Ann: Ryoncil Commercial Launch Update and Product Pipeline, page-244

Please note this post contains confronting details about intestinal GvHD.

A common propaganda tactic used in the legacy media and on this forum is the encouragement to reason through association. IMO it’s the most dangerous way to think in the stock market and, far more importantly, in life. My strategy is to try to look at the thing itself and nothing else, from all angles, then at the context in which it exists.

In the case of Ryoncil, there are three main things:

• The product (MOA, manufacturing process, safety and efficacy)

• The condition of acute GvHD (immunology and size of market)

• The payors (This is one I find difficult because I have zero industry knowledge. I don’t know how insurers think but I offer a third-hand tidbit that may give some insight)

TLDR: This post is my attempt to apply my reasoning to Ryoncil to get an idea of reality. IMO MSB has a significant data set to support label extension for adults. Insurers could be prepared to pay around US 800k per patient (a price mentioned in the AGM huddle in 2023). A price of approximately 1 million per patient could be set against healthcare costs which can run into the millions for a badly surviving child or young person. Steroids are a false economy. Ruxolitinib is doing more harm than good. Insurers have invested in a BMT, which is very expensive, and it makes economic sense to protect your investment. There’s a specific reason why they should favour Ryoncil over Rux: a very good study is in the public domain and can be circulated to insurers.

There is No Effective IV Therapy for GvHD, Other than Ryoncil

After a delay of over four years, Ryoncil has been approved for children and adolescents. This has introduced a whole new level of cruelty to sufferers of GvHD and their families.

I recently searched for Ryoncil on fb. The first comment I came across was by a woman who’s relieved about the approval because her husband is undergoing a BMT. On the forum I belong to, a mother asked if she’s stupid to hope her young adult son could survive severe GI GvHD. One of the replies asked if she’d considered the new drug.

(It’s a reasonable assumption to make because it’s unusual for a drug to be approved in children before adults)

What happens in such a case? Sorry, you’re over 19. You’re getting increased doses of tablets Jakafi and Rezurock administered concomitantly? That’s what's going on, including for children under 12. One suggestion was to crush them up and mix with water. It comes from a place of kindness but it’s not helpful if the patient is nil by mouth. In the study by Neumann et al., all four patients with severe diarrhea died, even though the Ruxolitinib tablets were crushed up. I suggested asking the doctors to contact MSB about the EAP. I hope it’s still available.

Sufferers and/or their family members have reported spending months (“languishing” was the word SI used, which nails the reality) in ICU, and even a year in hospital on TPN (fed through vein in neck). They've undergone multiple operations to remove, in some cases, vast amounts of intestines and speak of tissue so friable doctors are afraid of doing a scope because of the risk of making a hole in the lining of the gut.

The need for an effective IV option is obvious. In this post:: 70277405, I reviewed most of the commonly used ones listed by Malard et al (Nature, 2023) for their SR treatment algorithm.

I’m confident in stating that apart from Ryoncil, there are ZERO effective IV therapies for anything other than mild intestinal GvHD (including steroids). Macmillan et al., 2002; Bacigalupo et al., 2017 give a good indication of the inadequate job steroids do, particularly for GI. Anyone can also check with a transplant expert, as I did.

If X is the case, we wouldn’t be seeing Y

If an effective IV option existed, Infliximab, which is known to deliver very poor results in both chronic and acute GI (Sleight et al. 2007), wouldn’t still be used as recently as in Reach2 and the Agrawal study, which includes data up to 2018. IFX is considered the best biologic for IBD but it was never that powerful, which is why soon after launch, recommendation was to use it early after diagnosis. In GvHD IFX is acknowledged to cause a very high rate of Infections.

The study by Agrawal et al. in IFX in SR-aGvHD is one of the largest. Authors don’t conclude by saying it’s promising or even active. They simply repeat that SR outcomes in aGvHD are poor. Out of 59 patients, there were only 16 responders and survival at 36 months was 42% for responders and 15% for non responders. That means only about 12 of 59 patients remained alive at 3 years. Authors report a high rate of viral and bacterial infections.

Patients and/or their relatives have reported that the GvHD couldn’t be treated because of an existing infection. They’re on multiple lines of immune suppression and doctors are concerned about therapies which may cause further suppression (This could be a signal from clinical practice of awareness that the incidence of graft failure is increasing.)

MSCs are increasingly referred to in literature as “immunomodulatory” (rather than broadly immune suppressive). Kadri et al (Nature, 2023) discuss current perspectives on MSCs and specifically mention remestemcel-L. In the abstract they say (my emphasis),“MSC-based therapy has shown an exceptional safety profile.” In his public reply to me at the last AGM SI stated they’re not seeing relapses in malignancies.

