Ann: Mesoblast Type A Meeting with FDA, page-254

The Other Assays. The Other Validation

MSB proposes an externally controlled single-arm registration trial design in adults and children over age 12 with SR-aGVHD who have failed both steroids and a second line agent, such as ruxolitinib.

In this great post 69959591 @otherperspective said there’s implied tacit support of the Magic Consortium. I think that’s a likely scenario, particularly after reading the Malard paper.

I refer heavily to this paper because it came out under the Nature umbrella, the most prestigious publication group, and is imo the mouthpiece for whatever force controls the information flow and therefore calls the shots.

The paper reads more like a treatise; the overarching message is a need to get an industry standard for GvHD, especially since the number of alloHCTs is increasing, particularly in North America and Europe. (Many BMT centers still do their own thing re. grading of organ severity and defining steroid-refractoriness.)

The authors stress an urgent need for a therapy for patients refractory to both steroids and Ruxolitinib.

Much focus has been on the potency assay. A matrix approach would be used. I haven’t commented much because I thought the specifics would be proprietary knowledge.

My focus is on predictive and response biomarkers in the patient who is suffering from this most heterogeneous condition. Patient selection and more precise timing are key to consistent results in a therapy that responds to the inflammatory milieu in the individual.

Malard et al., however, say:

“Overall, diagnostic or predictive biomarkers of acute GVHD are not used routinely in clinical practice owing to the lack of standardized commercially available assays”

They refer to the Magic algorithm which uses serum concentrations of ST2 and REG3A and set forth a panel of other biomarkers: IL-2Rα, TNF receptor 1, IL-8, and hepatocyte growth factor (HGF); authors say REG3A, HGF and CK18 are significantly elevated in lower GI aGvHD and in liver aGvHD.

We know Prof Kurtzberg has identified IL-2Rα and MSB was looking for IL-8 in ARDS trial (another heterogeneous condition) and a number of the same biomarkers are relevant to Crohn’s Disease and other pediatric cytokine storms.

An Industry Standard

Ideally, the instrument of measurement should be more accurate than the thing you want to measure against it. Both could be but while researchers (ie. Solan et al., 2019; Srinagesh et al., 2019) say the Magic algorithm is validated, it’s not yet widely validated or standardized, likely because some studies haven’t found a correlation.

Reach2 investigators in Ruxolitinib were criticized for not balancing patients in both arms according to ST2 and REG3A but the authors say these were not standard in clinical routine and that multiple biomarkers have been reported to be associated with outcome. They do say, however, analyses are ongoing.

Perhaps a panel of predictive and response biomarkers hasn’t been established conclusively because so many GvHD therapies don’t work well enough to produce a consistent response or while they produce responses, they don’t correlate to survival?

It may be easier to confirm an algorithm if you calibrate with a highly potent and consistent product. In vivo changes would be clear, those changes being most clear in the most severe cases, which respond best to this therapy. A therapy where response has already correlated to survival in the most refractory subset of severe lower GI graded according to Magic biomarkers.

@Southoz has said MSB should have matched patients prospectively, not retrospectively, with those in the Magic database. Not only were upper GI and liver biomarkers not validated at the time of designing GvHD001 (Malard et al say liver is usually diagnosed through a process of exclusion), surely there weren’t enough severe cases in the database to match prospectively?

I don’t see how it’s any less scientific to do that retrospectively when the data becomes available, particularly when you take the sensible approach of selecting severe lower GI, which has the highest death rate and is the most refractory (hence the increasing popularity of FMT) and find correlations with response, survival, being off immune suppression (and likely shift from M1 to M2 shown by increased IL-10, which Dr. Lightner independently verified in her work on MSCs for fistulising Crohn’s Disease).

An End to One Size Fits All?

Standardized biomarkers would also reduce the questionable practice of giving everyone steroids first-line and, in many cases, Ruxolitinib second line when a significant number don’t benefit and could be harmed.

