MSB 2023 - awaiting for Ryoncil approval, page-177

Si did mention in a Q & A that he believed the FDA wanted an additional potency assay.

But you have no source to share do you?

As far as I know, there is no information on what that essay is. It could be Inf Gamm for all I know. It simply has not been spoken about.That does not mean, it is not Inf gamma as JB keeps suggesting.

The potency assay has been spoken about in MSB announcements in general terms - its been described as optimised. A brand new assay isn't optimised (that's done on an existing one) and it isn't reverted too. (That's back to an old one).


Back to my original response, in any case I cannot see the FDA reviewing a BLA that demonstrates a high degree of efficacy, where efficacy correlates to a high degree with the potency assay, and high survival to then turn around and deny approval based on a tack on "whatif" question.

Ie... whatif something happens that they currently have no evidence to proove will or even could happen.


That whatif stuff is you characterising something I've said that you don't understand.

You didn't read the Klinker and Bauer paper I referenced from 2021 some time ago did you?


Big difference between what Klikner have done in a test tube, and what MSB have done in sick children with gvhd

Potency assays don't get done in sick children (thats in vivo - in the patients body when its in the child) potency assays get done to check for potency before they are put into the body (they are done in vitro - so yeah - in test tubes or in petri dishes or in plastic at lot release time BEFORE going into a patient).

Here is an MSB slide with in vitro written on it. And with three donors. And with a cartoon of a remestemcel-L cell






. Msb have prooven TNFR1 is linked to treatment efficacy.

I don't think you can produce a MSB statement to support that. They don't say TNFR1 in their announcements - though I would agree with you hadf you not exaggerated that that is what they probably meant. Its for the FDA to evaluate any alleged proof. MSB haven't used the word "proof" either. Show me I'm wrong with a reference to TNFR1 and proof in an announcement from MSB if you can.

Klinker has not. Its like MSB demonstrating the sheep disc regeneration in a sheep, which has appeared to not match what happened in human the trial.

.

for Inf gamma, maybe tnfr1 priming is linked with inf gamma since they both act on the process.

Both act on T cell proliferation inhibition in vitro. (If that's what you mean by "the process". But if you look above at MSB's slide the pathway from the CD 8 T cell that has INF Y on it going to IDO and coming back to inhibit CD4 T cells doesn't go through the TNFR1 receptor to NFKappaB.

So T cell proliferation inhibition is in common, but the pathway is not in common. And TNFR1 is on only one of the pathways to T cell proliferation inhibition.

What does come out of NFKappaB is CDX-2 and CCL2 (they could be alternative things measured as possible potency assays that are under the TNFR1 umbrella because they are downstream of TNFR1 receptor but INF y doesn't go through that pathway or touch TNFR1. SI did talk about other potential potency metrics under the TNFR! umbrella at ODAC. They could be candidates.



That is to say, maybe it is extremely unlikely to find low activity of inf gamma where there is high activity of tnfr1.

Something has to cause CD 8 T cells to produce INF gamma on the cartoon on the slide that MSB is using. I think (this is where I need to do more research still) I think CD 8 T cells will be producing INF gamma because they are "activated". Some second messenger plus T cell receptor combination is probably artificially activated so as to produce activated CD 8 T cells as part of the activated peripheral blood mononuclear cells that are a part of each of the experimental conditions on MSBs above slide. .

Maybe the INF gamma levels in the slide are kepy constant because the T Cells are all activated the same artificial way coming as they must be - not from natural T cells but from some artificial supply. Same number of activated T cells in the mix of CD 8 may mean same amount of INF gamma in the test conditions allowing TNFR1 expression to show up as the only difference. Maybe.

Maybe tnfr1 in high activity does not require inf gamma high activity to work ... none of this has been proven. Maybe msb know the answer, and that is how they selected their potency assay.

Nothing has been claimed to have been proven by MSB to the FDA's satisfaction.

We both don't know.

You aren't reading enough to cut down some possibilities that you could if you'd read more. Its fair and proper for you to admit what you don't know. And mischievious to suggest possibilities that are only possibilities because you refuse to process the available information to rule them out. Like INF gamma could be a potency assay. You become a kind of up ramper in chief rather than investigator of the truth when you do that. But its not fair to presume that what you haven't read and which I may have read that I also don't know any better than you. Its like someone doing some homework can't know more than someone that hasn;t done as much homework in your world - but then declares loudly that no one has done it - so we are all ignorant together. So let the ramping begin!

You as a holder could get in touch with MSB and ask them straight out - can you tell me whether INF gamma is part of the current potency assay or is that commercial in confidence or trade secret or something so that you the company don't want to disclose that?

They'd at least be able to tell you we can't tell you if you did that.

But just as you didn;t ask about an update when the BLA resubmission wasn't out as expected you haven't asked the company about INF gamma either have you?

I as a non holder did get in touch with the company and ask for an update on the BLA resubmission. And to some extent the market got one.

I'm almost certain they haven't introduced INF gamma - but when the time is right I can ask too.

I just have to work everything out as though holders are hostile not also interested in learning because you make the environment to learning here hostile.

I wanted to work with you not against you.