The comments about the bar for Covid ARDS being low and therefore in our favour are imo missing the point. We have a revolutionary and relatively expensive technology. I think ARDS results will need to be really good and unequivocal if this is to be our introduction to the world. It's a risk I'm prepared to accept.
While I've long been concerned about delays for GvHD, I'm still hopeful for approval. My reasons for thinking this are blunt and I put them in the section on GvHD. During the ODAC meeting, I got a sense that GvHD approval could be linked to ARDS results but I wasn't quite sure how. I don't know whether I'm entirely up a wrong alley, so I'd appreciate any help from the experts. I also have a personal interest in this candidate.
The Potential Importance of the ARDS trial to GVHD, Beyond that they're Similar Cytokine Storms
ARDS and aGvHD are not the same, but surely you can develop a specific product for a broader application. There are certain things you want to see in all cytokine storms: improved flood flow, no aberrant scarring, restored barrier integrity, a change in inflammatory markers, clearance of bacteria and endotoxins. If you take care of these the body can do the rest.
Am I right in thinking you can identify and select factors in assays and establish a matrix that you can then use to predict specific effects and confirm predictions by correlation - seeing the desired effect in living subjects? I read that this is what the FDA will accept?
When developing Multistem, Athersys found three cytokines (IL-8 was one) and VEGF were required for the desired effect of angiogenesis. Removal of any one of these lessened the effect and researchers were also able test the minimum level required by adding back increasing amounts of these cytokines into the depleted serum-free conditioned media.
Re ARDS, there are certain specific things you want. One, for example, is to clear fluid from lungs quickly. This is relevant to any cytokine storm because it speaks to regulation of vascular permeability. I watched Dr Matthay's presentation on YT. Removing VEGF from the cells resulted in cells not being able to clear fluid. Putting VEGF back in and cells could do it. Even the conditioned medium. No doubt imo about the importance of VEGF for this indication. If our cells are potent, then this effect should be consistent in the treated group relative to the placebo, not just the desired effect, but likely the time to achieve it. Dr Matthay was also specific about time.
Another important factor, crucial it seems, is CD146. Prof Caplan and SI have published on this. This is an important one because it's considered a marker of multi-potency of MSCs. CD146 is key in cell to cell signaling and BBB formation, so could it therefore play a major role in maintaining tight junctions?
MSB is also looking for IL-8 and IL-6 and TNFα biomarkers in patients and will hopefully have imaging re. edema, lesions in lungs and fibrosis, rather than just organ functionality. Fibrosis is important because this is specifically what causes death in organ failure. TNFα plays a role in preventing fibrosis but in vitro and in vivo findings have been contradictory. Maybe it's a case of needing the inflammation to respond accordingly? A bit of inflammation is a good thing. HGF is important for preventing fibrosis. Dong et al (2015) report on their experiment in a mouse model. After MSC infusion, HGF was elevated and TNFα and TGF-β1 (a major driver of fibroblast activation and collagen secretion) decreased. "Consequently, the architecture of the irradiated lungs was preserved without marked activation of fibroblasts or collagen deposition within the injured sites".
Antifibrotic therapy is something of a holy grail in itself because fibrosis is said to cause 50% of deaths in the developed world. It also leads to a high burden of long-term chronic illness.
Agha et al (2027) say that investigating the cellular origin of myofibroblasts in various diseases is a promising strategy for developing targeted anti-fibrotic treatments. They focus on new technology to identify the genetic lineage in fibroblast formation that implicates diverse organ-resident perivascular (MSC)-like cells. Authors say:
“The aforementioned myofibroblast heterogeneity likely reflects the complexity of fibrosis initiation and progression, and it partially justifies why a robust antifibrotic therapy has not yet been developed. It might be that a single anti-fibrotic magic bullet is simply unable to override such multifactorial and complex diseases.”
I usually look into things before dismissing them but I can’t see a drug tackling a single pathway working. Drugs that inhibit a single pathway can come with bad side effects. Also, as is the case of IL-6, which can be good or bad, fibrosis is part of the repair process and has distinct phases. In its early stage it might be a necessity.
Obviously the MOA is too complex to understand, especially for a layperson like me. You can develop a matrix but there will be other factors involved. Then there are transcription factors which I understand are like recipes (to enhance expression?) and I learned you can now grow mini organs to test drugs on. Even if I haven't understood much, I get a sense of just how long researchers have been able to see in incredible detail and I’d have thought MSB would have it all worked out a long time ago. I don’t buy the narrative of SI ‘blundering’ into a meeting with the FDA. And there’s such a thing as proprietary knowledge.
