then that's a new BLA.

In terms of what is required in terms of potency assays, well the FDA guidance requires that there is a demonstrated relationship between the CQAs and clinical outcome (in-vivo).

So that is what Mesoblast did, they pooled all the Rem-L trials from 2005 until the end of the phase 3 trial (over 3 studies) and demonstrated that the CQAs were optimised over time, and guess what.. the clinical outcome improved as well. So Mesoblast put together what they thought was a way to demonstrate the relationship between the CQAs and clinical outcome.

But of course the FDA picked holes in it and said the populations in the three studies were too different and the medications used varied too much, so they dismissed the analysis.

The FDA are simply interrogating the data presented by Mesoblast, and the points the FDA raised may very well be valid. It's obvious that the FDA are not going to budge on this, so there is no point of MSB banging their heads over and over again... it's time to go out and generate some new potency assays which meet the requirement of a 'demonstrated relationship between the CQAs and clinical outcome' and are free of the issues the FDA raised. How they are going about that, well that is anybody's guess. But we know they've spent a fair bit of coin on it and appreciate the gravity of the situation... so I expect them to take no short cuts and just give the FDA exactly what they asked for.

I don't know for sure, but I don't think the COVID ARDs trial would help in this instance.. neither would Temcell... as these are all using the optimised Rem-L. I believe what MSB need to demonstrate is that a version of Rem-L without the CQAs should perform quite poorly compared to the optimised Rem-L. I've said before, the easiest way to do this is to find children suffering from SR aGVHD on the same standard of care as the phase 3 study and give them sub-optimal Rem-L and see how they fair. If they do worse, then MSB have demonstrated that relationship... if they fair the same or better.. then MSB probably got it wrong and the FDA is vindicated. Are they actually doing this? I really don't know.. and it's hard to even think about, but that to me would be the most effective way to demonstrate to the FDA what they want to see.

I find that if you focus too much on one company, you can literally go crazy. I find it helps to break it up and diversify your research and investments... and learn new things. I've recently done a fair bit of research into cell therapy in the cancer space (specifically CAR-T therapy), and that is a few steps ahead of stem cell therapy in that it has 5 approved FDA products since 2017.. and it's literally curing blood based cancers. solid cancers are the next targets. If you want to know more about curing solid cancers... come on over to the other company's board (it's in my tag).. bit quiet there now, will be good to have you and anyone else interested in a more progressed (de-risked) cell therapy buzzing around