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Hi JB,There is ZERO chance Mesoblast will reveal the specific...

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Martin37

258 Posts.

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14/07/22

22:29

Post #: 62544561
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Originally posted by JB1975: ↑

Phaedrus (in bold) to me wrote:

"its good to see that you're reasoning your way through this, and starting to put the assays into a more detailed perspective. "If you think I'm stuck somewhere in the reasoning process that is stopping me moving ahead to where you are I'm happy to listen to what you have to say.

I say assays, but of course the release assays put forward by MSB to the FDA were in the form of an assay matrix - which can sound like a singular assay, when in fact its a plurality.
Yep

Steve Bauer acknowledged & agreed with the propriety of doing so at teh ODAC hearing. He did.

The assay elements may be biological or non-biological analytical i.e. 'analytical', as the FDA refer to them. They may even be some combination of these elements. All of that I agree with so far.

Confusing, I know.

But when Dr Eric Rose talks about "the assay" (in response to a dumb question from a stock analyst without notice), I think you should keep this in mind.
Dr Eric Rose certainly hasn't helped comprehension by referring to "the assay" (singular) that is for sure, because by speaking in that loose way he has given me cause to doubt the reliability of some of the other things he has said - once I conclude a speaker is dumbing things down (either for an audience or because the speaker is dumb) I then doubt the other things that speaker says more than I would have.

I'm not sure if I have already mentioned that Dr Rose didn't actually answer the whole question that he was asked - the whole question included an inquiry about the role of Phillip Krause - and that question was a rephrasing by Silviu Itescu - so I kind of expected Dr Rose to respect SI and I took his failure to mention PK in his answer as suggestive that Dr Rose might have too may seasons behind him to be still listening and speaking clearly. It seemed like he was saying talking points that he anticipated using earlier but then didn't adapt to the actual question that including Krause. Dr Rose spoke very very slowly and used a lot of ums and ahs. He had me thinking of media comments sometimes expressed about Joe Biden's state of mind.

I have an MSB announcement I printed out dated August 31 2021 - Operational Highlights (etc) that says (bullet point 4)

"FDA indicated that the potency assays"

(please note that is plural and specifically says potency assays not something else - like "in vitro immunological activity" which is a phrase which gets used in the 31 December 2021 announcement but which is imprecise in what it is referring to)

"currently in development appear to be reasonable based on in vitro results provided in the briefing document, the in vitro activity of the product appears to be relatively well established, through the relationship between in vitro activity and the product's actual mechanism of action remains theoretical".

You referred to and excerpted an entire page, page 8 in particular I suppose, because "3 Multiple assays (assay matrix) starts on page 8.

But that is actually the third section of III Recommendations for Potency Measurement part B
What Analytical Methods May be Used to Measure Potency? - that starts on page 7.

So you introduce it - but you haven't done anything with it in your post to relate it back to MSB's circumstances.

So, there is a huge degree of flexiibility available to MSB in meeting these requirements IMO

There might have once been a huge degree of flexibility available to MSB in meeting matrix assay requirements but that is not I submit the pressing matter at hand - which offers far less flexibility because a new potency assay that wasn't available at the time of the pivotal trial needs to be linked (shown to be relevant to) the results that were obtained from that trial - I think that the pressing matter at hand is better summarised by these paragraphs MSB's 31 December 2021 announcement page 1, 3 and 4 paras up from the bottom -

"Mesoblast has now generated substantial new data which it believes establish the relevance of the proposed in vitro immunomodulatory activity of remestemcel-L to the clinical effect of the product in the completed Phase 3 trial in pediatric SR-aGVHD, including to survival outcomes and biomarkers of the product's in vivo activity. Mesoblast will provide these new data to OTAT and address other remaining CRL items as required for the BLA resubmission.

(I'm reading the underlined bit to be a reference to the new assay)

"By demonstrating the relevance of the in vitro potency assay to clinical outcomes, Mesoblast believes it will be able to show that the remestemcel-L product used in the Phase 3 trial in pediatric Sr a-GvHD was standardized as to identity, strength, quality, purity and dosage form, and that this will address OTAT's recommendation for an additional adequate and well-controlled study"

The green bits - the statements of what MSB believes - I can see readily enough as serving as legal escape hatches for sued MSB executives if their beliefs are mistaken for certainties.

The bit I need help with is, where my reasoning process is getting stuck (if you are correct) or where I am failing to suspend enough disbelief (if I am correct) is associating the blue bits (which I assume is what Dr Rose is referring to as the potency assay they've reverted to) with the yellow bit by any possible plausible scientific or methodological means.

Now I assume its common ground by all readers of this forum that MSB have not disclosed publicly what the new assay is that would be the blue bit.

Where I part company with someone like ddwn for instance though is that I am not interested in or satisfied with just 'waiting and seeing' or with 'just trusting MSB management' have it all under control.

MSB is a listed public company and it could be either great buying or terrible buying now depending on whether the orange bit achieved in accordance with managements hopes or not.

