Everyone. Next, we have Mesoblast Limited. It trades on the Nasdaq under the symbol MESO and is a world leader in developing allogeneic, off-the-shelf, cellular medicines for the treatment of severe and life-threatening inflammatory conditions. Happy to welcome Founder and CEO Dr. Silviu Itescu. Welcome to the conference today. Thanks for having me, Anna. All right. So for our viewers who might not be familiar with your story, give us an overview of Mesoblast? Sure. Mesoblast is a company that's been public for a number of years now. We're developing platform technology on the back of mesenchymal stromal cells, which is an off-the-shelf cell type that is able to turn off severe inflammatory diseases. These cells are highly scalable. We have a supply chain from manufacturing site through to warehousing, through to distribution. And we're able to provide these cells for patients with devastating inflammatory complications. About the end of last year, in December, we received the first FDA approval for any kind of stromal cell therapy, the first of its kind in the US, the first and only FDA-approved allogeneic mesenchymal stromal cell product. And it was approved for children with a devastating complication called graft-versus-host disease, which is a fatal complication after a bone marrow transplant in as many as 70%-90% of children. A four-week course of our therapy results in long-term survival in a very large number of patients. This product will be shortly available in the U.S. to treat this complication. We're very excited about it. Yes. And congratulations on receiving FDA approval at the end of 2024. So provide a few more details about the product, the indication, and how you see this being adopted and used by physicians. Sure. So when a child or an adult gets a bone marrow transplant after they've had treatment for leukemia, for example, the bone marrow rebuilds their immune system. And unfortunately, 50% of the time, they get this terrible complication called graft-versus-host disease, or GVHD, where the bone marrow attacks their organs: the gut, the liver, the skin. And if they don't respond to steroids, then there's really nothing else that's available for children except for our therapy, RYONCIL. In adults, there is a drug that's available, but 40% or more of adults who get that drug fail. And for those adults, again, there's nothing available. So our product, RYONCIL, now approved for children after steroid failure, is used as an intravenous infusion weekly, twice a week for four weeks. And in a Phase 3 trial at 28 days, we saw a 70% responder rate. For those who responded early within that 28-day period, we now have long-term survival data that says 60% are alive six years out. Those are very impressive long-term cure rates, effectively. When you think about a therapy that is potentially fatal in 70%-90% of children within the first year, to have that type of survival benefit and cure rate is a transformational approach for this disease. Absolutely. So what is the market like for RYONCIL? And how do you see pricing for this product? All up, there are about 10,000 patients in the U.S. who get bone marrow transplants. About 50% of those will get graft-versus-host disease. The pediatric market is roughly about 25% of the adult market. And we see 20% to 25%, something like this. And we expect that the severe children who failed steroids will account for something like 375 children a year. And if we can achieve the type of long-term cure rates and survival that I've just talked about, then that's sort of the same type of ballpark as with a number of the gene therapies that have recently been approved for diseases like, you know, hemophilia or sickle cell disease, et cetera. So we see this as a treatment for a rare disease like GVHD in children. Pricing is likely to be in that sort of ballpark, although we haven't yet publicly provided guidance on the price or on the market adoption. This product has been used in about 300-400 children in the last few years under expanded access. It is, one could say, the standard of care already in all the major hospitals across the US where transplants are done. We work very closely with the key physicians. You know, we've been providing product to the key physicians for this disease. I suspect, I expect that really adoption will be relatively straightforward. We have a strategic partnership in Japan with a company that's under license at a similar product as this one, available for the last four or five years. Again, the adoption in Japan, which is a far more conservative market than the U.S. showed the product achieved about a 30% penetration rate within the first couple of years. We expect that sort of order of penetration in the U.S. market, pediatrics first. As I said earlier, the objective is to target the adult market, which is three to four times bigger in patients who failed the only available drug in adults. For that market, 40% of patients will have nothing else. We currently have a relationship with the Bone Marrow Transplant Clinical Trials Network across the U.S. which is a body funded by the National Institutes of Health. They're across the 80 biggest bone marrow transplant centers. They've agreed to run an adult study in patients who have no options, where we see who today have about a 25% survival rate with adult GVHD. We've seen under expanded