Thank you and welcome to Mesoblast Operational Highlights and Financial Results for the period ended December 31, 2021. With me on the call today is Andrew Chaponnel, our Interim Chief Financial Officer, and I'm delighted to welcome Dr. Eric Rose, our new Chief Medical Officer. Eric has been on our board, as you all know, for the past 8 years and has decided to step up into the critical Chief Medical Officer position at such an important period in the company's development. Eric is a renowned physician with extensive commercialization experience and a proven track record in successfully navigating products through the FDA, in addition to his extensive network across our various stakeholders at the NIH and BARDA. As a world-renowned heart surgeon and scientist, Eric performed the first pediatric heart transplant in the world, and he subsequently served as chairman of Columbia University's Department of Surgery for over a decade. I'm delighted that Eric has agreed to join us in a senior management role. Perhaps, Eric, you'd like to just offer a couple of words to the listeners. Sure, sure. I'm very excited by the prospect of cell therapy becoming mainstream. I think this field is now where monoclonal antibodies were two or three decades ago, and they've obviously had important major impact on a lot of different illnesses. I think cell therapy, allogeneic cell therapy that Mesoblast has pioneered, is going to follow that trajectory over the next few years. It's very exciting to be here. Aside from that, Silviu and I have worked together on the board for eight years, and we were together at Columbia as well. It's personally a pleasure to work with him as well. It's nice to be here, Silviu. Oh, terrific, and welcome. It's very exciting to be working together. If we could go to the slide deck. Indeed. If we go straight to slide four in the slide deck. Slide four is a summary of the platform technology that underpins the various products that we're developing and the mechanism of action of the core technology. As we've previously highlighted, we're developing therapeutic products that derive from mesenchymal precursor and stromal cells. These cells have surface receptors that are able to be activated by a variety of inflammatory cytokines. When the cells find themselves in various tissues that are inflamed, they then release a number of well-characterized factors that are able to modulate multiple arms of the immune system in such a way that the inflammatory process comes under control. Therefore, it's very clear that the potential opportunity here to develop therapeutics for diseases of severe inflammation where existing therapies, small molecules, monoclonal antibodies, et cetera, in and of themselves are not sufficient to turn off the damaging inflammation. If we go to slide five, this is a snapshot of our late-stage clinical pipeline. As you can see, we have a number of indications being developed using our remestemcel-L platform and a number of indications using our rexlemestrocel-L platform. The remestemcel-L platform provides us with products that are the most advanced by systemic delivery, in particular, a product for acute graft-versus-host disease. I'll talk more about it, but it's completed phase III and is currently before the FDA. A product targeting acute respiratory distress syndrome, initially with COVID-19, has completed the first study, and we have plans to initiate the pivotal trial. Finally, we've recently presented very exciting results for remestemcel-L in local delivery to turn off the damaging inflammation in inflammatory bowel disease in patients who are otherwise unresponsive to a whole range of biologics. We'll talk more about that in a moment, too. Rexlemestrocel-L is our product that uses immunoselection to derive homogeneous cells targeting inflammatory low back pain and targeting inflammatory heart failure. Both of those indications have completed phase III trials, and we'll talk more about them during this presentation. If we can now go to our financial results, and I'll go to slide seven, and I will ask Andrew Chaponnel if he could take us through the next few slides, please, Andrew. Thank you, Silviu. Turning to slide 7, revenues in the quarter were $2.4 million. These revenues were primarily from TEMCELL royalties on sales of GVHD in Japan, which increased 7% on the comparative quarter last year. In November, we completed a refinancing of our senior secured debt facility with a new $90 million 5-year facility provided by funds managed by Oaktree Capital Management. Cash on hand at the end of the quarter was $95 million. We also have up to an additional $40 million available to be drawn down from existing financing facilities subject to certain milestones. We saw a 40% reduction in net operating cash usage. Our quarterly cash burn is now down to $18 million. Regulatory and manufacturing activities related to our planned BLA resubmission for RYONCIL in GVHD accounted for over half of this cash usage. Now turning to slide 8. Within R&D expenditure, we saw a 28% reduction of $4 million as we reduced spend on clinical trial activity. We continue our steady investment in manufacturing, including the production of RYONCIL inventory to support the long-term commercial supply of GVHD, COVID-19 ARDS, and IBD. To date, we have manufactured $28 million worth of RYONCIL inventory in anticipation of launch. This pre-launch inventory will be recognized on the balance sheet if we receive FDA approval. Within our finance cost, we recognized a $4.3 million increase due to a non-cash gain on revaluation of borrowing in the comparative quarter. Thank you, and now I'll hand the call back to Silviu for the remainder of the presentation. Thanks, Andrew. I'm going to provide an operational update on activities relating to RYONCIL and activities relating to remestemcel-L and rexlemestrocel-L, our two platform technologies. If we can go to slide 10, please. RYONCIL