We’ve been informed BMT CTN will run a pivotal trial in adults. Ryoncil, being so consistent, can be used to validate the MAGIC algorithm. It will be good to have an industry standard and hopefully biomarkers ST2 and REG3α could be used as a “liquid biopsy” to reduce the need for an invasive scope. Enrolment could be faster now we have approval for children and teenagers but how long will the process take?

IMO MSB has enough data set to support label extension for adults now.

Real World Evidence

RWE can be confounded by prior or concomitant treatments but in the condition of SR-aGvHD - the thing itself - that’s not the case. This is not my opinion but anyone can check for themselves, as I did:

Years ago, there was disagreement on this forum that MSB’s cells cured stage 4 SR-aGvHD intestinal hemorrhaging in a child treated on compassionate grounds.

In fairness to the naysayers, at first reading, the published article was ambiguous because of its title (I contacted the journalist and there was confusion between the “two transplants.”)

Before contacting the journalist, I emailed a transplant specialist. I chose this physician/researcher because of the simplicity and precision of their writing and research ahead of the curve.

I asked a general question along these lines: I”d read an article (I gave a link to) about a child suffering severe GI SR-aGvHD. The way the text read she was cured by MSCs but the title suggested the child could have been on another drug. Perhaps this other drug was doing something or there was a delayed effect that might have kicked in or some kind of synergy?

Physicians don’t usually comment on specific cases but can give a general principle.The answer was a polite and unequivocal No. My point was well taken but in this condition, if the treatment is not working and something is added, the effect is attributed to whatever you added.The effect was that the child fully recovered from aGvHD, which can be attributed to Ryoncil.

KOL Dr. Susan Prockop’s statement IMO supported this. I recall her saying in an interview that in this condition spontaneous remissions do not occur.

Patients are referred to the EAP in a very bad way. They’re referred because whatever treatment they had hasn’t worked. That means any remissions or cures can be attributed to Ryoncil.

Safety

(I thought it best to give my take on potential AEs here in light of knowing MSB’s cells healed grade 4 intestinal hemorrhaging which the child’s father said would take a miracle to cure and my recent WTH?? moment when I read the FDA insert listing “hemorrhage” as a potential reaction. I figured it was just legal stuff but even so, “reaction” is a loaded term that implies causation to me, tho I doubt physicians familiar with this condition will see it that way:

The literature acknowledges that in SR aGvHD, treatment-related AEs are difficult to separate from the disease itself, particularly in the worst cases. Kurtzberg et al. say of GvHD001:

“A total of 16 TEAEs in 9 patients (17%) were assessed by investigators as possibly related to remestemcel-L treatment. Ten of these events were nonserious and expected in this disease population.”

I’ll use hemorrhage as an example. The conditioning regimen is known to damage the gut. Hemorrhage and respiratory failure (gut/lung axis) are common in severe aGvHD, particularly in our severe GI cohort. Physicians would know this. Nevo et al. (1999) say acute bleeding is common after allo-BMT and bleeding events occurred in 40.2% of their GvHD cohort. They were late events compared with non-GvHD, occurring up to 100 days after onset of acute GvHD.

Skin is usually the first organ to show aGvHD, so perhaps in the case of non response to steroids, Ryoncil was administered but the damage to organs had been done and could take time to show (ie blood in stools). The MOA of the cells is to set off a healing cascade, so I doubt they’d work instantly (The body likes to heal from inside out), tho the cells could still have reduced severity. It's important that there were no grade 4 or 5 reactions.

Further, the sheet states hemorrhage “is a composite which includes multiple related terms.” One of those could be hemolytic uremic syndrome, which can cause bleeding symptoms, and Kurtzberg et al. say is expected in this population and unlikely to be causally related to remestemcel-L)

A significant number of adults have been treated in the EAP, so we could have a data set to support label extension. Having said that, there are still those who say randomization is the best evidence to support efficacy and safety. This is speculative, but perhaps we have a data set from that too?

ARDS RCT

SI did a recent interview with Bloomberg in which he referred to Ryoncil’s potential application for inflammatory lung conditions. He mentioned Covid ARDS. We have the first ever approval for a MSC product. That being the case, IMO it’s uncharacteristically clunky to mention a “failed” Covid RCT in the same interview. Unless it didn’t actually fail?

When the ARDS RCT was designed (with help from the FDA), I thought it very clever in that it might have a secondary purpose in saving high-risk SR-aGvHD adults in the control arm of a RCT from getting Ruxolitinib. The Covid ARDS under 65s subgroup were prespecified (Most BMTs recipients will be under 65.)

Covid is a respiratory disease and the lung is now finally officially recognised as a target organ of acute GvHD (Malard et al. 2023).

Lung GvHD is significantly underreported because it’s difficult to diagnose and treat once fibrosis sets in. Patients have reported suffering no GvHD for months, even years, after HSCT but then get a diagnosis of cGVHD and other conditions of the lung. Chronic lung conditions have a high health care burden both in terms of treatment and hospitalisations over years.

