A Few Rays of Hope from a Coincidence Theorist. This is my take...

A Few Rays of Hope from a Coincidence Theorist.

This is my take after listening to the webcast. In this post I discuss:

• The Malard Paper: A major wake up to the reality of GvHD and four very interesting coincidences

• The smoking gun in the Macmillan paper (reinforced by the Malard one)

• A third possibility for delay that isn’t incompetence or malfeasance

The Malard Paper

This was published in June 2023 under the Nature umbrella. I monitor this publishing group, not just because of the highest impact factor, but because imo it’s a portal through which declassified information tends to come out.

IfMSB survives (or even turns out to be the spearhead company, the custodian of revolutionary science), it’s reasonable to think there could be a global force at work.

At first glance, the Malard paper reads like a guide for an industry standard. There are recommended protocols and a treatment algorithm.

It also reads like a script for Mesoblast. The abstract states a therapy is urgently needed for aGvHD refractory to steroids and Ruxolitinib.

Coincidence 1: Ryoncil is being positioned by MSB (according to Leftyahoo) or someone else (I suspect) for exactly that place. The reason I think the positioning comes from a party other than MSB is because it’s different from what I recall SI saying in a webcast a year ago, which I’ll mention in my next post.

Coincidence 2: Malard et al. state Japanese patients have a significantly lower risk of grades 3 or 4 aGvHD. Note MSCs on their list of recommended therapies (algorithm) for aGvHD refractory to steroids and Rux.

Coincidence 3: Malard et al. say the lung (also the nervous system) is a target organ of acute GvHD. On page 13 of MSB’s recent presentation the target organs listed are skin, liver, gut, and lung.

(The mention of the lungs is important because there’s much denial and under-reporting of damage to this organ, likely because lung GvHD is difficult to diagnose and treat. Once fibrosis sets in, it can’t be reversed.

MSCs migrate first to the lungs. Like the gut, there is a large mucosal surface area and there’s cross-talk between the two microbiomes. The gut/lung axis is well acknowledged. Srinath et al. (2022) discuss this in relation to Covid-19 and provide an overview of other research in other lung conditions. Top immunologist Prof Robert Clancy gives a good explanation for the layperson.

Coincidence 4: Malard et al. describe how the conditioning regimen affects gut integrity causing “...barrier damage, allowing increased translocation of pathogenic bacteria and amplifying the inflammatory cascades in GVHD; they mention intestinal dysbiosis as a contributor: “loss of microbiota diversity contributes to loss of epithelial and immune homeostasis”. List FMT is there, which members are saying. This is a labour-intensive therapy, which can be risky if the colon is severely ulcerated; results can also be variable because donors vary.

All this speaks to the importance of the need for a therapy that can heal severe GI inflammation, which Ryoncil specifically targets and whose efficacy in GvHD001 the FDA now doesn’t dispute.

The photo provided by Malard et al. of severe lower GI ulceration shows the horrific reality of grades C/D GI aGvHD. Lower GI is most refractory to steroids and Ruxolitinib. The subtext imo is intentional: children, even those below the age of twelve, and adults are getting a TABLET for THIS.

Overall, my take is that the Malard paper really puts the boot into Ruxolitinib. The authors are very precise. The “positive” results from Reach2 refers to the response but they make it clear that response didn’t translate to a durable effect:

”60.4% of the patients required a third-line immunosuppressive therapy or had died”.

(That doesn’t mean Ruxolitinib worked for the remaining 40% in the absence of long-term data, especially for patients with lower mortality risk (such as skin only) from both Reach2 and Reach1. MSB is correct to say there’s a lack of data showing survival beyond two years. I’ve noticed that too in the years I’ve been researching.)

Malard et al. say that allogeneic BMTs have been increasing world-wide. If you look on the websites of various BMT centers in the US, you’ll see in recent years an increase in the proportion from unrelated donors which increases the risk of GvHD. The rise in this category of BMTs is likely because of the perception there’s “something approved” for steroid refractory GvHD.