access, the use of our product in those adults give us about a 73% survival rate at three months, which is a big, big difference and improvement. Our initial focus is children. We expect to have this product launched in children in this quarter. Then, of course, we're going to build it out into adults with this potentially fatal complication. Then we have a whole strategic plan to both move into other pediatric inflammatory diseases and other adult inflammatory diseases. I'm happy to talk about some of those. Yeah, talk a little bit about that. Since you have approval, how is the product launch progressing and what's next? Yeah, tremendous amount of work has been happening in the last four weeks since approval, and, you know, I know people would like to see this product on the market yesterday, and we have physicians and children now waiting for this product, but we have to work with the FDA in terms of getting all the documents signed off to be able to release the product. It's in the hands of the FDA to give us the green light to provide the manufactured batches to the hospital, so I think that will be happening imminently, and we're working with payers. We will be announcing shortly the pricing of the product. We expect it to be covered by all major private insurers, and of course, it'll be covered by Medicaid as well. There are a number of other very severe inflammatory conditions in children with an approved product that we will be looking to expand using investigator-initiated studies, for example. One of the big areas of focus for us is actually inflammatory bowel disease. Crohn's disease is a big problem, obviously, in both adults and children. 25% of the total Crohn's market is in adolescents. So it's a bimodal kind of disease where it presents for the first time in adolescents, in 12, 13-year-olds, 15-year-olds. And of course, the second peak is in much older adults. We already have some pretty exciting data in patients who failed an anti-TNF agent, a single anti-TNF agent. Now, in adults, there are other experimental drugs and some other approved drugs that are potentially available for those patients. In children, after you've failed a first anti-TNF agent, there's nothing else that works. It's a particularly devastating complication in children or adolescents. About 50% of adolescents will fail an anti-TNF agent. In that population, we think that we've got something that's pretty special that we expect will have a major impact on the Crohn's disease population. You'll be hearing a lot more about that shortly. Talk about any potential partnerships, like you kind of mentioned, collaborations that will accelerate your commercialization efforts in the U.S. maybe globally. Sure. So for this first indication, of course, we're building our own commercial sales force. 50% of bone marrow transplants occur in the 15 top volume sites, 80% across 40 sites. We've hired a commercial team with account managers, et cetera. So with about 12 to 15 people, we can manage the GVHD footprint pretty effectively across the US. But in these other areas, like Crohn's disease, for example, or inflammatory bowel disease, for this approved product, we will be working potentially both in the US and ex-US with strategic partners that have established commercial footprints and leveraging others' sales forces, particularly in Europe. So whereas the US has really got one regulatory environment and payer environment, Europe is a little bit more complex. We are currently in discussions with a number of commercial partners potentially to take our product into Europe and leverage the FDA approval into EMA approval, which is relatively straightforward. That's a major focus for us. In fact, in one of our second-generation products, the back pain product, which has already completed one phase three trial and is now currently in a confirmatory second trial, we have a partner in Europe, Europe's largest pain company, who will be, if successful, distribute that product in Europe across various European jurisdictions. So I think that's our strategy, right? For the European market, we'll be looking for European partners. For larger opportunities like inflammatory bowel disease, even in the U.S. we'll be working with strategic partners. Of course, for cardiovascular disease, which is one of the largest opportunities, we're in the middle of multiple discussions with potential cardiovascular partners. I can tell you a lot more about that. Wonderful. Well, looking at the rest of your pipeline, you have a second-generation product in the cardiovascular area, which you alluded to. So elaborate on this program and what indications are you targeting? Yeah. So a second-generation product is extracted. We isolate the cells using monoclonal antibodies. The cells are more potent and being developed for, again, inflammatory conditions where the cells are directly injected into tissues that are under attack from the immune system, and so inflammatory heart disease is a big one. It's a large unmet need, and despite the fact that there's a variety of new drugs on the market, they target symptomatic heart failure, shortness of breath due to too much volume, if you like, and they sort of improve symptoms, but don't really have an impact on the major complications of cardiovascular death due to cardiovascular causes, mortality, heart attacks, or