MSCs being immunomodulatory, seem to be the natural replacement...

MSCs being immunomodulatory, seem to be the natural replacement to the biologics. It’s not just the superior technology, but recent circumstances seem to favour our entry into the market (assuming continued good results and approval).

I focused on IBD and RA as they’re large markets and chronic GvHD has recently been found to have features of autoimmune illness.

How Effective Have the Biologics Been?
IBD (Infliximab and Humira)
I've posted a ref to a large study (database of 58000 patients) by Kin et al (2017) comparing colectomy rates in pre and post biologic era that concluded they'd increased since Infliximab use. Also based on recent papers on fistulising CD (eg. Yassin et al), the recommended treatment is to combine surgery with IFX. We can conclude that IFX hasn’t prevented surgery in fistulising CD.

With respect to children, Mattoli et al (2015) say ulcerative colitis has increased in the pediatric population: “It appears to manifest more aggressively in childhood and 60-80% of all cases present with pancolitis, a frequency that is approximately 2-fold higher than seen in adults. Because of the increased severity of UC in children, even the colectomy rate 10 years after onset is higher when compared with adult data (40 and 20% respectively).”

It’s fair to say, though, that it's difficult to judge efficacy of the biologics because during the same time period cases of IBD increased significantly. Maybe there will be more success starting patients earlier and keeping trough levels high, but there are very many cases that are already refractory. (MSB’s p3 CD candidate rarely gets a mention. I find this frustrating. MSB’s stem cells were successfully used in a child featured in an article posted on this forum who had aGvHD with grade 4 intestinal hemorrhaging; this suggests to me a potential application in severe, even fulminant, ulcerative colitis. Maybe these are not the same stem cells though?)

New Arrivals in IBD

Takeda’s gut-specific Vedolizumab/Entyvio is a recent arrival on the market . Sandborn et al (2013) report on Gemini 2 results saying, “The modest effect of Vedolizumab on the induction of clinical remission and its nonsignificant effect on the CDAI-100 response at week 6 require consideration.” The online reviews by patients imo reflect this modest efficacy and raise the issue of side effects, some of which sound very debilitating.

Check out what revenue from Vedolizumab alone has done for Takeda in a relatively short period of time.

Ustekinumab has recently been approved for CD. At first reading it appears to be more effective than Vedolizumab, although Kotze et al (2018) say the ‘gestalt’ that it’s more clinically effective is largely unfounded. Feagan et al (2016) report that 2b clinical trials in UTZ showed clinical response but not remission; it’s fair to say dosing and timing across studies have varied a lot. Ma et al’s study (2017) is important imo because they make real-world assessment of remission using radiographic or endoscopic evidence. This is important because, while mild IBD can sometimes burn itself out, moderate and severe IBD will keep coming back unless there's full mucosal healing. After 12 months, using the stricter guidelines, remission was achieved in only 27.9% (31/111). They also found arthralgia (joint pain) was a common side effect. This is a worry as many IBD patients are also prone to inflammatory arthritis.


Inflammatory Arthritis

I posted a large study comparing surgery rates in RA in pre and post biologic era; findings were that while hand and foot surgeries have declined, large joint replacement rates have remained the same. During this time, the most common biologics were Enbrel and Humira.

Abatacept is a newer and popular biologic used in juvenile ideopathic arthritis, as it’s considered to have a better safety profile. Ruperto el al (2008) conducted a multi-centre study enrolling 190 patients. Only 24 had inactive disease status at day 113.

Abatacept is often paired with methotrexate (as are many biologics in RA) for increased efficacy (also used for prophylaxis in BM transplants) and is considered the ‘anchor drug’ for RA (Alten et al, 2018).

The problem with Methotrexate is that it increases gut permeability. There are numerous studies to support this but Lifschitz et al.’s (1989) is notable as it’s in pediatrics and low-dose MTX.

As far back as 2000, Picco et al found increased intestinal permeability in all forms of juvenile ideopathic arthritis.

Visser et al (2017) say, "There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD (Celiac Disease) and T1D (type 1 diabetes)"; that being the case, looks to me like the writing’s on the wall for MTX and if it is, it will be also for many biologics that are paired with it.

Newer il-6 inhibitors have come on the market but there's been a lot of publicity in the US over Actemra deaths; this calls into question the safety those that work in same way. I've already mentioned JAK-inhibitor Tofacitinib was refused a licence for 4 years by EMA over safety concerns. I don’t know if these are being prescribed for children.

I'm no scientist but I believe we're accepting an increasingly substandard situation as normal, based on what's available. You need deep mucosal healing in IBD for long term remission. You need to stop RA in its tracks so it doesn't continue to grind its way into the joints. SI is right to say there has to be remission.

Why are MSCs Superior Technology?

MSCs have the specificity without toxicity that pharma have been trying for (not very successfully imo); they're immunomodulatory but don't suppress the immune system too broadly. We know this because they don't appear to affect the graft versus cancer.

I think MSCs may offer the best chance of the deep tissue healing that appears to have evaded us. While not our cells, I'll be keen to know how Alofisel does in clinical practice, whether deeper healing in fistulae can be achieved, rather than just closing off.

10/08/17 I wrote:

“In aGVHD, if a significant number of seriously unwell patients survive when there's a high death rate, that imo is a good sign of cause and effect. So is local injecting with MSCs into a Crohn's fistula and seeing it heal.”

In the same post I said approval for Cx601 would benefit us; I didn't consider a deal. I thought it would pave the way for allogeneic mscs and the quickest way to overcome any remaining scepticism is to appeal to the visual.

MSCs may have another advantage over drugs in that they not only don’t damage the gut but may signal to the intestinal stem cells to repair it. Studies are very recent and in animal models. McCulloh et al (2017) reported that all four types of stem cells (including BM) preserved gut barrier function in necrotising enterocolitis; Gong et al (2016) found MSCs stimulate intestinal stem cells to repair radiation-induced intestinal injury.

I feel strongly that there needs to be a rethink in the way we approach pediatric autoimmune illnesses. I often wonder if MSCs were given first line, whether we would see a decline in chronic diseases persisting into adulthood?

Please feel free to make any corrections as I'm a layperson writing from a patient perspective.

All IMO. GLTAH