is being developed for the treatment of severe acute graft-versus-host disease. This is a disease that's driven by T cells. T cells within the foreign bone marrow in a patient who receives a bone marrow transplant as part of their curative process for an underlying cancer or other disease. Unfortunately, when foreign T cells recognize tissues as foreign, primarily the gut and the liver, they initiate a very severe process of cytokine release that ultimately ends up in organ destruction and is a potentially fatal disease. If we can go to slide 11, please. In particular, where there's a tremendous unmet need is in children with this very severe disease. More than 2,000 allogeneic bone marrow transplants are performed annually in children and adolescents across the U.S. Despite appropriate prophylaxis, approximately 50% develop this disease, acute GVHD. The first-line treatment is steroids, and response rate is no more than 50%. A substantial proportion of children who get bone marrow transplants will end up with steroid-refractory graft versus host disease. For children under 12, there are no approved treatments. For these children, who fail steroids with nothing available, the potential mortality approaches 90% when involving the gut and the liver. This is a real severe problem with a tremendous unmet need that we are addressing. Slide 12, please. This slide summarizes the results of three different studies that support our application to the FDA for approval of RYONCIL in children with severe steroid-refractory graft-versus-host disease. Notably, in each of these three studies, a randomized controlled study, an expanded access program, and the most recent open-label single-arm phase III trial. In each of these three studies, we see a very consistent day 28 overall response in yellow between 64%-69%. In each of these studies, we see a very consistent overall survival that approaches as high as 79% in children who received RYONCIL. In contrast, in control children who received maximal standard of care, response rates are as low as 38%-43%, and survival is as low as 54%-57%. Those differences are substantial between RYONCIL treated children and best available therapy. If we look at slide 13, on the left-hand side, you see a single center experience with 370 children and graft versus host disease. After 6 months, the steroid-refractory population, despite treatment with maximal available therapy, demonstrate as low a survival rate as 35%, 2 years out. In contrast, if you look at the figures on the right, which is a survival curve from our phase III trial data presented to the FDA, you can see that at 6 months we see a 69% overall survival. For those children who are alive at six months, the curve remains relatively flat beyond that, effectively a long-term cure. Now if we move to slide 14, the continued unmet need in graft-versus-host disease in both children and adults is in those patients who have the highest level of inflammation. As you can see in this slide, a validated biomarker of severe inflammation is called the MAP score, and a threshold of above 0.29 delineates those patients who are very unlikely to respond to any therapies and who are unlikely to have a reasonable response or survival. In fact, survival in these patients with a MAP score above 0.29, which accounts for about 50% of patients with severe GVHD, with steroid-refractory GVHD. In these patients, survival is as low as 10%. As you can see in slide number 15, data from an investigator-initiated study from investigators at Mount Sinai, published in Bone Marrow Transplantation just two months ago. In this particular study, 52 patients were studied, 27 of whom were treated with RYONCIL from our phase III trial, and 25 of whom received maximal standard of care, and who were matched for both disease severity and stratified by the biomarker MAP score. As you can see, the figure on the left is day 28 response. Figure on the right is 6-month survival outcome. As you can see, in the control, children treated with maximal standard of care, overall response was seen only in 1 out of 10 children with a MAP score above 0.29, and survival was only seen in that 1 child out of 10. 9 out of 10 died. In contrast, in those children matched with disease severity and matched for severe MAP score, 67% achieved treatment response at day 28, and 64% were alive at day 180. Both of these outcomes were significantly superior to those seen with children matched for disease severity, and treated with other available therapies. Let's move on to slide 16. Where are we with respect to regulatory commercial update for RYONCIL in this very, very bad disease? We met with FDA's OTAT in November. OTAT indicated that our approach to address the outstanding CMC items is reasonable, and asked us to understand how the immunomodulatory activity of the product can be measured appropriately using a potency assay that provides relevance to the clinical activity of the product using clinical outcomes. Well, I've just shown you some of the data that indicates that our product is highly effective in patients with the highest levels of inflammatory biomarkers, and we've now generated a substantial body of new data that we believe establish the relevance of the in vitro immunomodulatory activity of the cells to the in vivo clinical effect, including survival in children with this devastating disease. We expect to be providing these data to OTAT in short order and to address those outstanding items in the CMC that supports our Biologics License Application resubmission. We continue to be in a well-established process and have an ongoing dialogue with FDA CBER, and if the resubmission is accepted, we will be in a review process to hopefully proceed towards approval. Let's move on to other indications of RYONCIL, the first of which is acute respiratory syndrome due to COVID-19. Slide 18, please. COVID-19 is a respiratory virus with a high