Ann: FDA Notifies Clinical Data Sufficient for Refiling aGVHD BLA, page-554

Ryoncil, More Than Acute GvHD?

At the last AGM in the group at the end SI said something a bit jarring - uncharacteristically glib for someone who usually has gravitas.

He asked us to guess what medical insurers were willing to reimburse for Ryoncil. There was a brief silence, so I suggested 500k (US). If I recall right, the figure stated was 800k (US).

Then I suddenly saw the focus on the potency assay in a new light. This is a window onto the process of turning science into a product. This is what a REAL standard looks like, not telling but showing. IMO this is a public demonstration of respect.

Dr. Rapaport’s Sympathy for Patients and Insurers

Anyone interested can follow (and comment on) the row on Dr Rapaport’s fb page. IMO it’s relevant to us in several ways.

Select Health of Utah is no longer reimbursing an extremely expensive mab drug for eczema, which has been heavily advertised on TV in the US.

Dr. Rapaport is a mainstream dermatologist who brought the condition of topical steroid addiction (TSA) to public attention. He says most cases of severe eczema are misdiagnosed and are actually TSA.

While I disagree with him that the drug is useless (IMO his view is understandable because he’s getting so many of its failures), I do think it’s likely maintaining a condition and even preventing a cure.

(Re. IBD, IMO insurers are likely to have a jaded view of the original mab biologics which haven't been as effective as we were led to believe. They haven't reduced surgery rates and many patients are refractory; those who are not refractory have to take them long-term to maintain trough levels. Infliximab is the best. It does work. My eldest daughter has had infusions in hospital every 3 months for a decade for Crohn’s colitis. IBD, however, can be cured by dietary therapy, particularly if done in childhood. I advise dietary therapy under medical supervision, as per Seattle CH.)

My younger daughter suffered from TSA. She, like many others, took herself through a severe acute phase under the supervision (including medication) of our family GP and ended up with a cure.

Don’t take my word for it. You can find articles and papers by Dr. Rapaport (who’s got a long publication record in top journals but since the expensive drug arrived on the market, he’s been rejected by 4) and case studies on the Itsan site: https://www.itsan.org/ You can look through hundreds/thousands of people’s photos, as I did, who document the daily progress of their skin.

The documentary Skin on Fire has over 100k views on YT. I put a link below to an article by the Royal Australian College of General Practitioners showing the distinctive ‘elephant’ skin, edema and flaky skin that falls off like sand.

This is a long-winded way to say that, at least for our largest organ, this “incurable chronic” condition is a myth and, while not every case is cured, the proof that it can be is indisputable.

It’s specifically relevant to us because it speaks to a therapy that’s able to support the natural process of the body.

The Benefit of Acute Inflammation

I know instinctively the benefits of fever. I don’t take anything to reduce it if I get a virus. When I had inflammatory arthritis, I didn’t want to take the Methotrexate the rheumatologist recommended, so my GP prescribed an off label drug. I had fevers for days. After they subsided, I went from being unable to walk without support to being able to almost run.

My question for the experts: Can acute inflammation be harnessed to prevent fibrosis?

Anti-fibrotic action is something of a holy grail. I wonder if it has to do with allowing acute inflammation to do its thing but not overshoot? I’m NO scientist but does this perhaps relate to what Prof Caplan (RIP) said about the tip of the finger being able to regenerate if you don’t put a stitch through it?

Heart

Re. our Dream HF trial. Highly respected cardiologist Valentin Fuster didn’t appear to view it as a failed trial. He seemed very impressed, particularly by the finding of CRP, a biomarker of acute inflammation.

Does Valentin Fuster suspect/know acute inflammation could prevent further fibrosis?

Re. LVAD Injecting cells is invasive but consider how invasive it is to put in an LVAD, which raises IL-6, another biomarker of acute inflammation. It makes sense to inject at the same time. Most surgeons are looking for ways to improve results.

I don’t understand the mechanism - the cells have myriad pathways - but I do believe we have compelling evidence of vascular repair, which speaks to a deep truth.

Amidwesterndoctor is a group of elite doctors who IMO have control of the pharma industry. They say we fundamentally misunderstand the heart, that it’s more than ‘ a mindless pump’ but directs the correct type of blood to where it’s needed. They just “happened” across research by Goncharenko based on studies in the 1970s.

AMWD are (rightly) critical of these cruel animal studies that showed damage to the heart caused necrosis of tails and other extremities; however, if any good can come of them, they support MSB’s finding of remote benefits in both LVAD and Dream HF.

Most importantly, it speaks to the sense of using cells which can communicate intelligently with an intelligent organ.

GI GvHD

Obviously you can’t let acute inflammation rampage in the gut because of the risk of malabsorption, severe diarrhea and infection, which can all be life-threatening.

