Mesoblast Limited

I'm Silvio Tescu, I'm the Chief Executive of Miseblast. Together with me this morning is Marcella Santoro, our Chief Commercial Officer, and Andrew Schapanel, our Interim Chief Financial Officer. Today we're presenting our financial results and operational update for the half year ended December 31, 2024. We could go to slide four, please. Mesoblast is the global leader in allergenic cellular medicines for inflammatory diseases. We have one product already FDA approved, Rioncil. We have multiple locations globally. We're listed duly on the ASX and NASDAQ. We have more than 1,000 patents and patent applications that support our products. Beyond our first approved product, Rioncil, We have two other major products in phase three, and we have a whole pipeline sitting behind these. We have scalable manufacturing that have been FDA inspected, and we have a supply chain capability that allows us to meet the global needs commercially. Next slide, please. Our platform technology is based on a shared mechanism of action across all of our products. Our mesenchymal lineage precursor stromal cells are highly purified to very high concentrations in final cryopreserved vials. These cells have on their surface a range of receptors for inflammatory cytokines, including interferon gamma, TNF, IL-17, IL-6, and IL-1, and others. And when the cells are placed in regions of severe inflammation where these cytokines play major disease roles, they're able to respond to inflammation with the release of multiple anti-inflammatory factors that act in concert to turn off the damaging inflammation that results in severe diseases and potentially life-threatening outcomes. Next slide, please. This slide provides a snapshot of our clinical product pipeline. A platform technology based on Remy Stem Cell, our first-generation product, trade name is Rioncil, has now been approved by the FDA for the treatment of children with severe steroid refractory acute graft-versus-host disease. I'll be talking a lot more about this product, which today we've announced pricing for, that physicians can access. This product is also being developed for adults, the steroid refractory GVHD, and will be developed for life cycle extension into inflammatory bowel disease in both children and adults. A second generation technology platform is termed Rexlamistrocell. These cells are immunoselected using monoclonal antibodies to high purity and potency. This technology is being developed for inflammatory cardiovascular disease, and inflammatory back pain. More about that later. Next slide, please. Now I'd like to turn to Andrew Schapanel, who's going to be discussing our financial results for the period ended December 31, 2024. Thanks, Sylvie.

Turning to slide eight for the financial highlights for the year. Our cash balance at December 31, 2024 was US$38 million with pro forma cash of approximately US$200 million after the successful completion of a global private placement which raised US$161 million. Net operating cash spend was US$20.7 million for the first half of FY2025 which was a 22% reduction. on the first half of FY2024. As a result of FDA approval of Ryonsol in December, a $23 million provision against the value of inventory manufactured and expensed in prior periods was reversed and is now recognised as an inventory asset on the balance sheet. Turning to the next slide, you will see our P&L statement. in December resulted in non-cash balance sheet adjustments, including the write-up of the value of inventory. Starting with the line items most affected by the non-cash balance sheet adjustments, let's look at the results of both the revaluation of contingent consideration and the revaluation of the warrant liability. The increase in these line items in the current half year were as a result of FDA approval. Within contingent consideration on FDA approval, the probability of success of pediatric GVHD increased to 100% and resulted in a non-cash re-measurement, increasing by $4 million to $4.3 million for half-1 FY2025, compared to $0.3 million for half-1 FY2024. Within revaluation of warrant liability, As a result of FDA approval and the consequential share price appreciation, our warrant remeasurement increased by $16 to $12 million US dollars for half one FI 2025 compared to a gain of $4.4 for half one FI 2024. Within manufacturing, as a result of the FDA approval, the $23 million US dollar provision against the value of inventory manufactured and expensing prior periods was reversed and as a result we are now recognising 24 million US dollars of inventory on our balance sheet. The increase in expenditure for both our R&D and management and admin was due to non-cash share based payments primarily for STI in lieu of cash based payments. So as described above the BLA approval resulted in a number of non-cash balance sheet adjustments, which drove the loss after tax of $47.9 million for the half-year. Pleasingly, for the same half-year period, our total operating cash flows were only $20.7 million, a reduction of $5.9 million on the comparative half-year. Back to you for the call, Phil.