mortality rate due to severe inflammation in the lungs. The inflammatory syndrome is due to cytokine storm, and the ongoing mortality rates, despite the fact that there are vaccines and that there are antiviral drugs out there, indicate really the sheer numbers of patients who will continue to be exposed as this virus mutates and new variants continue to arise. Despite a reduction in overall severity, the numbers of patients who progress to needing ventilators, and once you're on a ventilator, continue to have a very high mortality rate, continue to be very high, making this an ongoing unmet need, both during the pandemic as well as when the disease becomes endemic. We intend to move forward with a pivotal trial for an emergency use authorization as per our discussions with the FDA. The FDA has asked us to provide them with a pivotal trial design, as well as refer the potency assay of the product to our acute GVHD biologics license application. That will, of course, all be in place prior to commencement of the trial. Just to show you a couple of the data points, slide number 20 is where we see a signal of efficacy in the 222-patient study, randomized controlled, that was performed in conjunction with the CTSN, an NIH sponsored organization across the U.S. You see on the left-hand panel, the survival benefit overall in patients who are under the age of 65 was about a 46% reduction in mortality. On the right-hand side, you see that in this younger population, we see a substantial improvement in respiratory function at each of the time points measured over a 30-day period. We believe that the dose regimen that was used in patients under the age of 65 was an appropriate dose for the degree of inflammation. Of course, it's well established now that as older patients get infected with the same virus, their inability to handle viral load results in a much higher order of inflammation. We expect that in older patients, we would need a more prolonged or a higher dose of cells, and that will be explored in subsequent studies. However, the signal seen in younger patients, we think is strong enough to justify moving to a pivotal trial to support an EUA in this patient population. In particular, in slide 20, you see on the left-hand side that in conjunction with dexamethasone, we see a tremendous synergy that resulted in an 87% reduction in mortality through 90 days, and that correlated with a similar synergistic effect on pulmonary function throughout the 30-day period of follow-up. That would be the patient regimen in a pivotal confirmatory study. I've just mentioned to you going to slide 21, that in fact we plan to move forward with an additional phase III trial in that target population, but together with our partners and clinical investigators, we expect to agree on the final protocol and put it in front of the FDA for their agreement to move forward. Let's move forward now to inflammatory bowel disease. Very exciting area that we provided an update just last week. Slide 23 please. The unmet medical need in inflammatory bowel disease continues to be very high. In fact, 30% of patients who are treated with biologics fail to respond, and even amongst those who do respond, there's loss of response of at least 10% per year. There is a very large patient population who requires different approaches to settle down the severe inflammation particularly in the colon in diseases such as Crohn's disease and ulcerative colitis, each of which represent at least 33,000-38,000 patients per year across the U.S. This is a large unmet medical need, and the mechanism of action that we believe ourselves can leverage is the same mechanism by which they're affected in the gut component of GVHD we think is at play as well in inflammatory bowel disease. Together with a world-leading investigator at Cleveland Clinic, Dr. Amy Lightner, who has initiated an investigator-initiated study. Up to 48 patients are being randomized in a controlled fashion in a 2-to-1 randomization to receive a single intervention with remestemcel-L injected under visualization into the colon directly or placebo in patients who have either ulcerative colitis or Crohn's disease refractory to medical intervention. That's defined as resistant to an antibody, anti-TNF, anti-integrin or other monoclonal antibody. The results of this study of the first 12-patient cohort were just presented at the Congress of European Crohn's and Colitis Organisation. If we go to slide 25, at a high level, the results showed that a single injection of remestemcel-L into the inflamed colon resulted in early response as early as 2 weeks and a high degree of remission by 6 weeks in all ulcerative colitis patients and in all Crohn's colitis patients. The measurement of disease remission is using the gold standard, which is direct visual visualization by endoscopy. Evidence of improvement in disease activity was also seen by measuring biomarker activity in this tool called fecal calprotectin, which was substantially reduced within a 3-month period. Importantly, no improvements were seen either in terms of endoscopy or biomarker activity in controls with ulcerative colitis or Crohn's disease. The fact that we see this level of improvement, both endoscopically, clinically, and by biomarkers that relates to similar inflammatory biomarkers that we've seen impacted in GVHD supports what I said earlier, that there's an underlying mechanism of action that is common to both steroid-refractory GVHD and biologic refractory inflammatory colitis that remestemcel-L can address. Let's move on now to the activities relating to rexlemestrocel-L, our second platform technology. Slide 27. The burden of illness for inflammatory back pain is substantial. In fact, 50% of opioid prescriptions in the U.S. are for patients with chronic low back pain, and so the opioid epidemic is in large part interrelated to the inflammatory back pain that we're attempting to target. Over 7 