Okay. Morning, and welcome everyone to Mesoblast's Inaugural R&D Day. We've got a wonderful morning planned and appreciate you all investing the time to come along and hear the Mesoblast story. Before we get started, I'll just draw your attention to the slide, the forward-looking statement that I've got displayed on the screen. Okay. So the format will be presentations from Mesoblast program heads and our leaders, and that'll be followed by a fireside chat with KOLs, and then we'll conclude with Q&A. We're delighted to have such a distinguished lineup of industry key opinion leaders for you to hear from today, and we're very grateful for their time. With that, I'll now hand over to Silviu, Mesoblast's Chief Executive.
Good morning, everybody, and thank you for coming. We're very excited to have our inaugural R&D Day, and it's great to have so many friends in the audience. Nice to see you all. Mesoblast is the global leader in allogeneic or off-the-shelf cellular medicines. We are located in the United States and Australia, and Singapore, and we're listed dually on the NASDAQ and on the ASX. We're developing product candidates for distinct indications based on two leading platform technologies, our remestemcel-L first-generation technology, and rexlemestrocel , our second-generation technologies, and you'll hear about both of these. Importantly, we have the only and first FDA-approved product launched successfully, for any indication across the U.S., but most importantly for children with a devastating complication called acute graft-versus-host disease.
We have a very extensive global intellectual property portfolio with protection across all the major jurisdictions through to at least 2044, and we have devoted a lot of time and effort to FDA-inspected commercial scale manufacturing that underpins everything that we do. Our proprietary stromal cell technology platform positions Mesoblast to be first in class. Our unique mesenchymal lineage cells are cells that fight inflammation uniquely. They're derived from healthy donors. They home to inflamed tissues and respond to inflammatory signals. They secrete factors when activated that turn off multiple inflammatory pathways, but importantly, are otherwise inert in the absence of inflammation. That underpins their extensive safety profile. Otherwise, the mechanism is to reduce inflammation and to improve tissues and result in tissue repair more broadly. We have proven first and second-generation technology platforms, and as I mentioned, the first generation is called remestemcel-L .
That's the one that's FDA-approved, and we'll talk a lot about that shortly, and that focuses on rare pediatric and adult orphan diseases. Rexlemestrocel is our second-generation product that is based on immunoselection for precision. It's highly scalable, has greater potency, and is geared towards blockbuster high-volume diseases. Our unique off-the-shelf properties, the allogeneic properties of this technology underpin our business model. These cells do not express certain surface co-stimulatory molecules that otherwise would be detrimental, and therefore do not induce immune reactions. There's therefore no need for immunosuppression, unlike many other types of cells that people are focusing on. Ultimately, from a single donor, we can generate products that treat thousands of unrelated recipients. This has been a vision for many years, both from our former various collaborators, but more importantly, we've been in this space for a long time. We know this.
People were skeptical that we would be able to make an off-the-shelf product to treat unrelated people, but here we are. We have an industrialized process. It's based on a very well-understood technology, and we can really scale this up with a supply chain from end to end that makes business sustainable. In fact, our manufacturing process, which you'll hear more about today, is a highly scalable proposition with expansion, without differentiation, with validated potency assays which ensure batch-to-batch consistency and reproducibility, and equally as important, proprietary media formulations that enable substantial scale-up ultimately to be used with bioreactors for footprint reduction. This slide speaks to the underlying mechanism of action of all of our technologies and how we use them to target severe diseases of inflammation, the so-called cytokine storm syndromes. Our cells are well-characterized.
They have on their surface a variety of surface receptors that bind to various pro-inflammatory cytokines, including IL-1, IL-6, IL-17, TNF, interferon gamma. You can imagine when you put these cells right in the middle of a cytokine storm where all of these big cytokines are generated at high levels, and you'd all be familiar with the cytokine storm that we all were worried about with COVID some years ago.
You put these cells right in the middle of all that, and they get activated, and then they turn on their precision-based responses, turning on and producing various factors that are also very well-characterized and switching off the multitude of immune cells that are responsible for the diseases that these cells ultimately aim to turn off. We've understood all of this, and it's the basis for how we select the appropriate diseases that we target, the appropriate patient populations, and how we structure our business going forward in terms of not just precision medicine, but aiming for remission induction outcomes. We are the first-in-class leader in allogeneic cellular therapies. Our business is based on at least these three pillars, the technology, the commercial capability, and the pipeline. Our technology has resulted in having our first successful U.S. launch.
Net revenues today approach $100 million since launch just last year and continuing to grow. We've got a highly profitable single product on a standalone basis. If this was a company that only had one product, this would be a profitable company. More importantly, the revenues that we're now generating quarter on quarter are used to support our internal programs. We're able to now match our internal spend on our programs to the strength of our revenues. We invest in our label extension programs, and we invest in our blockbuster opportunities. Our commercial capability is now well established. We've got infrastructure that supports our product launches across multiple expansion indications, and we just announced yesterday that the FDA has allowed us to initiate a Phase III trial in Duchenne's muscular dystrophy.
Gone straight from preclinical data straight to a registration trial on the basis of the extensive safety data that we have, on the basis of the infrastructure that's in place to ensure that the products are safe and are reproducible, and the FDA had no concerns based on our own data to allow us to move directly into a registration trial. We've also built a specialized sales team that focuses on the patients, on the hospitals, on the centers, and on the specialists who deliver this therapy. Finally, we have those blockbuster programs. We've been working on this for a while, but they've now come to fruition. Our Phase III programs for our second-generation pipeline product, rexlemestrocel-L, will transform the treatment of big unmet needs, including the treatment of low back pain from degenerative disc disease, an inflammatory process, and inflammatory heart failure.
You'll hear from very distinguished key opinion leaders on their views of the data generated and where we're going with these important programs. Beyond that, we also have our Phase III programs to extend the life cycle of Ryoncil, the FDA-approved product, in adults with the same devastating disease as in children, graft-versus-host disease, and in other pediatric rare diseases. I just gave you one example, the Duchenne opportunity. Ryoncil has a trajectory towards profitability that will fund our growth pipeline. I just mentioned to you how we intend to do that. We just reported net revenues of $30 million in just this quarter, which was based on $35.3 million in gross revenues. I've said that we're approaching $100 million in sales since just last year's launch.
That allows us to project internal operational needs and to adjust according to our quarterly revenue so that we're able to efficiently manage our cash flow. In terms of our operating performance, it was very strong in the period, allowing us to invest in a well-considered way into R&D and into the programs, both the ones that are in Phase III and those that are for life cycle extension. We're in the process of commercializing manufacture of our second pipeline program, which you'll hear more about. What we have built, importantly, is a commercial capability that is second to none. We've got commercial infrastructure, we've got specialized sales and marketing teams, we've got market access and payer engagement. We've established strong manufacturing supply chain capabilities. We've leveraged clinical data and real-world evidence to support product positioning and physician uptake.
We've established medical affairs and educational programs, and we've ensured beyond all of that we continue and will be the world leader in this space by continuing access to next-generation cutting-edge technology that you'll hear about today in terms of genetically modified mesenchymal lineage cells that have the potential to open up a whole range of new indications. Our pipeline for the blockbuster opportunities is really near-term, and so you need to look at us not just in terms of our first product for graft-versus-host disease. That becomes really the shining light and the example of what we can do in terms of regulatory approvals, in terms of getting payer engagement, in terms of getting adoption by the physicians, in terms of selling product.
If we can do that with remestemcel-L for the smallest indication, imagine what we can do with rexlemestrocel for cardiac indications and for inflammatory pain indications. Those are the real future as we move forward. Those opportunities have total addressable markets, not $1 billion, which is sizable for the acute graft-versus-host disease indication, but their addressable markets represent north of $10 billion for each of the back pain and heart failure opportunities. This slide is a snapshot of where our products and their indications sit in timeframes. You can see we're a mature, late-stage company with an initial product that's been launched and several that are in Phase III. We're not talking about years away. We're talking about completing a pivotal trial for the largest opportunity in back pain now with a potential 12-month readout and then engagement with the FDA for approval.
These are not long-term waits. We've been at this game for a long time. We're now in the end zone. The anticipated major upcoming milestones for these programs, for our blockbuster opportunities, chronic low back pain, we've completed enrollment of our pivotal trial end of this month. Our top-line primary endpoint readout will be about 12 months away, middle of next year. Assuming that we have a positive readout, we intend to file for BLA approval third quarter of next year, and all going well, potential FDA approval and the U.S. launch is targeted for the second quarter of 2028. Our cardiac program is the other one that we're very excited about. We have a regulatory strategy in place to gain approval for this blockbuster indication as well.
In order to do that, we will be filing with the FDA for a BLA for the smallest, highest unmet need patient segment, those with end-stage heart failure who are being kept alive on an artificial heart, an LVAD. That will allow us to leverage an initial approval and move to a post-approval confirmatory study in the much larger opportunity in Class 2-3 heart failure. Finally, the label extension approach for Remestemcel allows us to move into both adults with acute graft-versus-host disease and children with various inflammatory diseases, Duchenne's being the first amongst several. Again, funded very carefully by our internal resources, but in collaboration with various groups. The adult program is partnered with the Bone Marrow Transplant Clinical Trials Network. The pediatric study is partnered with the advocacy group PPMD, and you'll hear a lot more about that today.
Finally, this is entirely driven by innovation. We've been the leader in this space for many years. We've innovated what we do. This is why we're at the space that we're in today, and we continue to innovate. We're innovating in new technologies. We've brought in genetically modifying our cells through a number of ways, including chimeric antigen receptors for enhanced homing and enhanced potency of our products. We've brought in genetically modified oncolytic viruses that are best in class in terms of encoded with immunostimulatory factors for treating cancer. This is just a sampling of the way we see ourselves maintaining a leadership position and, in fact, growing it in a whole raft of new areas by taking advantage of technologies that weren't around years ago, that will take us from where we are today to a whole other level.
In terms of manufacturing efficiencies, second-generation media formulations, which are proprietary to us, have allowed us to increase our manufacturing to meet the scale and volume needed for some of these large indications. You'll hear from Justin Horst, our Head of Manufacturing, about some of those. We seem to have lost our audio-visual. I think on that note, I hope I've given you a little bit of a tantalizing view of the many things we're going to talk about today. Let me start by introducing you to our Chief Commercial Officer, Marcelo Santoro, who's going to be telling us about his experience and how he's built this company in the last 12 months from an R&D company to a truly commercial stage company, which is generating substantial revenues already.
Thank you. Thank you very much, Silviu. Good morning, everybody. It's a pleasure to be here. Thank you for coming today. It's been exactly one year, a little over one year since we received price approval, or we published the price in the U.S. compendia for Ryoncil, and we couldn't be more excited about what this product's doing for patients. It is really transforming the treatment of acute graft-versus-host disease. Let's talk about the patients a little bit. First of all, when we first started this conversation, this launch, we said that we would redefine what was possible in the treatment of these children. That's exactly what we're doing right now, and the feedback from clinicians couldn't be more positive to date. We hear that every day. In fact, from one of our very first patients, a patient who was extremely sick.
We treated that patient, the clinicians treated that patient, and eventually they gave us a call. Her name was Josie. Baby Josie. They gave us a call to say that baby Josie could not be controlled anymore because she was running around the hospitals like crazy. For us, look, at the end of the day, this justifies what we do. We are here to really save the lives of these children. That is the purpose for our product in acute graft-versus-host disease. As I age, I can only remember three things. I have four in this slide, so it's a stretch. There are some takeaways here. Please. The first one is that, again, we're transforming the outcomes of pediatric steroid-refractory GvHD with very strong feedback from treating physicians. You will hear from some of them today, right?
The commercial uptake has truly exceeded our own expectations, and believe me, they are not low, right, outperforming benchmarks from comparable successful launches. We have established the capability to scale with a clear path to doubling our U.S. revenues from Ryonsu. By the time, by the end of this presentation, I think you will understand why we believe we can get there and beyond, right? This is coming. Then finally, we are super excited about the adult indication opportunity, not only because of what we believe the product can do for these patients and the medical needs, but also due to the fact that this will triple our franchise as we move forward. Let's just talk a little bit about some of the accomplishments so far, right? First of all, again, all about the patient. The initial real-world experience could not be better.
84% survival, I remind you that all of these patients were severe patients, grades three and four of disease, right? Silviu mentioned that we're approaching $100 million in net sales. We're just starting. That's where we are right now. We as a team took a long time to build the infrastructure to make Ryonsu as successful as it can be. In the past year, we onboarded 50 centers. We received formulary approvals in 30 of them, and that is very important because it allows, if a clinician wants to make a clinical decision to use the product, being on formulary facilitates that clinical decision quite dramatically. 13 of our accounts use our partner for specialty pharmacy, which may or may not require the product being on formulary. This number is even bigger than the 30 that I mentioned before.
Virtually everyone on label can get access to this product. 98% of U.S. lives covered to date. We never had one single claim denied for patients on label, and that reflects the exceptional work done by the market access team, which I'm very proud of. Medicaid is in place, and in fact, just a story here. We were able to achieve Medicaid approval in 24 hours. I believe that has to be a record for the industry. We had a patient who needed the drug and was a Medicaid patient. We appealed to the government. They listened. We got an approval in 24 hours. That reflects what this product can do for these patients and the belief that all stakeholders have in this product. We also received J-codes in October 2025.
Having a specific J-code is important because it allows the states to have clarity on reimbursement levels at the state level from a Medicaid standpoint. For us, that was very helpful. Finally, as I mentioned before, we're expanding into the adults marketplace. Michael Schuster will walk you through the program. Phase III is underway. It will be also a meaningful expansion of the GvHD franchise. This is the team that made it happen. I'm very proud of the team. I couldn't be prouder of what was accomplished to date. As you can see, this is a small, specialized, super passionate, incredibly committed team to putting these patients on therapy. I've been doing this for a long time. I have never seen a more committed group of people to helping these children. Talk about we care. We really do care.
It's all anchored in the key account executives. Those are the folks who are responsible for all the transplant centers and engage support as needed from the MSLs, from field reimbursements, making sure that they get patients on therapy, and supported by a digital ecosystem to expand our reach. A small, focused team that is taking us to where we are today and will take us to our next levels of performance. I mentioned we could double the size of the net sales. Again, we're approaching $100 million net sales at the moment. This strategy underpins on three key factors here, right? First of all, we've had a large number of institutions that have used the products, and not only used once, but had repeat use for the product.
We want to make sure that all 64 of them have a chance to experience what Ryonsu can do for these patients. There is absolutely no reason why they wouldn't. That is a good opportunity for us to expand the utilization and the experience with the product. Second is, and we heard this feedback loud and clear from one of our KOLs, Ryonsu needs to be available at the sites of care for immediate dispensing once the clinical decision has been made. That's exactly what we're doing right now. We're implementing a program that will place the product in most, if not all, institutions to be able to do that. Don't take me wrong. I think we are really good. We became really good in getting these products very fast to the treatment centers. If you place an order today by 10:30 A.M., I can get you the product tomorrow.