Thanks, Andrew. We can go to slide 10. I'd like to talk now about Rioncil, our launch strategy, pricing, and other facts. Rioncil is the first mesenchymal stromal cell therapy approved by the FDA. Next slide, please. The first FDA-approved off-the-shelf therapy for children aged two months and older, including adolescents and teenagers, with steroid refractory acute GVHD, a life-threatening condition with high mortality rates. Next slide. We have the opportunity to address a very critical unmet need in children two months and older. Across the U.S., approximately 10,000 allogeneic bone marrow transplants are performed annually. Acute graft-versus-host disease occurs in about 50% of patients. Approximately half of these fail to respond to steroids. And for those who fail to respond to steroids, mortality is very high. And there are significant extended hospital stay costs. We believe that the addressable market in the US is approximately 375 new children per year with life-threatening steroid refractory acute graft-versus-host disease. Next slide, please. In our phase three trial that underpinned FDA approval, Brionsell delivered high overall response rates at day 28, which is a measure well established to predict long-term survival in this disease. Overall response rates were 70% at day 28, significantly higher than is achievable with other therapy for this disease. Importantly, Eighty-nine percent of the children enrolled in this trial had the most severe form of the disease, grade CD, which involves the gastrointestinal tract and liver in addition to skin. Rionsel treatment was not discontinued or interrupted in any patient for any laboratory abnormality, and the full course was completed without interruption in more than 85 percent of patients. This is very different from the profile with other therapies used in these children with very severe disease, as well as in adults with acute graft-versus-host disease. Next slide, please. Now, the cost of treating children with steroid refractory GVHD who subsequently die is very high. The cost of treating a child who dies within 12 months of a transplant from steroid refractory GVHD is approximately $2.5 million, and notably, It's $1.8 million higher than for those children with steroid-fractured GVHD who actually remain alive. Next slide, please. Well, Ryonsil has demonstrated long-term survival free from acute GVHD. In a long-term follow-up of Ryonsil by the Center for International Blood and Marrow Transplant Research, CIBMTR, in the 51 patients who were followed long-term, notably 88% of whom had life-threatening great CD disease. Two-year survival was 51%, and beyond that, survival was relatively plateaued, with four-year survival of 49%. Notably, only 14%, seven children, have died due to acute graft-versus-host disease through four years and beyond. One would have expected a much higher number to have died from acute GVHD if treated by other therapies. Next slide, please. What is the value of Rioncil in treating pediatric patients with acute GVHD? Well, the total benefits of patient outcomes using Rioncil range between $3.2 million to $4.1 million. And this is based on health economic models for lifetime ultra-rare disease and high-impact short-term therapies. including quality of life he has gained. And the benefits comprise long-term survival, cost offsets, and cost savings. Next slide, please. So for treating pediatric patients with acute GVHD, the recommended dosage of Rioncil, based on our FDA-approved label, is 2 million cells per kilogram body weight, given intravenously twice per week for four consecutive weeks. The wholesale acquisition cost of Rioncil is $194,000 per intravenous infusion across all body weights. Next slide, please. This is the mandatory hub that has been established, termed my mesoblast. This is set up to assist patients with insurance coverage, financial assistance, and access programs, ensuring that no patient is left behind in receiving this potentially life-saving therapy, a comprehensive patient services hub which provides access and helps both patients, their families, and institutions. Next slide, please. is being made available for pediatric GVHD in the United States in March. We are approaching this in a staged manner, targeting those transplant centers with highest volume and with established experience using the Rionsel product. We're establishing and have established already a targeted sales force with experience in bone marrow transplant centers, 15 of the highest volume centers account for 50% of the patients, and the 45 highest volume centers account for 80% of patients. And you'll hear more about this from Marcelo Santoro in the Q&A session. Beyond acute GVHD, we have a strategy to expand the label and establish a life cycle for the product. Number 21, please. In particular, We're focusing on inflammatory bowel disease, inflammatory Crohn's and ulcerative colitis. The pathology and the clinical aspects of these diseases are very similar to the inflammatory bowel complications of acute graft-versus-host disease. And the ability to respond to Rioncil is similar and has been evaluated in previous studies. The unmet need is large. in both adults and children. And in particular, more than 60% of patients fail to respond or subsequently lose response to anti-TNF agents, which are the first line of biologics in this patient population. About 25% of all inflammatory bowel disease patients are of pediatric age. And in these patients, an anti-TNF agent is the only approved therapy. This represents potentially as many as 7,000 children, 50 to 60 percent of whom are likely to be refractory to antigenic therapies and where