Morning,Apologies for the long post. I did a little digging into...

Morning,

Apologies for the long post. I did a little digging into Exhibit 5 which was part of the BLA objection submission and thought it might be useful to provide the full transcript from the panel discussion on GVHD on June 8 with Drs Ferrera and Gutman, rather than the selectively edited quotes.

Louise Chen, who according to LinkedIn is the MD of Cantor Fitzgerald and covers MSB, asked a series of questions specifically about Mesoblast.


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MS. CHEN: All right, guys. I'm going to hop in there, then, since you guys don't have additional questions for now.

So I wanted to ask you about a company called Mesoblast. They have a drug called Ryoncil, and it has shown some good data. And I'm curious if you could run through that data with us and let us know what you think of the prospects of this product if it actually gets approved.

They've got a PDUFA date coming up in September.

DR. FERRARA: Right. So Ryoncil, which is essentially a mesenchymal stromal cell or a mesenchymal stem cell, you know, in some ways it's very interesting. This idea has been around. It was -- the concept was very popular about ten years ago. There were -- but then there was at least one phase 3 trial that failed. So, you know, it didn't work. So it's got that fairly significant baggage to it.

Now, they say that they've made some adjustments, and the data that I've seen, they've now got a -- so in children it does seem to work, at least in patients who have bad gut disease. So we talked about gut disease before. Bad gut disease is bad, you know, like fatal bad. And in a trial where they had, you know, over 50 patients, they had --what's impressive is that they had not only a high response rate, which was 70 percent, but they had a very good survival three months later, as well as some of the things that you would expect like tapering steroids, which would be very important. So that phase 2 data looks very good. It has -- it does have the problem that it's phase 2, it's not phase 3. It's got this additional problem that previous phase 3 studies have failed. So, you know, how is this one better? And so you have to take that into account. And then there's just a third issue, which is the mechanism of action of this is -- seems to be multiple. You can't -- this isn't like a drug. It's a

cellular therapy. But when -- in the animal models when they did this, well, where are the cells going and what precisely are they doing? The data weren't particularly clear, so it's a little bit fuzzy around some what we would have called the harder science, and now you've got -- and now you've got this previous phase 3 that didn't work. Now you've got a really strong phase 2, but is that the luck of small numbers? We'll have to -- we'll have to see whether the FDA will approve it. But it's my -- since I trained as a pediatrician and I know a lot of pediatric colleagues, they would certainly use it if it's FDA approved. Let's put it that way.

And, you know, pediatric studies are hard to do because there are even fewer patients compared to the adult patients. It's about only 20 percent of transplants are in pediatrics. So but it did -- they did manage to get a 50-patient trial, which for a pediatric population is

actually fairly large. So let me stop there.

MS. CHEN: Dr. Gutman, did you have any thoughts?

DR. GUTMAN: You know, I guessI would say as an adult-trained person, I think this notion of this particular product or a permutation of it and mesenchymal stem cells in general, it's

certainly been around for a long time, and I don't think we've sort of seen the home runs emerge yet. And I think that they're, to my mind, again, just sort of with my knowledge, there is a large stigma attached to this agent, I would say on the basis of it failing in a real randomized phase 3 trial. Again, there are always the details of trial design, but this was only just published in 2020 in our bone marrow transplant journal, the long-term results of the phase 3 study that included adults and kids, and there were secondary therapies that also had to be involved. So there are some issues.

But I think it points – that was a randomized trial where you're really going to get an objective look at the data, not just the interpretation of individual people, and it just, the benefit wasn't there. And I understand through my review of the literature, I think, and from my knowledge of my pediatric colleagues, you know, that for whatever reason that the data has been most positive in that pediatric population with the very bad disease, maybe it's very bad disease, period, but it emerges most strongly in the pediatric population, I think -- as an adult doctor I think adult doctors would be somewhat wary of something that only seems to work in pediatric patients. And I don't know whether that would have anything unique to do with the population or not, but I think the market is obviously considerably larger in the adult population, and I think it's a therapy that probably has an uphill battle

to gain traction in that space, especially considering the alternative options that are out there right now.