I don’t dispute Rux works for some people, to some extent, for a period of time but imo there’s compelling evidence this drug has negative efficacy overall and is killing more people than if it had never been approved for acute GvHD. I can’t prove that in the absence of long-term data on survival but there’s no doubt its impact has been minimal or there wouldn’t still be a state of urgency.

The Macmillan Paper

Of all the stakeholders, one important perspective is the one who’s paying - the insurers.

I think it’s likely they care less about mortality in the under 18 age group than their bad survival. Anyone can find a forum for sufferers of chronic GvHD and get an idea just how much one individual with chronic GvHD can cost in multiple hospitalisations and procedures, particularly for lung GvHD. Despite Ruxolitinib approval for chronic GvHD, there's been no decrease in expensive in-hospital therapy ECP (also listed by Malard et al) If anything, I noticed an increase in members mentioning it.

Mallard et al say:

“Overall, patients who survive for >1 year after alloHCT, and particularly those with a history of acute GVHD, are a high-risk population that must be monitored for long-term transplant complications, including chronic GVHD, multiorgan dysfunction and secondary malignancies”.

The authors present a table with a recommended follow-up protocol and top of the list is pulmonary function tests at baseline, 6 months, 1 year and annually after allo HSCT.

Macmillan et al. report on response to steroids in 370 children with acute GvHD. Apart from shocking mortality at two years, the other smoking gun is the very high incidence of chronic GvHD among survivors. At two years, of 203 survivors, 83 had chronic GvHD. Holton et al. also show a high incidence of patients who survived aGvHD going on to suffer cGvHD.

Leftyahoo has said that Ryoncil should not replace steroids any time in the near future; however, if I may borrow a phrase from Prof Vinay Prasad, if something isn’t working, we should stop doing it.

Ryoncil targets the most severe gut inflammation. Consensus is steroids don’t work here. There have been refs to studies on this forum (Bacigalupo et al. Biavasoco et al.) and anyone can check this with a transplant expert, as I did.

Evidence is not only that steroids don’t work for severe gut inflammation but are a driver of chronic disease (because of the superficial healing job they do). I’ve referred here before to my younger daughter’s and many others’ experiences of red skin syndrome from topical steroids for eczema. One of her friends from the Itsan forum has done research pointing to eczema not persisting beyond childhood before steroids. I have yet to look into this myself but my daughter (as did many others) took herself through a cytokine storm and has an absolute cure for her chronic eczema. Perfect skin for six years.

I’m not advising doing anything without medical supervision. Our GP monitored her and prescribed something to help with the symptoms. In fact, it’s the lack of hubris of Australian GPs (who were reading about RSS on social media) that brought this condition to light.

Trialling against steroids is risky, however, if the PE is response at 28 days. Steroids can get a very good response, particularly with skin, but as with Ruxolitinib, the effect is often not durable. Carpenter et al. say only ⅓ of cases get a durable response.

What of the evidence that Roncil could reduce rates of chronic GvHD, particularly of the lung?

Admittedly the information is limited but one key thing I picked up was in the subgroup analysed according to MAP biomarkers 87% of the study group were able to come off immune suppression within 6 months, which speaks to lack of chronic illness (although that doesn't necessarily rule out ECP) but effect on the lung is key here, particularly with respect to fibrosis, which the ARDS trial stated MSB were looking for. It would be useful to have an update on how survivors trial are doing relative to the controls. I find the lack of information frustrating but surely there are data from the EAP as to incidence of lung GvHD, which would be easy to compare with other treatments such as Ruxolitinib?

The Third Option that is not Incompetence or Malfeasance

Krause said the FDA wanted to ensure the product intended for commercial use was the same one trialled, which hinges on the potency assay.

