@JB1975 Thank you for your reply: 71919120
My response is very long. You’ve been generous in providing information on this forum and said you don’t mind responding in detail to those who want to learn. I hope you can answer a few questions. Please feel free to correct any errors:
Dr. Krause said the FDA accepted the efficacy of GvHD001. In support of this statement is the timing of the FDA document stating a single-arm trial in SR aGvHD could be acceptable
Despite this, you and the doc duo have repeatedly said MSB should have run (what Whytee calls a “proper”) RCT.
I don’t know your motives for keeping the focus on the single-arm trial design but I know mine. IMO it shows:
Much of the content of your post is ad hominem, which you say you despise. You say your aim is not to mislead but I see a pattern of omission in your posts.
1.In this post67033517I asked you why you quoted the authors’ statement that OR wasn’t statistically significant but you didn’t mention the subset of high risk graded according to MAP.
Nearly one half of the Remestemcel group were diagnosed withsevere steroid refractory lower GI measured by MAP but 67% survived compared to 10% of MAGIC controls.
If you dismiss this data, I wonder if you've taken the time to learn in depth about the condition of acute SR lower GI grades C/D or severe inflammation of the colon.
There’s limited data on children because they tend to be tacked onto adult studies. Bivasco et al. (Nature, 2022) say there is a lack of information specifically on lower gastrointestinal tract therapy-response,
You’d expect survival in children to be higher than adults; most studies state younger age as a predictor of better survival; however, accepting lower GI tends to be more severe in children (a pattern seen in IBD, which shares similar features), it’s reasonable to think survival in this subgroup could be on a par with adults or even worse.
Lower GI involvement is known to have the poorest outcome.
In their study of 443 children's response to first-line steroids, Macmillan et al (2002) found lower GI had lower response rates; there were few upper GI, only 24% at grade 1; rectal involvement was 3% at grade 3 and 1% at grade 4. Despite a low percentage of severe GI involvement, survival at 1 year was only 55%
A more recent study (2019) by Macmillan et al. reported on response of 377 children to upfront steroids There were no cases of upper GI beyond grade 1 and lower GI grades 3 and 4 were 5% and 2% respectively. Despite less severity of GI involvement, 165 children had died by 24 months.
Hooker et al. (2021) say steroid response decreases with increased disease severity and mortality for lower GI can be around 80%.
Biavasco et al. analyzed only GI response finding lower response and higher NRM than studies which include all organs. Authors say GI involvement is associated with steroid refractoriness and lower NRM (with my emphasis):
“Survival data of our analysisclearly confirm the dismal outcome of patients with SR-GI-GVHD in terms of OS and non-relapse-mortalityreported by others, supporting the importance of early and intensive treatment of SR-GI-GVHD patients”,
Authors say the treatment of GVHD affecting the lower GI tract is “particularly challenging, due to the fluid- and electrolyte loss caused by secretory diarrhea, the risk of severe bleeding, especially if concomitant thrombocytopenia is present”.
Barker et al (2005) say gastrointestinal bleeding in children was disproportionately represented in intensive care unit admissions (5/27) and 100 day mortality (5/21). While this study is quite old and you’ll read that incidence of GI bleeding has decreased over time, recent data indicate it’s still significant:
Reach2, included 4 children under 18 on the treatment arm. 19 patients (12%) who had received ruxolitinib and 11 (7%) who had received control therapy had grade 3 or higher bleeding (hemorrhage). The most common AE up to day 28 was thrombocytopenia: 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group.
In the study by Biavasco et al., out of 144 patients, two (possibly three) died from GI bleeding.
Interesting Docmcstuffins referred to the Zaidman study because it appears to support MSB’s data. It’s a weird study IMO. Given the current severe censorship, I wonder if its purpose is to draw attention to MSCs and if it could be a sign the dogs have been called off the kids?
I live in hope.
Zaidman et al. report on high survival (71.4%) in 35 children with severe aGvHD. They say the cohort “includes lower GIT” but don’t give the percentage and grading for this organ.
Steroid nonresponders were treated with a variety of second and third-line options: pulse steroids, ECP, anti-TNF, MSCs, Methotrexate, Campath, Sirolimus and JAK1 inhibitors.
I looked into most of these therapies for SR aGvHD in this post70277405. Additional to that:
Campath(Alemtuzumab) gets highly variable results and is one of the most immunosuppressive drugs, associated with a high rate of infections.
Khandelwahl et al. (2016) report on a study in Alemtuzumab in 15 children. Almost half (7 patients) of the cohort had zero or low GI involvement and the best response was in skin. 7 required additional immunosuppressive agents. Survival (12) is only given for six months.
IMO the authors included less severe GI involvement because of their previous study (2014) reviewing the charts of 19 children and young adults (median age 4) suffering grade 3 and 4 SR aGvHD with majority GI involvement. (Lower GI isn’t specified.) In two years, 14 patients had died, two of acute hemorrhage.
Methotrexate,Sirolimushave been used for decades, usually for lower grades. I doubt either would be suitable for severe GI. Sirolimus is orally administered. Lifschitz et al. (1989) found Methotrexate increased intestinal permeability in children even in a low dose.
Authors don’t specifyJAK1 inhibitors(Rux is Jak1/2). Schroeder et al. (2020) report on a phase 1 trial in JAK1 inhibitorItacitinibcombined with steroids. Most of the cohort of 29 were grade 2 and 3. 58% had lower GI. Nonresponders generally had higher levels of ST2, TNFR1 REG3A compared with responders at most time points. There were 17 deaths and 2 patients withdrew. Grade 3-4 hemorrhage occurred in 4 patients.