million patients are estimated to suffer from this particular disease across the U.S. Let's talk about the patient journey here, what is available to these patients. Slide 28. After conservative treatments have failed, and that includes non-steroidal drugs and physical therapy. Really, the only thing that's available is opioid analgesics, which are very weak in terms of pain relief, and their lack of efficacy really is a major reason for people continuing to increase the use of opioids and ultimately the high potential for accidental overdosing. Beyond that, there's really only interventional therapies including epidural injections, spinal cord stimulation, intrathecal pumps, or ultimately surgery. We think that our treatment approach, rexlemestrocel-L, targeting moderate to severe inflammatory back pain, will be used very early in this disease process and aims to avoid opioids and of course, well before any kind of intervention. Slide 29 is a schematic of why we think our cells are effective here. It's severe inflammation in the middle of the disc that is the driver of the disease process, and it's due to macrophages and T-cells, which we know our cells are able to turn off. Slide 30 is a schematic of the mechanism of action of our cells. It's a dual mechanism. On the one hand, it turns off the inflammatory cytokines produced by the inflammatory cells within the disc, and on the other hand, there are factors that the cells make that directly are analgesic and induce long-term pain reduction. Slide 31 is a summary of the data to date, but maybe I can show you schematically the figures across all patients in a phase III trial that completed testing of cells in combination with hyaluronic acid, and is the basis of what we have shown the FDA. Slide 32 shows that overall, over a 36-month period, in red, the combination of cells plus hyaluronic acid gives us a significant reduction in pain at 12 months, 24 months, relative to, in green, placebo-treated patients. In blue are the cells without hyaluronic acid, and they also show substantial pain reduction, but the combination of the two appears to give us the greatest effect, and it's synergistic. That endpoint of pain achieved across the entire study, we think is the basis of an approvable endpoint for the FDA. Importantly, slide 33 shows that patients most likely to respond are those who are treated within the first 5-6 years. That's patients below the median timeframe with pain. Here you see that the reduction in pain at 12 months and at 24 months and 36 months is highly significant at levels of p less than 0.001 compared to the saline-treated controls. It is this patient population that we think will allow us to have the greatest likelihood of both success in the confirmatory study, but as well as provide a therapeutic that has the greatest likelihood to make a difference as soon as possible in these patients with severe inflammatory back pain. Now, the other key point, slide 34, is that despite the fact that both physicians and patients were told not to change their medication during the phase III trial, as many as 25%-27% of cell-treated patients through 36 months came off opioids. These are patients who were on opioids at baseline, and about 40% of patients affected in this trial were on opioids. In contrast, in green, only about 7% of control patients came off opioids in the same timeframe. This difference was significant, and it demonstrates the fact that the pain reduction seen, which is so durable with a single intervention of our cells, allows patients who were otherwise using opioids to potentially come off these opioid drugs. It suggests that this may be an opioid-sparing approach to this disease. At slide 35 is a summary of our interactions with the agency and our plans moving forward. We met with the FDA in December. They had reviewed the data in great detail, and the FDA agreed with our proposal for pain reduction at 12 months to serve as the primary endpoint for potential approval of this product and for the endpoint in a confirmatory study. A key secondary endpoint would be to demonstrate also improvement in function and to demonstrate that the reduction in pain may result in reduction in opioid usage. The planned upcoming U.S. trial will include at least 20% of subjects in Europe to support a concomitant submission to both FDA and EMA and to support our relationship with our partner in Europe, Grünenthal. Finally, let's move to our heart failure program, slide 37. The mechanism of action by which we believe our cells impact outcomes in patients with low ejection fraction heart failure is by attacking the inflammatory process that is within the myocardium in these advanced patients. It's the inflammatory cytokines within the myocardium shown to be there activate our cells. Our cells then release anti-inflammatory factors that turn off the inciting inflammation and at the same time also induce a microvascular network, which we think is critical to impacting the hypoxic nature of the myocardium. If we go to slide 38. In the completed randomized phase III trial of 537 treated patients, in this slide you see that a composite of time to first event using cardiovascular death or non-fatal heart attack or non-fatal stroke showed a significant benefit in the cell-treated patients over a mean 3-year follow-up, that achieved significance of P value of 0.02. There was a 33% overall reduction in time to first event of a 3-point MACE. This was a post-hoc analysis. When you look at slide 39, those patients at greatest risk for the severe outcome, and those patients in an analysis of risk adjustment are patients with either myocardial ischemia or diabetes. In that group of patients, which accounted for about 70% of all enrolled patients in the trial, we see that on the left-hand side, rexlemestrocel-L resulted in a 37% risk reduction in the 3-point MACE over a mean 3-year period follow-up. Even more dramatically is