That was not enough. We want to make sure that the product's there so that the moment the clinical decision is made, you start using the product, and you don't use an inferior alternative because you do not have the product available on-site. Then finally, our biggest opportunity here, and it's a combination of education plus experience with the product. This broader utilization of the products first-line, right after steroids, will really propel us to next level performance. Really, it's just consistent with our label. Consistent with the, if you look at the PI for Ryonsu, that's exactly what it should be, and that's where we must get there. That's really the journey. The path to get us there is through these three key main strategies, and again, we're working on all of them as we speak. What are our priorities for the year?
For 2027. First and foremost, this is rare disease. Every patient counts. You've got to find these patients. This will always be the number one strategy. Finding the right patients, putting them on therapy, making sure that we are serving these patients well. That is our first strategy. Second is we need to continue to reinforce the outcomes in first-line. Again, it's a combination of experience and education. So when people have both, obviously you start migrating and using more and more the product in first-line. Lastly, we'll give the caregivers a voice to demand Ryonsu to their children.
As a father of four, I can tell you that if one of my children had this devastating condition, I would want to know about it, because then I could talk, I could engage the treatment teams, I could ask, and I could see if this was a possibility for my own child. This is what we're doing. You'll see a couple things. You will see a large campaign focus on caregivers as we evolve. You will also see that we've been partnering with advocacy associations such as the Meredith Calvin Foundation, the GvHD Alliance, and MZP, among others, to be able to get the message out and to be able to provide education at the points of care so that the caregivers do have a voice. Some key takeaways here. Again, approaching $100 million in net sales, but that's just the start.
I think I showed you the path to more than double the net sales we have. The excitement regarding the adult's potential. Combined, children and adults represents over $1 billion in potential total addressable market here. For us, it is really a good opportunity to expand our GvHD franchise. You will hear from all of the presenters, but I believe one of the underpinning factors is that the commercial capability that Silver mentioned that took us so long to build will really support the launch of different extensions for Ryonsu, which will greatly increase our performance. Finally, we've been actively working on opportunities to expand outside of the U.S., but one of the most important things here is keeping the most favored nation pricing. You don't want to obviously destroy value.
You want to make sure that you benefit kids outside of the U.S., while respecting most favored nation pricing. With that, let me ask Michael Schuster, our head of business development, to talk about the adults program, and we will entertain questions in the end.
Thank you, Marcelo. Adult steroid-refractory acute graft-versus-host disease really represents the start of our label extension strategy. We believe this is a huge opportunity for Ryonsu growth. Approximately 50% of all adult steroid-refractory acute graft-versus-host disease patients are Grade 3/4. These are the patients that are at highest risk of dying. Despite ruxolitinib, which is also known as Jakafi, being approved for adults, this remains a major unmet need. The market size, as Marcelo indicated, in adults is approximately three times larger than that of pediatric patients. Therefore, when you combine the pediatric and adult revenue potential, we believe it's well over $1 billion. There's a large overlap across the adult and pediatric call centers. Therefore, the existing pediatric commercial and medical affairs infrastructure that's already in place can be leveraged and expanded.
The lessons learned will allow us to enable quicker onboarding and faster time for market penetration once the adult product is approved. Finally, the pricing structure will be maintained given the high mortality risk and orphan nature of these adult high-risk patients. Now, we know ruxolitinib is the only approved therapeutic in the adult setting. As you can see here, their registrational trial from REACH1, it's actually quite effective in the less severe Grade 2 graft-versus-host disease patients. In this setting, it primarily affects the skin, and they're able to achieve approximately an 80% day 28 overall response rate. However, as you can see, about two-thirds of the patients in this study were Grade 3 and 4. This component of the disease primarily targets the GI and liver. Unfortunately, ruxolitinib was far less effective.
Only about 40% of the patients for these Grade 3/4 disease settings are able to achieve a day 28 response. It's these patients that are at highest risk of dying. In fact, when any of these patients fail to respond to ruxolitinib, and then additional therapies the investigators may put them on, their survival rate is dismal. Only about 25% of the patients will survive 100 days, as you could see in this left-hand figure, with a median survival of only 28 days. In contrast, we've now been treating through emergency INDs over 25 adult patients who have failed steroids as well as a second-line therapy, the majority of which have been ruxolitinib. We're able to achieve a 76% day 100 survival, as you could see in this Kaplan-Meier curve. Therefore, this is significantly better than the expected 25% survival rate at day 100.
Furthermore, there's evidence from a single-site pilot study that has shown there could be an additive benefit when MSCs are used concurrently with ruxolitinib in severe GI steroid-refractory acute graft-versus-host disease, where these investigators have been able to achieve almost a 90% day 28 overall response. Therefore, we really believe that the potential combination of Ryoncil plus ruxolitinib could perhaps address these high-risk patients. As such, we've designed a registrational trial for adult steroid-refractory acute graft-versus-host disease patients in partnership with the NIH-funded Blood and Marrow Transplant Clinical Trial Network, also known as the BMT CTN. We will enroll 180 patients, Grade 3/4, so again, these high-risk patients who are steroid-refractory acute graft-versus-host disease patients in adults. Adults are defined as 18 and older for this trial. It'll be randomized one-to-one. The groups will be ruxolitinib plus Ryoncil versus ruxolitinib alone.
The dosing for Ryoncil will be identical to the pediatric commercial dosing already in place, 2 million cells per kilogram twice a week for four weeks. If you're a partial responder, you're then eligible for an additional infusion weekly for four weeks to get a total of 12 potential doses. The trial's primary endpoint will be the assessment of overall response at day 28. This is a surrogate for survival that the FDA prefers, and in fact, it's the same primary endpoint we achieved in our pediatric registrational trial. The trial's key secondary endpoint is overall survival at day 180. We are very confident that we will be able to achieve this trial's primary endpoint for a number of reasons, one of which is the fact that the trial is designed will allow us to administer Ryoncil as soon as they fail steroids.
As Marcelo indicated, the sooner you can get our Ryoncil therapy to the patient, the earlier after steroid refractoriness, the better the outcome, we believe. Second of all, you've already seen the data that we're able to salvage and rescue these patients in the adult setting who failed ruxolitinib, who otherwise would have died. When you do the math, there's about 30% additional patients that would have survived by receiving our therapy that will now be able to contribute to the treatment arm of this trial. Finally, we believe that the combination of ruxolitinib and Ryoncil could be additive and synergistic. Therefore, we are very confident we will be successful. We'll be enrolling across 45 of the largest BMT CTN network centers across the United States. This represents approximately 5,000 out of the 8,500 allotransplants performed in the United States each year.
The FDA has now signed off on the protocol. The DSMB has now signed off on the protocol, and the NMDP Central IRB recently met, and we do not have any material protocol changes required. Therefore, we believe we'll be able to initiate the first sites and activate them this quarter. Now, the trial, we believe, will recruit very quickly within 18 months, but because it's very conservatively powered with only a 20% delta, we've also built in an interim analysis to potentially stop the trial for early success. When 57% of the patients have been recruited and randomized and then followed for 28 days, the primary endpoint will be assessed, and if instead of 20%, we're able to achieve a 26% day 28 overall response rate, we'll be able to stop the trial early for success, and then soon thereafter, file for marketing approval.
This could result in a net 6 months time savings. Now, the label expansion into adult graft-versus-host disease provides a significant revenue upside. The partnership with the BMT CTN consortium will allow us to perform this trial in a subsidized and cost-efficient manner and create end-user awareness and market adoption. Remember, these top 45 centers, the end users, the physicians, they're ultimately the physicians that will be prescribing this if the product is approved. We really believe there's a potential to shorten the time to launch by 6 months through a successful interim analysis. The label extension into adult steroid-refractory acute graft-versus-host disease will allow us to maintain the existing Ryoncil pricing structure and WAC. Of course, we're able to leverage Marcelo's existing commercial infrastructure and allow us to utilize that for an adult approval.
Importantly, the adult steroid-refractory acute graft-versus-host disease represents a market opportunity, again, that's 3 times the size of that of pediatrics. When you combine the pediatric revenue plus the potential adult revenue, we believe that's over $1 billion in annual sales. Finally, it really comes down to the patient, as Marcelo always emphasizes. Marcelo is now able to make a real difference and save lives in children. We believe if the adult trial is successful, we'll be able to offer a similar new treatment paradigm for patients in adult steroid-refractory acute graft-versus-host disease and extend life. I think with that, we'll now stop and segue to a discussion with some of the key leading bone marrow transplant KOLs for a fireside chat that Silviu will now lead. Thank you.
I'd like to introduce our two key opinion leaders for this session. Joanne Kurtzberg, who's Professor of Pediatrics and Pathology at Duke University School of Medicine, and we have by video link, Dr. Susan Prokop, who's Director of the Clinical and Translational Research in the Stem Cell Transplant Program at the Dana-Farber in Boston. Let me start by asking Joanne, who's been a strong supporter of our program for a long time and was a principal investigator of our pivotal Phase III trial. Joanne, maybe you could give us some of your reminiscence of some of the patients in particular who you can remember have benefited from this therapy.
Sure. As you said, I'm a great supporter of the product because I treat children who have severe life-threatening GvHD, and I know that before this product, there really weren't options for these children. Best story I can tell you is the first child we ever treated who had a MUD, unrelated donor transplant, five weeks out overnight, developed severe acute GvHD with very high volumes of diarrhea and vomiting, and we tried all the drugs available in the day and nothing worked. I was able to get Remestemcel for him, and he responded. We thought he was going to die. He responded. He didn't have any overlapping toxicity. A lot of times these kids have renal failure and infections and all kinds of other problems that are life-threatening as well. This drug was able to be given without any of those additional complications.
Very long story short, he responded, he did well. He was able to be discharged from the hospital. He stayed in North Carolina even though he was from California to later attend high school, where he was valedictorian. He went to Harvard. He went to Harvard Med School. He had a first author paper in the "New England Journal of Medicine," and now he's an oncology fellow in UCLA. Honestly, I can tell you with my many years of experience, he wasn't going to survive his GvHD. Along the way, we've treated many other children, who again, are resistant to steroids, have toxicity from all the therapies, and are end-stage, and finally get this drug, do well, and recover, and go on to lead productive lives.
We just had a little girl who had essentially lung failure, and again, had failed everything, including ruxolitinib, which isn't even indicated for children these days. She's been treated and is coming off oxygen and is recovering. You just don't see that kind of response typically with the drugs we have available to treat the disease. I'll just say as a pediatrician, the fact that it's IV is great because we know it gets into the child. There's no resistance to taking the medicine, and that's very important, both because of the children and also because GvHD causes diarrhea. You don't always absorb oral drugs as well as you might think you should.
Thank you for that. Let me address a question to Susan. Susan, maybe you could talk a little bit about your experiences since the product has been launched. In particular, if you could just give us your insights into how you think the product is being used immediately after steroids at your place, and just given the safety considerations and how safe it is, et cetera, is there any reason why people would not want to use it as quickly as possible if it was available immediately, especially in those children with gut and/or liver disease?
Yeah, no. First question first, I guess, and then I go on.
We hear you very well.
Okay. We treated two patients with the clinical product at this point, and for both of them, both had both liver and GI involvement, which I think both increases the risk of the graft-versus-host disease, both had steroid-refractory disease, but also makes nutritional support in these very ill children challenging. The hepatic involvement, especially our first patient, had transaminases that were over 10 times the upper limit of normal. It makes it challenging to try to give enteral nutrition with TPN, and the GI disease makes it challenging to give enteral nutrition. I think for her, the use of Remestemcel in first-line for steroid-refractory or second-line treatment was very appealing. My prior experience would emphasize that the responses tend to be quite rapid. In my personal experience, especially for hepatic disease, and she proved that to be true. Her liver disease responded relatively quickly.
We were able to ramp up enteral nutrition and give her full calories with IV nutrition. As her GI tract improved, we were able to transition her to enteral nutrition. That was a very important part, I think, of giving an IV therapy, giving a therapy that has a relatively rapid response. Our second patient similarly had hepatic as well as gastrointestinal disease, both increasing the risk of poor response to additional therapy and increasing the risk of toxicity from agents like Rexulti and because of the hepatic involvement. I think the answer to the second question is harder. It's harder to be in other people's heads. I would say overall, pediatricians, I think have become. As you pointed out, the studies that led to approval for Rexulti in pediatrics were in a very limited number of patients.
I think early post-approval for Rex, there was some hesitance because of how small that cohort was. I think people over time have become a little bit more comfortable with Jakafi as first-line. I totally echo what Julian said. I think in very small children, it's really not a good option, and the oral administration can be an issue. As I mentioned, the hepatic toxicity can be an issue, as well as cytopenias that many of these patients have as manifestations of the severity of their graft-versus-host disease. I think from the safety profile, Remestemcel is a very appealing agent. I think part of it is about time and comfort with it, and part of it is about both the accessibility and the sense of accessibility.
We have a pretty robust team here that got Remestemcel onto the formulary before our first patient was identified and had sort of a pathway built out for how we administer and get approval rapidly for medications like this. This sort of fell into place with that process. We did not have to invent a new process to be able to use Remestemcel. I would say when our first patient was treated, our contracting with Sequoia had not been completed, and that did lead to a 1 or 2-day additional time for our second patient that was in place. That second patient was actually not covered by insurance. It took some time to get the payer for that patient aligned.
I think overall, I see even here that my colleagues have gotten more comfortable with thinking of this as an appropriate agent for first-line after identifying something that's steroid refractory and sort of have more confidence in the process that we can get it relatively quickly.
Thank you, Susan. Appreciate it. I think as we heard from Marcelo, we think we can really facilitate things by having Ryoncil available at the point of care immediately, and that's our objective.
Yes.
Yeah.
I think that absolutely, and I think you've heard from others that I think that will absolutely be beneficial. I do think the importance of having an embedded team that is familiar with how to get approval will also be important as part of that, and I know that you provide a fair amount of assistance along those processes.
Thank you. I might just turn to Joanne. Did you want to add to that, or shall we move on to the adult program?
I think you should move on.
Yeah. Question to you, Joanne. Do you think that Ryoncil can fill a major gap in the treatment of adults with severe disease?
The answer to that is yes. At our center at Duke, we've been using Ryoncil, and been involved in the clinical trials for many years. My adult colleagues often call and say they have a patient with resistant disease, how can they get it? The company has been very enabling through EINDs or whatever to make that happen because this is considered off-label, currently treating an adult. I think once a center has experience with the product. Again, sees that it's not a big sort of barrier to administer it, number one. Number two, it doesn't have overlapping toxicities. Number three, it works. They become supporters and want to use the drug more. You mentioned, and Michael mentioned, the BMT CTN trial. I can just say it's an amazing accomplishment to get the BMT CTN to do a cell therapy trial.
This is their first one. They are not the easiest group of people to bring on board, and they have embraced this. Multiple centers have indicated they will enroll patients. Again, you're moved to have drug available so they can give that first dose without having to compete with the drug that's in the pharmacy, I think psychologically will make a big difference. It's an amazing accomplishment for the CTN to actually have adopted this. I congratulate you all on that, and I think the trial will be successful. I think the general experience is once a physician uses the drug in a patient who is end stage, and then it works, and it didn't cause other problems, is going to bring them on board.
