Hey, guys. Thanks for coming back. Last one, but certainly not the least one. To me, this is the best for last, is Mesoblast, M-E-S-O. Dr. Silviu Itescu is back with us again, CEO, and we've been covering and working with Mesoblast for over a decade, it seems. And we put out a note recently on Mesoblast, but the cell therapy space in general, particularly regenerative medicine side of it, is really at a crossroads. Like, this is it, right? We think, and we've been talking about this all conference long, for anybody who's been involved with cell therapy, talking about Mesoblast kind of as that bellwether at the moment.
They have a PDUFA coming up in early January for pediatric graft versus host disease, and there's a long story in how it got there, but it is, to me, a seminal moment for regenerative medicine. It also opens up opportunities for filings in heart failure and other things for Mesoblast, as well as other companies that are left still standing in regenerative medicine, and that includes Capricor and some other companies that we've spoken to over the course of this conference, but to me, it all started with Mesoblast, and it's here with Mesoblast that we're looking at that PDUFA and, you know, really, this space finally changing to the good. So, Silviu, you know, welcome back. I'll give it to you to give an update on the company.
Really, I, I'd like you to help everybody understand what's gone on over the last decade, and, and how we ended up here, and why this period is critical to regenerative medicine.
Look, thanks for having me. We've been at the forefront of this field for more than a decade. The truth is, it's a first-in-class technology. We're developing allogeneic cell therapy for inflammatory diseases. This concept of regenerative medicine also is a little bit has moved on, right? The truth is, we're targeting inflammatory, very severe inflammatory conditions, and the inflammation destroys tissues. And so what we've learned over more than a decade is that in order to get a good outcome in diseases where you require, I suppose, regeneration, is you've got to handle the inflammation at the front end.
And the quicker and the more effectively you turn off the inflammation, the more likely you are to get repair and go into remission of those diseases. So that's required large studies, randomized controlled studies, and it's required a much better understanding of the mechanism of action of the technology and of how to measure outcomes, how to measure potency, how to measure consistency of your product. And unless you've got all of those things in place, you don't have the ability to bring a product to market, right? We learned all that in a more than a decade or fifteen years of hard work and investment and clinical trials and outcomes. GVHD has been, you know, the mother of inflammation, right?
It's a disease of many, many cytokine pathways that are turned on by various arms of the immune system that result in destruction of your gut, your liver, and other organs. It became very obvious to us quite a while ago that unless we turned off that inflammation, we had no way of turning off the disease and improving the dismal outcomes of children and adults with this disease. It continues to be the number one cause of that prevents the good outcome from a bone marrow transplant. As many as ten thousand people get allogeneic transplants across the U.S. every year, and that's in order to rebuild and repair the bone marrows, and their immune systems after chemotherapy for underlying cancer, usually leukemias.
And the transplant sees the person as foreign, attacks them, and the transplant itself destroys gut, liver, and other major organs through inflammatory cytokines. So we provide a product, it's called remestemcel-L , or Ryoncil now is the commercial trade name, that is able to respond to the sea of cytokines, of inflammatory cytokines, by releasing factors that turn off the multiple arms of the immune system. And by turning off the immune system, children and in the future, adults, hopefully go into a remittive process, where the disease is turned off, which allows the tissues that have been attacked to repair themselves, to regenerate, right? And the regenerative process is one of normal healing that occurs in the absence of inflammation. So the inflammatory process drives the disease.
Our cells respond to inflammation and turns it off, and that results in amelioration of the disease. Look, the pediatric children with this disease have as high as 70%-90% mortality rates. There are no approved therapies for pediatric GVHD. We've successfully completed a phase III trial, which met its primary endpoint of both day 28 response as well as survival, secondary survival benefits at six months, and those data were previously reviewed by advisory panel of the FDA that voted 9 to 1 in favor of the product's efficacy.