I think a stock discussion forum is just the right place to consider what the blue bits could possibly be. I think doing some speculation constrained by analysis is actually good.

Linking the blue bit to the yellow bit is essential for the success of the orange bit. So correctly identify either some possible way to make the blue bit link to the yellow bit could be profitable (a person could buy now) as could identifying that there is no possible way to make any possible value of the blue bit link to the yellow bit (perhaps a person could profit by shorting). BTW - I don't short.

If it is impossible even in principle to link the blue bit to the yellow bit with any science or method that anyone can think of then the orange bit is doomed and some share holders might end up discovering the importance of the green bits as escape clauses but not for them.

When I try to come up with a way that might make the blue bit match up with the yellow bit to possibly achieve the orange bit the best I do so far is this.

Suppose the new potency assay (the blue bit) is Interferon Gamma Receptor expression. Suppose that inhibition of interleukin 2 receptor alpha expression on co-cultured activated T cells (the activity test from the first BLA and from the ODAC papers) is valid. This (activity test from the time of the phase 3 trial) might then provide a hook (something to be correlated with) to all the yellow bits (the biomarker stuff, the survival stuff).

Could Interferon Gamma Receptor expression be a potency assay? I don't know. I don't have quite enough science knowledge to know but I have enough to spit ball it as a possibility.

Interferon gamma is a pro-inflammatory cytokine like tumor necrosis factor alpha but it binds to a different receptor - the interferon gamma receptor and so activates a different pathway which produces IDO which can act on T cells. All of that could be done in vitro. Lots of interferon gamma related papers exist - even Klinker and Bauer have written papers that seem relevant to interferon gamma activity in T cells in vitro.

In some of SI's investor slides (he has IDO and IFNgamma indicated in red. And IDO is also linked to pathways that affect T cells.

If interferon gamma receptor levels did prove to be a meaningful measurement of anti-T cell activity via the INFgamma IDO pathway then so what? Can that be linked to IL2Ralpha data as a sort of hook for correlating data associated with the 3 donors and 40 odd lots that were already used in the phase 3 trial? I don't know.

But I prefer to think like this - to look for possibilities than to just wait and see.

Expand

Hi JB,

There is ZERO chance Mesoblast will reveal the specific approach (potency assays) they intend to use for product release criteria and in the re-submission of the BLA. This would at this stage be strictly commercial in confidence (and so it should). To be honest I agree with (@dachopper) that you will be unlikely to find the answer on this board. However I admire your persistence in search for the answer. For this reason I will give my 2 cents worth for entertainment purposes.

Maybe the answer lies in MSC apoptosis (programmed cell death) measured by cytotoxic assays:
1. There is evidence that MSC undergo apoptosis in the lung following an infusion - and apoptosis is required to 'activate' the MSCs. This 'activation' is hypothesized as a reason/necessary for their immuno-suppressive effect.
2. There is evidence that MSC apoptosis requires, and is induced by, recipient cytotoxic granules.
3. There is evidence that cytotoxic assays can predict clinical responses to MSC therapy for GVHD with high sensitivity and specificity. Evidence exists that patients with high cytotoxity respond to MSC infusions; while those with low/absent cytotoxicity do not respond to MSC infusions. [This reminds me of our CHF trial, patients with high inflammatory biomarker CRP responded much better that those with low CRP levels].
4. Cytotoxicity T Cell assays are widely commercially available and measure CD8 T cells. This may be combined with other markers to look at the purity of T cells, CD4 to CD8 T cell ratios (important for release criteria).
5. Last but not least, in the subset patients (40 from memory) who where enrolled in an elective biomarker sub-study to explore the biological and mechanistic effects of Rem-L: The baseline biomarker profile was consistent with an inflammed state and elevated plasma levels of Reg3alpha, ST2 and frequencies of activated CD4+ and CD8+ T Cells & levels of activate T Cells declined over the course of the study. [This IMO would explain Dr Rose's change of assay - via a nudge maybe from Dr Krause - to a cytotoxic assay which may in theory link in a beneficial way to improved in vivo outcomes explained by T Cell immuno-modulation properties of Rem-L].

Another not so unrelated 'clue' IMO came from the recent investor presentation when CEO Itescu was informing the audience that the upcoming CLBP trial (albeit for Rex-L in this instance) will employ additional imaging tools (dyes and agents) to measure change in metabolic activity plus a number of biomarkers. This rang a bell because cytotoxicity, cell death and metabolic activity are linked.

Finally there is also evidence that upstream IFNγ and TNFα synergistically induce apoptosis of mesenchymal stem/stromal cells via the induction of nitric oxide however IMO I think the cytotoxic assay will be the leader in the group for potency/release criteria.

Main sources:

1. ODAC Briefing Document:

2. https://www.frontiersin.org/articles/10.3389/fimmu.2020.01338/full#B60

Please note I am not a Cell Biologist so please do not make any financial decisions based on this post. Remember this post was intended for entertainment purposes only.

Last edited by Martin37: 14/07/22

MSB Price at posting: 84.0¢ Sentiment: Buy Disclosure: Held
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