And just kind of looking through the material that you had sent about it, I think it's kind of odd in presenting a balanced picture of this that, like, there's no discussion of a negative

phase 3 trial or anything like that, that it's just sort of it feels like it's putting a lot of positive spin on the pediatric experience. But, again, it's also, it's sort of not -- it's historical controls and comparisons, which is always something to be very wary of, particularly against the

backdrop of the alternative emerging therapy.

That said, I think that these patients who we do have, who are very sick and who are not responding to options, we are desperate for options, and if there is an approved agent available, even if it's approved for pediatric patients, I think that with a bad acute GVHD patient, I would probably be looking for it off label before I move to some of the more traditional extremely immunosuppressive therapeutics. But I think overall I'm a little bit dubious about its overall potential.

MS. CHEN: Okay. Can I follow up really quickly here? So I do know that in the data they showed good efficacy in gut and liver, and you had mentioned the interesting point on the gut side. What about the liver side? Is that important to you? And then the second question I have was just on the grade of severity that you saw of the patients that were involved

in the trials versus other trials that are out there for GVHD.

DR. FERRARA: So a couple of things. Isolated liver is vanishingly rare. So the way the physiology works is that the liver is kind of downstream from the gut, so if you've got bad gut, since the liver is a big filter and since we don't often biopsy it and the measurements are crude, the fact that the gut – that the livers got better, that they were sick and that they got better when the guts got better doesn't surprise me, and it'sjust -- it didn't make much of an impression. So that was number one.

The patients were sick, but the problem is, if you'll notice, the data that they show for I think it was grades 3 and 4 and grades C and D, that paper was published, was published in 2005, and that means that the data of those patients is between 18 and 20 years old. So that's -- I don't know what -- 3 to 4s these days don't have disease that is that bad. You don't see --all of those patients died. And grade 4 is still bad disease, but it's not 100 percent fatal.

So I think that that's another grain of salt to put in there. And just one final thing. Dr. Gutman's absolutely right. In general GVHD occurs less frequently in children and is more easy to treat in children in general.

So when you see something that works in kids, many of my adult, you know, adult physician colleagues will say, you know, there may be something special about kids there and mesenchymal stem cells in kids and their healing properties or the resilience of their guts, whatever. So I think that the -- it is going to have, I think, a little bit more of an uphill climb, even if it is approved for children.

MS. CHEN: Dr. Gutman, did you have anything to add?

DR. GUTMAN: No. I agree with all those things. I would say too, though, with respect to acute graft-versus-host disease of the liver, again, in my experience it just in this day and age doesn't tend to be a tremendously significant issue for us. We see a lot of, I think, GVHD, chronic GVHD of the liver manifest by we look at the liver a couple of different ways by what we could call kind of a transaminitis and some sort of an angry liver. But the classic liver acute graft-versus-host disease that I think probably even before my time was a very fundamental issue, we just don't tend to see it very much these days. Whether that's a function of some other things like Ursodiol or Actigall and conditioning regimen stuff that we look at, I just don't consider liver GVHD in my experience, acute liver GVHD to be a prominent issue.

MS. CHEN: Okay. One last question from me is just the side effect profile that you saw in peds for the study,what did you think of it?

DR. FERRARA: Okay. I mean, I didn't see anything. Those patients are so sick that it's really hard to see a separate profile. Again, the baseline is so high. So I wouldn't -- I didn't see

anything. I didn't see a red flag for sure.

DR. GUTMAN: I agree. And, I mean, I think, you know, a theoretical benefit of this therapy is that it would be one that hopefully wouldn't add a ton of toxicity, although perhaps have some immunosuppressive qualities. But I didn't see anything overwhelmingly concerning to my mind either.

MS. CHEN: Okay. I'll turn it over back to my colleagues.

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@LeftYahoo There was also much discussion about Kadmon, who I understand from a little more digging, demonstrated in a 132-patient study, almost three quarters of chronic GVHD patients treated with a daily oral dose of belumosudil (KD025) saw an improvement in symptoms that lasted for at least six months. It appears that Kadmon will seek an FDA filing before year-end. Was this company on your list of competitors? Grateful for your thoughts? From my reading they are targeting adult market only, but might they be seeking to explore the pediatric market? Also is it possible that Kadmon is behind the objection?

Apologies if this ground has already been covered- I couldnt find reference to it previously

GLTAH

V