potentially Rioncil may make a difference. Next slide, please. A recent pilot study in adults demonstrated positive outcomes with Rioncil directly injected submucosally. in biologic refractory patients. Rionsel was delivered a direct endoscopic injection to areas of inflammation. In addition, we have data showing that remic stem cell induces early remission in Crohn's disease adults who failed a single anti-TNF agent following a course of intravenous treatment. Given the effectiveness of Rionsel in treating children with gastrointestinal-related GVHD with inflammation of the gut, and the existing data in adult Crohn's disease patients, we plan to further evaluate the immunomodulatory effects of Rioncil on GI inflammation in medically refractory pediatric Crohn's disease and ulcerative colitis patients. Next slide, please. In addition to inflammatory bowel disease, we have a strategy to expand Rioncil use in adult patients with TBHD. This continues to be an unmet need, particularly in patients who fail ruxolitinib, the only approved drug in adults with GVHD. This accounts for about 40 to 45% of all ruxolitinib-treated patients. In addition, survival of these patients who fail ruxolitinib is very dismal, around 20 to 30% by 100 days. And for this patient population, there are no approved therapies. Treatment in a pilot study of third-line agents using Rioncil demonstrated 73% survival at day 100. And that provides us with the confidence to move forward into an appropriate pivotal study in adults of Rioncil for refractory to ruxolitinib. We're collaborating with the Blood and Bone Marrow Transplant Clinical Trials Network an NIH-funded body responsible for approximately 80% of all U.S. transplants to conduct this pivotal trial. And you'll hear more about that in due course. Next slide, please. Let's move forward to the second platform technology, RexLimistroCell immunoselected STRO3 positive cells that are expanded and used for local delivery into areas of inflammatory tissues. Slide 25, we move to the use of Rexlimistrocell for chronic inflammatory low back pain due to degenerative disc disease. This is a disease that affects more than 7 million patients across the US, similar number of patients across the EU5. After failure of nonsteroidal agents and other conservative therapies, there are minimal treatment options. 50% of opioid prescriptions are for this particular indication. And we all know the problems with opioid addiction and the epidemic of opioid overusage and overprescription across the US. We have established that there's durable improvement in pain from a single injection of our cells in prior studies and currently are in a confirmatory phase three trial. If we go to the next slide, slide 26, is the patient journey and really the point of this slide is to demonstrate how how rapidly patients go through conservative approaches to go through opioids and then really what's left are interventional therapies with all of the related adverse complications we aim to be establishing a best-in-care class testing class approach to the treatment of inflammatory back pain and as soon as conservative treatments have failed. Slide 27 summarizes the outcomes in the first phase three trial, where, as you can see here, the comparison was the change in pain from baseline in red of our product Rex-Limistro-Cell in combination with the carrier, and comparison at month 12, which was primary endpoint of the study in terms of pain reduction against placebo-controlling green, that difference is highly significant. And just to put this into context, the minimal pain reduction that is seen in the green at 12 months is roughly what you would expect to see with opioid usage. That difference between the two is a very large difference in terms of mean pain reduction but I think it's important to note that this is mean pain reduction for the group as a whole and that 50% of patients treated with Rexlimistrocell showed complete remission or no pain at all at 12 months. And these patients who were improved with pain at 12 months showed very durable long-term maintenance of pain-free outcomes through 36 months. Moreover, 40% of patients were on opioids at commencement of the study. And despite the fact that they were told and their physicians were told not to change medications, almost 30% of patients in the treated arms were able to completely come off opioids versus mid-single digits in the control arm. And this was a significant outcome. We're currently enrolling this trial. We're increasing the enrollment rates through various interventions, including increasing sites from 15 to 40 sites. And we'll be updating the market shortly in due course. Next slide, please. Slide 29. Let's move to Rexlimistrocel for ischemic heart failure. Heart failure with low ejection fraction due to underlying ischemia continues to be a major problem in the Western world, in the US more broadly, increasing in prevalence and associated with the high risk of death, heart attacks and strokes. Heart failure with low ejection fraction occurs in about 50% of all patients with heart failure. 