And the holdup has been really to work with the FDA towards assays that allow us to be confident that the commercial product that will be provided more broadly is exactly the same, with exactly the same characteristics, and the same potency, and the same clinical benefits as a part of the win in the phase III trial. And I think the understanding that the FDA is looking for that type of consistency and reproducibility, and extension from the clinic to the commercial product, is a critical part of the learnings to date. But we think we're there. We've had a few hiccups along the way, but that's what happens with a first-in-class product always.
The ability to get this product approved in children will be a huge story when we hopefully get it approved. We have a PDUFA date that is January 7th. We're working very closely during this review period with the FDA to provide them any outstanding questions right now. And the plan is post-approval to focus on adults who continue to have a major unmet need. 40% or more of adults who are treated with the only approved agent in adults, Jakafi, ruxolitinib, are refractory fail. And if you fail that first line agent, survival is as dismal as 25% at about 100 days.
In our expanded access program, in exactly this adult population that's failed ruxolitinib or others, we see something like 60%-70% survival rates at day 100. So we're very optimistic about this product in the adult setting. We will be working with the Blood and Marrow Transplant Clinical Trials Network, NIH-funded body, to initiate a post-approval study in that population. But in the meanwhile, in children, there remains a complete unmet need, and ruxolitinib is not approved in children because of toxicity issues. There are no approved therapies. We're very optimistic that we'll get approval.
Can you talk a little bit about what's changed this time around? And it comes down to that FDA meeting back in March. You can see it if you look at the stock chart. But how, how did you end up getting to be able to refile with PDUFA in GVHD, the pediatrics, without the need for an additional trial ahead of that?
Well, look, the FDA acknowledged that we had a successful phase III trial, right? We met the primary endpoint. They had an advisory group that voted nine to one, that the efficacy was evident. But, you know, a product that is brand new and first-in-class, always has people who continue to have question marks, and want more data, and more clinical confirmation, etc . So as recently as last August, there were still questions around, should we do another study before the product's ready for approval? We met with the FDA in September.
We met with them again in March of this year, and we proposed the kind of adult study that I just told you about in patients who have failed the only available agent in adults, which is ruxolitinib. And we laid out the plan, and the FDA reconsidered our pediatric data and said, "Look, for the potential pediatric approval, go ahead and file because the data are sufficiently compelling." And the two are distinct populations, the adult and the pediatric, that one should not hold up the other, right?
And that was a view that the FDA, you know, really came to as recently as March. So that allowed us to be confident to proceed with the filing, which we filed in July. We needed a couple of months to get our documentation together, of course. So we filed in July, and the filing was accepted within two weeks, and we're currently in the midst of the review process. So I think it's more reflective of the FDA's continuous review and evaluation of data sets, the continued unmet need, the strength of our own data, the continued evidence under expanded access and compassionate care, that the product continues to perform and is safe. That I think provided the confidence to the FDA to allow us to move forward.
What about changes in the FDA, just generally? Because we always, we keep saying, like, innovators are always ahead of the regulators, and cell therapy, unlike, l ike, they're looking at large data sets. They didn't really, nobody really knew what the endpoints were over the last decade, but they get good data that's consistent, and you have end values. They're now going back and looking at these things and saying, "Okay, maybe you could file, maybe you can file." You know, we're seeing more of that just recently.
Yeah. Well, I think that's right. We've also had a very positive meeting with them a couple of months ago on our cardiovascular data. We've generated extensive randomized controlled data in two large studies in adults with inflammatory heart failure. And again, the FDA reconsidered their earlier position on those studies, looked at them and agreed with us that there's a strong signal in the inflamed subgroup of patients to the extent that they have given their support in us proceeding with an accelerated approval filing in a subgroup at highest risk, where there's evidence of a signal of efficacy.
So I think it's, there's continued evolution inside the cell and gene therapy group, and understanding that that something that CBER, for example, has implemented many years ago, and that in life-threatening conditions, first-in-class or novel therapies, that there are ways of bringing these products to market when they've demonstrated safety and signals of efficacy. And I think really all that we're seeing is a maturing of an industry, cell therapy, and I guess regenerative medicine is part of that, that is being looked at using the same standards as small molecules of biologics across, you know, harmonization, if you like, across the various arms of the FDA. So I, you know, I think this is good.
