"That question could be answered by another question.Speaking after a question is asked isn't answering a question if what is said doesn't to change the subject but its not really answering it is it
Consider the FDA wants, the public wants, safe and effective medicines.
So they ask the applicant how do you know the proposed new medicine is effective?
The applicant replies - firstly that question could be answered with a question.
On further reflection the applicant offers - "the fact is" (our shareholders and us think we) "have thousands of treatments on the shelf that we know work and we know could save thousands of children".Do you reckon the FDA is likely to be amenable to privately asserted facts that aren't demonstrated to themselves as being facts? I really, don't."But JB - Your views never seem to consider
1 - Unmet need.
2 - No approved treatments.
3 - High Mortility rate.
4 - The efficacy that has been demonstrated through a mortality reduction.
5 - The opinion of the treating doctor in an open label study.
6 - The opinion of the ODAC who considered all of the above.
My question is - why don't you show how you have considered the above, in forming your opinion that you believe there is not enough evidence to approve. All you seem to be trying to do, is discredit the efficacy that has been shown, by trying to go down rabit holes such as what if this doesn't happen in the future.... and:
Ok - so it does appear the treatments have improved mortality - how do you know that it wasn't becasue of 1 donor.... well because we have a load of children that we have demonstrated unmixed efficacy, along with almost 300 in total that have had mixed and unmixed donors that have also demonstrated efficacy....... So so far the evidence is not supportive that 1 donor is responsivble for the mortality reduction. No evidence - if you have that please share it with everyone. If you don't have it you are speculating without evidence.
So on the basis of what you believe is possible..... you would deny children a treatment that is probable ( GVHD 001 and the EAP ) to help them.... considering they
have no alternative, they will be trying unproven medications as they have
no choice,they have a high death rate, and it has demonstated a significant mortality reduction looking at MAP.... If the cells do nothing at all there should be no difference at all with MAP. MSB should have bought a lotto ticket if they get that lucky that the map scores are all fluke...... In fact it would probably look so bad it would discredit the use of MAP as a predictive biomarker alltogether - because that would have to happen if the cells did not demonstrate efficay.
"If the only evidence you have from laboratory testing is that the ammount of TNFR1 expression, has been linked with T cell proliferation.... why would it all of a sudden not be linked to T cell proliferation as you suggest.Well, you are saying T cell proliferation, not T cell activation, I didn't use either of those phrases in my questions. My questions were more broadly phrased and they are still there.
Here's a slide from MSB's ODAC presentation CC-22
Look at the grey lines with IFNy going from CD8 to IDO then back to CD4. Note that there is nothing in MSB's figure that suggests that either TNFa nor NF-kappaB are involved in those grey lines going to and from IDO. IDO is indoleamine 2,3-deoxigenase in short form.
Remember Dorronsoro et al 2014? The principle supporting reference in MSB's Mechanism of Action section 2 of the Briefing Paper.
fom page 5 "Our study demonstrated that TNFalpha is sufficient to trigger this immunomodulatory capacity in human MSCs, which contrasts with the results observed in mice, where interferon gamma seems to be a required factor [8]. Our results do not rule out that IFN gamma could also trigger human MSC-mediated immunosuppression. For instance, human MSCs do not make indoleamine 2,3-deoxigenase in response to TNFalpha, but clearly do so to IFN gamma (Supporting information Fig 1.) Thus, further investigations will show whether other cytokines, or cross talk with other signalling pathways (e.g. TLR signalling), could enhance the human immunoregulatory response".
Here's another quote for you from page 3 of 9 in Dorronsoro - (bearing in mind IL2Ralpha (also known as CD25) inhibition on co-cultured T cells, is another part of MSB's matrix approach to potency assays along with TNFR1 expression) -
"Our data suggest that MSCs regulate T-cell activation (as judged by surface expression CD69 and CD25) and T cell proliferation by independent mechanisms, the latter being linked to activation of the NF-kB pathway)."(My opinion? - Should be a good thing, not a bad thing, for MSB to have a potency assay based on two independent mechanisms (T cell activation mechanism plus separate T cell proliferation mechanism if there really are two separate mechanisms and activation of T cells doesn't cause T cells to proliferate) rather than one of those only).