Anti-TNFagents aren’t specified either but my previous post referenced studies with poor results for survival withInfliximabandEtanercept.
After the research I’ve done, I’m sceptical that any of the above options was a significant factor in averting a dismal prognosis.
Zaidman et al. attribute nonsurvival to the sourceof stem cells andpoor response to steroids. GIT involvement had a worse prognosis. They attribute higher survival to a variety of factors but the only therapies they specifically mention in the context of survival are ECP and MSCs.
ECP is known to do the best job in cutaneous skin GvHD, which has the best prognosis.
While authors don’t specify the number who received MSCs, I think a physician familiar with severe aGVHD would home in immediately on MSCs because everything else listed has been standard practice for decades (ie. close monitoring for infection, antifungal and antiviral prophylaxis).
I’m no scientist but I thought it was as much about reasoning as facts and trying to be precise in your terminology. When you talk about whether or not a therapy “works”, what do you mean?
In the Zaidman study, survival was high but there was a high rate of chronic GvHD (37%), which is the same percentage stated by Hooker et al. (2021) and consistent with the Macmillan (2002) study (42%) but lower in their more recent study (22%) Notably, the primary cause of death in both Macmillan studies was GVHD.
No mention as to whether survivors could come off immune suppression, which is important for long-term survival and quality of life: GvHD is profoundly immune suppressive in itself, as are the drugs used to treat it.
In the case of GvHD001, survival for children with lower MAP was consistent with MAGIC controls: however, for the subgroup with high MAP scores, the difference in response and survival was stark.
Despite extensive crypt damage, Remestemcel group not only achieved response within 28 days but 87% were able todiscontinue immune suppression within 6 months.
I have no doubt any physician familiar with treating high risk patients suffering aGvHD would conclude MSB’s trial shows efficacy incuringSR aGvHD.
2. You and the docs focus on Professor Kurtzberg but you don’t mention Dr. Susan Prockop.
It’s the very low key people who get my attention. Dr Prockop gave her talk with that din going on in the hospital. Her testimony from the EAP supported the data from 001 (a child treated relatively late but was still able tocome off all immune suppression).
If I recall right, Dr. Prockop said after her experience of treating 3 patients with Ruxolitinib, her center wouldn’t be participating in a clinical trial. Most importantly, she firmly but tactfully dispelled a myth. That’s why I looked her up.
You know a lot about MSCs, so surely you’ve heard of Darwin Prockop (RIP)? His obituary says he was an expert on stem cells and gene therapy.
And don’t forget Dr. Paul Carpenter. I wouldn’t be surprised if he was highly influential (I don’t know him but I know has a lack of hubris and his research is ahead of the curve (ie. vitamin A to restore gut integrity) but you can tell all that by the simplicity and precision with how he writes.
Not one, but three, highly influential experts who demonstrate superior knowledge of a complex condition who are (to use your words) “presuming against the science” the cells work?
When you say “the science” here, do you mean the effect on patients, the validity of MAP, the design of the trial? What aspect are you referring to?
3. You and the docs use the same argument that Osiris managed to run RCTs. You ignore the passage of time and the human factor: MSB has since positioned forsteroid refractorygrades C/D, has an improved product, physicians (KOLs) have become familiar with it and word is likely to have got around of Ruxolitinib’s and Ryoncil’s performance in clinical practice (MSB’s cells even curing grade 4 intestinal hemorrhaging).
By ethics, I’ve been writing mainly about the wrongness of treating children as mini adults and the importance ofproper informed consent. Surely you don’t view that as religious righteousness?
As you appear to have industry knowledge, based on what Professor KurtzbergandDr. Prockop have said in the public domain, can you give an idea of what written informed consent might look like for a trial you would consider appropriate?
4.You keep the focus intensely on the potency assay. You really seem to really know your stuff and I appreciate the information you provide and agree it’s important.
I just don’t buy the narrative of an issue with the potency assay that was within the control of MSB (or even the FDA) as the reason for the CRLs.
The FDA guidelines say the potency assay is the absolute cornerstone of such a product. I don’t see how MSB could have screwed this up! SI is an immunologist. He knows inflammation has benefits but shouldn’t overshoot and cause tissue damage but are you saying SI dropped the ball on IFN gamma which has a key role in cytokine storms?
There’s the other side you don’t discuss much: The cells have myriad pathways and respond to the milieu of the individual. Do you fully understand the pathways and complexity of the immune system, in particular that of adults or children suffering from aGvHD?
Isn’t science about considering all potential confounding factors?
I wouldn’t ask this question if I hadn’t formed the opinion our acute platform hasn’t been impacted. (All interested parties would find the data on 70+ adults reassuring, especially given the salvage position.)
Having said that, you still need to deal with the way people think. From an immunological standpoint (patient history), since GvHD001, could there have been any potential confounding factors that would have needed to be investigated and ruled out?
You’ve said SI is a “businessman” but his and Dr. Krause’s knowledge of immunology and manufacturing across both platforms would have been invaluable because they’ve both made predictions and been been proven correct.
https://www.nature.com/articles/s41409-022-01741-3
https://pubmed.ncbi.nlm.nih.gov/12171485/
https://pubmed.ncbi.nlm.nih.gov/31477785/
https://pubmed.ncbi.nlm.nih.gov/15908980/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556206/
https://www.frontiersin.org/articles/10.3389/fped.2023.1194891/full
https://pubmed.ncbi.nlm.nih.gov/27664325/
https://pubmed.ncbi.nlm.nih.gov/24384050/
https://pubmed.ncbi.nlm.nih.gov/32324888/
(20min delay)