Scheid et al 2022: “According to current literature, approximately 50% of patients develop a cGvHD after allo-HCT [2], with a subsequent 10-year disease-specific survival of 51%.” They found this population has a high rate of hospitalisations.

Prevention is best. Cytokine based and other biomarkers (ST2 and REG3α) could identify who is most at risk in chronic as well as acute GvHD. Depriest et al. (2022) found REG3α was predictive of chronic GvHD of the gut. Iacobescu et al (2024) discuss proteins of the extracellular matrix which could predict bronchiolitis obliterans syndrome and GVHD with pulmonary involvement.

Ryoncil as a Prophylactic

The paper by Bowdish et al. is a compelling indication to me that the reason for the neutral overall effect had nothing to do with our product. I’ve cited Remy et al (2020) who say severe Covid was not a cytokine storm. I think, however, Bowdish et al are correct about the existence of two subphenotypes, one characterised by hyperinflammation. What they say is supported by clinicians such as nurse Gail Macrae (who found very high CRP in patients) and critical care physician Prof Paul Marik and other physicians. They favoured using high doses of steroids (I think I was wrong about this) and were highly critical of the in-hospital treatment protocol.

If it’s the case that remestemcel-L was appropriately administered according to inflammatory biomarkers (as in the EAP) in the first half of the trial, and four-year follow-up data show the prespecified under 65s in the treatment group are doing better than placebo + SoC, then that would speak to an anti-fibrotic effect, which is highly relevant to GvHD.

(Further, on potential adverse reactions: While the Covid ARDS trial used only two infusions, if Remestemcel-L had caused serious AEs, you’d expect to see a safety signal. In Table 2, I can’t see any signals of the adverse reactions stated on the FDA package insert for Ryoncil. I can see a clear signal for kidney damage from Remdesivir, however, which ⅔ of the cohort were on concomitantly because of the government-enforced treatment protocol. Cardiac issues from Remdesivir have also been reported, such as arrhythmias (Dhaliwal et al. 2022) and even heart blockage (Nabati et al. 2021)

The price for Ryoncil should be high because it’s a curative therapy. Cure means being able to taper off steroids (as Kurtzberg et al state) and thereby reducing steroid-related AEs, not suffering chronic GvHD symptoms, not suffering malignancy relapse and having to undergo a second BMT, which is not uncommon, at a time when the rate of graft failure is acknowledged to be increasing.

BMTs are very expensive and It makes sense to protect your investment. I’ve emailed MSB the paper by Moiseev et al, reporting on their prospective study in Rux in severe SR acute and chronic GvhD with a high proportion of severe GI involvement. They found no difference between children and adults. The paper is of high quality because it used biomarkers and it’s one of the few long-term follow-ups. Rux inhibits gamma interferon which is said to preserve the graft versus tumour effect. Only interferon gamma showed a marked decline in their study, which also found a high rate of malignancy relapse.

The Macro: The Revolution and The New Administration

The US and Canada have IMO the brightest, best informed and fiercest health activists. RFKjr’s campaign was built on Warrior Mothers. His running mate was Nicole Shanahan. Relevant to us, dietary therapy in IBD was driven by activists in the US, indicating the root cause was dysregulation of the microbiome ( later affirmed by Prof Borody’s work in FMT). Itsan was founded in the US and provides irrefutable evidence (hundreds of photos and peer-reviewed literature) that eczema is entirely curable. While it’s a long and difficult road to recovery, the work of dedicated physicians and laypeople is showing chronic disease, particularly in a child, is not incurable.

UK cardiologist Aseem Malhotra is the face of the revolution and a key adviser to the new administration. In lectures and interviews he speaks of an epidemic of chronic disease. He stresses the importance of prevention and a diet to improve metabolic health. I think the Malhotra plan will be the way the US will go because Intelligence Operatives are already in place in leading US hospitals to drive it. (A couple of years ago, I got a reply from someone at Mass General to a comment I made on the forum of a journalist mentioning the metabolic theory of cancer. I can post it on another thread if anyone’s interested.)

Part of prevention is to halt the inevitable progression in those who already have CHF. It makes economic sense to protect the original organ amid rising healthcare costs. AM is a close friend of RFKjr, who’s a supporter of stem cells, which is why he could be good news for us. I’ll judge him on what he does tho.

I’ve listened to RFKjr directly. What he says about Remdesivir fits exactly with my research and investigation. He also said he had a misconception about something I’ve written here. He thought that of all stakeholders, insurers would want the population to be healthy but an insider told him they would want 100 Titanics to go down, rather than just one, because they make money on premiums. The entire system is rigged to foster a sick care industry. AM recently tweeted that the whole “psychopathic house of cards will fall.” If RFKjr keeps his promise, the industry will get a long overdue boot up the a$$ and we could return to ethics and doing what’s best for the patient, which is in reality a win for everyone.

All IMO GLTAH

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