@LeftYahoo said:

“How could we NOT have that in place. I suspect previous efficacy data were invalidated precisely because a validated potency assay was not in place. This nonsense plus 70+ adult patients who were apparently treated without informing the market is the type of incompetence and opacity I'm complaining about.”

I couldn’t agree more about the lack of information. MSB seems to act like some kind of secret society! I agree also that not having a validated potency assay is nonsense, which is why I don’t buy it.

I’ve mentioned before that I’d have thought MSB would have got the matrix worked out a long time ago. I’m NO scientist but I got a sense of real precision dating back from years ago. I mentioned this in a post on ARDS 49277039 in the hope of nudging and learning from debate on this forum at a time when I was less sure (as you appeared to be) that our RCT would meet its PE. Removing any one of the (cytokines?) from the matrix, and the cells couldn’t achieve the desired effect.

My question is also why now?

Especially in light of getting a real sense this technology is way more advanced than is in the public domain (I’ll take a wild shot in the dark and suggest that perhaps years ago Cell Mogrify were supplying transcription factors to MSB)

And from years ago, scientists have had the ability to test a matrix on living subjects more easily. Ara et al. (whose paper@otherperspective posted a link to) discuss “a gut organoid culture system”. My question to the experts: What is this exactly? Does it mean we can simulate a variety of inflammatory milieu in a (in a sense) living subject?

Specific to MSB, I find it hard to accept that physicians of the quality of Kurtzberg, Prockop and Carpenter would align themselves with a bumbling operation. I don’t buy that someone with Krause’s experience and standards would screw up the second BLA.

In order not to be labeled and dismissed as a “conspiracy theorist” in this world, we’re groomed to accept an almost pantomime level of incompetence and villainy, a great number of coincidences (“correlation doesn’t equal causation”- How many freakin correlations does it take?) with increasingly ludicrous “rational” explanations for them. Governments even seem to employ the same script writers!

It’s a fake world. It really is a stage. So I guess if you’d introduce real science into such a world, you might have to address it in a fake way. It’s not just what a product is. It’s what people think it is. You have to consider all potential stakeholders.

What made me sit up and take notice was the first time Dr. Krause’s comment sounded like it could be marketing coming from (via?) the company.

The difficulties in getting consistency for a biological product such as MSCs are well acknowledged. I don’t deny it’s a huge challenge. The product would have to be consistent, and guaranteed to be consistent:

Ryoncil would be far more expensive than Temcell because of the size of patients, the size of the market and its potential to extend to IBD, which is in a state of disaster, particularly in pediatrics.

There’s also a subtext here, which in a sense, is another coincidence. Insurers are picking up the tab for another class of immunological product because of the gap between the science and the product which early on, did not perform as advertised: there’s no consistency with regard to immune effect in the individual, the lots/batches are not the same, there’s evidence of vial to vial variation and according to the FOIA document available on the TGA website, the trialed product is not exactly the same as the one in commercial use. All of this has come out in the mainstream media or been reported in peer-reviewed papers.

The second CRL may hold us up and prove a major drawback for the company. I don’t deny there’s RISK for investors and I’ve always accepted it. Or could it be a reflection of a guarantee of high production standards that Drs. Krause (and Gruber) clearly stand for (or they wouldn’t have walked) and talked, as “professional scold” and prodigy Prof Vinay Prasad, who has taken a stand against pharma corruption, has been at pains to point out?

Many of us here know that the fundamental MOA cells respond to the inflammatory milieu sales. MSB would have a sales force to guide physicians as to that but insurers just want a product that's consistent and performs as advertised. Perhaps these are the potential stakeholders being addressed?

That's just my speculation and my hope. I'm a shareholder but I'm also (as I know many, many others are) genuinely enthusiastic for a safe therapy that doesn't stop working after a few months, come with listed side effects as bad as or worse than the disease itself, can give durable results for conditions we know, and can prove, are curable through other means, albeit difficult and labour intensive.

https://www.nature.com/articles/s41572-023-00438-1