60% of these patients have heart failure due to ischemia. that they are at highest risk of cardiac events, including death. The target market is very large in the US, likely to be around 1 million patients with ischemic heart failure and inflammation. Slide 30, please. This is a complex slide. We have shown this previously, where the patient journey for heart failure is on the left-hand side. New York Heart Association class 1 and class 2, the bulk of heart failure patients, these patients are on a whole range of different oral medications. But inexorably, over 5 years to 10 years of the disease, they move into the class 3, class 4, and end stage spectrum. Despite being on maximal oral therapy, they move into this area of high risk or progression to death. We have performed two large randomized controlled studies in this patient population. The DREAM trial, 537 patients in class 3, and the LVAD MPC trial of 159 patients, both randomized controlled studies. That is, in end-stage patients being kept alive by an artificial device. Next slide, please. Slide 31. This slide shows the effect on cardiovascular death. of a single MPC injection in our Phase III trial. On the left-hand side, in patients who were categorized on the basis, pre-specified, of a simple blood test for inflammation called CRP. And on the right-hand side, a slightly more fancy measurement of inflammation, measuring a cytokine called interleukin-6. What you see in both the left and the right panels is that control patients have a very high risk of cardiovascular death over a five-year follow-up period. And in both analyses, a single intracardiac injection of 150 million MPCs or rex lamistro cells significantly reduced the risk of cardiovascular death by approximately 80% in the CRP categorization on the left and by about 60% in patients determined by high or low IL-6 levels. What this demonstrates is that despite the fact that patients are apparently well treated with a range of approved drugs for heart failure, which improves their symptoms and reduces their hospitalizations due to symptomatic shortness of breath, they remain, particularly if they've got measurable inflammation, they remain at high risk for death, which is over the subsequent three, four, five years of follow-up, and that a single injection of rex lamistrocell substantially reduces that long-term risk of death. Next slide, 32. Also from the recently published paper in the European Journal of Heart Failure, we analyzed composite endpoints which were pre-specified from the DREAM trial of either two-point MACE on the left or three-point MACE on the right, MACE being defined as time to either cardiovascular death or heart attack or stroke. Two-point MACE is just time to heart attack or stroke. And what you see in both analyses is that overall patients showed a significant reduction in heart attacks or stroke. That was notable particularly in the setting of ischemia, particularly in the setting of inflammation, and most notably, the greatest risk reduction, 90% risk reduction of heart attacks or stroke, and almost 50% risk reduction in heart attack, stroke, or death in those patients who had both ischemia and inflammation. And that represents clearly the highest risk population and the population most likely to respond to a single treatment of ourselves. We can go to slide 33, please. So based on meetings with the FDA, we have a clear pathway towards accelerated approval for Revascor in adults with heart failure with low ejection fraction. I've highlighted the outcomes from the DREAM trial of a median follow-up of 30 months and beyond. We also have results from the second LVAD study, MPC number two, which demonstrated that at 12 months of follow-up, there was a significant increase in the proportion of LVAD patients with ischemic failure, heart failure, who were successfully weaned and then had a reduction in both hospitalizations and mortality. Based on the data from both of these trials, when we met with the FDA, we were informed that the totality of the trial results from these studies may support an accelerated approval pathway in ischemic heart failure patients with low ejection fraction. On that basis, we intend to meet with the FDA further, get clarification on our various components of it. One needs to go into a VLA filing to discuss clinical data, particularly the data that would be required for a confirmatory study in order to file for accelerated approval in ischemic patients with heart failure. Slide 34. talk in a lot more detail on additional areas of focus in cardiovascular disease, but as I've previously highlighted, we have also obtained data in children with congenital heart disease and the hyperplastic left heart syndrome, where we have both an ARMA, orphan drug designation, and a rare pediatric disease designation based on the data that's been accrued to date, and we will be having meetings with the FDA to discuss whether the controlled study can be used to support regulatory approval for this life-threatening condition using Revascor. And my final slide, if we can go now to slide 36, is where we see our key objectives for each of our programs over the coming six to 12 months. And really, we have three major programs and products and objectives. For Ioncil, which is developed for pediatric and adult inflammatory diseases, Rioncil will be available for use in steroid refractory acute GVHD at US hospitals this quarter. Studies will commence in both pediatric and adult label extension indications, as I've talked about, including adult GVHD and pediatric and adult inflammatory bowel disease. Revascor for heart failure in adults with low ejection fraction heart failure and in children with congenital heart disease are being prepared for meetings with the agency for accelerated approval filing. And finally, Rexlimistrocel for chronic low back pain. We have a phase three trial that we have and will continue to actively progress and invest in order to accelerate enrollment across multiple sites across the US. This has a 12 month primary endpoint of pain reduction, subsequent to which we could be in a position to file for approval. On that note, I think I'll stop. And thank you very much. I'd like to open it up to questions, please.