Yeah, we're very excited about this program. It's where the growth curve needs to be. Just in the last couple of minutes that we have, you've been a pioneer in the use of MSCs for neuroinflammatory diseases, including HIE, hypoxic ischemic encephalopathy, autism. You've also used our cells to treat children with chronic GvHD. I just wonder whether you might want to touch on some of these areas as potential areas of focus for the company.
I think all of these areas are one, situations of unmet medical need. Two, situations where patients have desperate illnesses and symptoms and don't have an option in the conventional medical armamentarium. For HIE, which is hypoxic-ischemic encephalopathy in newborns who had a normal pregnancy and were supposed to be okay, and suddenly during or around the delivery have some event that deprives them of oxygen, and then they're born severely ill with an encephalopathy that can cause a 50% mortality and 80% of kids can get cerebral palsy. Here are these new parents who thought they were going to have a normal baby, and they have this tragedy. We've had a limited experience treating six of those babies, and they had spectacular results. Maybe that was good luck with those six babies, but it justifies moving forward with an approach.
Again, it's safe, it's tolerated, it's easy in the sense of sick babies to administer. If it protects the brain, it will have major improved outcomes for these kids who were otherwise be damaged for life. I think there's opportunity to treat older kids with autoimmune encephalitis. We've talked about it. That's an area of opportunity to pursue another disease where you have a normal kid and suddenly in adolescence, they seize, they change their personality, and they become debilitated, and there's no effective treatment. I think that's an area. Autism, which is an inflammatory disease of microglia, also will respond to this therapy. We have to figure out the dose, the schedule, the timing. Again, it's an opportunity where there's no treatment for these diseases. Those are neuroinflammatory diseases that we have limited but positive experience.
In chronic GvHD, I've used it in a handful of patients who again, had extensive debilitating disease, both in skin, liver, sometimes gut, and they have responded. Their quality of life has improved. They've been able to get off many other drugs that weren't working anyway and move forward. I think chronic GvHD should be one of your targets.
Well, you can all see there are fruitful areas of collaboration that we'll be talking much more about in the coming months and years. I'd like to thank our distinguished key opinion leaders for being here today and I think providing terrific insight. Thank you both.
Thank you.
Now we'd like to move forward with the next segment and introducing our head of the musculoskeletal programs, Roger Brown, who will talk about the blockbuster opportunity in back pain.
Thank you, Silviu, and thank you for the opportunity to talk about this really exciting program. I joined Mesoblast 17 years ago with the idea of coming here and working on this to find a way to treat back pain without having to go to surgery. I had worked with companies that looked at surgical options, and I go, "There's got to be a better way." Through my 30 years now and 20 years in orthopedics, I've been just amazed at the amount of suffering that goes on from back pain. These are people that are in the prime of their lives, prime of their earning years, and it just absolutely is heartbreaking to get the emails going, "Can I get in your trial?" They can't sleep. They can't sit for long periods of time.
You'll see the people on the plane, they're up and down all the time trying to move to keep their back mobile to try and get rid of the pain. It is heartbreaking to see when they can't pick up their kids or can't pick up their grandkids. They aren't dying from it, but man, it is a lot of suffering. We have a huge opportunity because of all this suffering. There are 35 million patients in the U.S. that have chronic low back pain, and about 60% of that is due to degeneration of the disc between the vertebral bodies. About 25% of the entire U.S. population will develop back pain every year, of the adult population. Of those, 32% will become chronic, meaning it's lasted longer than three months and hasn't responded to physical therapy and analgesics. The problem is massive.
In a very conservative estimate, we believe there's about 7 million patients that have moderate severe back pain with moderate disc degeneration and have less than 5 years of diagnosis. As we found in our previous Phase III trial, that patients that had had at least 6 months of back pain but less than 5 years actually responded better to our treatment, which makes sense because that's when the inflammation is greatest and our cells respond to the inflammation. If you look at 7 million patients, if we can just treat 10% of those patients at $20,000 a year, that's a $14 billion opportunity and countless lives made better. I tell my team, and I said it at the investigator meeting that Doug Beal attended, not many people have a chance in their life to make millions of people's lives better, we have that opportunity.
That's our responsibility. That's what we're trying to do. I'm happy to tell you guys today that we are going to be completing enrollment this month in the back pain trial. That puts us on a very defined timeline going forward. That would give us top-line results in about a year, in the middle of 2027. This is now a near-term opportunity. This has been going on for years. It is now coming to fruition. We're ready to realize this. As Sylvia said, that would put filing a BLA in the third quarter of 2027, and then because we have RMAT designation from the FDA, we will have priority review. That would hopefully give us a BLA approval in the second quarter of 2028. We've been talking about it for years. This is now a real near-term opportunity for the company.
When you look at the size of the market, it's not just the U.S. The U.S. has 33 million people with back pain. Japan has 14.9 million. Those geographies are unpartnered right now. We're planning, and Marcelo will come up here in a little bit and talk to you, that we will either find a strategic partner that will help us penetrate that market sooner, or we will go ahead and commercialize ourselves and maintain all the value for Mesoblast. In Europe, the size of Europe is just as big as the U.S., and we are already partnered with Grünenthal, which is one of the top two pain companies in Europe.
We will receive milestone payments as well as royalties from them, and they will take the data from the Phase III trial that will complete next year and work to get EMA approval in parallel with us working with FDA to get approval. This is in real terms, not just in the U.S., but there's also the opportunity with our partnership with Grünenthal to expedite getting approval in Europe and treating even more patients. Why is this such a big problem? Well, at about age 18, you lose your notochordal cells that help build the body from a baby all the way through the end of adolescence. As those go away, the ability of the disc to repair and regenerate itself becomes less. From 18 on, we're all degenerating, and our spines are getting worse over time.
At some point, the inflammation will become too great, and we'll start having pain. The disc will start breaking down. It is a constant downward trend that we're on. By treating with cellular therapy, we're putting the cells back in there. We're giving it a regenerative potential that will respond to the inflammation. It will tamp down the inflammation, prevent the ingrowth of the nerves and the blood vessels that then will reduce the pain, and we've seen pretty tremendous results, as I'll show you. What are the options right now? Why hasn't this been solved? This has been around for decades. Well, there aren't any really good treatments right now.
The patients that have that first flare of back pain, they'll get treated probably by themselves initially, take some Advil, some Aleve, and then if it continues for a few weeks, they'll go see Dr. Beal and go, "Hey, Doc," or they'll go see their primary care physician. They'll prescribe them some NSAIDs and send them to physical therapy. By that point, if they are not better by about 3-6 months, they're probably not going to get better with those therapies. The only options then are opioid analgesics, which have huge complications. We all know about the opioid crisis that was largely fed by use of opioids for treating back pain because they have no other options. These patients are coming to Dr. Beal, "Please help me. Help me get my life back." What are you going to do? You don't have any options.
The other options are unproven, unapproved interventional therapies. They're just grasping at straws to try and find something. At the other end, it's surgery. About half of the surgeries, the patients still have pain after they've had a major invasive surgery. There are no good options for these people once they get past being in acute back pain. If it doesn't resolve, there is nothing for these people. We're going to be offering a non-opioid, non-addictive treatment for pain that these people have no hope for otherwise. In our last Phase III trial that we've completed, we showed improvement in the mean change in pain, which is the standard way most drugs are approved for treating pain in all subjects at both 12 and 24 months.
What we saw, as I said a little bit earlier, in the patients that had a shorter duration of back pain, so they'd been dealing with it less time, we saw a significant enhanced response in the people that received Rexlemestrocel with HA, the red line on the graph here. What you can also see in the green line is the control. It was an intradiscal injection of saline. The response you see on that is about the same as what you would see in an opioid that was studied for three months. They haven't even been studied opioids for longer term, and the effects of that are unknown. We know that with opioids, they will develop hyperalgesia, and so they won't be as effective over longer periods of time. We beat a very, very high bar with the intradiscal saline.
In the trial we're doing now, we're doing a sham injection. We actually believe that the injection of saline probably was a weak therapeutic and added to the benefit in the controls. With the sham injection, we actually think that the control response will probably be less in this trial, while we anticipate that based on what we've seen in both of our trials, that the cells with the HA will maintain the response we saw. If that's the case, we have a very high probability of hitting our endpoint of mean change in pain at 12 months. We've already hit it once. FDA's agreed that that's an acceptable endpoint for this trial and for approval. We just have to wash, rinse, repeat here. We are not breaking new ground. It's just proving that we did it once, we'll do it again.
The other thing that was really interesting is that in a quality of life measure, we saw substantial. You can see the P values are huge, particularly at 36 months, where they improved their quality of life. It's a measure of mobility, self-care, usual activities, pain, and mental health. Because that's the sort of quiet thing about these patients. That because they have no hope, their mental health gets worse, and their relationships suffer. It is absolutely devastating. What was absolutely amazing, at 12 and 24 months, we had two-thirds of the patients had no or slight problems in all five domains. They basically went from having significant quality of life problems to having no problems. We're talking about remission for pain and remission of quality of life problems from a single injection for up to 36 months here. That is absolutely remarkable.
We're talking about remission of something these people have had for up to five years. Where do these people go now? Most of the patients, they'll go to their primary care physician, or they'll go to a pain specialist or anesthesiologist for initial diagnosis. Once they get past that sort of acute back pain Phase, those primary care physicians will refer them to people like Dr. Beal to just manage their decline. That's what we're talking about. It's almost like cancer where you're just managing their decline because there aren't any other options. We're really meeting a huge unmet need. In market research we did with over 50 pain specialists, 85% of them said they were likely to use and prescribe rexlemestrocel for treating their back pain patients. You can see that this is something that the doctors, the patients are begging for.
This is not something that we're going to have to push, that they are going to pull this because they need it. They have no other options. When you look at the market, about 35 million people in the U.S. have back pain. Of those, 21 million have associated with degenerative disc disease. They've had a disc, at least one if not more, that are degenerated that are the source of the pain. Of those, about 12 million are moderate. If we conservatively estimate that have back pain with moderate DDD and less than five-year duration, it's about 7 million patients. That's a very conservative estimate of our addressable market. We believe based on the market research we've done that if we can show the benefit that we've seen in the previous trial, you'd be looking at a price point of about $20,000.
In speaking with medical directors of over 20 different payer groups, they've said a price point of $20,000 would be very reasonable for the benefit you'd be seeing. With 85% of the pain specialists saying that they're willing to prescribe it, if you just get 10% of those 7 million patients, you're talking about a $14 billion opportunity, which is massive. That is just the U.S. It does not include Europe, does not include Japan or the rest of the world. Pleased to say we are going to complete enrollment this month. We're very excited, we're very positive and confident that this trial is going to be successful. That really puts us on a very defined timeline. There is not guessing of when we're going to be done. We know when the time points are. Last patient will be consented this month.
They'll go through the screening process and then get treated probably mid-year this year. That would give us a primary endpoint and know the top line results of the trial in mid-2027. That would put BLA submission, and Sylvia talked about the LVAD. That will help a lot of the work to go into the BLA submission will have already been done. It's the same product with just some minor differences that we need to update for our BLA submission. We think we can do that very rapidly, submit that in Q3 2027. With the RMAT and priority review, you're looking at approval in Q2 2028. This is now very real term, very near term. I'm going to turn it over to Marcelo to talk about the commercial
Yeah. The question now is: how do we launch this drug? Right? We need to be prepared to launch. We want to do it ourselves. Again, CLBP, this opportunity is transformational not only for the patients, but also for the company. There is no question about it. I hope you're all as excited as I am when I hear what it can do for patients, but also the potential for $14 billion revenue. This is really at another stage, if you will. Right? What we'll do is, look, we're 12 months away from data readout, so we already started the strategic work, the HEOR work, health economics, the value propositions development. Obviously, the strategic portion of the work has been started.
As we get closer to data readouts, we'll start engaging with payers, we'll start engaging with physicians to be able to really develop these markets, right? Disease awareness, right? Eventually, we'll launch the drug. The launch, my proposal is a Phase launch based on milestones achievement. In other words, Phase one, we'll go to the most productive accounts, pay managers, 70% represents a lot of this market, 90% plus, right? We'll have limited consumer type of engagements, limited contracting with payers, and that's the launch. At some point, we achieve some milestone, and we're talking billions, right? We go to our second stage of the launch, where we expand. We expand to primary care physicians, great source of referrals, every single pay manager in the U.S., a greater ability to negotiate into contracts with payers, as well as more consumer direct engagement.
Then at some point, and again, we're talking $ multiple billions, we'll have a conversation again on does it make sense to go to direct to consumer, to expand the uptake even further. I've seen this happen. I've done it multiple times before. At some point in the U.S. market, it just makes sense to engage the patients so the patients have a chance to seek for this treatment with their treating physicians, right? Obviously, maintaining the share of voice, obviously optimizing the contracting situation with payers. That's our go-to-market plan for CLBP. Again, super exciting next opportunity for the product. With that, let me ask Silviu, invite Silviu to come back to stage for our next steps.
Thank you, Roger, and thank you, Marcelo. Very exciting. I'd like to invite Dr. Doug Beal, please, to the stage. Dr. Beal is a principal investigator in our most recent trial and is experienced across this industry, is the number one in this industry. Let's get some of his insights. Doug.
Thank you.
I'd just like to start by asking you to give us a little bit of your sense of some of the patients that you've treated, particularly in our most recent Phase III trial that preceded the current trial. I know there are patients in various parts of this country that came to you, and maybe you could give us a sense of how they were when they initiated the trial, and then you followed them up over several years, I think.
Sure. This is a huge patient population, and all due respect to Roger, the 7 million people with chronic low back pain, there's no way it's that few. Look across this room of young, healthy, good-looking people. How many of you guys have had back pain, right?
A lot.
Look, it's the lifetime debilitating incidence of back pain is 80%. 80%. These estimates are based on things that are using Occam's razor to the nth degree, and it's all the way down to 7 million people. The way that I categorize the trial is this is a friends and family members trial. Right now, I'm on my 60th clinical trial. I started when I was 5 years old. This is something. If you were to come to my house for Christmas, you would see people that had cellular therapy of the disc. It's because it doesn't really affect old people. It's not like a lot of things we do. It doesn't affect people that are 85 years old, walking like this. It affects young and healthy people.
Degenerative disease and discogenic back pain is a disease of 18- to 40-year-old people. I've had people that wait till their 18th birthday to get into the trial. It takes people, robs them of their prime of life. The example Roger gave about seeing people in the airplane, absolutely. You can't sit. You can't drive for very long. You walk into the exam room, people are standing up. It's one of those things, this is a blinded trial. When they come in for the follow-up, they see me down the hall. "Oh, Dr. Beal, I'm doing great. I'm great. I have no pain." Yeah, there goes the blinding, right? Based on the timeline, we're here Q2 of 2028. It's about time.
I was interviewing on Fox News a couple of weeks ago, and they said, "Oh, I heard the person that I treated," she says, "Oh, I'm doing great." Is a local attorney. "Doing great, I have no pain. Dr. Beal injected me 9 years ago." I got to thinking, "9 years. It's been 9 years." In regulatory, but the BLA pathway is a very high bar. It's difficult. By the same token, if you clear that bar and clear it with height to go, you're going to tap into a market that is absolutely not only massive, but this stuff just works. It just works. I've got personal experience with it. Surprisingly to me, I don't think there's anybody that's done more cellular therapy of the spine in the world than I have. I started doing it very early. I love it. It's super common.
