This is a very long postFIBROSISFibrosis DefinitionTA Wynn...

This is a very long post

FIBROSIS

Fibrosis Definition

TA Wynn (2008):

“Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli...there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis”.

I highlighted the last sentence because it relates to previous discussion that the secretome of MSC contains both pro-inflammatory and anti-inflammatory cytokines. I used to worry about MSCs being said to dampen inflammation because I knew it was the cure. I think it’s all about balance. Also, the evidence that MSB cells improve blood flow will surely have a positive impact on fibrosis?

MSCs have been extensively studied for their anti-fibrotic effect. Usunier et al. (2014) say, “Altogether, the objective analysis of the literature supports the antifibrotic effect of MSCs... there is, to our knowledge, no example showing MSC transplantation to have a profibrotic effect on a developing or established disease”.

“The future of MSC therapy for fibrotic diseases mostly relies on a comparison with current management strategies. Results from preclinical and clinical trials highlight the ability of MSCs to act on fibrosis through different mechanisms: (i) immunosuppression, (ii) inhibition of the TGF-β1 pathway, (iii) reduction of hypoxia and oxidative stress, and (iv) restoration of ECM degradation. Thus, the potential of MSC therapy lies in the ability to act simultaneously on various fibrogenesis parameters. There are currently several therapy protocols for fibrotic therapies under assessment in clinical trials. Most of those treatments are designed to act on a single pathway underlying fibrosis development and progression, unlike cell therapy”.

Drugs to target fibrosis will have off target effects on other organs, which is particularly to be avoided in ARDS as patients can suffer multi organ failure and secondary infections.

Do MSB have Evidence of Antifibrotic Effect of Cells?

In TWST, March 23 2020, shortly after the company announcement of investigating Remestemcel-L for Covid-19 ARDS, the prof is quoted making specific reference to fibrosis:

"Multiple arms of the immune system are activated, and the cytokines produced by these cells result in progressive debilitation of the heart — fibrosis — which results in hospitalizations and death"

From the same interview re. GvHD: ‘if you are alive through six months, you are effectively cured of the disease’. This is a strong statement and for someone who is particularly understated. Implicit in that imo is that patients wouldn’t be going on to suffer sclerodermatous and fibrotic features of chronic GvHD.

JCR saw application for Temcell in EB, a terrible condition affecting more than the skin, a condition of the connective tissue and particular collagen deficiency.

ARDS: FIBROSIS IN THE FAST LANE

The title is from a paper by Marshall et al. (1998) According to Burnham et al. (2014), “While excessive fibroproliferation is clearly detrimental, an “appropriate” fibroproliferative response may have beneficial consequences in guiding lung repair, for example by serving as a scaffold and providing a reservoir for nutrients and growth factors [68] for the regenerating alveolar epithelium. Thus, markers that distinguish “appropriate” fibroproliferative activity from excessive and potentially harmful fibroproliferation are desperately needed”.

Bellingan et al. (2000) say, "Although a significant number of patients with ARDS die either from the initiating insult or later from sepsis and multi-organ failure (MOF), it is clear that progressive fibroproliferation is, directly or indirectly, a significant cause of death"..."There is now compelling evidence that the fibroproliferative process begins much earlier than previously believed".

Smith et al. (2013) say, ”The fibroproliferative phase of ARDS begins at the time of intubation and initiation of mechanical ventilation, rather than after inflammation, necrosis, and apoptosis have resolved.[146] Failure to resolve the inflammatory response and dysregulation of the fibroproliferative phase may result in chronic ARDS and fibrotic lung disease, which occurs in up to 30–50% of adult patients with ARDS and is associated with a mortality of up to 80%”

Cabrera-Benitez (2014) et al. discuss mechanical stress as an inciting factor for lung fibrosis. Authors say, “Patients who die of ARDS show clear evidence of pulmonary fibrosis, even when they die in relatively early stages of ARDS. Yet, it is hard to find much trace of fibrosis in ARDS survivors”.