the figure on the right, where in fact, in patients who have evidence of circulating inflammation as measured by a simple measurement CRP, in that group of patients with ischemia or diabetes, the treatment effect was 54% reduction in the major events of cardiac death, heart attacks or strokes. If we go to slide 40, this table is a summary of major trials evaluating SGLT2 inhibitors or GLP-1 agonists in patients with diabetes, where this exact three-point MACE endpoint, myocardial death, so cardiovascular death, myocardial infarct or stroke, was used as the endpoint that the FDA has used to approve GLP-1 agonists on. You can see in the top three rows, treatment benefits of the order of 6%-13%. In contrast, if you look at the dark blue at the bottom, as I just mentioned to you, rexlemestrocel-L in similar patient populations result in 37%-54% reduction on top of existing maximal standard care. If we go to slide 41, really we are right now submitting our data to the FDA of our new analyses that have evaluated the outcomes in our phase III trial in those patients at greatest risk of adverse events, MACE events. That's in line with the request by the FDA to identify those patients at greatest risk and to see what the treatment effect of our cells in that patient population. That's exactly what we've done, and we expect to have discussions with the agency on the potential pathway towards approval. On that note, I think I'll leave it there, and operator, I'd like to open it up to questions. Thank you very much. Thank you. If you wish to ask a question, please press star one on your telephone and wait for your name to be announced. If you wish to cancel your request, please press the hash or pound key. If you are using a speaker, please pick up the handset to ask your question. Your first question comes from Louise Chen from Cantor. Your line is open. Hi. Good afternoon, everyone. This is Harvey on the line. Thank you for taking our questions. Our first question is, you have guided previously additional phase III study initiations in chronic back pain and COVID-19 ARDS. Can you provide more color on how these studies would impact OpEx for 2022 and onwards? Secondly, based on your discussions with the FDA, what kind of results from these studies will be considered as successful? Thank you so much. Sure. I think with respect to the COVID-ARDS program, we will expect to be providing the market with granularity. It should not have any impact on Mesoblast's OpEx in the short term, and we expect to be working with our partners. We've previously worked with NIH-sponsored investigators, and I think we will provide much more granularity on that in the short term. This is a major unmet need. It continues to be an unmet need, and we think that the data that we've generated, the data that would support potentially an EUA, and that's certainly the guidance that we've received from the FDA, is that a single trial would potentially, if reproducing the data already shown in the previous study in collaboration with the NIH investigators, would support an EUA if mortality reduction is evident. With respect to our Low Back Pain program, I've just shown you the data that showed a significant and a durable reduction in pain as early as 12 months and for as long as at least 3 years from a single intervention. That endpoint, the FDA is in agreement, is an acceptable endpoint for approval, and we're in the process of formulating it, the powering for the appropriate clinical trial, and we expect to be working with strategic partners on this program. Again, we don't have any plans that this would impact our OpEx in the short term. Okay. Got it. Thank you so much. Super helpful. Thank you. Your next question comes from Jason Kolbert. Your line is open. Hi, guys. Great rundown. Really appreciate the comprehensive review. Couple of quick questions. With remestemcel-L coming up on GVHD, can you just go through maybe as much granularity as you can on the timing of the OTAT resubmission and when you think that could commercialize? And also, what lessons from a commercialization point of view have you learned given the launch in Japan? And then the other part to that is once you're commercialized in GVHD, does that open up a fast pathway for you in IBD, UC, Crohn's? Because, you know, obviously the market size there is pretty substantial. I have a follow-up where we can switch gears into degenerative disc disease. Great. Thank you, Justin. Those are very insightful questions. I think your first question was how confident or how are we approaching the resubmission and where do we think our timelines are at? I would say that we've worked very collaboratively with the FDA to understand precisely what they want us to provide them. It was unfortunate that we received the CRL a year ago. We had a 9-to-1 vote by the advisory panel in support of approval, and I guess that demonstrates the strength of the clinical data. I think what the FDA said to us really is that we need to have a better handle on the mechanism of action by which the cells generated the tremendous clinical results. Part of that is having a potency assay in place that reflects the mechanism of action and that demonstrates, as we move forward, that every product that we make that goes to a child with a severe disease, we can predictably say, meets a potency that reflects an activity level that will give us similar results that we've achieved in phase III. I think that's exactly where we are. We've understood now far better than a year ago the mechanism by which the cells provide their activity, and I showed you some of the data from the investigator-initiated study at Mount Sinai, demonstrating that our product is particularly effective in patients with the greatest levels of inflammation, which goes to the heart of how the cells become activated and how they are able to target those children with high levels of inflammation and turn that