Elias Zerhouni used to say, he was my chair at Hopkins when I did residency. He's a former director of the NIH. "You want to research something, Doug? Do something that's common. Make a difference." He did it with the heart, and I'm doing it with the spine. This is something that we're very nearly toward the finish line. Man, it is about time because this is something that people need. This is something people here in this room need. You don't even have to tell me. I know because I do something radical like actually see patients and practice medicine every day. This feeds everything else we do. This is something that I appreciate being here.
I'm headed to Barcelona for a stem cell conference over there, and I get invited all over the world to talk about this stuff, and this is the lead marquee for cellular therapy. This is the leader. This is the opening slides of what I talk about, and so thank you for making it all possible.
Well, we really appreciate you being here, actually. I think you've touched on an important point. Not all stem cells are the same, right? We've taken great care and focus to do the right thing here, to do the randomized controlled trials, to get our manufacturing right, to work with the FDA around regulatory. We've demonstrated we can get products across the line because of our rigor in manufacturing. I think that's ultimately we've got a cell that is well-characterized, it's reproducible, and importantly, you want to know that every vial that you get guarantees the exact same dose, the exact same product, and the same potency. With that in mind, can you sort of just touch base a little bit on the supply chain? Given the volume of patients that you see, you've felt our cells. You know how they come.
You know how easy it is to thaw them and draw them and use them. Maybe talk a little bit about that, how you see this as being an easy-to-handle product that you would have readily available if we could either provide it in real-time on an as-need basis or perhaps if you had some storage facilities that you could keep our vials in.
Yeah, it's not a barrier. It just isn't. The Dewar that they came in as a FedEx box, it was big, like a small refrigerator. That was way back when. Even that wasn't a barrier. The staff kind of looked at it, and they took the cold packs home so they could reuse them at the lake on the weekends in their ice chest. What we have now is not a barrier at all. For me, knowing exactly what you get is huge. Let's take BMAC, for example. You aspirate somebody's bone marrow, and you give it back in the disk. Even that works pretty well, not nearly as well as directional master cell, but it works reasonably well. What are you getting? You're getting maybe 1% or 2% stem cells. You can get a lot of everything else, including white cells and everything in there.
To be able to get an off-the-shelf allogeneic dose that's consistent. I know a lot about this cell, and it was engineered specifically for this reason. It regrows cartilage. Also, it can regrow bone. It can regrow blood vessels. This is something that has a certain degree of potency beyond just regrowing cartilage. You give a dose of 6 million cells. We don't give a dose of 1 million. We don't give a dose of 18 million, because that's been tried. 18 million wasn't quite as good as 6 million. Maybe it's like Lower Manhattan, a little too crowded. People are fighting over resources. We know that giving it with the carrier is the way to go.
The carrier provides a little bit of life to the cells, provides a little bit of water in the Gobi Desert, and it's a better thing. This combination of 6 million cells with HA as a carrier, that's the secret sauce. It was mentioned about placebo saline. Saline is not a placebo. I used to use saline as an active treatment. It washes inflammatory mediators out. It hydrates the disc. It objectively resets the zeta potential. You inject saline in a disc, you get 40% pain relief at one year. The problem is it fades off very quickly after that, and the patient, what are they going to do? We've known this. In the 1990s, we used to inject saline into the disc as an active treatment. Suddenly, the regulators are new since COVID.
They have no institutional memory, and they're, "Well, let's use a placebo." That bar has been cleared, and that is not an insubstantial bar. That's the wall that most people run up against. There's a ton of really good therapies that have gone in the disc to die right there. A good friend of mine, Aaron Calodney , says, "The disc, where most good therapies go to die." That has been true. I think I've been through 12 clinical trials testing out various sundry things for the disc, and all of them done at the end. This one not only cleared the bar, but you could just see it, even in Phase II. I started watching this thing shortly after Phase I. Phase II, Kasra Amirdelfan , who's a good friend of mine and colleague, was primary investigator in that.
To quote him, he said, "Man, this stuff just works." It's one of the things that is going to be interesting to see how this is used, probably overutilized, frankly. In my world, my buddy from Jersey calls it 3 whacks and a back, meaning 3 epidural injections and fusion surgery. I talked to Blue Cross HCSC. This is my local Blue Cross, Oklahoma, Texas, Montana, New Mexico, a few other areas. They said, "Well, compare this to the landscape." Rexlemestrocel, compared to fusion surgery, which is its only viable competitor, works 2.5 times better. It's 5 times cheaper, no incision, no downstream adjacent segment disease, no recovery. I have no idea how you guys are going to make up an excuse not to cover this. It's not the first time they've been in front of him.
They rolled their eyes, and they expected that. Thank you, Dr. Beal. I was appropriately condescending to them. The way is paved. We are now teaching. I will teach tomorrow. Last weekend, I taught how to inject a disc because people are prepared for this. Not only do you have the product, you have to have a way to get it in the spine. Every time I talk to my colleagues, I said, "This is the decade of the anterior column," because that's where the disc lives. That's where the pain is. 70% of the pain comes from the anterior and middle column. Hardly anything we do traditionally treats the anterior column. You're doing rhizotomies. You're doing medial branch blocks for back pain. Yeah, that's 20%, 30% at most. What about the other 70%? Finally, this is the decade of the anterior column.
Finally, we are going to be able to treat people, the lion's share of people for their back pain, that next to the common cold is the most common cause of a doctor visit. Huge problem.
I think we're all salivating here. All of us with the kind of back problems. How do we get this product? Look, I think this has been extremely helpful. We really appreciate both your enthusiasm and your work with our programs, and we look forward to a great result and then working towards how we're going to educate the rest of the physician community.
Well, on behalf of all the people I see on a daily basis, and I'll run through 25-35 people a day, and most of those will have exactly something that this can treat. On behalf of these people, thank you.
Thank you very much. Now we'll move to a whole different program, which is the use of our product rexlemestrocel for inflammatory cardiovascular disease. Let me introduce Kenneth Borow, who is our Head of the Cardiovascular Program.
Thank you, Silviu. All right. Let's talk about the magnitude of the problem as well as the opportunity. Chronic heart failure has a rising incidence of high morbidity and mortality. Cardiovascular-associated inflammation is the leading cause of death in the United States. Think about atherosclerosis. Okay? Number one killer, really, in the U.S. Okay? Our cells are extraordinarily capable of dealing with the consequences of that disease, and I'll tell you more data. Now, heart failure in the U.S. is projected to affect more than 7 million people by the year 2030. Approximately 50% of these will have heart failure with reduced ejection fraction. That's bad pump heart failure. About 50%. Chronic heart failure is a progressive disease with mortality that approaches 50% at 5 years and at least 75% after an initial hospitalization. This slide looks a little bit busy. Let's make it simple. Okay.
The heart failure program has two components. One is the DREAM heart failure program, and the second is the LVAD program. The difference between the two, the DREAM program are patients who have established disease, established heart failure, and at the same time, they are not at a point of being a candidate for a left ventricular assist device. Okay? That's the DREAM program. All right? The LVAD program are those DREAM patients who have progressed to the point that they need an additional therapy, which is an implantable left ventricular assist device. That's an LVAD. All right, now, for both of those programs, the cells that we use have the same formulation, we use the same dose, and the potency assay for the product is the same for both of the indications, so for the pre-LVAD patients as well as the LVAD patients.
The MPC are injected into viable but dysfunctional myocardium. They are activated by local cytokines in the heart. Silviu talked about that in his earlier presentation. The MPC exert anti-inflammatory, neovascular, and immunomodulatory effects. What I'm going to show you is that there have been successful outcomes of the same dose, 150 million cells, that are injected intracardially, okay, in both of the programs, the DREAM program and in the LVAD program. This is some data from DREAM, and the cells significantly reduced cardiovascular death, that's the Y-axis, in patients with inflammation. Okay? The P value was 0.003. You can see. Oops, sorry about that. You can see the control patients over a time point of five years just have a stepwise increase in badness. Okay? More and more patients die from their disease.
In contrast to that, the cells over the course of 5 years have a marked reduction, and this differential between the two continues to grow after 5 years. Now, this slide is a slide that I'm particularly favorably inclined to. This shows in the DREAM trial the effect of the cells on 2-point MACE, so that's time to first event for a myocardial infarction, an MI or heart attack, or a stroke, and that's the data that I'm going to show you in panel A. Three-point MACE, which is the time to first event for a myocardial infarction, a stroke, or cardiovascular death. Okay. This is in all patients, and I'll show you data in all patients, and then subgroups with inflammation and subgroups with ischemia plus inflammation. Let's start with the 2-point MACE. Okay. This is for all patients.
You can see that this is statistically significant. This is MI or stroke. Okay. When we look at the patients with inflammation, okay, we go from a treatment effect of 58% to a treatment effect of 75%. When we go to the patients who have inflammation and an ischemic etiology, we end up with an 88% reduction in myocardial infarctions. Think about the patient who has had a heart attack and has a bad pump, has a bad left ventricle pump, a ventricular pump, okay? When you tell them that we potentially have a therapy that can decrease the likelihood that you'll have an MI or stroke as a complication of your intrinsic disease, and it will certainly worsen your heart failure and may kill you, okay, by 88% is quite remarkable. That's the two-point MACE side.
I should mention that both 2-point MACE and 3-point MACE are well-established endpoints in clinical trials of all kinds of therapies that have been used for establishment of standard of care. All right. Let's talk about the B panel, which is a 3-point MACE. Okay. Here we see all patients, and that's a 27% treatment effect, so this is above and beyond the control, okay? The control is a sham procedure that is conducted during the time that the patient either receives the cells or a mock procedure for administration of the cells. For the inflammation group, the 27% goes to 37%, and then for the ischemia and inflammation group, it goes to 52%. 52%, okay? Keep that number in mind, 52%. This very busy slide, okay, has some very important messages.
The slide itself looked at standard of care, okay, so the whitish and the blue rows are standard of care, and then the dark blue at the bottom are the cells. If you look at the risk reduction, so that's this column, the average risk reduction for the guideline-directed medical therapies is about 10%. Okay? This is for three-point MACE, standard endpoint, three-point MACE, time to first event, MI, stroke, cardiovascular death. In contrast to that 10% average, 52%. We're talking about a more than five-fold improvement on top of standard of care, on top of this 10%. Okay? We basically build the 10% to 52%. Quite remarkable. Right? Now, I want to mention one other thing, that the data that I showed you here was published in the "European Journal of Heart Failure," which is a very prestigious cardiology journal. The first author on that paper was Dr.
Emerson Perin, who will be part of our fireside chat group. Okay? He's got a lot of experience of many types, but he really knows the DREAM program well. Okay, let's look at the addressable market size. Conservatively, I think that we start off with 6.7 million patients who have heart failure. Patients who have bad pump heart failure or heart failure with reduced ejection fraction is about 50% of that number. We have, at the very bottom, for patients with heart failure with reduced ejection fraction, an ischemic etiology to their heart failure, plus inflammation. It's around 1 million. I think that's probably conservative. Okay? Now, if we talk about a sales price of $150,000, remembering that these patients are not only surviving, but they're surviving with better quality of life because they're not having the hospitalizations for MIs, strokes, things like that. Okay?
The sales price of $150,000 would be supported by the data that I just showed you from our DREAM study, and the potential annual revenue would be greater than about $15 billion if we just assume a 10% penetration. Okay? I'll say again, 88% reduction in MI or stroke. Patients are going to want to be lining up for this therapy. Okay? We're assuming 10%. 10% will give us a $15 billion yearly revenue. Right. Now let's go and shift to our LVAD program. We're going to be looking now at end-stage chronic heart failure with reduced ejection fraction in patients who are given an LVAD. An LVAD is essentially a cannula that's placed in the bottom part of the left ventricle. It goes out into the chamber.
What it does is it sucks the blood that returns from the lungs to the left side of the heart, the oxygenated blood, through the cannula to the pump, and then it goes up to the aorta and out to the body. It can take a patient who has a poor cardiac output, a poor amount of blood being pumped to the body, and goes ahead and makes it something that's much more functional. Okay. Despite an LVAD in the left ventricle, progressive right heart failure continues due to ongoing inflammation of the right ventricle. What this means is the left ventricle doesn't get blood. If the right ventricle doesn't get it to the lungs so that it can return to the body, to the left ventricle, there's nothing to pump. It becomes a progressive problem for these patients.
Progressive right heart failure occurs in about 15%-30% of patients and is the primary cause of multi-organ failure and death. A further complication of right heart failure is potentially life-threatening major mucosal bleeding, predominantly gastrointestinal, that's seen in about 30% of patients and is the main cause of recurrent hospitalizations. In this slide, let's just look at a couple of quick takeaways. Okay, this is from the INTERMACS Left Ventricular Assist Device Registry. This is a national registry. Okay? And what this shows is that for patients who have moderately severe or severe right heart failure, they have a 28% mortality rate, okay, at 12 months, a 24% incidence of first-time GI bleed at 12 months. Both of these are major problems, okay, that the underlying patient population who get an LVAD face.
Okay, in our LVAD study, the cells in these end-stage patients with left ventricular assist device are injected at the time that the LVAD is implanted in the operating room. It's a single procedure. The cells are injected, the operation is done, and that's it. Okay? Then the data down here show you just bar graphs looking at the major mucosal bleeding, GI bleeding. What you can see here is for the control group is in red, and the cell group is in blue. We have a P value that is highly significant at six months. We get a marked reduction in this GI bleed kind of problem. At 12 months, it's sustained, okay, and it's still twofold with a P value of 0.004.
Part of that reduction is due to some of the control patients actually dying, so they're not around to go ahead and have an event. Okay, now what's our tactics and strategy that tie the DREAM program together with the LVAD program? Okay, we're about to file with the FDA for full approval of the cells in patients with LVAD. Okay? The filing is based on GI bleeding, I showed you some of the GI bleeding data, being an FDA-acknowledged indication. In addition, we have an orphan drug designation, which has a number of beneficial effects from a regulatory perspective. The orphan drug designation is for GI production and GI bleeding. The FDA stated preference for randomized controlled trials has resulted in Mesoblast seeking a full FDA approval pathway with the benefit that an additional confirmatory trial is not required.
We can get a potential approval on the trial that we have, the data that we have. The FDA approval of the cells in patients with LVADs will facilitate subsequent approval, we believe, of Mesoblast's pre-LVAD program, our DREAM program, okay, chronic heart failure patients. Rather than starting from scratch with a submission, it would be a label extension. That has a tremendous advantage when the time comes for the pre-LVAD population. Okay, let's look at what the addressable LVAD market is. Again, start off with about 66.7 million patients with heart failure. By the time you get down to the real world, the real world has somewhere in the neighborhood of 2,000-3,000 LVADs that are given per year. At a sales price of $200,000, or a price of administration of $200,000, which would be supported by our Phase III results.