Above you'd asked - "If the only evidence you have from laboratory testing is"....But its not the only evidence even I have. Klinker and Bauer at the FDA do have MSC potency assay related evidence beyond what MSB has given them.Their 2017 paper Morpholgical features of IFN-gamma-stimulated mesnchymal stromal cells predict overall immunosuppressive capacity shows at figure 1 that "The relative immunosuppressive capacity of MSC lines varies according to T-cell activation measurements and MSC concentration".
They measured each of the six lines at 6 different concentrations of MSCs for % CFSE diluted (which is a proliferation measurement), %CD25 (which is a T cell activation measurement), and for the amount of cytokines (TNFalpha and INF gamma) secreted (where what is measured is the reduction of those relative to a control - though in some cases low concentrations of MSCs actually increased the amount of TNFalpha and INF gamma rather than decreased it relative to control).
So four separate ways for measuring in vitro (surrogate) immunomodulatory activity were compared. And Klinker and Bauer looked at CD8+ T cells not just CD4+ T cells.
On page 2 they write "Using data from a single T-cell activation measure or from a single MSC concentration to quantify immunosuppressive capacity could lead to spurious conclusions.
To address these issues, we developed an analytical approach that incorporates various measures of T-cell activation and integrates data obtained from multiple MSC concentrations into a single value representing a given MSC line's overall immunosuppressive capacity".{Me again] Each of the 3 donor lines used to get the results you refer to where 25 remestemcel-L patients were matched up against 27 others would have been like 3 separate cell lines. Add a new donor that's another cell line. Klinker and Bauer's own experiences will have shown them that cell lines from different donors give different measurements on different immunomodulatory metrics."So what evidence has Klinker and Baur produced to link their labratory experiments to invivo MSC behaviour. We all know that stem cells operate differently invitro verses invivo, as evidency by the fact they respond to their surroundings and test tubes do not mimic the human blood stream.... as MSB and Osiris found out. MSB's outcome base efficacy invivo is far more compelling than a handfull of labratory expirenments that never got off the ground and into people. I also believe one of those two holds medical patents which go against MSB's MOA. So they obviously have a vested interest to disprove MSB's MOA in my opinion. Remember they have also repaired and grown new tissue in test tube using stem cells.... but not humans......
MSB also said that they are commited to improving manufacturing and makeing a more potent product where ever they can, the issue is that could take 3 - 5 years, and the evidence so far is that will cost childrens lives.... needlessly.
At the end of the day. Theory is great, but at some point others that are suggesting MSB change everything need to proove their own theory works in a human...... have any of them?
"Even if it is indirectly linked, it should be fine as a potency assay, and if not the company would all ready have seen no correlation with results.The company may have seen correlations between TNFR1 expression (with reverted to, new assay) and in vitro inhibition of T cell proliferation (and attribute that to being a causal relationship) but they can't have used the reverted to assay in the 54 patient trial or in the 25 that were matched with the 27."Nothing is stopping them from testing samples from the same batches that were given to those 54 patients, and the same donor bank.
"Now they are saying specifically they have linked results with the potency assay, and used the EAP to increase the ammount of data not because it is worse I would assume, but because it is better?This is what the company said in their July 29, 2022 announcement -
"Additionally, Mesoblast has now generated data from the expanded access program (EAP 275) of 241 children which confirms the ability of the in-vitro potency assay to measure product activity relevant to survival outcomes".
But if your argument is that either T cell proliferation inhibition or TNFR1 expression levels in vitro are themselves relevant to survival outcomes (which it seems to be) that's not a particularly high hurdle they are claiming to have leaped.
"Relevant to" doesn't mean "causes" survival outcomes. Its better than being irrelevant to though.
All the measures of immunomulatory activity Klinker and Bauer looked at in their paper could also be characterised as relevant to survival outcomes if mere relevance is the standard.
