Ann: Appendix 4C Quarterly Activity Report, page-81

Thanks for the reply OP. I've printed off your linked article and can see your slides from the recent presentation and I do believe I understand their significance. I'd also like to say that I like your style of posting and have enjoyed reading exchanges between yourself and pfeifer previously.

From your linked open access article its clear that the MAGIC algorithm probability (MAP) is based on serum readings of two biomarkers being ST2 and REG3alpha.

When I read the slides you've posted I first miss read MBS as MSB. MBS is an acronym for MAGIC Biomarker Score not a dyslexic mangling of Mesoblasts ASX stock code - which is how I was reading it. I assume those slides were from the Bone Marrow paper which is not open source but which found its way into the Mesoblast presentation recently.

To be clear about what ST2 and REG3alpha do (page 2 in the intro of your linked article says)

"Regenerating islet-derived 3 alpha (REG3alpha), .. is released into the systemic circulation (ie the blood) from Paneth cells in the intestinal crypt that are damaged during GVHD. 13 Suppressor of tumorigenesis 2 (ST2), the soluble receptor for the alarmin interleukin-33 (IL-33) is shed from multiple cell types when the gastrointestinal crypt is damaged. "

So both of those biomarkers, ST2 and REG3alpha, get into the blood (and so the serum) from cells (but not from MSC's there is no suggestion of that) but from other cells in a patient suffering from GvHD.

So those biomarkers are characteristic of and markers of (not Remestemcel-L the product - which TNFR1 and IL-2R alpha was argued to be) but rather, the levels of unhealthiness of different sets of GVHD patient's, such that those with MAPs of greater than 0.29 are regarded as sicker (more likely to die of nonrelapse of cancer reasons - so of GVHD) and so normally would have a worst prognosis than those with scores lower than 0.29.

Now its possible that I am misunderstanding something but I suspect that I am not. I say that because I am open to discussion with you if we disagree. I did revisit a lot of the documents, transcripts and slides from the FDA to the ODAC when I was reading stockrocks post of 31 December 2021 recently, (in fact to keep this post short I've just deleted about two pages of quotations from Steve Bauer for the FDA and OTAT in the transcript of 13 August 2020) And its my opinion that unless ST2 or REG3Alpha or MBS or MAP are new biomarkers of the product Remestemcel-L itself (and it seems pretty clear that they are not) then I don't think the FDA is going to be satisfied without a further trial as well.

Showing the patients with poor MAPS or MBS outcomes that were poor had their actual survival outcomes improved in a single armed trial simply isn't enough. Its a wrong use of statistics in my opinion.

This is because the FDA isn't going to be satisfied with mere statistical correlation applied retrospectively in my opinion - ST2 and REG3alpha not being measureable in the remestemcel-L product either in vivo (in the body of human or animal) or in vitro (in glass like in cell culture) makes them not markers of the product unless they can be directly and causally linked to another marker say a very high correlation with TNFR1. (And there seems to be some existing problems with using TNFR1 data arising from averaging and arising from there not being an association between TNFR1 levels and the outcomes of patients - according to the FDA transcript. To avoid a further trial MSB seems to have a need to change or massively supplement and so change the statistical interpretation of some TNFR1 data). They want and I think need (in the absence of a two armed placebo controlled trial, where the potency or effectiveness factors can be present and absent for comparison) to have a much better understanding of the mechanism of action because they need to know that the potency factors in one batch of remestemcel-L will also be present in other later batches.

The FDA's need, the scientific need, is to correlate the potency factor, the effectiveness factor batch to batch. And to do that they have to at least be able to identify the potency factor or factors in any and every batch. So features of particular batches of the product need to be trackable in vivo and in vitro. Then the cell culture could be a predictor of in vivo (in the body) potency.

Whether its the presence of TNFR1 plus the relative absence of IL2R as detectable both in vivo and in vitro or any other factors present or absent - they could be presence of X, Y and Z and absence of A, B and C - but the X, Y, Z and A, B, and C must be features/factors of the product not of the features/factors of particular patients (ST2, REG3alpha, MBS, MAP seem to be markers of patients). Because its the product not the patients that the FDA has to assure the quality of.

Hard as it is, it isn't enough to say product Remestemcel-L (or any cell product from any supplier) works in patients that have these characteristics 1,2,3 if you can't also pin down exactly what it is in the product that causes it to work so that you can ensure the same thing is in all batches.

Sorry for the length of this and it might contain some errors but its post or not post time and I'm going with post. I'm interested in what you think OP and @stockrock too. I think MSB isn't taking enough to the FDA on the basis of current annoucements to address their previous concerns without either also doing another trial or without showing some previous data like TNFR1 data was incomplete.