MSB (ASX) Ann: Mesoblast Type A Meeting with FDA

Originally posted by stanjupiter ↑

@whyteeThis IMO is the biggest clue the FDA knew at least from 2020 that Ryoncil worked

Mesoblast’s ann 20/10/2020:

“FDA recommended that Mesoblast conduct at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of Remestemcel-L for SR-aGVHD”.

Or children

On the surface, the “and/or children” recommendation looks like a concession to the ethics JK and others stood up for in the ADCOM: if the study used a contemporaneous control, the adults would make the “choice” of a 50% chance of landing in SoC.

In reality it’s the sacrifice of children for adults.

Mallard et al. acknowledge enrolment of refractory patients in a trial might not be possible; however, assuming it was:

If MSB recruited from centers which run the EAP, prospective participants would have to be given proper informed consent by KOLs such as Dr. Prockop and Prof Kurtzberg about their dismal chance of surviving even a year if they landed in the control arm randomized to any of the BEST therapies for SR aGvHD listed by Malard et al., who are familiar with aGvHD, as I went through in this post 70277405. Or the study could be against Ruxolitinib alone, which is no better than any of these therapies and likely worse than at least one.

If MSB recruited from centers not familiar with Ryoncil it would likely be a case of taking who we could get at a time when it couldn’t be guaranteed that objective biomarkers of baseline severity would be used.

There was a possibility of getting older patients. (According to the Center for International Blood and Bone Marrow Research, the proportion of patients over 65 who received allo-HSCT increased from 4% in 2005 to 27% in 2020.) They could also have depleted T cells because of prior treatment such as with Inolimomab. They could have severe aGvHD but be less “stormy”, which could affect their response.

I’m no scientist but I know the basics. Children are immunologically different to adults; there’s plenty of literature covering, and giving examples of, differing responses to drugs in children and adults. This is highly relevant to Ryoncil which responds to inflammatory signals in the individual. There’s no way the FDA doesn't understand this basic MOA.

I mentioned EEN in a previous post. I don’t usually like analogies but this is a perfect one IMO because it’s a therapy commonly used for gut inflammation in IBD and GI GvHD, which have similar features. A RCT is difficult, if not impossible, to do but there’s no doubt whatsoever that it works, even though it isn’t a consistent product. (I imported a high quality product but the accompanying book had instructions for mixing up your own; Seattle CH are experimenting with their own smoothies.)

EEN is well known to work less well in adults, which is why it’s recommended first-line in paediatric Crohn’s Disease in Europe.

Response at 28 days has been the usual PE in trials in aGvHD. In their recent document the FDA said: “Pediatric patients may have response profiles that differ from adults”.

They didn’t know this back in 2020?

For various reasons, a trial in adults might not provide further evidence of efficacy and you’re saying if that turned out to be the case, it would be conclusive proof Ryoncil doesn’t work for children? How on earth is that in any way scientific?

Anyone who truly believes randomized, controlled studies are “proper” science should require one is run in children AND adults. The FDA knew that was impossible to do in children who are SR:

There’s nothing approved for under 12, which means having to exclude this age group who have a stronger innate immune system and whose response is important to know.

EAP has been going for well over a decade. Parents would have to be given proper informed consent in writing by physicians who wouldn’t mince their words. Children would have a 50% chance of being assigned to a tablet. JK went over the practical difficulties in the ADCOM.

JK has seen children “cured” by Ryoncil. If I recall right, Dr. Prockop said it had been given relatively late to a child who still responded completely and was able to come off all immune suppression. Coming off immune suppression must be unusual or she wouldn’t have mentioned it.

You wrote here 70345913 in response to a post about Ryoncil’s safety profile:

“Actually it f it doesn't work then the harm it does is by financial cost for no benefit, delays in accessing other treatments and seeding false hopes and misleading avenues of investigation”.

Maybe it’s my imagination but the part I underlined echoes the reasoning I used in this post
69188548
a few months ago that the EAP is another major clue the FDA knows Ryoncil works:

“Even a safe therapy could arguably be dangerous if it occupies a window of opportunity in an acute indication where things can escalate quickly and another therapy (ie. FMT) might stop progression”.

Taking your point about cost. Consider the cost of a BMT in the first place. Insurers have already invested in this. Why would they protect their investment with a therapy that doesn’t work which could cause children to remain at hospital longer with “misleading avenues of investigation”?

I don’t understand the complexities of the human body or the exact MOA of MScs. Do you? Does @DocMcstuffins?

RCTs are the application of science and more of an art IMO. They’re designed by human beings who select endpoints and measurements which can be subjective or objective, and make decisions about who to include/exclude. Results can be affected by poor design, changing circumstances, emotion or bias.

As for the “failed” randomized trials you keep on about. Najima et al. (one of the pioneers in FMT for SR aGvHD which Malard et al. recently said was one of the “most promising” therapies) don’t appear to agree with you that the clinical trial NCT00366145 actually failed:

“Prochymal significantly improved the response of liver（76% vs. 47%, P＜0.05）and gut（82% vs. 68%, P＜0.05); the response of skin was not significantly different between Prochymal and the placebo groups（78% vs. 77%, P＝0.9)”

Response in skin caused the trial not to meet its overall PE. That was a case of poor design because milder cases were enrolled and skin is known to respond well to steroids.

The FDA knew Ryoncil worked so well investigators would refuse to subject children to SoC and they could make the delay look like it was because of a "standard" and blame it all on MSB.

I don't buy this degree of incompetence from either the FDA or MSB. I think Ryoncil has been deliberately held back by the powers that be. For what reason, I don't know but I have an idea.

https://www.jstage.jst.go.jp/article/hct/6/3/6_16-031/_pdf

Expand

I see no "clue" in that statement "that the FDA knew Remestemcel worked" in aGVHD.
It's a simple recommendation for a new trial that addresses the objections about a randomised trial in children.

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Ann: Mesoblast Type A Meeting with FDA, page-532

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