Again, the justification is a reduction, among other things, of cardiac ICU hospitalizations, reduction of bleeding events, et cetera. The total addressable market potential is about $400 million, and this is a market that initially could be justified across 190 LVAD-certified centers in the United States. Okay, so a big opportunity, and we're only beginning with it. All right. Now, we're going to turn from this presentation to a fireside chat. Dr. Emerson Perin from Texas Heart Institute, who again, was the lead principal investigator on the DREAM 1 trial, and Dr. Eric Rose, who is one of the foremost authorities in left ventricular assist devices, will be part of the panel. Thank you very much.
Thanks, Ken. That was a very exciting introduction to the whole space. Delighted to be here with Emerson and with Eric. We've all been in this field for a long time, but I think we're there. Emerson, I'd like to ask you, first of all, you were the principal investigator of the DREAM trial of 565 patients, a big trial in this space, and you saw just some of those data, and you were, of course, the lead author in those major publications. Just talk to us a little bit about what you thought about the data and about the technology and where we're at.
Yeah. One point I wanted to make is I looked at the piece of paper you have there on the titles, and it says "inflammatory heart failure." Well, if this audience was full of cardiologists, they'd be like, "Well, what do you mean?" Okay, the word inflammation is not part of the lexicon of heart failure in the mainstream cardiac world. All these drugs that we have, Entresto and Coreg and Inspra, they address one half of the problem, which is the maladaptive changes that happen when you have heart failure. Your body tries to fix it, but does a bunch of bad things. We have different medicines, beta blockers and things that help kind of undo some of that damage. The real problem of heart failure is not the maladaptive changes. What starts heart failure is inflammation. What keeps heart failure going is inflammation.
We have never treated the other half of heart failure, which is inflammation. This is sort of a paradigm shift that everybody's sort of coming to terms with. You look at these data that Ken was showing you. Look at those P numbers, 0.003. It's ridiculous. Of course, this should be approved already. Why is it not approved? Because we're just not ready, right? The world hasn't been ready. The FDA hasn't been ready. They're ready now. I think, to make myself feel a little better, I think about ACE inhibitors, which are common drugs approved in the mid-2000s for heart failure. They started investigating lisinopril back in the 1970s. When you think about it's like 30 years. I injected the first guy with NPCs in Newcastle, Australia, I think it was like 2007. It's been about 20 years.
We're going to get there. We're ahead of schedule. These data are obviously overwhelming. They're very positive. We know the recipe. Okay, this is one problem during the whole development of this field, is we didn't kind of know how this worked. When we did the very first trial, we really was thinking, "Oh, well, maybe there's some magic going on." No, there's no magic. With these cells, specifically from Mesoblast and these NPCs, we have been able, through the DREAM trial, actually, to reverse engineer. Now I can explain to you very eloquently what the mechanisms are of benefit, and I can sit here and tell you how important inflammation is in heart failure. None of this was. Dream actually made this happen so we can understand what's going on. Now we have a treatment that is extremely powerful.
One thing that's really beautiful, in the DREAM trial, we did a look at the controls, and we used CRP, which comes from soluble IL-6, which is a marker for inflammation, and the cells react to it. We used a CRP of 2, which is pretty standard, to identify the patients that have inflammation. Well, what happened is just take the control people that didn't get treated, and we looked at them throughout the study, and we found that people with a CRP of greater than 2 had 4 times the mortality than the people that didn't. We know that these cells are treating inflammation. Also, you feel bad, say, "Oh, man, okay, we're only going to give this treatment to the patients that have a high CRP." Well, those are the guys that are going to die. Okay?
You can see 52% reduction. When we're talking about the Jardiance commercial with the chubby girl dancing, okay, we're talking about a 7%-10% reduction. We're talking 50%-80% reductions in heart attacks. This is just a matter of time. We've got the recipe down. We know what we're doing now, and it's just exciting. I think the world, the FDA, everybody's ready to be able to treat probably the most important part of heart failure, which is inflammation.
Speaking of the FDA, it's interesting the point that you raise, and the leadership of the FDA recently actually published in the New England Journal position papers around large volume indications which historically have required two randomized controlled trials or confirmatory evidence. Even the FDA has recognized that well-conducted trials which make an impact on major outcomes like mortality don't need necessarily two trials, but actually could see technology accelerated through the regulatory process and approved on the basis of a single well-conducted randomized controlled trial. Do you think the trial that you ran was a well-conducted, adequate randomized controlled trial? Tell us about your view of that trial relative to other trials in the industry.
Yeah. Oh, my God. I mean, the FDA made us jump through all kinds of hoops. I could not go to a certain part of the hospital on the day that patients were getting treated. There was a true firewall between the people that knew that were doing the injections on the patients and treating the patients, and then the people who screened the patients who were going to follow them up. Nobody communicated. It was a true blinded. The patient, we gave them all kinds of meds. We did what I call Masterpiece Theater, which was great. The patients that didn't get the treatment, we put a cath. What we did is, to do this, we mapped the ventricle and we put these injections straight in the heart in a very strategic way that, thank God, seemed to work very well.
Everybody has a hole in their groin because we go in there and we take a picture. With that picture, you feel a lot of heat. In everybody, they got the catheter in, we did the picture, and then we gave them a bunch of drugs. We sat down, and either we actually injected the cells into the heart or we just sat down and did Masterpiece Theatre. Oh, catheter, needle out, injection number one, complete, waited for it. The patients took the time, and they really had no clue because usually patients talk among themselves all the time. They're going to go, "Oh, man, did you get this?" There was a completely very well-executed blinded study with all kinds of firewalls. In 587-- You can't fake a result in 587 patients.
I mean, in our Phase II trial where we figured out that 150 million cells was the right dose, there were no events. Zero in three years. There were no events in the people that got the 150 million cells. You'd think, "Well, okay, we're a little lucky. This is 60 patients. It wasn't that much." Okay, this is 587. The results are amazing. They speak for themselves. This is just at a time now where with some open-mindedness and straightforward thinking, this should get approved, and it'll help the people that die of the number one cause of death in the world. I mean, I think that's another barrier because heart failure is a high bar. It's a big problem, and it's the thing that kills most people.
Oh, well, we have to be really careful to approve something that we could treat everybody with.
You saw that the reduction in heart attacks of 88% was, I think, a significant reduction in the entire study without any kind of subgroup analysis. Does that sort of outcome surprise you, and does that sort of outcome tell you that this is a technology that is going to make a big difference on that basis, on that trial?
Ken was on the phone. I almost fell out of my chair. The safety committee that guided the DREAM trial, we wanted to keep going because I wanted more data, and there's a whole study with all the follow-up. The mean follow-up is about three years, but it took five years to do this. I wanted more patients because we need to know more and all that. They said, "Listen," Dr. Jean Rouleau is a fantastic guy, the head of the Montreal Heart Institute, and he says, without telling us very much, says, "You have all the data you need," and it's like, "Just stop the study." I'm like, "Okay. Yes, sir. We'll stop the study." When. That's right. That was just on heart.
It's complicated to look at a study like this, and then you tease out the things, and you figure out the mechanisms. It just makes so much sense. Now we're introducing this concept to the cardiology mainstream that we're now able to treat heart failure, not just with all the drugs that everything that we do. I see heart failure patients every day, and we give them all the drugs, and yeah, it makes them better, but there's the whole other half that has not been addressed, and we can now do it, and it's unbelievable to see these patients doing better. It's incredible.
No, that's great to hear. Look, on that note, let me shift to Eric, because I think the theme is the same theme. We've got one product. That product has been, as you call it, engineered. We have proprietary ways of manufacturing it that optimizes the protective response to inflammation and has a similar effect across the spectrum. Not only do we see a reduction in these major events in the inflamed patients in the DREAM trial, but we saw the same benefits in a way in the LVAD population. Eric, of course, is the world leader who was responsible for getting the first FDA approval for permanent use of an LVAD device in patients who are the typical heart failure patients who then progress from advanced stage to end stage and who otherwise have a 50% one-year mortality on medicine treatments.
Eric championed that, and despite his clear demonstration that you could increase survival by putting one of these devices in, it's pretty evident that the field has not dramatically moved forward, and the number of devices that are used is still pretty low. I wonder if you could comment a little bit on the progression of right heart failure disease and how you think our cells might have had a benefit on the results that we showed.
Thank you. It's clear that cells in two randomized trials improve right heart failure and decrease the instance of GI bleeding, major mucosal bleeding, almost all of which is GI. That's clear. The reason is probably improvement in RV function, which we've also demonstrated in two randomized trials as well. This was work that was done actually as part of a grant that we got at Columbia when Sylvia and I were there to look at the human biology of long-term mechanical circulatory support. When we first reported this trial, everybody was disappointed because we were hoping we'd administer cells and get people off LVADs. That proved a bridge too far.
As we look closely at the data, it's clear that patients who get cells, who have pre-existing inflammation in particular, do better with the LVAD in, which arguably may make LVAD therapy safer and better for a larger number of people. The biggest problem with LVADs still is the perceived quality of life that these patients have. I think if you end up hospitalized for bleeding or right heart failure or die during the early period, enthusiasm for them is minimum in the cardiology community, which is why there are only 2,000-3,000 implants per year done in the United States. That being the case, though, this is a perfect orphan scenario in which to pursue an FDA approval now.
I guess we were surprised and really a little bit late in our thinking process, but in fact, the difference between the LVAD patients versus the pre-LVAD patients is that their left ventricle is protected and is dependent on an artificial device, but their right ventricle isn't. Whereas the pre-LVAD patients, both ventricles are at risk. I guess this is an experiment of nature in a sense, where these patients have a progressive disease of the right ventricle, that injection of our cells which we injected in the septum, facilitated an improvement in this population, but it's really a continuum from the other patient population. So what's your view of the two randomized control trials that demonstrate kind of a continuum and a similarity in terms of mechanism?
Well, I think before I comment on that, I want to acknowledge Sylvie's role in this, because Emerson and I were both speaking about a meeting that we had years ago. This product was initially licensed to Cephalon about 15 years ago, in that range. Very enthusiastic CEO, Frank Baldino, who paradoxically died due to acute leukemia about 6 months after they took on DREAM population and the DREAM trial. Those early trials used MACE as the primary endpoint. I forgot about the Phase II showing 0 events, which n equals 60, you say, "Maybe this is luck." Somehow the drug ended up with Teva at a time. Yeah, Teva acquired Cephalon. Teva, a generic drug company that had no business in a cell therapy indication to begin with, screwed this up so badly, it's amazing.
They changed the primary endpoint to this ridiculous joint frailty thing, which works fine for the other half of the non-inflamed half. Yeah. Well, Sylvie, and I joined his board at this point, reacquired the asset in the middle of the trial, which I think is heroic. At the time, I thought maybe it was crazy, but it was heroic. I think the availability of the DREAM data could only been realized with that kind of courage. I think you deserve enormous credit.
Thank you For that.
Thank you. Look, I appreciate you saying all that, but I think the message really is this is an incredibly powerful technology.
Yeah.
How else can you get a powerful technology that's new and first in class to patients and to the market if you don't go for it, right?
Yes.
You don't really know the power of something like this until you actually try it out.
Yeah.
I think that's the message in the cardiac space. I think it's also the message in our first approved product, Rayonsul, which without the fortitude of people here in this company, and without all of the, frankly, the agendas.
Mm-hmm
At the table among regulators, would never have seen the light of day. I think this is what you got to do.
Yeah
New technology, first in class, you just got to keep going for it, and trust your scientific rigor.
I think the other group we should acknowledge is patients that agree to these randomizations. We have an obligation to them that goes beyond any primary endpoint. The reason that all these trials are designed to measure lots, you would think would be to look at other data besides the primary endpoint in order to see whether or not there's something else learned. These examples, there's plenty learned. Plenty. To say that these trials were failures is ridiculous.
Well, especially when they relate to improvements in mortality.
Yes
or other hard endpoints.
Yeah.
Yeah. A quick story about that. When we got the data from the DREAM trial, again, it's a fall off your chair kind of result. I'm like, we put this manuscript together and I send it to New England Journal of Medicine.
Yeah.
Okay. Well, what happens? Well, because of all the shenanigans, the primary endpoint got changed. Originally it was MACE, so we'd be here on a very extremely positive trial. It got changed to recurrent hospitalization. Well, are cells diuretics? Are they decongestant treatments? No, they're anti-inflammatory. Guess what? Although people died less and had less heart attacks and strokes, we missed the primary endpoint that you have to put in because of how things are in science that's established. I get it back in three days later from the New England Journal of Medicine. That's how silly.
Yeah
The academic world we live in. The results, you can see them. Yes, now we know the recipe. With my blindfold on, I can put on the primary endpoint for the little confirmatory trial that we'll do, and then we'll be fine.
To Eric's point, this is really all about patients, right? It's about making sure that we can deliver therapies today, which are life-saving, and not five years from today, and how many patients would die waiting for these therapies. That's what this is about.
Yeah.
They deserve it, right?
Yeah. They deserve not to wait another five years to have the DREAM population benefit from this therapy. I think that's still a pipe dream. I think that's the reason the company has to persist in pursuing both indications. Both in the LVAD patients, where there's evidence of improvement of morbidity in the patients. An orphan population, but the regulatory bar, fortunately, is lower. Ken got the RMAT designation for that indication, and I think we should go for it.
I can't use the language up here, but we're some persistent guys.
Yeah.
I tell you what.
Yeah
patients are lined up for this. We're ready to get this thing approved. We're finally ready. The regulatory environment is good. We're on our way, and let's just get this thing going.
Right.
We will revolutionize how heart failure is treated.
Yeah.
Thank you. Thanks to you two.
Sure.
Both of you are giants in your fields. Thanks.
Thanks.
Let's shift again and now talk about some of our other opportunities of label extension, particularly in the pediatric rare disease space. Michael Schuster, please.
Well, thank you, Silviu. As Dr. Kurtzberg indicated earlier today, there's certainly a large number of applications in the pediatric orphan space where Ryoncil could potentially be effective. Our objective is really to leverage our FDA approval of Ryoncil and identify new pediatric label extension indications. I'll talk today about the first one that we'll be advancing with into the clinic. Duchenne muscular dystrophy, what is it? It's really a disease of inflammation with a very large unmet need. It's a genetic X-linked disease, meaning that it's a disease that impacts young boys. It's a disease in which about 15,000 of these children live in the United States.
The symptoms typically develop by the age of 3-5, and when the underlying inflammation continues to advance in the first decade of life and the skeletal muscle dies off, it's replaced with fat and fibrosis, and it results in loss of ambulation or the ability of these children to walk. By 12 years old, the majority of these children are all wheelchair-bound, and soon thereafter, they'll develop respiratory failure and cardiomyopathy with a median survival of only 24 years. It's really a horrific progressive disease. The only therapy that is somewhat effective is steroids. That has been shown to delay the loss of time to ambulation and actually improve survival. Even steroids, their improvement plateaus after about 6 months.
As we know, long-term usage of steroids has some serious side effects, just one of which is the stunting of growth, which as you can imagine for boys entering their teenage years, height is extremely important. In fact, some of these children choose to go off of steroids. Now, one would have thought that gene replacement of dystrophin could have perhaps been curative. It makes sense. Replace the missing gene. Unfortunately, it's only been able to show modest effect. I think that's due to a number of reasons. Firstly, the dystrophin that is upregulated on the skeletal muscle is actually viewed as foreign, and there's an immune response. This suggests inflammation is even more relevant to this disease than one may have initially thought. Second of all, about 20% of all Duchenne's muscular dystrophy patients have pre-existing anti-AAV antibodies, preventing the administration of the gene therapy.
