SCEPTICISM OR DOGMA?
This is a follow-up to this post 62450704 on biomarkers and clinical trials in CHF. In the following post, I focus on IBD and GvHD. Please note it contains very confronting information about the reality of gut inflammation. Dr. Lightner’s work is important IMO because:- The features of aGvHD and IBD are well known to be similar when the gut is involved.
- There are no steroid-sparing drug options for children other than Infliximab and Humira. As I said in a previous post, the most popular biologic (infliximab) is not that powerful because it’s used as a bridge to 6mp and Imuran (mild chemo drugs) and often administered concomitantly.
- The biologics haven’t reduced surgery rates. Surgeons want to avoid surgery, particularly in children and adolescents where disease is driven by hormones. CD hates being touched and can go crazy (I know this from asking about a small external skin tag that was no longer even florid) Surgery for UC is curative (although quality of life can be impacted) but sufferers of moderate/severe CD can not uncommonly expect multiple, non-curative surgeries and procedures.
- There is an issue of ethics here with the acknowledgement of the major role played by the microbiome; not only do none of the current drugs address this but the use of broad immune suppression is called into question (Note these last 5 years terminology to describe MSCs has changed from “ immunosuppressive” to “immunomodulatory”)
- The discipline of IBD has been confronted with its own dogma in the past decade. The success of FMT has meant more openness to new therapies.
- The newer, targeted drugs that were hyped a decade ago have proved less effective for the biologic-refractory population and more dangerous (Tofacitinib wasn’t approved by the EMA for 5 years due to safety concerns).
- There’s already a precedent for direct injection of MSCs in Takeda’s Alofisel. CD fistulae are known to be monstrously difficult. That, and the stringent ADMIRE trial, where the control group received an extremely high SoC, makes me think Alofisel results are a lot more robust than Ustekinumab's, which has been approved. If Alofisel didn’t work, surely its use wouldn’t be expanded.
Biomarkers for IBD
The incidence of IBD is increasing in young children (Rosen et al., 2015; Sykora et al., 2018) where it can take a more aggressive course and can be refractory to conventional drugs.
You can see a reflection of a public health disaster if such a difficult therapy as EEN is recommended as the first-line treatment for paediatric CD in Europe and becoming increasingly popular in the US.
Prognostic biomarkers for IBD have recently emerged, although Halligan et al. (2021) say research is haphazard and of variable quality, with a tendency to confuse diagnostic with prognostic biomarkers.
CRP (an acute-phase protein), fecal calprotectin and lactoferrin (Sipponen et al., 2008) have for some time been used as non-invasive biomarkers for active bowel disease. (Multiple biomarkers are needed because sometimes there can be disease activity but CRP can be normal)
(Re. my previous post on biomarkers and CHF, it's interesting that lactoferrin has also been linked to heart disease. Referring to Hunt 1, a large study in Norway, Vengen et al., 2010, found that increased baseline concentration of lactoferrin strongly predicted the long-term risk for fatal ischemic heart disease in patients with newly diagnosed diabetes).
I put a link below to a talk on YT (2019) by Dr. Suskind MD professor of pediatrics, division of gastroenterology at Seattle Children’s Hospital who uses The Specific Carbohydrate Diet (The original celiac diet developed by paediatrician Dr Sydney Haas) for IBD patients; Dr. Suskind says diet in IBD is “truly transformative”.
Dr. Suskind says that the success of dietary therapy can inform other treatments. Cui et al. (The Lancet, 2021) say CRP and fecal calprotectin are accepted as biomarkers but discuss others, such as mucosal gut microbiota profile, which could help evaluate who will (or won’t) benefit from anti TNF drugs.
The success of FMT and dietary therapy provides strong evidence that the microbiota can contribute to progression or remission of disease (and it’s well accepted that more diverse gut flora are strongly correlated to increased survival in GvHD)
MSCs themselves have an advantage in maintaining gut homeostasis: Nagashima et al. (2017) discovered a sub-epithelial mesenchymal cell which not only induces gut microbiota diversity but also regulates the production of IgA which preserves gut symbiotic equilibrium.