“On the basis of the open-lung biopsies, Papazian et al.16 found evidence of pulmonary fibrosis in 53% of ventilated patients who had ARDS for 5 days or more. In a prospective cohort study of 25 consecutive patients with ARDS who were receiving mechanical ventilation, Martin et al.13 reported that the mortality rate was 57% (8 of 14 patients) in those who developed lung fibrosis with zero mortality in patients without evidence of fibrosis. Madtes et al.17 studied 74 consecutive patients during the first 2 weeks after the onset of ARDS. Transforming growth factor-β (TGF-β) was detected in the lung lavage fluid of 90% of patients with ARDS but was not detectable in 13 normal volunteers. The mortality rate was four times higher in patients with both increased concentrations of TGF-β and procollagen type III (PCIII) in lung lavage fluids at day 7 compared with that in patients who had low TGF-β and PCIII levels. Marshall et al.18 demonstrated that the PCIII concentrations were significantly increased in nonsurvivors of ARDS as compared with survivors.”

Life After ARDS

Patients who survive are at greater risk for death and suffer long-term complications.

Angus et al. (2000) report on a study that demonstrates that patients who appear in good health until presenting with primary ARDS are at significant risk of death for several months beyond the traditional endpoint of 28 d. Furthermore, the quality of life in those that do survive is markedly impaired. Integrating these two findings produces a low quality-adjusted survival in the first year after ARDS.

Matthay et al. (2019) review studies and say survivors of ARDS demonstrate exercise limitation and poor physical quality of life. “This same group of investigators continued follow-up to 5 years after ARDS and noted persistence of disability and compromised QOL, which were associated with increased cost and health-care use218. These findings are robust and have been replicated by many other investigators”.

If MSCs are given earlier at the first sign of lung failure then we could have better outcomes, particularly with regard to fibrosis. Maybe MSC group survival could be 100% but then if the cohort isn’t patients who failed everything we may or may not replicate the EAP results in terms of survival.

All cause mortality is a brave end point and Josh Farkas, whose blog is Pulmcrit, is critical of this, saying it would be better to focus on ‘softer’ end points, which aren’t soft if you think about it; he gives the example that survival but with end stage renal failure would not be a good result. Ventilator-free days are important because of the link to fibrosis.

I would also expect the treatment and placebo groups to further separate out as time goes on.

In summary, I’m hopeful for good p3 results in ARDS but nothing is certain and I know it takes time to design clinical trials and we didn’t have much time, so whatever the results, I’m going to go over them carefully and think about them. If there’s any sell down I might buy more.

FIBROSIS IN GVHD

Chronic GvHD of the skin and lung is common and expensive to treat. ECP, an in-hospital therapy, is still widely used. Chronic GvHD most commonly affects the skin, but it appears to be more than that as patients report deep muscular aches and pains, so my concern is that inhibition and suppression may get quick results for skin but I wonder if deeper healing of the connective tissue remains not fully resolved?

The focus is on better prophylaxis to prevent GvHD. The Abatacept trial to prevent severe acute GvHD showed marked efficacy in the mismatched 7/8 group (n=40); however, in the matched 8/8 group (n=140) the P value of 0.065 for this is not significant compared to placebo. Chronic GvHD was not affected in either group. Nevertheless, it has been granted Breakthrough Therapy Designation by the FDA.

I think it’s highly likely Ryoncil will go into clinical practice ahead of steroids and that it’s likely in the not too distant future to be moved to prophylaxis.

Re. MSCs in GvHD prophylaxis, Morata-Tarifa et al. (2020) performed a meta analysis on studies and concluded “based on this meta-analysis, our recommendation would be to administer MSC at day 0 in patients undergoing HSCT and to carry out a clinical trial using MSC as an adjuvant therapy from disease onset”.

Gau et al. report on a multi-centre randomized double blind study in 124 patients (62 in each group). The 2-year cumulative incidence of cGVHD in the MSCs group was 27.4% (95% CI, 16.2% to 38.6%), compared with 49.0% (95% CI, 36.5% to 61.5%) in the non-MSCs control group (P = .021).