Thank you. If you wish to ask a question, please press star 1 on your telephone and wait for your name to be announced. If you wish to cancel a request, please press star 2. If you're on speakerphone, please pick up the handset to ask a question. We have the first question from the line of Edward Dentor from Piper Sandler.

Please go ahead. A lot of really exciting success going on here. I wanted to get a sense just with respect to the Riancel launch, and I appreciate the color on the pricing. How large is the sales force? And because you've sort of had the expanded access program in place, How many centers are already trained on using Rheonsil? So just trying to get a sense of how quickly this could really be launched in the U.S. And then I have a quick follow-up question.

Thank you. I'll just say that Rheonsil is already the standard of care in children with serotrophic acute GVHD. We have been providing it, as you mentioned, under extended access. Most physicians and most transplant centers are very familiar with the product and are waiting, literally waiting for this product to be commercially available so they can use it freely. I'll ask Marcelo Santoro to talk a little bit about his commercial team, which is already in place. You know, as I mentioned earlier, 80% of the transplants are performed across 45 sites. And Marcelo, maybe you can talk about your strategy to get across all those sites.

Please. Oh, that's great. So thank you very much, Silvio. Thank you for the question. It's a good one. So I think as Silvio mentioned, right, so we've built and are continuing to build a world-class sales force with transference experience. It's a small, appropriately sized sales force of nine in total key accounts managers along with the head of the sales force that will be focusing on this 45 key transplant centers. Obviously, we'll treat each transplant center as a key target, a key customer for us. That represents 80% of the potential. And, you know, onboarding has already started. It actually started before we even hired the sales force. We've been in discussions with a lot of the centers at the moment, so that by the time the product's available at the end of the month, we're ready to roll.

Yeah, and I would say the other point that's important is we've already had inquiries, inbound inquiries, from at least five to ten, for at least five to ten children who are very sick, who are waiting for product as we speak.

Wow, that's great. Well, it just shows you how important a product this really is and a life-saving product this is. My second question is going to do with respect to the chronic lower back pain ongoing trial, and again, this being another really important product. How far are you guys along in terms of enrollment And when do you anticipate actually reporting data from that phase three trial? Is your goal to launch that yourself in the U.S. or seek a partner?

Thanks. Well, I would say that if we're successful, this is a huge market opportunity. I mentioned earlier there's about 7 million people in the U.S., same type of number in EU5 who meet the criteria that patients are being enrolled at for this trial. And if successful, a single injectable, you know, will be a major immunomodulatory pain management therapeutic. You can imagine that the sales force required for targeting this patient population is substantial. In Europe, we already have a commercial partner in Grunthal, the largest number one company in the pain space. they have the expertise across the major jurisdictions, both in terms of regulatory and reimbursement, we would presumably enter into a similar partnership in the U.S. rather than invest our own in the distribution. You're going to see a ramp-up of enrollment in short order. invested substantially in sites. The number of centers that are coming on board that are on board now is approximately 15. We expect over the coming four weeks to get up to about 40. And what happens is that as the physicians have more and more experience in terms of screening, evaluating, turning through the backlog of patients, it becomes easier and you get that sort of hockey stick takeoff. And so, you know, we have something like 20 patients currently in screening, and that, on a weekly basis, that turns into an additional 15 to 20 new patients. So these numbers are rapidly increasing, so we have a target enrollment by toward the end of this year, but if we can compress it and bring it faster in, then we'll certainly try to do so.