@LeftYahoo has said steroids shouldn’t be replaced any time soon. Malard et al. seem to beg to differ:

“Biomarkers that are predictive of the risk of NRM and resistance to treatment in patients with acute GVHD115,116,117 have been developed and efforts must be made to implement their use in routine practice to evaluate first-line treatments for acute GVHD in patients with a high risk of resistance to steroids. This is particularly important given the irreversible tissue damage in refractory acute GVHD caused by epithelial stem suppression by steroids”.

Malard et al stress the need for steroid-sparing therapy, which is particularly relevant to children.

One reason perhaps centers define steroid refractoriness differently is that people can be refractory in different ways. Steroids “worked” for my younger daughter who had Crohn’s Disease but her doctor couldn’t get her off a high dose; steroids didn’t work on my eldest daughter at all (as in zero effect, even with FOUR HUNDRED mg IV). Then you have a category who may have had a partial but unsatisfactory response.

It must surely be possible to predict from biomarkers who will be steroid refractory as you can through other means? My daughters’ doctor told me EEN had the power of 60 mg steroids in my younger daughter who had Crohn’s Disease (I’d say more like 100 mg) but it hadn’t worked in my elder daughter (lower GI IBD) and therefore steroids wouldn’t. I never understood the logic of that but he was right.

Over the years, we’ve been regularly informed that steroids “work” for GvHD.

I’ve referred to studies here (ie. Bacigalupo et al) that steroids don’t work that well for anything other than mild GI. Carpenter et al. are specific in that only ⅓ of cases get a durable response. In the durable response category, we have to consider the percentage of predominantly skin (which steroids do a good, often temporary, job with) and milder GI and also that among those responders, there could be patients like my daughter who couldn’t taper off a high dose.

Peer-reviewed literature, highly respected BMT experts, patients and caregivers report a different reality:

A couple of years ago, I came across a beautifully written blog from 2018 by a mother whose little boy underwent two BMTs at the RCH here in Melbourne and suffered acute GvHD. He was being starved on steroids and begging for “just a little bit of porridge”. She said her son’s reality was literal torture:

“Whilst so many sophisticated measures are instituted to address the suffering from pain and nausea in paediatric patients, it floors me that there is no alternative to the treatment of gut GvHD”.

Six years later there is still nothing on the market for gut GvHD.

IBD: A Move to Precision Medicine.

Biomarkers are emerging in IBD which shares features with GI GvHD.

There are three phenotypes of Crohn’s Disease: fistulising, inflammatory and stricture-causing. The market is substantial for each in pediatrics alone. Lower GI is particularly refractory.

While biomarkers in acute conditions seem more easily identifiable than in chronic ones, there is great interest in doing so, even in CBP, which is challenging because there are so many different causes of pain. Even without biomarkers, surgery is known to cause acute inflammation and there’s obvious application to inject at the time of spinal fusion to optimize results.

Chronic illnesses are not stable in my experience anyway; they cycle through acute phases as the body tries to cure itself. This is particularly true of children who are prone to higher fevers and skin rashes. A standardized panel of biomarkers would identify the best point of intervention (to prevent strictures, for example). Patient selection is as much about timing.

ST2 is emerging as a promising biomarker in IBD (Boga et al., 2016) and in addition to TNF alpha 1 that we know of, Boucher et al (2022) found 13 analytes with “highly significant association” with Crohn’s Disease, among them IL-2Rα, IL-8, and HGF, as per the panel proposed by Malard et al for GvHD.

Many thanks to @Wilba32 for posting the link to a talk by Dr Amy Lightner. Her (now independent) observation is consistent with what MSB reports in that the patients with the most severe inflammation respond the best. The thrust of Dr. Lightner’s talk is that identifying the individual is key to optimal efficacy.

