Going forward..., page-1580

I agree with the main thrust of your comment. Yes placebo plus standard of care (being corticosteroids) is control. And yes it would be a harder sell to take the trial with a one in three chance of getting the control arm if MSB had approval by then.

But MSB can't get a BLA approval until it makes a formal BLA submission and it seems its not planning to do that until it gets feedback from the FDA/CBER on the data its already sent in - a strategy I agree with by the way - its less risky but will take longer - but the FDA/CBER may take quite a while to respond to the IND file update - and what is most to the point is that they may not think what they've been given is enough to satisfy the CRL.

In one of my recent posts on MSB there is a link to a paper from 2021 by Klinker and Bauer that looks at potency assays and specifically priming of MSC lines. They find INF-gamma to be more influential than TNF-alpha (which acts through the TNFR1) on t cell proliferation inhibition - but they also find TNF-alpha adds in a synergistic way to what INF-gamma priming does.

The problem I see for MSB is that they've never reported measuring INF-gamma in a potency assay.

MSB's ODAC slides CC-15 and CC-22 show INF-gamma involvement so they recognize its possible importance but they don't report measuring or tracking it anywhere.

In my opinion Bauer and Klinker and others at CBER are going to, based on their own research, think the TNFR1 expression and IL-2Ralpha inhibition may not be capturing the key potency factors in the medicines that MSB is producing.

All MSBs longevity data, the good results comparatively for four years come from three donors that provided cells to the 54 patient trial. Those three donors might have had cellls that were effective because of INF-gamma handling not just or TNFR1 handling but that doesn't appear to have been measured anywhere. This matters because MSB will not be able to keep using the same three donors - they'll need new ones and unless they have potency assays that can be shown to be potency predictors there isn't a way to show the new batches will be potent.

INF-gamma doesn't operate through the TNFR1 pathway. It inhibits t cell proliferation another way through IDO and it doesn't seem to be something that MSB is capturing in its potency assays.

All above is my opinion. I think it less than an even money chance that CBER can agree that MSBs existing data (what MSB have provided and said they have provided) is sufficient to predict future potency even though they may agree that MSBs 54 patient trial seems to have worked.