Seven patients in the non-MSCs control group had severe lung cGVHD, but no patients in the MSCs group developed typical lung cGVHD (P = .047). The authors say, “In this study, we found MSCs have potential applications in the prevention of lung cGvHD. Bronchiolitis obliterans (BO) is a typical manifestation of lung cGvHD, characterized by subepithelial inflammatory and fibrotic narrowing of the bronchioles”.

FIBROSIS IN CROHN’S DISEASE AND ULCERATIVE COLITIS

I think it’s highly likely Ryoncil will get label extension for Crohn's Disease. This would include ulcerative colitis and there can be difficulty in diagnosing between the two. IBD is increasingly being diagnosed in younger children, where it takes a more aggressive course.

Re. incidence of pediatric IBD in the USA, according to Ye et al. (2019), "in 2016, 1 in 209 adults and 1 in 1299 children aged 2–17 were affected by IBD. Prevalence of IBD has been increasing compared with previously published 2009 data".

74 million children in the USA.. Approx 56 000 children suffering from IBD (Over 60 000 if you include Canada, which has among the highest rate in young children.)

“Intestinal fibrosis affects both ulcerative colitis and Crohn’s Disease, and no specific antifibrotic therapy exists”. (Latella et al, 2017)

Rogler et al. (2017) report on how the thinking re. fibrosis has changed in IBD, that fibrosis continues on from inflammation as a separate process, which echoes what Bellingan et al. said of ARDS. Note the anti-fibrotic research in IBD at the time of writing is at the stage of animal models:That last sentence is interesting because I always saw fibrosis as something rigid that couldn’t be reversed.

"The concepts on the pathophysiology of intestinal fibrosis in Crohn’s disease (CD) have changed in recent years. Some years ago fibrosis was regarded to be a consequence of long-standing inflammation with subsequent destruction of the gut wall matrix followed by scar formation and collagen deposition. Fibrosis in CD patients appeared to be an irreversible process that could hardly be influenced. Therefore, the main target in CD therapy was to control inflammation to avoid fibrosis development. Many of these assumptions seem to be only partially true. Inflammation may be a necessary prerequisite for the initiation of fibrosis. However, when the pathophysiologic processes that lead to fibrosis in CD patients have been initiated, fibrosis development may be independent of inflammation and may continue even when inflammation is under good medical control.Fibrosis in CD also may be reversible”.

Primary Sclerosing Cholangitis

According to Laborda et al. (2019), “primary sclerosing cholangitis is common in children with IBD; it affects at least 10% of children with ulcerative colitis”.PSC is a progressive disease characterized by inflammation and abnormal formation of fibrous tissue in the bile ducts. According to final report summary on the Merlin study of MSCs to reduce liver inflammation, "Liver transplant is ultimately the only viable treatment for many people with PSC"

With PSC the difficulty is that it would be diagnosed too late but there are recently discovered biomarkers that may predict progression and severity of PSC.

Stricturing Crohn’s Disease

There are three types of CD: Inflammatory, fistulising and stricturing. Stricturing is the leading cause of surgery in CD. I find it difficult to get statistics on how many patients end up with short bowel due to multiple or extensive resections. According to Thompson et al. (2014). 3% of the patients with Crohn’s Disease develop SBS.

CD is among the leading causes of intestinal failure. In 2 large North American HPN registries from the 1990s, patients with CD constituted 11% and 17% of the recorded 2916 and 5357 patients on HPN.

Note the above data are from a study before the era of biologics but my research leads me to conclude they have delayed, rather than prevented, surgery, and they’re often not potent enough to control severe acute inflammation, which is why they’re combined with the thiopurines (low dose chemo) and steroids are still commonly used. In the case of intestinal failure, TPN goes into a vein in the neck and it can damage the liver, so if there are signs the liver is failing doctors would want to get patients off it quickly.

In summary, I think reimbursement would be likely if the liver is at risk.

GI-GVHD AND IBD: THE SAME GOALS

Apart from fibrosis, in GI GvHd and IBD there is the common goal to restore gut integrity and improve the microbiome. In children IBD flares, particularly UC, can be severe and acute and can be exacerbated by hormones in teenagers. Despite the biologics, colectomy rates are significant and higher in children than adults.Romano et al. (2016) say that approximately one-third of children with ulcerative colitis will experience at least 1 attack of acute severe colitis (ASC) before 15 years of age.