Those that do get the gene therapy will then develop these antibodies, preventing repeat administration. When this is taken together with the high dose of AAV resulting in liver toxicity and more recently deaths, this is accounting for why the uptake more recently has been limited with gene therapy. We really view DMD as a revenue growth opportunity where we're able to leverage Rhinceil's anti-inflammatory mechanism of action. We've shown that Rhinceil has been proven to be very efficacious and safe in pediatric steroid-refractory acute graft-versus-host disease following steroid resistance. Now, graft-versus-host disease, as we know, is really a disease of massive inflammation of cytokine storm, and we're able to shut down T-cell activation and proliferation. These are the same modalities that are involved in the progressive nature of DMD.
We've been able to show that Rhinceil has now demonstrated benefit both alone as well as in combination with gene therapy in animal models of DMD. Because of this, when we take the totality of the Rhinceil safety dossier, the BLA package that supports the manufacturing robustness and potency assays, combined with the preclinical data, we've been able to now receive IND clearance to proceed directly to a registrational trial that will allow us to extend Rhinceil label, if successful, for the treatment of ambulatory patients with DMD. Now, these are young kids we're going after, 5-9 years of age. The reason that age group is critical is because that's where inflammation is maximal. Inflammation increases in the first decade of life, but then when the muscle is replaced with the fat and fibrosis, inflammation goes down.
The science drives us to actually want to intervene where inflammation is maximal, and our objective is to intervene before the patients have lost the ability to walk. We want to make a real difference and delay, if not reverse, the likelihood of them needing a wheelchair. Ultimately, we'll be able to label extension into DMD will allow us to maintain the existing Rhinceil pricing structure. Similar to steroid-refractory acute graft-versus-host disease, a relatively small number of centers, about 38 certified DMD centers in the U.S. account for about 50% of the market opportunity. Therefore, Marcelo's existing commercial and medical infrastructure can be leveraged to support a commercial rollout once approved. Now, our proprietary Mesoblast MSC technology has been shown to improve muscle function in Duchenne mice.
These are mdx DMD mouse models, and we've been able to show the downregulation of T cell, macrophage, and neutrophil immune activation pathways. We're able to inhibit T cell activation and proliferation. We're able to take M1 pro-inflammatory bad cells and convert them into an M2 immunomodulatory cell type. These are the same themes you've heard Roger and Ken talk about. Mechanistically, this occurs across all of our diseases. In addition, we've been able to show an increase in muscle regeneration pathways. Despite when we administer RYONCIL alone, we're not able to increase dystrophin, we're actually able to increase regenerative pathways of the muscle and improve muscle contractility. Taken together, this resulted in animal models an improvement in exercise-induced muscle fatigue. Just to show you one piece of data in the mouse model, this is a RYONCIL reduction of serum creatine kinase.
This is a biomarker that is used clinically to show the progressive nature of the disease. Higher amount of serum creatine kinase activity reflects muscle damage. As you can see in these mice, on the left-hand side, these are the DMD mice alone. On the right-hand side, these are the DMD mice that received Rhinceol. We're able to significantly reduce the amount of CK release over a two-week period, bringing it back to near normal levels. Now, we've also been able to show that Mesoblast proprietary MSC technology when combined with a micro or subtherapeutic dose of dystrophin gene therapy has demonstrated additive benefit in Duchenne dogs, so a larger animal model. We've created a composite score index that includes a variety of components such as mobility, limb function, muscle atrophy.
Basically, a quality-of-life assessment for dogs was developed, a 0-30, 30 being a worse quality of life and increased severity of disease, and the lower score is better. The DMD dogs that have not received the MSC therapy over 2 years have a very high severity. Yet those dogs that received the MSC therapy over 2 years have a very low severity of score. What does this really mean? Let's look at the video. The upper panel will be the video of the DMD dogs without the therapy, and the lower panel video will be the DMD dogs that received the Rhinceol therapy. This is 8 months post-therapy. You could see in the upper panel, the dog that received the DMD is a DMD dog without the therapy. It's walking very slow. It's lethargic.
It doesn't look that healthy, has to be coerced to move, clearly not in great shape. The dog on the bottom is able to run very briskly, faster than I could even talk, and it's clearly much healthier looking. It really suggests that we're able to improve muscle function in these animals. We've been able to show a wide variety of other factors as well. We're able to improve and demonstrate that we're able to inhibit T-cell activation in these dogs. Importantly, these dogs over two years have cardiovascular deficiencies that we're able to completely reverse. Taken together, when we combine the safety profile of Rhinceol with the preclinical data, we've been able to advance directly into a registrational Phase III trial, where we'll be targeting children aged five to nine years of age for Duchenne muscular dystrophy.
This will be a randomized controlled study, 76 patients, 1:1 randomized. The group that receives the treatment, Rhinceol, will receive 7 infusions over a 9-month period compared to placebo control. We'll be enrolling patients 5-9 years of age. Again, those are the patients that have high levels of inflammation. As Dr. Perin indicated, inflammation is important. We'll be taking all comers, so patients could have had gene therapy, or they could not have been candidates for gene therapy. All patients must have had steroid exposure for at least 6 months. We want to make sure that initial approval hump, the initial benefit of steroids has been met. Essentially what we're trying to accomplish between the inclusion/exclusion criteria is to capture patients who, despite maximal medical therapy, are still declining, which unfortunately, in the real world, is the majority of these children.
The primary endpoint, which is an FDA-validated endpoint, will be 9-month change in time to stand velocity. Basically, the kids are laying flat on the floor, and we time them how long it takes them to stand up, and that has been shown to correlate with the delay in time to loss of ambulation and ultimately survival. We'll be performing this study in collaboration with the Parent Project Muscular Dystrophy patient advocacy group, and this group was paramount in helping Sarepta obtain approval for their gene therapies. They'll be helping us with patient identification and trial awareness in the community. We expect this trial will take approximately 12 months to enroll, and the prevalence of just this 5- to 9-year age group is about 2,500 patients, and again, with 500 new patients each year. Therefore, we think this is a billion-dollar-plus annual opportunity.
Just bringing it back to the patients, we really believe that this is an opportunity to, if Rhinceol is approved, to really make a difference and offer potentially disease modification in these patients. With that, I think I'll stop, and Dan Devine will now talk about some next-generation MSC therapies.
Thank you, Michael. Good morning. I appreciate the opportunity to present to you. My wife told me not to be sarcastic. Don't try to be funny because I'm not, and keep it short. I could promise the last one I will follow, but don't mistake the brevity of the presentation. It's not correlated to the value of these technologies for the company going forward. Ryan Sill has actually set a new bar for everybody in the industry, and it's reinvigorated interest across the board. It's been truly revolutionary, and we want to leverage that revolution to create long-term value. The way we view it is we're moving from revolution to evolution, and that evolution includes incorporating new technologies into our platform. The way we do that, we focus on two areas. We can increase the targeting of our cells.
Right now, when they're administered IV, they go to a lot of places where there's inflammation. We can put a binding moiety on the cell to bind to specific antigens. That's very important. Secondly, we can increase their potency, and I'll talk about those two in a minute. Excuse me, a little hoarse. The two technologies that we've acquired are CAR MSCs developed at Mayo Clinic by Dr. Kenderian, who's here today, and oncolytic virus delivery with MSC developed at Baylor. We're looking at IND in about 24 months. What is a CAR MSC? A CAR MSC expresses an antibody binding moiety on the surface that triggers an intercellular pathway to enhance potency. Basically, we home the cells directly to target tissues, and when they get there, it triggers a reaction inside the cell to produce desired molecules.
The technology was developed by Saad Kenderian, and I've had a cold this week. I'm sorry about that. It can be plug and play in the sense that we could pick different antigens to target, including CD19, ECAD, COL2A1, and others, and we could choose different pathways within the cells to trigger depending on the disease indication. Again, we're looking at an IND in Mayo within the next 24 months. The first product we have is ECAD CAR MSC. This product is, you will be familiar with the company that in the past, we had a product for Crohn's of unmodified cells. In this particular case, we believe that the CAR modification can take those positive results and exponentially improve outcomes.
If you look at the panel on the right, that is the presence of ECAD CAR MSCs in inflamed colon compared to the left, where unmodified cells are present, but not nearly as much in number. You're looking at a 10-20-fold increase in the presence of the cells with better outcomes. We're very excited about that technology. This is an example where we could take a current product that works in the clinic, make it better, have better outcomes, have lower dosing, and as a defensive matter, that means anybody who's coming up behind us is going to have to reach a new bar therapeutically to be successful and overcome our leadership position. We're very excited about that.
In addition to its own effect, the MSC, when it is in those tissues, it also reduces harmful CD3 T cells, and it increases the presence of positive-acting CD4 positive T cells. The second product we're looking at Mayo is a CD19 CAR MSC for lupus nephritis. This is an indication. The last indication was an example where we could take a product that could be treated with first generation MSCs, but we think we could get much more potency, lower dose, better results for patients. This is an example where we could take our MSCs and deploy it in a field where we frankly haven't considered using MSC therapy because of the more specific targeting.
This has a CD19 antibody fragment on the surface of the cells that can bind to B cells that are at the heart of the pathology of lupus nephritis and other immunological disorders. When it binds to the B cells, it triggers the release of molecules that change the activity of that B cell from negative to positive without killing the B cell. This is important. I think some of you may be familiar. There's been recent reports of CD19 CAR T cells in the clinic, which have been very successful at Phase II. Every time they talk about the success of those products, they talk about the safety problems with those products, including cytokine release syndrome and the fact that they eliminate the B cells, so you put the patient in an immunocompromised state, and it leads to infection. MSCs do not have those safety issues.
In addition, the CAR T cells are really singular in action, whereas our MSCs not only act on the harmful B cells, but they also inhibit CD3 positive T cells and recruit and induce Treg cells. They have multiple mechanisms compared to the CAR T. They'll be much more safe. We're really excited about this indication. As I mentioned before, this is an indication that we couldn't go after without this technology, so it enhances our competitive position, expands our patient access. That's the CD-CARs, and we'll talk about that in the Q&A after this presentation with Dr. Kenderian. The other platform that we have is for the delivery of oncolytic viruses. If you looked at clinical trials in 2022, 2023, there were 400 oncolytic viruses in the clinic. Today, there's one approved product. There's two reasons for that.
Number 1 is when you administer an oncolytic virus, not surprising, it gets negated by the human immune system, so it doesn't last very long. Number 2, there's no specificity in its delivery, so it has a lot of off-target activity. What researchers have found at Baylor College of Medicine is that if you load MSCs with the oncolytic virus, they can protect the payload and deliver it to tumors because they home to inflamed tissues, and we go after hot tumors. The MSCs are like a Trojan horse. They protect the virus. They home to the tumor. Eventually, the MSCs will die from the virus being payloaded, but that's a good thing because they deliver the virus to the tumor, then go away. This technology is really very exciting.
There's a lot of papers in this space, but we've found the most advanced technology in this space has been developed at Baylor by Malcolm Brenner, who is very well known in the oncology cell therapy space. The lead product that we're advancing at Baylor is a product that expresses a cytokine in IL-12. It expresses a PD-L1 checkpoint inhibitor, and it also expresses a bite which causes or facilitates the homing of the virus to tumor cells, binding to tumor cells, and bringing in CD3 positive T cells, basically recruiting the immune system to the tumor. This product for us actually has four mechanisms. Number one, it has the cytokine, number two, it has the checkpoint inhibitor, number three, it has oncolysis, and number four, it has the bispecific T-cell engager molecule.
We're taking an oncolytic virus, adding three mechanisms, and protecting the virus with our cells for delivery. A really potentially valuable option for cancer patients, and this is certainly an indication that even 5 years ago, Mesoblast would not have considered would be possible with MSCs. We think it's not only possible, but we're looking for an IND in the next 12 months. The payload that we're evaluating, a prior version of that has actually been in the clinic, and there's data there. Got responses of 5 out of 7 patients, but not surprising, it had to be administered intratumorally because it couldn't be administered IV, which caused Baylor to reach out to us and ask if we wanted to partner around use of MSCs to deliver the virus. Next slide. You've heard a lot today.
Silviu, you started off by saying we're the leader in this space. Everybody says that, but I think the presentations that followed show that we are a leader in this space, and that was not easy for a lot of people. Eric hinted, pointed out at Silviu's role in persistence and staying around. This is a little bit emotional for me because I've been here 20 years, but that was a hard road. That was difficult. There were a lot of people who were very critical, skeptical, and even active negative during that time. We persisted, and we got to approval. That type of experience does two things to people. It either makes you tired and want to retire or do something else or go away or just avoid the pain. I think we've embraced the pain, and we've taken that and gotten stronger.
The other thing that can do to people is make them very resilient and resolved to be successful. I think you saw that in the people today. I think that's a common characteristic of everybody who comes to work at this company. When we look at our competitive position, we're not very happy that we're the leader. I'm not very happy about it. I'm not comfortable that the gap is wide enough between us and the others who are in this space and the more people who are coming in because we've been successful. I think by securing these two technologies, we've really put ourselves in a position that 5 and 10 years down the road, I don't care what MSC you're developing, you don't have a CAR MSC, or you don't have an MSC OV delivery.
The first generation, our goal, my goal, is to put first generation 10 years from now as first generation and focus on second and take the competition away. And not only that, but obviously, if we can expand our capabilities to cover things like lupus and cancer, that's obviously better for patients as well. The other thing I want to leave on is we understand fully that the focus of this company is primarily on commercial and is on our late-stage clinical programs. Every day, we don't have to be reminded. We remind ourselves of that fact. It's important not to distract our regulatory quality manufacturing clinical folks on the new programs, and we don't have to because we're doing them at Baylor, and we're doing them at Mayo Clinic. This is really important not just from a management perspective capabilities, because they're the experts.
We're going to leverage that power, those capabilities, those competencies going forward. It avoids the distraction inside. The other benefit of doing it at Mayo and Baylor is financial prudence. They have all the infrastructure. They have all the laboratories. They have the staff. They have manufacturing, and it's a very different world than 5 years ago, even 10 years ago, when a university would license something, and that was the last time they were involved in it. I mean, Sylvia, if we look back at MPCs or MSCs or other technologies, you take it in, and then it's yours. That's not really the way that things are working these days. We are truly partners with Baylor, and we're partners with Mayo. Going forward, their contributions to the programs will greatly minimize the financial demands on our company.
These programs, you haven't heard about them because they're not material to our cash runway, and we don't have to disclose those. I'd rather not tell people about them until the patent stays in place, our competitive position stake is put in the ground, and we've done that with these two technologies. We filed a patent on MSC CARs as early as 2 days ago, as recently as 2 days ago, which enables us to talk about it today. The OV MSC IP is very long as well, so we're in a good position there. I want to thank Dr. Kenderian for being here today, but that's just the beginning of our relationship, so we'll be working hard there the next 2 years to get those products in the clinic. For Dr. Brenner, I'll express the same sentiment when I go down there next month.