It's a maturity of a field that I think reflects some companies that have got a lot of clinical data and a lot of safety and a lot of underlying understanding of mechanisms of action and good science. So I think it's more of a timing issue and a maturation than anything else. But it's good news. It's good news for those companies that are able to generate those kind of data sets.
Now, there, there's a lot more going on at Mesoblast on the other side of that GVHD PDUFA, which we think right now the market might be holding its breath, watching for that PDUFA date, and you're not really getting the credit for the heart programs. So could you talk about, the two potential near-term filings that you have in heart disease?
Yeah. So, with cardiac disease, we've got our second-generation product that we call remestemcel-L, immunoselected using monoclonal antibodies, which gives us a more concentrated product. And, that product's been in development for a number of years in inflammatory heart disease and inflammatory back pain, locally injectable. We've generated three sets of data, all randomized, controlled, in pediatric congenital heart disease and in adult heart failure with reduced ejection fraction. And the data are remarkably consistent.
In the pediatric group, we've addressed a major unmet need, which is hypoplastic left heart syndrome, a disease in children that is fatal without surgery, where these kids are born with a very small left ventricle and are living on the basis of the right side doing all of the work. And the definitive surgery is something called Fontan surgery, which creates a permanent right-sided circulation, and whilst that's life-saving in the short term, in the longer term, the Fontan procedure results in a high incidence of right-sided heart failure because of the stress on the right heart, cirrhosis, and high risk of death over the subsequent decade that these kids remain alive. New surgical techniques are urgently needed.
A group of surgeons that we work with at Boston Children's have championed a procedure called biventricular surgery to create a normal left and right system. However, very few kids are able to tolerate that procedure because the left ventricle is so small at the outset. In our randomized controlled study, a single injection of remestemcel-L into the left ventricle, into the tiny little left ventricle remnant, resulted in a very significant increase in its size and volume 12 months later. In fact, such a substantial increase that 64% of the kids were able to tolerate the definitive procedure to give them a functioning left-sided circulation. That is really exciting.
We've got an orphan drug designation and a pediatric rare disease voucher for this, and we'll be meeting with the FDA, we hope, over the coming months to talk about how to proceed with a filing for that patient population. But I think the important thing to think about, and that in itself is a huge opportunity for Mesoblast, right? But I think the message here is that the enlargement and the strengthening of the function of the left ventricle is exactly what we've also seen in the adult population with low ejection fraction heart failure and inflammation. In those patients, echocardiography showed substantial improvement in ejection fraction at 12 months in a randomized controlled study, and that was published last year in Journal of the American College of Cardiology.
That was subsequently followed by a reduction in major adverse cardiac events, like heart attacks and strokes and deaths. That was complementary to a further randomized controlled study in the sickest of the sick patients who are being kept alive on a VAD, ventricular assist device, where again we saw at six months a significant ability to come off the device, to switch off the device, and the function of the left ventricle was strengthened, and by 12 months we saw an improvement in survival. Those data in totality, the complementarity of those two large randomized controlled studies in adults, which mirror what we see in the children in terms of strengthening of the left ventricle, were presented to the FDA earlier this year.
You know, they give us the opportunity for an accelerated filing for accelerated approval in that subset of patients who are being kept alive on a VAD and have got inflammation. You know, there's a lot on our plate, and to be frank, we have to focus first and foremost on the GVHD filing approval and commercial launch, and that will be followed in relatively short order by the cardiovascular opportunities, both for pediatric and adults.
You know, we then have our slightly longer term program, which is our inflammatory back pain, which is, while non-life-threatening, is a major cause of morbidity. The inflammatory back pain due to inflammation in the disc affects about seven million people across the U.S. annually, about the same number across the major five European jurisdictions. A first phase III trial showed that a single injection into the culprit disc maximally reduced pain at 12 months, and durably maintained that pain reduction for at least three years. A second confirmatory study is currently underway. It will take about 12 months to complete enrollment, and we'll read out a year after that. That's our sort of, if you like, our longer term value proposition.