GvHD001 targeted the most acute inflammation. It shows benefit not only in long-term survival but good survival because 87% were able to come off immune suppression within 6 months.

The study comparing MAGIC controls was retrospective - couldn’t have been prospective because biomarkers for all organs weren’t validated at the time of trial design - but almost half of Remestemcel-L group had severe lower GI as measured by MAP and 64% survived vs 10% with high MAPs of controls despite greater weighting of severity in the Remestemcel-L group.

Anyone who really knows this condition or has taken the trouble to learn about it will have no doubt whatsoever the cells work.

Not only are there all these correlations within the lower GI GvHD subgroup and negative correlation with MAGIC controls, the MAGIC controls correlate with IBD too, which is known to have similar features and the lower GI subgroup known to be particularly refractory and severe in children and young adults (See below for a doctor telling it exactly how it is). My elder daughter's doctor has PTSD from her case.

MSB targets the most severe C/D cases - skin, liver, gut and lower GI (Of the 32 patients followed through 180 days, there were only 8 cases of chronic GvHD, 6 mild, 1 moderate, only 1 severe. 46.9% discontinued systemic corticosteroid use.

I think children able to come off steroids alone would be very attractive to medical insurers because of the AEs they cause.

The Acute Platform

At the 2023 AGM in the small group at the end, SI said they all thought this time Ryoncil would be approved. I said I hadn’t been so sure and he asked why.

I said I thought they all did the right thing and mumbled that IMO Ryoncil was hit by its own goodness (I put forward my theory in this post 70277418 that our poor reliable tortoise would be used to validate the MAGIC algorithm.)

I don’t think this is the reason for the 2nd CR tho. I put my concerns in this post 68523605. My speculation is that the timing was unfortunate. Higher powers may have moved to protect our precious platform from any untoward association.

Dr. Krause and SI have IMO demonstrated their integrity and superior knowledge of immunology and manufacturing across both platforms, which would put any fears to rest.

During his presentation, SI showed one science slide and said it was the only science one - the cytokine storm one.

There are obviously broader applications. Any product that targets severe lower GI and can even heal grade 4 intestinal hemorrhaging has pediatric colitis written all over it. (Diagnosis of UC and Crohn’s colitis often overlaps.)

Colorectal surgeons are wary of operating on Crohn’s cases, particularly in children and young adults because it can go crazy. They work closely with physicians to avoid surgery; however, surgery can, in many cases, greatly improve QOL and save lives.

Boston Children’s Hospital is seeing some very severe cases of IBD and looking into therapies targeting IL-2. Michael Goderre (2023):

“The current therapeutic arsenal for ulcerative colitis is grossly inadequate; more than half of patients do not go into long-term sustained remission,”

IBD can grind away in a chronic phase then suddenly erupt. There are fevers and skin rashes during this stage, as in the case of JIA.

I’ve previously quoted Peter A Nigrovic, who asks in his review published in 2014 in Arthritis and Rheumatology, if a window of opportunity in systemic JIA exists:

“While some patients continue this so‐called systemic phase for years, a more common course is for fevers and rash to fade away, leaving behind a chronic, destructive, and often therapy‐resistant arthritis. Recent data have raised the possibility that early cytokine blockage might abrogate this latter phase, reflecting a potential “window of opportunity” in the care of these challenging patients".

Researchers are looking for biomarkers to identify this window. Ziegler et al. report on their study finding soluble interleukin-2 receptor (sIL-2R) predicts relapses in JIA.

JIA is treated with various biologics but steroids are still used and NSAIDs which damage the gut, which in turn risks the heart. (Vioxx caused many heart attacks and was known to have GI effects) Koca et al (2016) report on cardiac involvement in JIA.

In summary, acute inflammation, particularly with children and young adults, presents an opportunity to intervene and prevent a long-term chronic phase. There’s a tendency to start with the cheapest options - steroids and NSAIDs - but the more heavily a patient is treated, the more risk of becoming fibrotic. It’s a false economy.

If a lesson could be taken from IBD, how children respond and the experience the early biologics, it’s to use your big gun early.

https://www.racgp.org.au/afp/2016/june/topical-corticosteroid-addiction-and-withdrawal-an

https://www.midwesterndoctor.com/p/how-the-heart-controls-exactly-where?utm_source=publication-search

https://pubmed.ncbi.nlm.nih.gov/34471240/

https://answers.childrenshospital.org/ulcerative-colitis-il-2/

https://www.researchgate.net/publication/260755334_Review_Is_There_a_Window_of_Opportunity_for_Treatment_of_Systemic_Juvenile_Idiopathic_Arthritis

https://pubmed.ncbi.nlm.nih.gov/27417551/