That's the end of my presentation. My group used to be called 2GT. I'm going to get a little bit revenge here for a minute. We were called the 2GT group, and then our head of manufacturing and his group came up with a new approach for manufacturing that has the potential of increasing our yield by sixfold, and he called it second generation. Not surprising, that title got taken from my group, and I was made head of special projects, and everybody says, "What does that mean?" I say, "Exactly." A little bit stealth. I'm not used to talking, and I'm used to being a little bit more secretive about the function, but I appreciate the opportunity to see everybody here today and tell this story. Thank you. Sylvia, do you want to bring it?
Thanks, Dan. If we could have Dr. Kenderian, please. Dr. Kenderian is the developer of the technology from the Mayo Clinic that you just heard from Dan. We're very excited about these technologies, and as Dan said, this is work that has been long coming from your group. We're excited because you came to us, have identified us as the leader, which we are, in this cell therapy space. We have had many technologies that we have evaluated, and of course, we decided that what you were doing is so exciting and gives us yet another trajectory and yet another arrow to our bow. I'd like to talk to you a little bit about the potential for using this technology in lupus, in B-cell autoimmune diseases.
I'm a rheumatologist by training, and lupus nephritis has been a disease that's been. Not much has changed in the treatment of lupus nephritis. It's young ladies, often young patients, terrible outcomes, kidney disease, transplants, high mortality, and we've had nothing in the armamentarium. Recently, the CAR T developers have learned from the use of CAR T-cells for leukemia, B-cell leukemias, et cetera, and have adapted that sort of technology for B-cell diseases in the autoimmune space, and the field has rejuvenated. With potential downsides. I'd like to hear a little bit from you about why you decided that perhaps a superior approach might be to use the same technology, but harnessing the power of MSCs.
Yeah. Thank you, Silviu. We are equally excited about this partnership and about the potential for us to work together with CAR MSCs to take that to the clinic. I think what we see when we incorporate the CAR into the MSC, that we enhance two functions for the MSC, that they home better to where they're supposed, where we want them to go. With the signal of the CAR, that will make them more immunosuppressive or that desired function that we want them to get to. I think for lupus, we are excited. As you mentioned, we are seeing now patients getting treated with CAR T-cell, for example, CAR T19, and we're seeing remarkable outcomes in some patients. I'm a hematologist, so in my clinical hat, I see patients that go through CAR T-cell therapy. Patients with autoimmune diseases, they come to our service.
We have one cell therapy service. What we're seeing is, unlike in cancer, where we're able to accept cytokine release syndrome, neurotoxicity, the use of lymphodepleting chemotherapy prior to CAR T-cell therapy is common, is accepted. Patients with cancer commonly have received chemotherapy. These toxicities are kind of like the bar is low for cancer, right? This is the last resort that we have, and we accept the risks of toxicities. For autoimmune diseases, and as you said, when we have with treating rheumatologists, the bar for accepting cytokine release syndrome, neurotoxicity for the patients, for the treating physicians is higher, right? Patients are not used to these toxicities. Even the use of lymphodepleting chemotherapy, higher doses of chemotherapy, patients are not used to such therapy.
When we use MSCs that are engineered with CAR 19, we have the advantage that we're not going to see cytokine release syndrome and neurotoxicity. This is an allogeneic platform, unlike the autologous complex platform with CAR T, does not need lymphodepleting chemotherapy. Then there is no long-term side effects. With CD19 CAR T, patients have long-term B-cell aplasia, and about one-third of patients have long-term cytopenias, long-term neutropenia, higher risk of infections, and make them ineligible for future therapies, and that risk will not be existent in MSCs. In addition, CAR 19 depletes the B cells, and that's what it does. What we see with the MSC is that their multi-functions is through the incorporation of the CAR, we're able to suppress B cells, but in addition to that, they secrete suppressive cytokines. They suppress T cells.
They will be more effective in diseases that are not purely B-cell mediated. You mentioned lupus nephritis is not necessarily purely B-cell mediated. People are surprised by the responses with CAR 19. We're very excited about this technology. We're excited about the preliminary data, and we're doing more studies trying to understand how we can optimize that and further advance it for lupus and lupus models.
Well, lupus and B-cell autoimmune diseases are an important part of our trajectory in terms of diseases that we'd like to target, and we look forward to collaboration with you and your lab. We'll be hearing a lot more about work with Saad in the future. Another area that I'd love to just touch on is a big space for us is neuroinflammation. We heard earlier from Dr. Kurtzberg in children neuroinflammation. We have an interest in Alzheimer's disease, in Parkinson's disease. I'd like to hear from you how you see potential targeting of the cells to the CNS.
Absolutely. Definitely, these are areas in our docket, in our list of diseases that we're targeting. I think Dan had mentioned in the pipeline, we have an engineered MSC with a CAR that targets MOG. MOG is a myelin oligodendrocyte glycoprotein, and that is expressed on the myelin sheaths. Now we have really encouraging data, very significant data in preclinical models of multiple sclerosis, where these cells are effective in improving, completely resolving the phenotype of multiple sclerosis in mouse models, as well as inducing the downstream changes of T cells and changes of the mechanistic pathway, as we expect with these cells. That's an area that we're actively pursuing. There is no reason why we can't see development of such a platform for other immune inflammation or degenerative diseases like Parkinson's or Alzheimer's. I think we know MSCs have multiple functions.
They are important and powerful cell, and we know that we can enhance their homing and their functioning with the incorporation of the CAR.
Terrific. Just a flavor of where I think Mesoblast is going and why not only are we at the forefront today, but this type of technology gives us a 10-year runway to continue to develop, ensuring, as Dan said, that we keep our focus today on our lead programs and our commercial programs. This represents where you can see the Mesoblast with genetic modification of our cells will continue to create life cycle opportunities in areas that are as big, if not bigger, than the areas we've already targeted. Thank you very much. I look forward to working closely together.
Thank you. Same here.
I'd like to now ask Justin Horst, our head of manufacturing, to just give you a high-level overview of what actually is a very complex manufacturing strategy that's in place, but Justin has got it all very simply under control.
Thank you, Silviu. Good morning. I'd like to take this opportunity to talk through some of the manufacturing developments and innovations to support all these programs that we've heard about today. Right. Obviously, we have an existing portfolio that's approved. We're looking to label expand that and extend into additional indications, and we have to be able to support that from a supply chain and commercial manufacturing capacity. This is a quick look at how we see these innovations in manufacturing that we've developed will take us to that next level of manufacturing to be able to support all these indications. Where we are today is with our gen one platform. This is what we've heard about with the Rhinceil and the pediatric GBHD products that have been approved. This is a two-dimensional or what we call a 2D manufacturing process. The cells are adherent on a culture surface.
They are expanded through our proprietary and closed system manufacturing process. It's very controlled, very robust. In fact, we've been manufacturing this way for many, many years. It's been very stable throughout the development of these programs, both MSCs and NPCs, and it has gotten us to where we are today. This is our base level Generation 1 program. A little bit of the thunder that Dan stole from me earlier is what we call our Generation 2 platform. This is actually based on some work that came out of our bioreactor program. We found a proprietary recombinant growth factor supplement that we can add to our existing platforms and boost our output by about sixfold. This comes through increased expansion of the cells and also shortened duration of the culture process. The advantage here is obviously we can plug these into where we are today.
It's a process that's already been inspected by the FDA, so we're able to leverage a lot of that. Really, we're just simplistically putting a frozen growth factor supplement, adding it to existing media and existing cultures. This has given us a tremendous increase in the output of the cells, and also reduced costs, obviously. We've also demonstrated that this is able to sustain and maintain all of our critical potency aspects for the product. We've put this through the validated methods that we use for Rhinceil and the other programs and demonstrate no difference in those products that are produced. Stepwise, next step of that is once we've generated all these extra cells, we need to be able to actually get them cryopreserved and frozen, and stored quickly. This is what we call the downstream portion of our manufacturing process.
The upstream is handled by this growth factor supplement where we see these significant increases in yield, and now we actually need to be able to handle these cells and get them efficiently through into a frozen state. This is not an easy process, as we've talked about. When you see some of these indications, we're talking about millions and millions of patients, so that translates to millions and millions of vials that need to be handled. We've been working with some partners to establish a downstream automation pipeline that can feed into our existing manufacturing platforms and handle these cells. This will significantly reduce operator manipulations, the manual handling that we have to do for this, reduce some of the variability of that process as well, and ensure that we have a consistent and robust way to deliver these cells.
These are all activities that we can do in our existing facilities, in our existing platforms with minimal additional modifications needed. To this point, I've talked quite a bit about scaling up of our manufacturing process. We are also looking at scaling out of our manufacturing process. We are working currently with partners here in the U.S. to establish or onshore those manufacturing capabilities here in the States. This will help secure that supply, ensure continuity, also quite significantly reduce some of the cost of goods associated with transporting products across the globe to distribute them here within the U.S. That is also actively underway. Then lastly, we've talked in the past quite a bit about a 3D or suspension bioreactor program that we have.
This has been a long-running program with the organization, and ultimately where we do see the programs heading towards a really significant commercial scale manufacturing platform. This will even further reduce the COGS and also increase automation. It'll remove quite a bit of manual intervention and operators, which all, again, translates to a consistent product and a cheaper product. Just quickly, would like to touch on then how we're going about these and how we're actually managing this, and managing this with our milestones that we hit. We can't just run out and establish a new manufacturing process without proper milestones in place. First and foremost, we are continuing to support and supply our commercial product for Ryan's Son for pediatric patients, and then the near-term label extensions that you guys have heard about today. That's our key position.
We are, I think, well-positioned to supply those products commercially for these indications with the existing platforms. we do have these second-generation platforms that come in utilizing these growth factor supplements, where we're able to significantly reduce cost of goods, also increase the supply from existing manufacturing facilities. this will be a much more efficient process as those are introduced. we're working to actually introduce those in the next 12-18 months. This will depend on a case-by-case scenario as to how it will be introduced for the regulators, whether it's through clinical studies or through post-approval changes. I mentioned again the automation we need to match our production scale as we increase, and we've been working with partners as well to sequence this to match our commercial milestones. we're not just running out and implementing this today.
This is a very well-thought-through process that's based on data-driven and where we need to implement this, and when we need to implement this. That's also an activity we see taking place over the next 12-18 months. Then lastly, we are working towards validating our Generation 1 manufacturing processes here in the U.S. and onshoring some of that manufacturing. Again, this helps de-risk us from tariffs from import and some of the other current geopolitical challenges that are faced with this. We are currently working with partners. This is probably a process that will then be a post-approval supplement to add these additional sites of manufacture here in the U.S. Those are kind of a high level of our activities for manufacturing. I think with that, I will transition to Jim, who's going to speak about the financials.
Hi, everybody. I'm going to spend a couple of minutes talking about our current financials and our strategy going forward. We reported this week net revenues for our fiscal third quarter of $30.3 million. In February, we reported our first-half results, where we had reported $44 million of gross profit on Ryan's Son, and that had $7.7 million worth of direct selling expenses to it. Our net cash usage for the first half of the year ending in December was $30.3 million. At the time, we messaged to investors that our spend in the back half of the year will be lower than it was in the first year. Our cash burn is actually going down as receipts for Ryan's Son go up. As a result of that, we'll be using less cash in this back end of the year.
We've really implemented a cost discipline approach so that we're really matching what we're receiving in from Ryan's Son to what we're spending. All along the way, we are still supporting the clinical trials that we've talked about today, our BLA filing, and maintaining our commercial inventory. We have $130 million of cash on the balance sheet at the end of December, a very strong balance sheet. We also entered into a new term loan, $125 million term loan at the end of December, retired some debt, and we'll draw another $50 million on that later this year to retire all of our debt. After June, we will have no current debt. We've got a five-year term on it. It's a very flexible balance sheet to be able to work with all the programs that we've talked to you today about.
From a strategy standpoint, I just wanted to emphasize a couple of points. We're looking at various ways of making sure that we fund the company, most importantly, on a non-dilutive basis. We're matching our cash generation to our cash spend. We've already messaged to the markets that we expect full fiscal year net revenues to be between $110 and $120. Our costs are well controlled. Our margins are really terrific. We're very pleased about that. As Marcelo mentioned, we're looking to target to double our revenues in Ryan's Son. We have a long-term debt facility, which I will also mention that it carries only an 8% interest rate on it. It doesn't encumber any of our assets to then be able to get into other partnering discussions and licensing that we're active with Michael and I leading the charge on that.
We're looking at other ways of bringing sources of cash into the company to fund our needs. Yeah, I want to make a point very clear that we're very cost discipline, making sure that we're not overspending where we need to be and really preserving our cash balance sheet. With that, I think I'll turn it back over to Silviu, who's going to just have some closing comments.
Thanks, Jim. We really are a financially disciplined company, and I think that's the message that you're all hearing. Really what I'm excited about, and I think you're all excited about, we've heard some fantastic data today and some real aspirational stuff. What are these MSCs? What's the magic? What makes these cells so special? Well, they've got multimodal anti-inflammatory mechanisms of action, which means they can concurrently act on multiple pathways of the immune system, not just one. When they're inert and they're self-regulating, so in the absence of inflammation, there's no adverse events. There's no safety issues. These features result in superior efficacy without any concerns of off-target adverse events that are typical of small molecules and typical of antibodies. This is a paradigm shift in drug development.
Precisely what the pharmaceutical industry is concerned about, off-target effects, which forces them to go down very narrow paths, is exactly what we don't have. We have a product that is multimodal, does not have the off-target effects, and we can take advantage of those multimodal pathways to deliver outcomes. The body is not a single pathway individual, right? We are all complex. These cells are able to respond and, in a complex way, turn off disease states. The platform technologies that we've developed can be leveraged therefore across many indications with high unmet needs that are not accessible to other drug developers. There's no requirement for matching or immunosuppression. These cells are highly expandable and scalable. This was a feature of the cells that led us and drove us to build a manufacturing process that underpins a business model that's sustainable.
The industrial scale of these cells give us a sustainable, high-margin business model that can only improve with the innovations that you heard from our head of manufacturing. We've developed a moat, meaning we've developed an entire strategy around what sets Mesoblast apart and protects our market leadership position. We have a global intellectual property portfolio of more than 1,000 patents that provide us with commercial protection through greater than 2044. We have a dominant IP position protecting a cell type whose unique properties underpin a scalable commercial business model. We have a first-mover advantage, and this is really important. We have the first and only FDA-approved MSC product. We can take advantage of that. We've completed large U.S.-based randomized clinical trials which provide evidence of efficacy. You heard some of these today.
We are the benchmark in complex manufacturing with IP protection, with significant know-how, with FDA alignment. We've demonstrated that FDA alignment, scale of capacity, and ability to leverage. In addition to that, you've just heard the tip of the iceberg today about next-generation technologies that we're accessing and rolling up in order to enhance our leadership position and be able to develop new products moving forward for the next decade to continue and separate us from the rest of the pack. These allow us to move into new areas that we haven't even talked about yet, including, as you heard today, lupus nephritis, a major disease of unmet need, including potentially areas like Alzheimer's disease and other neuroinflammatory conditions and, interestingly and excitingly, potentially even cancer.