inflammation off. Our potency assays are able to show exactly that, how the cell which demonstrates activity in vitro demonstrates activity in vivo, both in terms of biomarker activity as well as survival outcomes. That's precisely, I think, what the FDA wanted us to generate as data, and we're putting that all together in a very detailed package as part of the resubmission. Now, once resubmitted, it's a process. That process includes the requirement for inspection of the manufacturing site. All of that needs to be performed. Our manufacturing site in Singapore was not inspected during the first review process, so that still remains as an outstanding item and will probably drive the timelines for approval. Statutorily wise, the maximum time that resubmission can result in approval is six months. We are working towards an approval in the second half of this year and putting our commercial team in place to be prepared for a successful launch. To your second question, in fact, what lessons have we learned from Japan? As you can see in today's financials, we continue to see growth quarter-on-quarter of our royalties coming from Japan, which obviously implies that sales of the product in Japan continue to grow and they have not plateaued. We're now on track to generate about $10 million a year just from our royalties from this product in Japan and still growing. I think, you know, that gives us very, very good line of sight of the way this product would perform in the U.S. in terms of penetration. We think that within 3 years or so, as we've seen in Japan, the penetration rate will be at least 40% of the addressable market. That's what we're targeting and of course, in parallel, we would post-approval plan to expand the indication into the adult population with severe steroid-refractory GVHD. As I've shown you, those biomarkers give us a very clear understanding of those adults as well who are non-responding to existing therapy. That would include, of course, the new biologic Jakafi approved for this indication. We have a life cycle plan in place beyond pediatric to expand to the adult GVHD market in the US. Then beyond that, of course, we've just had very exciting data in inflammatory bowel disease. The unmet need here, of course, is the refractory nature of the patient population means that these are at high risk of progressing to needing surgery, and a colectomy in a young patient population is a terrible outcome. We will collect the data from Dr. Lightner's study in Cleveland and be in a position to go back to the FDA and talk about what a pivotal study design would look like. Eric, you might wanna add your perspective as a surgeon here in terms of how you see the inflammatory bowel disease population refractory to biologics and the risk of surgery. No question that a cell therapy that were as effective would obviate a good deal of the resective surgery, which is basically destructive, for these patients right now. It can be administered endoscopically. We're very excited about this. Dr. Rose, that was my question. Since you're endoscopically- Yeah. You're delivering cells to the localized site of the inflammation, I guess that you know, as somebody who's never guided an endoscope, I don't know, is that pretty easy to do? Is that kind of typical and within the treatment paradigm? I think by a skilled endoscopist, yes. I mean, resections are done endoscopically all the time for surface lesions. For surface lesions for both UC and Crohn's, it's eminently feasible, which our investigators have shown with their trial. So far, it's And- Proven quite safe too. Thank you. My last question, which really was for you, Dr. Rose. I was talking a little bit about degenerative disc disease and the commercial potential in that. I know in one of the conversations you and I had in the past, you seemed very excited about the potential in degenerative disc disease. Could you kind of step back and talk about what you see as the potential, you know, changing gears here to rexlemestrocel-L and the DDD indication, which looks like it will be driving ahead of CHF? Yeah. I think the results that we've had now in two major clinical trials, both of which showed significant reduction in pain across the entire patient cohort. Pain reduction seems quite predictable and reliable. The magnitude of that reduction is set at a threshold that we've looked at at 50% or greater pain reduction as opposed to the 30% reduction in pain that FDA has treated as approvable, and which drugs like antidepressants and opioids, that standard is the standard to which they've been held. The durability of our response to a single injection is now out to three years. The results are measurable at six months, a year, two years as well. The safety issue that FDA had when we first started our phase III, and the reason that they insisted on a composite endpoint of pain and function improvement turned out to not be a problem. Safety with injection directly into the disc is just not a problem. For that reason, actually, they wanted a two-year endpoint with pain and function. They've agreed now that the confirmatory trial that we need to do is only 12 months of duration. The sole primary endpoint is pain reduction. Function is a secondary key secondary, but not part of the primaries. Based on our past trial experience, we think it's eminently achievable. The size of the- Dr. Rose? potential commercial market. Yes. No, I just. Can you hear me? Thank you. That really answers. Yes, I can. That really answers my question. Thank you. I have to say welcome aboard. Great to at least an operational role. Given our experience Yeah I know we worked together when you were at SIGA, and to have a former CEO, a board member, and now as a Chief Medical Officer, I think it just brings a lot of horsepower to Mesoblast at a time when it's very, you know, at that very critical juncture clinically. You know, I really appreciate you being there. Thank