Many thanks to Treed for this great post. I don’t have a science...

Many thanks to Treed for this great post. I don’t have a science background but I’ve been researching IBD for a decade and this fits with my understanding. I was also interested in Tigenix's sepsis candidate.

MSB’s p3 CD rarely gets a mention. While IBD is a third of the size of RA market, it’s a lot less crowded. GIs tend to stick to Infliximab. The large studies on surgery rates in the era of biologics, however, don’t reflect their confidence imo (I already supplied the references to these.)

I read that Alofisel will be used in conjunction with Infliximab. Karmiris et al. (annals of Gastroenterology 2005) raise concerns about using Infliximab in FCD as there is a relatively high rate of abscess formation because of the closure of the external opening of the fistula before the internal tract has healed, due to the rapid action of infliximab. Imaging found “traces of inflammation in fistula tracts exist even after repeated doses of infliximab for a long period of time.”

( I’m wondering, if the mechanism of MSCs is, as SI said, that they start a healing cascade, the cells all signalling like a supply chain. Could that deliver better and longer lasting results as the body heals in a natural order?)

There’s similarity between IBD and GvHD when the GI tract is involved. Considering MSB’s good results for gut, liver and skin, it would be interesting to know how their CD candidate has done in fistulising disease alone. SI said, though, the two candidates should be seen as complementary.

Around 1/3 IBD sufferers fail to respond adequately to biologics and 1/3 become refractory over time. What other steroid-sparing options do these patients have?

Takeda’s gut-specific Entyvio /Vedolizumab arrived with a fanfare. It’s being reimbursed in Canada, which is said to have the highest rate of IBD in the world.

Edward V Loftus MD, a gastroenterologist at the Mayo Clinic in Minnesota, said of Vedolizumab:

"When you look at the data, it raises the question: 'If you have a Crohn's disease patient who is steroid-dependent and has failed anti-TNFs and you're ready to pull the trigger on a biologic, would this be the first choice?' In the end, there is an unmet need for agents with a different mechanism of action for desperate patients.”

Online reviews of Vedolizumab are very poor, with the worst side effects I’ve ever read. One patient said a $40k drug that wears off after 3 weeks is unacceptable.

If Takeda is wanting to be a leader in IBD imo seems odd to have this drug in the same stable.

I thought the consensus was that MSCs were safe. I know a doctor who was looking forward to Tigenix’s candidate so I asked about an IV candidate and was passed a paper by Arango-Rodrigez et al. (2015). They address concerns that MSCs could potentially cause infection and cancer. They say that MSCs are something of a paradox and could be pro- or anti- bacterial depending on various factors such as the source.

Looking into this further, I found following references:

Krasnodembskaya et al. (Stem Cells, 2010) say, “ allogeneic human MSCs may be beneficial in bacterial infections because of their antimicrobial properties as well as their immunomodulatory effects.”

Lombardo et al. (WJSC, 2015) say, “The combined effect of reducing both the inflammatory response and the bacterial burden results in an improvement of organ function and higher survival rates. The promising results obtained in these, small animal, preclinical efficacy studies are encouraging and suggest that MSCs might be a therapeutic option to treat sepsis in patients.”

Alcayaga-Miranda et al. (Frontiers in Immunology, 2017) address concerns that MSCs could lead to increased risk of infection but say, “Conversely, recent data show that MSCs exert strong antimicrobial effects through indirect and direct mechanisms, partially mediated by the secretion of antimicrobial peptides and proteins (AMPs) In fact, MSCs have been reported to increase bacterial clearance in preclinical models of sepsis, acute respiratory distress syndrome, and cystic fibrosis-related infection.”

Laroye et al. (Stem Cells, august 2018) provide an overview of research and say: “Alcayaga‐Miranda et al. reported a lower level of bacteremia in mice with sepsis given MSCs compared with those given standard antibiotic therapy. This finding makes it possible to discern a genuine antibiotic effect of MSCs in their own right.”

Ottawa Hospital is planning a p2 clinical trial in sepsis after a patient named Charles Bernique was given allogeneic MSCs and recovered fully from a severe case sepsis having been ‘close to death’.

Drugs that pass clinical trials don’t always do well in clinical practice. If Temcell is performing well, that’s a huge plus point for MSB. Going on recently published papers, it’s hard to know what’s about Temcell or MSCs in general. I guess MSCs, being a novel therapy, were initially further down the line and the patient was sometimes in too bad a way to be helped. In some cases, though, even where there was severe infection, they worked. I initially inferred action against infection but a more likely interpretation is that MSCs have worked in some cases in spite of severe infection. If this is the case, I still think that’s important as you wouldn’t use Infliximab in such circumstances.

I’m wondering if it’s possible to prime MSCs specifically to enhance potential to clear infection? I’d be grateful to hear from anyone with expertise in this area.

While the suffering in IBD is great, the death rate is low, but a lot of stuff just isn't working and the new drugs that were being talked up 5 years ago haven't lived up to the hype. I guess local allogeneic MSCs is a major step forward in a discipline that’s taken over two decades to acknowledge the microbiome.

Arango-Rodrigrez et al. do say though, at the time of writing, 350 clinical trials were under way and safety didn't appear to be an issue. Even so, seeing as there are still concerns, I think with any new therapy you'd go with a company that’s been at it a long time because what hasn’t happened is as important as what has.