So we have an immediate opportunity in our GVHD approval, and then the rollout of that program in pediatrics and adults. We then have an intermediate focus of inflammatory heart disease that over the course of the next 12 months will become, will be front and center. And then beyond that will be a back pain program, which is, you know, obviously a very large interest.
There's the back pain program, just, because it's kind of at the end of the line right now for us, that's how we think about it. But because it's not life-threatening and it's a morbidity issue, are the parameters for getting towards an approval going to be different? Maybe another trial, larger trial, is it gonna be opioid-sparing?
No. As I said, so non-fatal indications require two confirmatory studies always in drug development. We've completed one trial, and the FDA looked at the data, and they said the 12-month endpoint reduction in pain, if you can confirm that in a second trial, that's an approvable endpoint. So the second trial is currently underway. It's underway, right? So this is the second trial. It will complete enrollment in about 12 months, and then readout will be 12 months after that. That's our pathway to a multi-billion dollar opportunity, frankly. We've partnered that product in Europe with Grünenthal, which is a major pain commercial company. In the U.S., we would expect that we will also partner because the commercial channels will require a commercial distribution arrangement.
That's very different from the small, targeted sales force that we're putting in place for GVHD, right? 50% of the GVHD, of the transplants for bone marrow transplants in the U.S., are done at 15 sites. So we think we can handle the footprint for commercial launch with about 12- 15 account managers and MSLs. So very, very different, right? The small orphan indications, highly reimbursable, small commercial footprint, are gonna be managed by Mesoblast as we build out a commercial company. The larger opportunities, including cardiac and back pain for the larger adult populations, will be partnered and strategically partnered. But the value proposition is driven by Mesoblast with completing our phase III programs.
So unfortunately, it's hard to do the Mesoblast story justice in just 25-30 minutes, but-
Yes.
Because you do have this near-term milestone with the GVHD PDUFA coming up on January 7th, I'd like to take things back to the top and see if you could just discuss a little bit about what sort of preparations, plans, and opportunity you see for launching in GVHD.
Yeah, look, you, as you can imagine, this is what we're focusing very much on, on making the launch a success. Yeah. And, I've touched on the size of the commercial team that needs to be put in place, relatively small. We've got. We've put together an internal team that's head of commercial and medical affairs, and, we're in the process of putting the right folks on boots on the ground, if you like, that will interface with both the payers and the hospitals, and the key opinion leaders. But it's, you know, a targeted commercial approach.
In terms of the spend, relatively modest spend, and we entered into a transaction just two weeks ago with our largest shareholder, with a $50 million convertible note that ensures that we are fully funded for the commercial launch plans. We're well covered for those requirements. You never want to be short commercially. You never want to not have enough cash to execute. We have enough cash to execute comfortably. You know, there'll be a period of ramp-up, of bringing the sites on board, of getting pricing and reimbursement with each of the major payers, and getting on formulary in each of the hospitals, and making sure that we've got contractual arrangements.
That'll be a period that is, you know, immediately post-approval. But that's exactly what we're working towards, and putting those building blocks in place. That will allow us to broaden the post-approval, not just into adults, which is obviously the next place to go, but also into other pediatric rare diseases, right? So pediatric inflammatory diseases such as inflammatory heart disease, congenital heart disease, such as some of the muscular diseases, some of the other autoimmune diseases. We're looking at all of those, and a first approval in children will allow us to target these other conditions.
All right. Well, thank you very much, Silviu. It looks like we're coming up on time. That PDUFA date coming up is a huge event, not just for Mesoblast, but for the space. And I know it seems like, you know, it's a long time coming, the light at the end of the tunnel, but really, this is just the beginning with those two next filings in heart failure, potentially following up shortly, another phase III ongoing, and as you mentioned, multiple potential expansion opportunities. So a lot to look forward to for Mesoblast. Thanks, Silviu.
Thanks for having us. This is a very exciting time for us, and hopefully for the sector as well.
Absolutely. Thank you. We'll catch up with you soon. Thank you, Silviu.
Thanks. Bye-bye.