The specific function of IgA is explained by Caruso et al (Nature 2020): “IgA has a role in maintaining barrier function by coating bacteria and binding to microbial antigens and their toxins as well as in shaping the composition of the microbiota through unresolved mechanisms”.
“IgA responses occur constitutively during homeostasis through T cell-independent and T cell-dependent processes that preferentially target distinct microbial species”.
(The importance of regulating the production if IgA speaks to efficacy in any acute condition where there’s dysregulation of the immune system).
I’ve previously referred to a page on permanent TPN on Pittsburg Children’s Hospital website; they’re also seeing increased rates of the most severe complication of IBD: primary sclerosing cholangitis. You’ll find studies saying this condition is “rare” (I take claims of rarity with a big pinch of salt these days, especially as PSC is often symptomless in its early stages.)
It’s important to deliver treatment before extensive fibrosis occurs. Vesterhus et al. (2017) report on novel serum and bile protein biomarkers that predict severity and prognosis for primary sclerosing cholangitis, which can result in liver transplant. Investigators focus strongly on calprotectin and IL-8 ( MSB was looking for IL-8 in the ARDS trial)
In an animal model of pulmonary fibrosis, Dong et al. (2015) found host secretions of HGF and PGE2 were elevated compared with controls. In contrast, TNF-α and TGF-β1 levels were decreased and there was a corresponding lack of fibroblasts and collagen deposits in the lungs of the MSC treated group.
(The ARDS trial was important IMO for evaluating the anti fibrotic effect of MSCs. If I recall right from an interview, Dr Grossman said they were specifically looking for that. Short-term mortality isn’t the PE most stakeholders want because patients go on to die after discharge and the main cost comes from repeated hospitalisations and rehabilitation. I thought it might take up to two years to see the maximum difference between the groups. There are several good quality studies that show the issue is bad survival and those patients being relatively young, as I said in this post:
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Re. Covid ARDS specifically, an interview can be found on Rumble with rheumatologist Dr. Robert Jackson, who's a mainstream physician and part of a huge network. At the 25 minute mark he talks about very impressive results he’s getting in stem cell therapy in CARDS patients who are discharged in poor shape in wheelchairs and on oxygen).
In an animal model of pulmonary fibrosis, Dong et al. (2015) found host secretions of HGF and PGE2 were elevated compared with controls. In contrast, TNF-α and TGF-β1 levels were decreased and there was a corresponding lack of fibrobroblasts and collagen deposits in lungs of the MSC treated group.
Dr. Lightner's work in IBD is very important in itself and will also provide additional biomarkers for aGvHD, lower GI being the most challenging in GvHD and IBD (Infliximab wasn’t on the PBS for UC for a decade after CD, presumably because it’s less effective, and dietary therapy EEN is also far less effective for lower GI).
The rapid mucosal healing that Dr. Lightner reports is very encouraging in light of newer drugs (Entyvio and Ustekinumab) trials showing delayed effect. In an animal model, Li et al. (which also includes Dr. Lightner) found that “MSCs and Evs can migrate to and throughout the colon without the need for subsequent injections in mice”.
I suppose if there’s significant existing fibrosis, it could affect MSCs' ability to migrate through and you might need further injections; in a recent publication, Dr. Lightner says it would be best to administer the cells before the colon is “burnt out”. This is particularly relevant to children, even if you only consider it from a cost perspective.
Biomarkers for GvHD
I value critical viewpoints to counter my confirmation bias. Critics are entitled to their opinion but when @@whytee and others say all the aGvHD trials failed, they leave out what IMO are key points:
Firstly, Remestemcel-L isn’t the same as Prochymal. MSB has had better technology since then. Also, I question whether the clinical trial NCT00366145 actually failed. Osiris included milder cases of skin, which caused the trial not to meet its overall PE; however:
Prochymal significantly improved the response of liver（76% vs. 47%, P＜0.05）and gut（82% vs. 68%, P＜0.05); the response of skin was not significantly different between Prochymal and the placebo groups（78% vs. 77%, P＝0.9) at 28 days, which is why the PE wasn't met.