I see the EAP 275 data as being about MSB showing that they can get consistent rather than inconsistent TNFR1 expression levels (p2s and p5s being consistent) when they use the reverted to rather than the problematic TNFR1 antibody. If your p2s and p5s were out of whack with each other you wouldn't have even "product activity relevant to" survival outcomes.Also MSB will want to use EAP 275 data from single lots to bolster the number of cases of patients getting treated with single lots (beyond just the handful from GVHD001) where they can. But EAP 275 data lots didn't go into GVHD001 patients and didn't go into that 25 versus 27. And some EAP patients were treated with other indications."You are starting to get side tracked in the technicalities of literature here. If it's relevant, than it is associated with. Why associated with....GvHD does damage all over the body. Do you die because of high Cytokines, or because your body has so much fibrosis there is none of your body left to function. Does your intestines being dead cause mortality, or the presence of inflammation?
Right - but there are no other proven indications to treat. It is what it is... The proof is what is available, and nobody is saying the cells show less efficacy than control equivalent.
I agree, the eap numbers will support the antibody issue, so now the potency assays will match survival outcomes to a higher degree, which is supported through the lab experiments also.
"Your question is based on your observations of the science, and not necessarily the scientific evidence that the company has from lab tests and medical trials..... As I said, even if MSB knows nothing and have selected by fluke a potency assay that is not real, then got cells that by fluke actually work as well as they have....The fact is they have thousands of treatments on the shelf that we know work and we know could save thousands of children...You aren't allowed private facts as being treated as facts. The company isn't allowed private facts as being evidence. That's not how facts work. Facts need to be shown to be facts. By answering questions (many of which are not traps - they are just questions - its not hurtful to ask if INF gamma competency rather than TNFR1 expression levels couldn't be an alternative explanation for the 25 doing better than the 27 - but it could be helpful to be able to answer.
I don't know enough right at this moment to know that there isn't an answer. When I write posts I often end up with questions as a result of laying out my thoughts that I then want to go answer for myself."The problem with going down this rabbit warren..... is where does it end, and how many children die without a single treatment, because an organisiation wants to lift survival from 68% to 100%, and won't approve any treatment until it's a 100% cure. They have correlation right now between TNFR1 potency levels and increased patient survival. That must be enough. They could take 3 years running another trial using interferon Gamma, only to find TNFR1 correlated better to survival outcomes.... Then when those results come out the FDA will have a better idea like individual cell morphological screening.... than another trial, then another 3 - 5 years.... maybe the survival goes from 68% to 74%,...... then something else....... all the while children are suffering without any treatment..... all for the sake of a few extra % survival... and at a huge cost for those that will die.
That is exactly what a phase 4 trial should be used for
Are you saying don't let them? There are no side effects, no alternative treatments, and nothing scientifically proving that TNF alpha handling is the " right " potency assay either?
I'm saying no private facts. Facts have to be proven. I'm saying questions shouldn't be answered with questions - this is science about health - not politics (where questions are answered with questions) about self enrichment.
I'm also saying that if incentives aren't in place to ensure sick kids get potent medicines not just placebos then the chances of sick kids getting impotent medicines that are just placebos becomes greater.
If GVHD treatments are going to be priced like CART treatments for multiple hundreds of thousands of dollars then that's a pretty strong incentive to move product now and to leave the sorting out of mechanisms of action to someone else.
The equation isn't just sick kids with little hope now versus more hope now its also how many sick kids yet to get sick will have poorer not better medications when they do. A BLA two years sooner might mean more kids getting medicines of inferior or dubious potency over 20 years. Get the potency more certain now more kids and more people may benefit in the long run.This is waffly but has some good stuff in it in my opinion so I'm posting it warts n all rather than deleting it.
If the FDA does it's job correctly - the company have committed to a phase 4 RCT. If they do not demonstrate efficacy the FDA pulls the BLA. That is exactly what should happen. That is why you don't end up with something that does not work 20 years later. That is the path forward.
I think - you bring up some interesting " possibilities" on the technical side, that maybe are correct, and maybe MSB will look at them, or have, or are in the future, and maybe they can make the product even better than what it is today..
But
I think in a court of law, with the efficacy that has been deomnstrated, with the opinion of the treating physicians, the observed steroid weaning, the ODAC panel of experts..... assuming the potency assay now matches, will look very damming to a group of ordinary people if the FDA deny it based on wanting more data, and an RCT in children
(20min delay)