strokes, and that's where our product seems to have a major benefit. So we've completed one trial of about 530 patients, which, and we've recently published this in two major journals, the Journal of the American College of Cardiology and European Journal of Heart Failure, both of which in the last 12 months or so have shown that a single injection of our cells into these very high-risk patients with inflammatory heart failure, inflammation and heart failure, a single injection gave about a 70% reduction in heart attacks, death, or strokes over about a 30-month or almost a three-year period of follow-up. And that's on top of maximal existing standard of care. So that kind of durable long-term reduction in mortality and heart attacks is unprecedented. And we've had meetings with the FDA. And the FDA has given us a clear pathway towards an accelerated approval for this unmet need. We would have to. We're working with them to get in front of them this year. We expect to have a meeting with them in the coming quarter, but be in a position to file for an accelerated approval towards the end of the year, subject to an agreement with the FDA on what a confirmatory second trial would look like. Based on the previous study that we've done, a second trial would be about the size of about 240 patients. It's a relatively small study. The objective being, again, to demonstrate the same thing again in these high-risk patients, a reduction in death, reduction in heart attacks, and reduction in strokes. We're very excited about this market. This potentially is a million patients a year with this condition. Sorry, a million patients overall prevalence rate across the U.S. have this condition. If we can demonstrate at least a three-year durable reduction in death, heart attacks, or stroke, we think we've got an incredibly valuable product. Provide an overview of the pathway to approval for pediatric and adult heart disease, including the ongoing interactions with the FDA. I've mentioned for adults, we've already had the FDA confirm that we're eligible for an accelerated approval with filing on the back of the previous data that we've already shown them. The other interesting area is the pediatric space, where we've done one randomized controlled study in children with a unique problem, congenital heart failure due to being born with a single right-sided ventricle, something called hypoplastic left heart syndrome. We showed that a single injection into the tiny little left ventricle of these children, which is a rudimentary, very small left ventricle, significantly increased the size of the left ventricle and allowed surgeons to then perform a permanent procedure that made the child have a normal circulation, left side and right side. That is very different from today's standard of care, which is to try to support just the one right ventricle. Some people are trying to stimulate that right ventricle to grow a little bit more. The problem is with the current surgical procedure with a permanent right ventricle. These children will ultimately die early due to right-sided heart failure, due to liver failure, and cirrhosis. So what we're doing actually is helping the surgeons create a functioning, strong, large left ventricle that the children can have permanently. That's a big deal. We've got a pediatric rare disease designation from the FDA. It's obviously an orphan drug designation as well. And we'll be having further discussions with the FDA this year how to integrate that into a potential approval for children side by side with our adult product for approval in adults. And so on to your back pain opportunity, provide an update on the progress. I believe it's a second phase 3 trial. Yeah. Look, again, the underlying problem is inflammation in the discs, in the intervertebral discs. And a lot of us who sit around working too long hours on computers, et cetera, have intervertebral disc problems. And this is a problem that affects as many as seven million people across the U.S. After you've tried nonsteroidal anti-inflammatory drugs, after you've had a shot of steroids, for example, other than opioids, there's nothing else. And, you know, you can go ahead and have invasive procedures and surgical removal of discs, et cetera, but there really is nothing else that is minimally invasive or that provides a kind of safety of ourselves. And of course, we all understand the opioid epidemic. And 50% of opioid prescriptions across the U.S. are for this exact indication for inflammatory back pain. We aim to be developing a drug, a therapy that replaces the need for opioids, that reduces the opioid dependence, and that avoids the need to progress to invasive surgery. In a first phase three trial of about 400 patients, a single injection of a micro dose of our cells into the inflamed disc resulted in at least a three-year substantial reduction in pain, where 50% of the patients had no pain at all at the 12-month mark, which was the primary endpoint, and remained completely pain-free for at least three years of follow-up. In addition to that, you know, about 40% of the patients were on opioids to start off with. And in that particular group, we had a significant number, as many as a third, completely come off opioids altogether, compared to only 5% of the control group. And that's despite the fact that we were explicitly instructed, "Don't