GVHD
I met this company at the AGM. I found them professional and authentic. Going for full approval is consistent imo with their ethics and ethos. I don't see they did anything wrong. There were imo red flags that Ryoncil approval would be delayed as far back as a year and a half ago. I noted the narrative constructed in the media of our similar trial design and that RUX would be a competing product in 12+ age group, as if it was some kind of alternative to our cells. There was Gottlieb's departure. Then an article posted here that the FDA would be going more on clinical trials rather than real-world data. In March this year I strongly suspected Covid would be used as an excuse for delay by the FDA. I wrote to the them just after I posted this Post #: 43544268:
"Before Gottlieb went to work for the FDA he was a vocal critic, accusing them of having blood on their hands for not getting drugs to market fast enough. He's no longer there to say this about Ryoncil. But I'm saying it".
I thought by the time Ryoncil reached the line RUX's inferior efficacy in survival would be proven (Reach2 results were published earlier this year) and if there were any issues the FDA would have raised them during the rolling BLA. After the ODAC vote. I was convinced I was a paranoid idiot. And I was glad of it. But here we are.
RUX was approved on the basis of a single-arm trial. RUX data in other conditions are imo irrelevant. I think we should look at the thing itself and nothing else. The thing that is acute GvHD, where gut involvement is most common and has the highest death rate. The thing that is gut GvHD, which causes large volumes of watery diarrhea. The thing that is RUX that is a tablet. What planet was the FDA on to have approved this drug for this specific indication in the first place?
And how could Reach2 results have come as a surprise to anyone? I already referred to the study by Neumann et al. The tablets were finely ground to enable better absorption but the patients with severe diarrhea still died. I found another study by Moiseev et al (2020) in 32 children and adults in RUX for SR acute GvHD. Authors say grades 3 and 4 GI GvHD was a risk for lower survival.
GvHD isn't a small market; allogeneic BMTs are rising rapidly in the world. GvHD must be common if it's a barrier to doing the transplant in the first place.as I've read in journals. Steroids are effective in 50% of cases of aGvHD but that doesn’t necessarily mean they work in this percentage. Only ⅓ of cases get a durable response. And what does 'durable response' mean? The gut is the organ which is most commonly affected and most likely to flare during a steroid taper. Are patients, like my child who couldn't come off steroids, classed as having a durable response?
The sort of healing steroids do on the gut is well known. Surely MSB has imaging on this? If our cells deliver superior mucosal healing, that's a clear sign of efficacy. The same should be the case for skin GvHD if they have evidence that edema has resolved. I note the photos in the study by Zeiser et al in RUX the edema is still there in the after photo but the angle makes it look less visible.
My hope is that the FDA are looking at the bigger picture with Ryoncil; there could be a clamour for off label use and a high bar needs to be set. Positive results in fibrosis would be highly relevant to GvHD. Fibrotic skin and lung GvHD are debilitating and a huge cost burden. In the study in RUX mentioned above, 38% of the acute cohort went on to develop chronic GvHD. While RUX does a reasonable job with skin, authors found no effect on joints and genitals. 15% of patients with mild bronchiolitis obliterans got a CR but those with moderate disease progressed to severe. Authors stress the importance of early intervention with lung GvHD.
With the biggest picture in mind, I've been thinking how you'd introduce revolutionary technology into the world as it is today. The First Ever allogeneic MSC product would be announced with a fanfare. A product is what it is (and I've done my work on that) but it's also what people think it is. If the intention is to save lives you have to deal with the way people think, dispel scepticism, show contrast to inferior competition, and the product itself needs to be unequivocal.
One thing at the back of my mind has been niggling for a while. There was a dispute on this forum as to what caused the recovery of a child featured in an article posted here who had grade 4 intestinal hemorrhaging. I contacted the journalist for clarification, a clearly intelligent and professional person. There was a lack of distinction on her side between the 'two transplants' , the transplant that caused the aGvHD, and the one that cured it. I think this uncertainty was why the message was lost and the recovery attributed to drugs in the title of the piece. I think this perception would not be uncommon.
If Remestemcel-L is approved for Covid ARDS, it wouldn't make sense to me if it's rejected or delayed for GvHD. What would happen in the case of ARDS caused by GvHD? In a study by Yadav et al (2016) on the epidemiology of ARDS following allogeneic HSCT, 15.6% of patients developed ARDS within a year. Do we know definitively if the Covid virus has caused the clinical infection that has led to ARDS? Even so, surely, as David Gorski says, there's a case for regardless of the cause? A cytokine storm is a cytokine storm.
Two years ago I did a post on all the conveniences, the confluence of events, that point to MSB being the right company at the right time v all those events that make it look not so great. I acknowledge that not approving our product for dying children couldn't look any worse. I sincerely hope it's not the way it's actually going to be. My faith is in Silvu and the team to win on this.
(20min delay)