That's really helpful. I know a lot of my friends are interested in a product like that. So keep up the good work. Thanks for answering the question. Thank you.

Thank you. We have the next question, a line of Michael Okovich from Maxim Group. Please go ahead.

Hey, guys. Thank you so much for taking my questions today, and congratulations on all the exciting progress. Thank you. I guess just to kick things off, quickly looking at the math, with a WAC price of $194,000 per injection, eight injections, that's about $1.5 million per course of treatment. Am I getting that right? And then just what sort of feedback have you gotten from payers on this pricing level?

Well, again, let me start by saying that based on health economic models, which reflects and net positive benefits of treatment with rioncela between $3.2 to $4.1 million, we have set the price per infusion at $194,000. The recommended dose for a child with stereofractory GVHD is twice weekly infusions of 2 million cells per kilogram for four weeks. So really, the price that we've set per infusion is based on the economic value of the treatment. products available this quarter for physicians to order. The question around how physicians see the product here is entirely based on the clinical efficacy and on the results delivered to date and on the long-term survival benefits given the high mortality rate of this disease and the absence of any other treatment other than Rionza for children under 12. So I think everybody's pretty keen to get hold of the product. But Marcelo, you might want to chime in. You were at Tandem. You led our clinical commercial interactions with all the payers and with the various clinicians.

So let's address both. So thank you, Silvio. So first of all, Tandem. You know, we saw Tandem as our scientific launch. We had multiple activities during the convention. I think we could see the enthusiasm for the products and you know, the level of questions asked in terms of availability, you know, when people can actually start prescribing the products. For us, it was very, very encouraging, and the feedback that we received from most centers was also very well, very important for us, right? So Tandem was a successful scientific launch. Now, in terms of engagement with payers, obviously, we've been engaging with all payers for quite some time now. I think there is an appreciation for the low number of kids that is affected by this condition, right? So it's 375 kids. And also, like Silvio mentioned, this price is fair when you consider the benefits that Ryan also provides to these kids. So overall, I think the discussions have been very positive. I think there is an appreciation for the burden of the disease, and there is also an appreciation for the long-term survival that Ryan also offers his patients. So we are very optimistic and we're looking forward to the next steps.

All right, thank you for that additional color. And then just one more from me. I wanted to see if you had any thoughts regarding December's FDA draft guidance on accelerated approvals, in particular, how that could pertain to the class four heart failure program. Is there an expectation that you'll need to start up the class two, three confirmatory ahead of that filing? And then just what are your thoughts on timing and next steps to get that confirmatory study going?

Yeah, I think this is the key, the right key question, and we expect to be meeting with the FDA in the coming month or so, two months or so, timeframe, to clarify exactly that. We've put into the so-called briefing board that will be reviewed by FDA the clinical trial design and the components of a confirmatory study that we would want to do post-accelerated approval. And so the details of that are really what we want to discuss with the FDA. We would expect that given the severity of the patients with advanced and end-stage heart failure and the mortality benefits that we've shown, that the FDA would want us to put the product on market as soon as possible. The arrangements or the discussions with the FDA around the startup and the agreement on the confirmatory trial design itself, I think, would be a gating event. I'll come back to the street as soon as we have more clarity on that.

All right. Thank you very much once again for taking my questions today.

Thank you. There are no further questions at this time. I'll now hand back to Dr. Itzku for closing comments.

Great. Look, I want to thank everybody on the line who's listened to our presentation today. We couldn't be more excited about how rapidly we're delivering this product to the children who need it. There's a lot of work that is going on behind the scenes at every level in the company from commercial to manufacturing to regulatory and the amount of effort that's going into doing this right and doing it in a way that we will save lives and we're going to work with our partners, the physicians, the institutions and the families to make sure that we deliver a top quality product that is going to save a lot of lives. Today was a summary of the activities in the last six months and I think you're going to hear a lot more from us in short order as we move forward to start putting out our product and making it available in the