you. Thank you. Appreciate it, J.C. Your next question comes from Kennen MacKay from RBC Capital Markets. Your line is open. Yeah. Hi, good morning. It's Jackie here for Kennen. Thanks for the questions. Just wanna make sure I heard it right, that you're going to submit the BLA, which itself should include everything and obviously the new data you have generated so far, rather than submit the new data first to the FDA, wait the feedback, and then file the BLA. By having ongoing dialogue with the agency, we're in a position to have our data evaluated as part of a resubmission. Got it. Super helpful. You know, another question maybe on the investigator-sponsored trial for UC and Crohn's. Very interesting early data there. I think now you've got, like, only 12 patients' worth of data, but going forward, you know, ultimately, what do you want to see there in order to, you know, bring the programs in-house and maybe look for a partner? Because, you know, those two indications are gonna require super large trial, and, you know, maybe get a phase II running. What do you want to see there in order to bring the programs in-house? That's, you know, maybe the first portion of the question. The second portion is that, you know, when do you think we can see some data on the histological or mucosal healings, if those are being measured, in that trial as well? Let me address several of those questions. First of all, remember that these patients are effectively no-option patients. They've already cycled through biologics and have failed and continue to have very active disease. From that point of view, the control arm here is gonna do really badly, right? I don't think- That the size of a pivotal trial will be anywhere near the size of trial that the biologics are targeting. Remember that the first line biologics have a very high responder rate within the control population, so they need large numbers. We expect very few responders, a very low response rate in the controls. As you can see in the first 12 patients, the control patients had no response and in fact got worse during the three-month period of follow-up. I think in terms of a design of a study going forward, I think the numbers are gonna be much smaller than you might anticipate. Secondly, I think whilst this study was set up to evaluate for up to 48 patients, it was not powered as such. The objective for us was to see whether we have a signal of efficacy and safety by this local delivery method in both a sufficient number of ulcerative colitis patients and Crohn's patients to have a view as to how to potentially structure a randomized controlled study that would be an in-house study with or without partners. I think the objective of that is, you know, we're a good way through this, and whether we stop, you know, after we've had all patients or whether we stop somewhere short of the 48 patients, that's, I think, is still up to the data sets to tell us, right? The science will tell us that. I think we're very excited by the data we've seen already. You know, I think this is an opportunity to address an unmet need that otherwise is not addressable today. We're very excited about this. Eric- Got it. Maybe, I don't know if you wanted to add anything to my answer, Eric. I don't think so. The endoscopic appearance as an endpoint also is something that's achievable with relatively short periods of observation to get to an endpoint that I think the FDA would consider it actionable. Yeah. It's a very exciting set of observations. Yeah. I think that's a very good point about the endpoint. The endoscopic endpoint is an acceptable endpoint for approval of a therapeutic. Your question around histologic data, we will generate histologic data as well, of course. But the validated endpoint is endoscopic as well as, of course, clinical benefit. Yep. Got it. Thanks again for all the color. Thank you. Your next question comes from Tanushree Jain from Petra Capital. Your line is open. Hi, Silvio. Thanks for taking my questions. Just a quick one. Actually, two quick ones from me. In terms of the remestemcel-L life cycle, you've got, you know, the adult GVHD application, you've got COVID-ARDS, and you've got the IBD application. Would you be able to talk about your priority ordering of those applications? Then secondly, just really potency assays, especially around the MAGIC algorithm probability biomarker score, how do you think that kind of translates to COVID-ARDS or the IBD indication? Yeah. Very interesting. Very good questions, actually. With respect to prioritization, number one priority by far is get the product approved for pediatric GVHD, where the unmet need is complete. There is nothing approved for children under 12. We are focused, laser-focused on getting that approval. We of course intend to then demonstrate a broadening of the indication to the adult population with severe disease, and that would be part of our discussions with the agency as we seek approval for children. Those two are part and parcel of the program. With respect to COVID-ARDS, it continues to be a large unmet need, and we're working with the NIH, as well as the FDA, to put in place a study that meets through an EUA, a continued unmet need. That's an important study. That's important for the company, but it's even more important for the ongoing pandemic. Inflammatory bowel disease, as you just heard, is a tremendous opportunity, again, targeting a patient population with no options. Here, the mechanism of action very much overlaps between the predominant GI disease in GVHD and the GI disease in inflammatory colitis. Mechanisms are probably very similar, and so the biomarkers that we're focusing on, that I highlighted earlier, and that have been published, you know, in Bone Marrow Transplantation for GVHD, are gonna be biomarkers that are very useful in monitoring disease activity and potential remission in the colitis patients. Right. Okay. shifting gears to the DREAM trial, this might be, you know, more general, but with the trial where it's just one injection, you're obviously depending on, you know, patients taking in during the trial, you know, a lot of other medication like we saw, you know, with opioids, et cetera. I guess when you've got more, you know, on a large number of sites involved. How are you gonna kind of control for all of these variability between patients and noise to kind of make sure that you're not losing data? Well, you've seen the successful 400-patient trial that was already accomplished in the U.S. It was performed across 40 sites. It took into account all alternatives that are out there. 