Dr. Lightner discussed the move from animal models to organoids (Do these qualify as what FDA called an in vitro diagnostic device?) which has surely allowed the study of a matrix in a dynamic environment by as Tran et al. (2020) say putting “ the patient in a dish”.

Malard et al. give a lot of weight to the importance of the microbiota, saying FMT is “one of the most promising” approaches. Evidence is compelling that restoring the gut barrier will switch off the cytokine storm, which in turn would improve or enable improvement of the microbiome. It’s well known that more diverse gut flora is linked to improved survival in GvHD survivors.

Using organoids, it would surely be possible to test your matrix not just on pro- and anti-inflammatory biomarkers but on the specific effect of restoring tight junctions, which Ara et al (2021) say is key to restoring gut barrier integrity. Authors say the mechanism through which GvHD causes gut injury has been “studied intensively using a gut organoid culture system”.

Re. chronic illnesses, specifically IBD, Tran et al. say, “Individualized cellular models of disease are a key tool for precision medicine to recapitulate chronic inflammatory processes”.

Pediatric Cytokine Storms

The cells responding best to high levels of inflammation means Ryoncil has pediatric cytokine storms written all over it.

For some reason, I got obsessed with these from around 3 years ago and wrote a few posts on MIS-C,HLH, MAS such as this one 47293890

Viral immunologist and computational biologist Jessica Rose has “a bad feeling” about the incidence of HLH. So do I. I’ve often wondered why journalist Alex Berenson picked up on a single case of sepsis. (HLH is said to be “rare” but is often misdiagnosed as sepsis.)

Rose embedded a comment in her article from a hematologist who had seen a big uptick in HLH cases - 1 case of HLH in 9 years but in the last 2 years, seen 5 patients with this condition. Only 1 survived because she was able to start early treatment with him.

Prompt diagnosis is essential for this condition, which is highly fatal, and Rose linked to a YT video (below) by the lovely Dr. Eric from Strong Medicine who gives a clear explanation of what to look out for. He says two important lab tests are rarely done:

Lowered NK cell activity

Elevated IL-2 receptor (CD25)

The steroid most commonly used is Dexamethasone because, as Josh Farkas (whose blog is Pulmcrit) says, it has superior penetration of the central nervous system.

MSB had an EAP in another cytokine storm MIS-C and has data on Remestemcel-L’s effect on NK cells in ARDS. We know the cells have particularly strong action on gut inflammation, including grade 4 hemorrhaging. HLH is known to cause bleeding disorders and hemorrhaging.

The Commercial Product

I appreciate the extreme difficulty of introducing paradigm shifting technology in the form of a biological product into the world as it is today. A product isn’t just what it is, it's also what people think it is. You have to deal with both and consider all interested parties.

MSB intends to generate a potency assay for the product used for GvHD001 to ensure “that commercial batches made for the pediatric indication will meet the same standard”.

My first thought when reading this was to ask who’s talking and who’s being addressed. This is imo the most powerful statement the company has come out with (especially considering the timing and wording) if you’re aware of the sh$t fight that’s blown up in the last week over a biological product of a different class (which could be the reason for the push for even more extreme censorship I referred to here a month ago)

Add to that we already know how crucial the process is in the commercialisation of a biological product. The cells have to be guaranteed free of mycoplasma and endotoxins. When I wrote here a few years ago that MSB was all about contrast, I never imagined to this extent!

This looks much bigger than MSB and the FDA to me. A global war is going on with a pattern of attack and counter attack. I can’t say what the future will be. What I do know for sure is that a disaster exists in all areas MSB has candidates for.

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

https://pubmed.ncbi.nlm.nih.gov/31816061/

https://pubmed.ncbi.nlm.nih.gov/28971905/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730700/

https://www.youtube.com/watch?v=LCZOjqv8-9I&ab_channel=ColorectalSurgeryVirtualEducationSeries

https://www.youtube.com/watch?v=uXDktSTsz5U&ab_channel=StrongMedicine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779798/