We have some major anticipated upcoming milestones that I think I want you all to focus on because that's where the business is. That's what we need to deliver in the short term. We have milestones for RYONCIL, our FDA-approved product, and some of those are commercial, and some of those are clinical and strategic around label extension. For RYONCIL, our commercial milestones, we talked about our net revenue approaching $100 million just since recent launch, but we have a plan to double that revenue, and you heard what that strategy is from our commercial leader. In addition, we're well-funded already to execute on our existing operational plans, and RYONCIL sales, as they grow, will continue to fund our internal pipeline. Discipline. We're focused on increasing penetration of the pediatric GvHD market. We have to continue to grow.
This product saves lives, and physicians who use it will endorse it, and they should be using this as soon as they have an inkling that steroids are not working well. This product is the only approved product that saves lives in these children. Beyond GvHD, this product should be used more broadly in other indications. You've heard about our strategy to broaden it into use in adults who otherwise also have a very severe disease with a high mortality rate, a market that is three times bigger than our current pediatric market. That program is in collaboration with the BMT CTN. Trial is initiated, and we expect it to complete somewhere as early as 12 months but certainly not later than 18 months.
You heard today about the new area that we're looking at, pediatric Duchenne's disease, another devastating disease where again, inflammation is at the core, and we think we can make an impact. Moving on, the real growth potential is in our blockbuster opportunities of Rexlemestrocel for back and Rexlemestrocel for heart failure. You heard a lot of discussions about those today, and we're extremely excited. Rexlemestrocel for back represents a blue sky potential that is really in front of our eyes. Here it is. You heard that we're completing enrollment this month of our pivotal Phase III trial. That then starts the clock. You will have about 12 months to wait, and the endpoint will be read out around the middle of next year. Every indication is that we'll be successful. We've had multiple trials that have successfully met the exact same endpoint.
We're very optimistic and confident that we'll have a positive outcome. If positive, we will have already pre-prepared most of the documentation for a BLA filing, a quarter post-readout. The reason for that, of course, is that all of the manufacturing and CMC activities are already underway and hopefully will have already been signed off by the FDA. The potential launch for this blockbuster product, which is really a multi-billion dollar opportunity for this company, will transform Mesoblast from where we are today to something that is 10 times bigger, maybe more, is an approval and potential launch in the second quarter of 2028. Finally, our cardiovascular opportunity you heard about today.
We have a strategy in place to start with the orphan area at the end-stage patient population, and then use that potential approval to move into the larger indication in heart failure for patients who really continue to have a devastating mortality risk. On that note, I think we'll stop. We hope we've gotten you excited and teased you with some of the many opportunities in front of us, and maybe we'll start with some of the Q&As. Thank you. Paul, you might want to get people to ask the questions, and we'll have a roving microphone, and I'll ask various people in the audience to then chime in.
Hey. Yeah. Thad here from Piper Sandler. Can you talk a little bit more about that interim analysis for the RYONCIL trial? What kind of ORR do you expect from the Rux only group, and what kind of effect size are you powered to detect at the interim and at the final analysis?
Yeah. The final analysis is looking for a very modest 20-point difference in the day 28 response. I call it modest. The field thinks it's a very important improvement on standard of care. It was exactly the same endpoint that we used in the pediatric Phase III trial, and exactly the same threshold, a 20-point improvement over other therapies, and we achieved it successfully. Dr. Kurtzberg was our principal investigator, and I'm sure she can tell you a lot more about that. We're very confident of being able to achieve this. Why are we confident, as Michael tried to explain?
It's because we're already treating the very patients who are not being adequately treated by existing standard of care, ruxolitinib, are precisely the patients who then come to us under expanded access as a last line of resort, having failed Rux and maybe having failed other agents, and with a potential 25% survival at 100 days. In our EIND studies, we see north of 70% survival in those patients. Since we can treat them when they're already gone too far, the earlier we can intervene, the more likely it is that we'll see a positive response. Together with our BMT CTN collaborators, the protocol design is such that it allows the cells to be combined with Rux, at the front end when a patient's not doing well, maximizing our chance that we'll see a treatment benefit.
Look, the data tells you why we're confident that we're likely to succeed. An interim analysis is great to put in place if you're confident about your own data, right? That bar to achieve a successful interim analysis is not much higher than the 20-point delta. I think you mentioned it was 26 points. If we can't do the 26-point delta, then we should go somewhere else. That's how confident I feel.
Thank you for the remarkable day. I'm Tom Schrader from BTIG. I'm actually here for Julian Harrison. Will your current lower back trials support redosing? Is that something that you expect to be a heavy lift at the FDA? Or if somebody wanted it again in two years, would that be easy? And then, for Dr. Beal, do you have a sense of any prognostics as to which patients do particularly well? And you also mentioned repair. Could this drug get a disease-modifying label? And would that be a big deal for pricing power and uptake? I have a cardiovascular follow-up.
For redose, redosing, it's not been tested, but the redosing in other cellular therapies appear to work about the same as the initial therapy. Let's say, I'm going to take another example. This is non-published data, but this is to-be-published data. Out of 100 people, let's say 85% still do pretty well in terms of pain and functional response. For the 15% of people that don't do well, they can be redosed and ostensibly do about as well as they did the first time, which is pretty good. When I say pretty good, the pain and functional improvements are in the range of about 60%-63%. In regard to. Let's see, redosing. What was the other question?
Prognostic factors for good results.
Prognostic factors are people with back pain, 5-6 years or less, and that's about it. In the Phase IIIa trial, if you separated the whole of the population between the ones that did better and the best, there was a dividing line of 68 months. Inside of 68 months, people did very well, and the pain and functional improvements approaching 70%, and that were ostensibly durable at 3 years. What we consider with back pain, if they're durable at 3 years, it's ostensibly permanent, and it appears to be like a regular disc. You can have a disc problem, it can heal on your own. You can do well. Any type of degeneration predisposes it for additional injury. You can look at this as a speed to heal the disc, and it can be re-injured.
It can be re-treated, and with every product coming down the pipe for the back, we always reserve the right for re-treatment. The only exception to that is something called basivertebral nerve ablation, and that's a wholly different animal than this.
I might just add to that. In addition to re-treatment, the other big area for this product is sciatic nerve injury. We've deliberately excluded acute sciatic nerve injury from patients being included in our trials. That's a whole other large patient population, as you know, and we're pretty confident that I think an injection of these cells is likely to have a substantial improvement in patients with predominant sciatica. Right? The other way to think about this is once we get approval for this as an immunomodulatory pain therapeutic, the growth of this product in other areas that have similar pathophysiology, like knee osteoarthritis, is obvious. Right? We already have data that we've generated with the same product in patients with post-ACL injury, for example, who are at very high risk of progressive osteoarthritis.
We've injected these cells into the knee joints in young, healthy athletes and published that over a 2-year period, we prevented progressive osteoarthritis and loss of function and loss of pain. That's a whole other area that this product will have potential use for.
I was going to respond to your question about disease modification. In the research we've done with the payers, they've said because everything else only goes out to three months, NSAIDs, opioids, they view any benefit 12 months or beyond is disease modifying in their question. I think that's what's really driving their willingness to pay the higher prices, is they see anything beyond 12 months with a single injection as disease modifying.
Yeah, it makes sense. A quick one for Dr. Perin. We've had some hints about powerful anti-inflammatory drugs in cardiovascular disease, the CANTOS trial, things like that. It's a vague question, I apologize, but the DREAM results are so remarkable. Are they more than you would expect for a remodeling drug and then a powerful anti-inflammatory? Is it too early to tell? It's a crowded area, and I'm just curious your thoughts.
Well, that's a great question. The interesting thing is there've been three trials of anti-inflammatory cytokines used, and Doug Mann has led these, one CANTOS against IL-1 beta. The problem is that it's one thing when you use TNF alpha or IL-1 beta. The beauty of these cells is they sit there with those receptors that got shown, IL-6, TNF alpha, IL-1 beta, all these things. The inflammatory cytokines plug into the cells, and they activate. Now you've got a cell that's putting out dozens of medications. Instead of just treating it with one thing, the cells are now treating it with a whole host of things. That's why these other trials have failed and the cells work, because we're just giving a whole soup of stuff instead of just one product.
That's exactly right. That's what these cells do. That is core to the mechanism of action. These cells sit in these tissues in our bodies. They sit in the heart, actually, and they're called sentinel cells. They sense inflammation. They have a whole bunch of receptors. What does that mean, sensing inflammation? They're being activated by cytokine A, B, C, D, E, F, G, right? When you're sitting in a cytokine storm, they get activated, and they can respond. That's a living interaction between cell to cell. That's what you don't have with any of the monoclonals that target just one cytokine. No wonder they failed. This type of outcome is unheard of and it will remain unparalleled because this product has unique mechanisms that are different from small molecules or antibodies.
Unheard of and unparalleled. I like that. I thought I heard when you were talking about the pre-LVAD market strategy that there was an indication of a label extension. Do you feel comfortable talking about that and expanding on that concept?
Well, really what I meant was we see a continuum between patients being treated in end stage with an LVAD because our cells are treating the only remaining ventricle that can be helped, which is the right ventricle. It's clearly reducing right heart failure and the consequences of right heart failure, which is GI bleeding. If we were to get approval for that group of patients, which is an orphan population-
That's correct.
We've had a successful randomized controlled trial. If we were to get approval, then that product, the exact product, the same dose, formulation, potency assays, becomes potentially a label extension strategy for other indications, particularly an indication which is a continuum of this disease, which is heart failure involving the left ventricle. This is our strategy to bring this cardiac product to the large numbers of patients who could use it.
That's what I thought I heard. Thank you.
Hey there. Michael Okunewitch from Maxim Group. Thank you for putting together an interesting event and pulling back the curtain to show some things that we haven't seen before. I'd actually like to start off just on that topic, in particular around the oncolytic virus program, given the activity in that space coming up later this week. What causes the MSCs to actually localize to the cancer? How long do the MSCs reside there before actually being destroyed by the oncolytic virus and releasing it? And then is there any risk to having mesenchymal stem cells present in the tumor microenvironment given the anti-inflammatory effects?
Yeah. These are critical questions, and this is why this is a very early-stage program. This is early pre-clinical R&D. Having said that, there are dozens and dozens of papers in the literature for 20 years of various people using MSCs and the properties of MSCs to target drugs, to target all sorts of things, including first-generation oncolytic viruses to tumors. In pre-clinical models, no evidence of downside. Why that should be the case is primarily because these kind of cells actually don't survive, and you wouldn't want them to survive. They die within 24 hours. All they're useful for really is homing and payload delivery. In this particular scenario, these cells are really fairly benign and inert and irrelevant. What's relevant is what's the payload that they deliver.
The studies that Dan is leading with really the world experts at Baylor is precisely what you've asked, right? How effective are these cells in delivering third, fourth generation oncolytic viruses, which are not possible to be delivered systemically unless they're cloaked. Really, our cells are cloaking agents that prevent these viruses from being destroyed by the host's immune system for a very short, brief moment while the cells take them to the tumors. The viruses destroy the cell that got them there, and then the viruses can do whatever they do. Look, we identified probably the number one group in the country that's leading the charge in building genetically modified oncolytic viruses that express all sorts of things. Dan touched on some of those things, but they're traditional immunomodulatory agents, anti-PD-L1 and various other factors, IL-12, et cetera.
We're leveraging the knowhow and the expertise of the Baylor investigators, and we'll know from their studies whether our cells are able to deliver outcomes that naked viruses are not able to. Thank you for that.
Just the homing cells are and there's a ton of data on that. I could share you, Frank Marini, who's a very well-respected oncologist at, I think, MD Anderson, just published a review in 2025, and he looked at 217 MSC trials over thousands and thousands of patients, and not one occurrence of any kind of contribution to an oncological event. We've always known that, but it's incredibly validated that there's no issue. On top of that, Dr. Brenner is very cautious. There's a suicide gene built into our oncolytic viruses that make sure the MSC doesn't in any way transform into something that sticks around for some time. We think it's an incredibly safe product.
Yeah. Thank you. Certainly very interesting. Just on the topic of some of the newly announced programs. Within DMD in particular, I'd like to see if you could talk a little bit about how you plan to contend with the potential presence of other cell therapies in that indication and how you plan to differentiate yourself.
We are differentiated. We've got the only FDA-approved cell. This FDA-approved cell should be available for patients with bad inflammatory diseases who have nothing else to help them with. That's why we're working with the PPMD, which is the advocacy group. They wanted us to do this study, right? Because they need something. They need an anti-inflammatory cell. The FDA-approved Ryoncil needs to be evaluated to see whether we can improve outcomes. Nobody is looking at cell therapy in children five to nine who have inflammation, who need something to improve their muscle disease and prevent them from becoming non-ambulatory.
I believe there's a question on the phone line.
Yes, we have a question from Edward Tenthoff with Piper Sandler. Your line is open.
Great. Thank you so much, and I'm so sorry that I can't be there today for this inaugural event. Really a lot of exciting data, and I echo Eric's words earlier about the long-term effort and persistence to get these therapies approved. I really feel like Mesoblast is on the cusp here of launching some really big therapies. My question kind of has to do with that point. How do you fund the company in this intermediate term to get Rexlemestrocel approved for chronic lower back pain? Is the plan to potentially partner one of these assets, whether it's heart failure and deep chronic, but how does partnering factor into the funding strategy for this really exciting late-stage pipeline? Thanks.
It's clear. Look, we laid out today our confidence in using the revenue from Ryoncil, which is growing, to fund internal operations. That's our number one strategy. We see our budget allows us to plan for that, and as revenues increase, then our investment in internal programs will increase accordingly. That's our number one strategy. We're well cashed up. We're well funded. We have important readouts coming up. The back pain program will read out in 12 months. If positive, that will be transformational for the company. We, of course, have discussions on an active basis with companies that have substantial commercial capabilities in pain, in back pain, in inflammation, et cetera. Whether we take that product to market on our own or whether we co-promote and maintain a relationship with others who have bigger commercial footprints is something that we'll decide in due course.
Certainly in Europe, which is a very different category, it's a segmented geography. We've already chosen Europe's number one or number two pain pharmaceutical company, Grünenthal, to be our commercial distributor. Grünenthal is awaiting with deliberate enthusiasm the readout of this Phase III trial. They've got the footprint across all the major jurisdictions. If it's positive, they'll be running to the regulator, and they'll be preparing for appropriate launch and reimbursement discussions across the EU5 and other jurisdictions. In the U.S., I think that we will evaluate the opportunities and the options when the trial reads out. With respect to cardiovascular disease, I laid out the strategy, I think, pretty clearly that we have a stepwise approach to approvals that start with the most extreme severe end-stage patients and then build out towards the larger opportunities.
Of course, to the extent that commercialization of the larger opportunity in Class 2-3 heart failure, that will be a partnering opportunity. We're in discussions with some major strategic partners, but that heart failure program is, of course, you saw the numbers. That program will be partnered at the appropriate time to take advantage of the opportunity. Ed, does that sort of address the question you're asking?
Yeah. Thank you very much.
Thanks, Ed. Okay. I think there are no further questions, and hopefully, you guys have had an exciting time because we think it's exciting, and hopefully, there'll be a lot more questions in due course that we can address. Thank you, everybody, for attending.