40% of the patients were on opioids at baseline. Despite that, you saw the very strong statistical numbers around reduction in pain at each of 12, 24 and beyond months. We think that the trial design and the potency of the product is such that it will override any confounding effects of other medications. Frankly, other medications just don't have much benefit in this patient population. As Eric said, I mean, you know, a large proportion of patients achieve more than 60%, if not complete remission in pain reduction in our patient population. The reduction in pain score of the order of about 35 points, which is a more than 50% reduction from baseline, compares to about 15 points that the average opioid achieves. We're talking about apples and oranges in terms of the degree of pain reduction, and I think that is accounted for in the trial design and the powering of the study. In your inclusion criteria, you're not going to restrict what medications the patient's allowed? No. Nor did we in the first study. In other words, we expect that the second study would confirm the outcomes that we've just seen. Yeah. Okay. Just lastly, on the cardiovascular application, can you just walk through what the next steps are, from here and the timing to progress that towards, you know, a new trial? Well, I think as I've said, we're in the process of providing the revised analyses as guided by the FDA. The FDA asked us to do these analyses on those patients at highest risk for adverse outcomes, and those data will be provided in a very formal submission to the agency. Again, Eric might wanna comment on the real world disease and MACE outcomes that we're targeting. Eric? Sure. The MACE endpoint actually was the primary endpoint for the phase II that we did. That was a smaller trial. It was originally the primary outcome for the more recent trial, but was changed to the joint frailty model by our partner, when we were partnered for this and stayed as the primary endpoint. 3-point MACE in the entire cohort proved to be a significant benefit, which was a truly remarkable outcome for a single injection type of therapy. Unquestionably, the data are the data. The FDA has asked us to pick a patient population that would maximize the public health benefit of cells as an intervention, which we think we're drilling down to. As Silviu mentioned, the diabetic and the ischemic diabetics, particularly those with high CRPs, seem to be a very large patient population that could accrue significant benefit. I think that's the direction in which we're headed. Great. Thank you. Thank you, Eric. I think we've got, one more. Sure. One question before we have to close out the presentation. Your last question comes from Jason McCarthy from Maxim Group. Your line is open. Hey, Silviu. Thanks for taking the question. This is Michael Okunewitch on the line for Jason. I'd like to see if you could just provide a bit more color and some clarification on what we might expect to see from the heart failure phase III in terms of endpoints and trial size. Would we expect it to be similar to the phase III or given the magnitude of the result in this population and the fact you hit a P-value in a relatively small set, could it be smaller? Is there the possibility, given the really meaningful reductions that you saw in mortality, that this study could be powered for that even as a secondary endpoint, given that this has been such a difficult endpoint to hit in heart failure? Yeah. Look, we were really quite staggered by the effect size, particularly in this patient population. 70% of the study were ischemics and/or ischemic diabetics. When we did the analysis that the FDA asked us to do, which is identify the groups in a hierarchical fashion at highest risk for this outcome, the group that showed the highest risk amongst all the pre-specified groups was this group, ischemic diabetic. They had an 87% greater risk of a MACE event than did any of the other groups in the controls. When we looked at where the treatment benefit was greatest, it was staggeringly in this patient population. Precisely where the unmet need is where the cells have the greatest benefit. Marrying those two things up is what the FDA wanted us to do, rather than look at things like subjective subsets like class two disease, class three disease, et cetera. This takes into account all of the all the subsets and concludes that the group at highest risk is precisely the group where these cells have most effect. Look, rather than preempt the discussions that we're now having with the agency, I think all I can say is that we're in the process of a formal submission of our documents, and we'll update the market in short order. Thank you very much. I think that Thank you. Appreciate the question. Operator, that may. It's the last question, so I think I see that we're just over our time. That brings us to the end of today's call. I'll now hand back to Dr. Itescu for closing remarks. Well, again, thank you, everybody, for attending our conference call on such a tumultuous day. I think we're very pleased by our operational deliverables in the last quarter, and our financials are robust, and we look forward to updating the rest of the market in due course on some very important near-term deliverables.