I would say pediatric IBD is more akin to acute GI GvHD than the chronic adult disease in our Crohn’s Disease trial, but if data is positive, it will reinforce label extension.

MSCs are being described increasingly as immunomodulatory, rather than immunosuppressive, which is correct.There are now ethical considerations in using drugs that suppress the immune system. Remission in CD can be induced by enhancing the immune system, which is effectively what exclusive enteral nutrition (EEN) does (including delivering superior mucosal healing to steroids), and it’s recommended first line in pediatric CD in Europe and increasingly used in the US. If you google ‘exclusive enteral nutrition in Crohn’s Disease’, you’ll see a lot of new studies published just in the last couple of years.

I mentioned dietary therapy before but I left out the most important thing Dr Suskind from Seattle CH uses EEN in clinical practice then kicking into the Specific Carbohydrate Diet (the original celiac diet) pioneered by pediatrician Haas who published his work to great acclaim. (The same therapy has been used in SR GvHD in the same hospital) It’s highly likely imo Dr Suskind would be aware that Dr Haas found children who followed the diet strictly for at least a year after the last symptom disappeared could go back to a ‘regular’ diet and the disease never returned. These children were cured. Even if you don’t accept this evidence that IBD can be cured, then at least there’s no dispute that children respond particularly well to EEN (better than adults) and a reason why they shouldn’t be treated like mini adults.

The Microbiome

The importance of the microbiome not only raises questions about a therapy that doesn’t address it, but there are bigger implications for drugs and developing them.

In an interview Paul Moayeddi (Gastroenterology and Hepatology, 2018) speaking of FMT trials in UC is quoted:

“In the past, inflammatory bowel disease (IBD) was thought to be an autoimmune disease, but the current thinking is that it is actually an immune disease mediated by an antigen, presumably a microbial antigen to which the immune system is reacting.”

What Dr Moayeddi says has implications for all autoimmune diseases. There’s not much research on MSCs’ interaction with the microbiota, but the cells would likely be able to sense gut homeostasis and regulate accordingly.

I watched the video of the lecture by Prof Caplan that was kindly posted here. The MSC bumps into bacteria and gets rid of it with an antibiotic protein, not only that but brings in a macrophage to get the carcass out so there’s no endotoxin effect.

The microbiome is considered a super organ in itself and there's a large body of literature discussing how the biome affects the efficacy and safety of drugs and developers of drugs are facing challenges in terms of reproducibility of results. Below are a couple of verbatim comments from the Australian Government National Health and Medical Research Council survey (2019) in response to how to improve quality of research:

“Be more transparent about the biome. From what I've read, the gut biome has a significant effect on results and this data should be captured and published so that the results can be tested/replicated in laboratories with different biomes”.

Awareness of strain genomic variations on microbiome and immune responses”.

In summary, in the unlikely event of failing all p3 trials, Ryoncil approval imo is a dead cert and the market for that alone is significant.

I listed my refs below in order of citing.

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ALL IMO. GLTAH

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693329/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123563/

https://thorax.bmj.com/content/53/10/815

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015132/

https://link.springer.com/chapter/10.1007/978-3-662-13455-9_19

https://www.medscape.com/viewarticle/807712_12

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991945/

https://www.atsjournals.org/doi/full/10.1164/ajrccm.163.6.2005123

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709677/

https://emcrit.org/pulmcrit/mortality/

https://gvhdhub.com/medical-information/tct-meeting-2019-or-results-of-the-phase-ii-aba2-trial-abatacept-for-acute-gvhd-prophylaxis-in-unrelated-donor-transplantation

https://stemcellres.biomedcentral.com/articles/10.1186/s13287-020-01592-z

https://pubmed.ncbi.nlm.nih.gov/31504515/

https://www.researchgate.net/publication/38092840_Intestinal_Fibrosis_in_Crohns_Disease_Medical_Treatment_or_Surgery

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500633/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354124/

https://cordis.europa.eu/project/id/602363/reporting

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513821/

https://pubmed.ncbi.nlm.nih.gov/27244779/