Secondly, MSB knows now that the cells respond to signals of the most severe inflammation, that the worst cases respond the best. That, combined with technology to improve potency, is reflected in the results of severe skin only cases in their single-arm trial.
Thirdly, MSB's trial included mostly severe grades C/D of the gut, which is the most difficult and refractory group with the highest death rate. Spontaneous remissions do not occur, as KOL Dr. Prockop stated. If severe GI GvHD is resolved, it's because of the cells and nothing else.
Steroids are first-line treatment for aGvHD but they don't actually work for severe GI aGvHD. It's taken a lot of going through studies (Bacigalupo et al. and others referenced on this forum) to come to this shocking conclusion. Those posters on this forum who say they’re doctors will no doubt be able to check up on this with a BMT specialist, as I did.
@Southoz has told us in this Post #:
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“What the FDA wanted was MSB to match at the individual level – a case control study. That is if the single arm study had a child 10 years old with prognostic factors XYZ find a similar child in the MAGIC database to match tomatch patients with those from the MAGIC database of similar age and prognostic factors prior to starting the trial”.
GvHD isn’t a disease but a heterogeneous condition. It doesn’t follow a standard course. MSB’s trial was in the most severe cases with the highest death rate (gut and liver). Did standard prognostic biomarkers exist at the time of designing the trial?
The Magic Consortium found REG3α and ST2 strongly correlate to non relapse mortality, which are endorsed by the FDA and NIH. In one of the letters published in the NEJM on Reach2, however, Zeiser et al. were criticized for not matching according to these biomarkers but the authors respond, saying these were not standard and that multiple biomarkers have been associated with aGvHD.
As for specific biomarkers for gut and skin Harris et al. (2016) say:
“Unfortunately, although validated plasma biomarkers specific to skin and lower GI GVHD have been identified, GVHD biomarkers specific to the liver and upper GI tract have yet to be identified”.
Further to biomarkers for the skin, Solan et al. (2021) report on studies where elafin has been identified but authors cite other studies in which no correlation was found. I’m not sure I buy the concept of “skin only” anyway. There might not be obvious inflammation but if skin is affected, there’s likely to be damage to the gut mucosal barrier:
(Taymount FMT clinic in the UK sounds reputable to me because they know FMT can be pro-inflammatory if the colon is severely inflamed. Glenn Taylor said in an online interview (link below) that, despite his scepticism, the clinic was getting some of their best results in cases of severe eczema)
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IMO it’s right to focus on biomarkers for the gut. Impaired gut barrier from the conditioning regimen is well known to be the driver of acute GvHD (Nalle et. 2015) Studies on therapies to restore the intestinal barrier such as that published (2017) by researchers from Technical University of Munich and Sloan Kettering Cancer Center in Translational Medicine:
Authors say:
“ Stress signals emitted by the dying epithelial cells and the arrival of intestinal bacteria in the previously germ-free areas of the gut due to the loss of the epithelium trigger the activation of aggressive donor T cells”.
Team leader Hendrik Poeck says:
“If the epithelium could be protected or quickly restored, the risk of an immune response would be much lower”.
Dr. Paul Carpenter, who called in our product on compassionate grounds for a child suffering from grade 4 intestinal bleeding, has published work using vitamin A to reduce gut leak in aGvHD (Vitamin A, like its partner D, is fat soluble and I strongly suspect that the lie and surrounding dogma about saturated fat being bad for us has increased gut leak and contributed to the rise in cases of IBD and heart disease).
As for the “gold standard” RCT, it’s been proposed here that it’s ethical to run because it would be against SoC (Rux) and not an actual placebo.
Southoz and others stated on this forum that MSB avoided a RCT because it knows it wouldn’t meet the PE. In the same post, we’re informed this is “a little bit of no-brainer”. Really? Are robots, rather than human beings, involved in trials? MSB may well have said they were willing to run a RCT in high risk adults. For such a trial to take place in the real world, though, patients have to agree to participate and investigators have to agree to run them. You need all three.
You can find RCTs in SR aGvHD that have been proposed but haven’t gone ahead. This is likely because of ethics and SR aGvHD with GI involvement is known to have a dire prognosis.