change your medications." So that gives you a flavor of how strong the pain reduction that we were able to obtain in that trial. We've had very good interactions with the FDA in this program as well. And the FDA has agreed that if a second trial achieves the same endpoint of reduction in pain at 12 months, that's an approvable endpoint, the product would be approved in the U.S. So that's the second trial that we're currently conducting. It's up and running across so far about 15 sites in the U.S. The objective is this quarter to have about 40 sites, 40 centers enrolled and up and running. And we hope to complete this trial this year, the enrollment piece of it. And then it's a 12-month follow-up on the primary endpoint. So the way to think about Mesoblast is, you know, we've got our first product, RYONCIL, approved. It's the only mesenchymal stromal cell product approved in the U.S. It's available today for children. It will be available for a host of indications in the short term. We're going to build out a business around that. But our nearer-term opportunity for the second major product is the cardiovascular space. And our intermediate term, if you like, opportunity, our third leg of the stool, is the back pain product. So this is what you're seeing is the emergence of a company that is bringing cell therapy products off-the-shelf, allogeneic products to the U.S. market in a stepwise fashion. So how does your current cash runway align with your projected milestones, commercial launch plans, clinical development, and other initiatives that you have over the next one to two years with all this important work you're doing? Yeah. Well, you know, this is always part of a company in growth mode, right? We just raised $160 million. We've got about $200 million on our books. And the use of the capital in the shorter term is to ensure that we've got adequate funding for our commercial launch plans, which we now do, of course. We've got plenty of inventory already made for the pediatric market for the next two years at least. But we need to invest in manufacturing. We need to continue to produce and scale up and have more inventory available for the other indications we've just been talking about, right? I expect that we're going to have growth and demand that would require further inventory build. And that's a major objective of the coming 12-month period. We have projections for the back pain trial to complete. And we now have capital that, when we agree with the FDA on a confirmatory phase 3 trial, relatively small size, about 240 patients, we have funds for that objective as well. So I think we have at least, you know, we were very careful in the last 12 months or so to ensure that we were very, we reduced our cash burn. In the last couple of quarters, our burn has been about $10 million per quarter. I would expect that's going to now probably double given our investment in commercial and investment in manufacturing. But on the basis of the amount of cash we have, we have probably at least two years of burn. So I think we're well cashed up to deliver on the near-term milestones that I've outlined. And I think it's going to be a very exciting 12 months for the company. Very exciting. Wonderful. So talk a little bit about long-term. What is a long-term vision? Five to 10 years? You know, I work, for me, three years is a long time. But I, you know, I have my year, one-year plan, two-year, three-year plan, that sort of thing. Look, I see Mesoblast. We are the leader in the allogeneic cell therapy space. We're creating groundbreaking new products. We're building new areas of focus in those diseases for which there are no treatments. There are no small molecules or biologics that address the kind of bad diseases with bad outcomes that we're targeting. And I think what you're seeing here is the emergence of a company where we own the space. We have more than 1,000 patents. We're the leader in this space by a long shot. And the FDA approval allows us to continue to open new areas and create a big gap between us and any competitors that may emerge. So I see this company as building products, bringing some products to market and building them ourselves, and working with partners in other products. And, you know, we're building the leader in an emerging new field. I see this cell therapy field in the way that monoclonal antibodies were when the first antibody got FDA approval 25 years ago. You know, in those days, one company had the first antibody. Today, there isn't a Pharma company on the market whose pipeline isn't dependent on monoclonal antibodies. So I see this as the beginning of a whole cell therapy industry. Wonderful. Well, thank you for your time. I want to give you any closing remarks for our viewers and everyone who's watching today. What would you like to say? Look, I think. Watch this space. Watch Mesoblast closely. We're emerging from, you know, the preclinical tough development phase into the new commercial growth phase. And we expect that Mesoblast will have a lot more news flow to our shareholders, to the market, and follow us closely. This is going to be a big year for the company. Wonderful. Well, thank you, Doctor, so much. We look forward to following you along with these important updates. Thanks for having me. All right. Cheers, everyone. We'll be right back with our next presenter.