There is a unique extra burden of ethics on the shoulders of investigators in that GvHD is a condition caused by a medical procedure. They will be hearing more of the following - the words of a teenage boy conveyed by his mother on a public forum:
“You did this to me. You fix it”.
You can find several published papers that acknowledge the pain from GvHD as “intolerable”. Patients will have to suffer this and investigators will have to witness pain so bad it can result in PTSD. With severe IBD and GI GvHD there can be edema of the colon, which is excruciating for every bowel motion. Effective painkillers are difficult to give because they can disrupt the rhythm of the bowel. My eldest child screamed all night she wished she was dead. All they had was freakin Buscopan.
Adults have also been treated in the EAP (Prof Kurtzberg reported on successful treatment of an adult case of chronic GvHD with Remestemcel-L) If I recall right, from the symposium in 2019 (I can’t find a link that works), KOL Dr. Prockop said after the experience of Rux in 3 patients, her center wouldn’t be participating in the clinical trial. That was well before Reach2 results were published.
In Reach2, Rux was trialed against the mother of all toxic crap in 50% of BAT arm, as I detailed in this post Post #:
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It SILL failed to show mortality benefit. I commented and provided evidence on this forum years ago that Infliximab looked to be the worst choice for SR aGvHD and Sirolimus the best. If I, a layperson, could see that, how could investigators have chosen Infliximab as BAT for 17 poor souls and Sirolimus only 3?
(Such selection means you can also claim your drug has “a favorable safety profile” and in today’s world, you can’t even be sure that physicians have read the supplementary material to see what the SoC in the control arm was)
Reach1 in 70 participants didn’t have nearly the same weighting of grades C/D of gut and liver that MSB targets and you can see that by day 28, 10 people had died.
Reache2 had to be run with a crossover, which is not advised because it makes it difficult to assess non relapse mortality benefit, which is the PE of most importance to stakeholders. Zeiser et al. say, however, that if there hadn’t been a crossover, investigators wouldn’t have agreed to run the RCT.
The gut is the driver of the cytokine storm, so it’s important to use what’s best for healing it. It’s not steroids. It’s not Rux. I was sceptical of the real world study by Zeiser et al. claiming success in rux in severe acute SR GvHD of the gut because they provide photos of two cases of skin (one of which looked to be regenerating at the time the drug was given because there was no edema and it was at the flaky stage) but there were no photos from scopes.
While only a small study, the one by Neumann et al. (2019) in SR acute and chronic GvHD sounds authentic to me because the report is simple and precise. All the patients (4) who had large volume diarrhea died, even though the tablets were finely ground up in a mortar to enable resorption.
There’s nothing ethical about running a RCT in high risk acute GvHD that could never be the “gold standard” anyway. It’s just another one of those lies we have to tell ourselves to cope with this world.
In conclusion, the increasing use and validation of prognostic and response biomarkers point to a coming era of personalised medicine, not only that but a potentially more ethical one where we may no longer have to experiment on human beings or even animals ( We also have recent technology in the form of 'a gut on a chip', 'a scar in a dish' and the ability to grow organelles to test drugs on).
Since my last post on CHF, the company has stated a connection between biomarkers of acute inflammation CRP (CHF) and IL-6 (LVAD trial?) I referred here once to a study that found IL-6 was raised in LVAD recipients and another in CBP which found that IL-6 was a strong biomarker for CBP associated with DDD. Amazing how this all seems to fit together! Dr. Lightner's work is important IMO because it will hopefully provide further validation, particularly with regard to imaging; however, having said that, looking at MSB's aGvHD and HF results alone, the mantra repeated here by critics: "correlation doesn't equal causation" is already sounding a lot like dogma.
https://pubmed.ncbi.nlm.nih.gov/28436956/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702263/https://pubmed.ncbi.nlm.nih.gov/29991879/
https://pubmed.ncbi.nlm.nih.gov/18752630/https://www.sciencedirect.com/science/article/abs/pii/S0021915010004260
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131410/
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00122-5/fulltext
https://www.ncbi.nlm.nih.gov/books/NBK571673/pdf/Bookshelf_NBK571673.pdf
(20min delay)