Mesoblast Limited

Good afternoon and good morning to everybody on the call to our operational highlights and financial results for the quarter ended March 31, 2023. If we could go to slide four, please. On the call with me today is our Chief Medical Officer, Dr. Eric Rose, and our Interim Chief Financial Officer, Andrew Schapanel. Slide four shows a snapshot of the investment highlights. We have a novel allogeneic cell therapy platform with two lead candidates, both being platforms for multiple product and indications. Remy Stem Cell, Rex Lemy Stroh Cell, each have got their own specific indications. And I'll be talking in detail in this presentation on both of those platforms. Financially, we have substantial cash on hand. And there'll be a detailed presentation by Andrew Schepanel on our finances for the quarter. Next slide, please. Slide five. This slide is a summary of our late stage clinical pipeline based on our zancomal stromal cell platforms. As you can see, remy stem cell for pediatric surgery GVHD graft as a host disease is the most advanced. And it's currently before the FDA. with a review of the BLA with a PDUFA goal date of August 2, 2023. The manufacturing inspection has been conducted, and I'll talk more about that shortly. Remy Stem Cell is also being developed for adult steroid refractory graft-as-a-host disease, acute respiratory distress syndrome, and inflammatory bowel disease. Rex Remy Stro Cell, our second-generation stromal cell platform, is being developed for chronic inflammatory low back pain, discogenic low back pain, and recurrent stroke is also being developed for inflammatory heart failure. And for both these indications, the FDA has granted regenerative medicine advanced therapy designations. We can now go to the next slide. And I'll hand over to Andrew to talk about our financial results, please.

Thanks, Sylvie. If you could please turn to the financial highlights for the third quarter of FY 2023 on slide 7. For the quarter, revenue from royalties on sales of Temso in Japan by our licensee were $1.8 million. On a constant currency basis, royalties grew 4% in the quarter to $2 million. For the 12 months, we recognised $7. net catch usage for operating activity in the third quarter was $16.2 million. This represented a 4% increase in the third quarter of FY22 and a 34% reduction of $8.3 million in the third quarter of FY21. we successfully completed a global private placement of $40 million for existing major US, UK and Australian shareholders. As of March 31, 2023, cash on hand was $48.8 million. We have proformed cash of $88.8 million after a general proceeds of $40 million raised in the April private placements. We also have up to an additional $40 million available from debt from existing financial facilities subject to achieving certain milestones. Turning to slide eight, you'll see we are reporting an improved loss before tax for the quarter. Revenue is predominantly from royalties on sale themselves in Japan. And despite an increase in underlying sales of 4% in the third quarter of FY 2023 compared to the third quarter of FY 2022, reported revenue decreased slightly given that Japanese yen has depreciated against the US dollar. Our R&D expenditure was reduced by 14% for the quarter. Our R&D spend in the quarter was primarily to support the Remy Stem Cell L BLA resubmission, and preparation for pivotal studies of Rex-Limistrocell. We continued our investment in manufacturing activities to support the potential launch of Remy Stem Cell for the treatment of steroid refractory acute GVHD. On FDA approval, $31 million of Remy Stem Cell relaunch inventory will be recognized on the balance sheet. Finance costs for the quarter include $3.8 million of non-cash expenditure comprising accruing interest and borrowing costs. Now, I'll hand the call back to Phil Buse at the end of the presentation.

Thanks, Andrew. Slide 10, please. This slide summarizes the... mechanistic process that is acute graft versus host disease, a fatal complication of an allogeneic bone marrow transplant. Essentially, following chemotherapy, there is extensive tissue damage in the patient who subsequently receives an unrelated donor bone marrow transplant. The transplant then attacks the body through defined pathways that are driven by T-cells, T-cells are activated. They're the orchestrator of multiple cytokines produced by other cell types, resulting in a cytokine storm, which is destructive for the gut, the liver, the skin, and other organs. And in those patients who have the most severe organ disease, mortality approaches 90%. If we can go to slide 11, please. So the market opportunity for mesoblast is large. More than 30,000 allogeneic bone marrow transplants are performed globally. Of these, about 20% are pediatric. We are targeting the most severe cases, initially targeting pediatric GVHD and intend to target the more severe adult cases as well. Next slide, please. Slide 12 summarizes the survival data across three different studies. involving more than 300 children treated with Remy stem cell. These studies were designed to demonstrate whether Remy stem cell provided an early survival benefit. The three studies outlined here include a randomized controlled subset of 27 children within an earlier study called Protocol 280. The second study was a pivotal phase three trial called study 001. And the third study was an expanded access protocol of 241 children who received Rimi Stem Cell having failed other available therapies. What you can see here is that in each of the three studies, there was substantial early survival benefit from 66% in the sickest children where Rimi Stem Cell was used as salvage therapy to 79% in the randomized controlled subgroup study. And the comparators for each of these outcomes showed substantially lower survival outcomes at day 100, from 54% to 57%. In the EAP275 study, a subset analysis comparing outcomes in grade D disease, the most severe form of the disease, against survival outcomes in the database at the International Bone Marrow Transplant Registry, showed a significant survival benefit of 51% in those who received remy stem cell versus just 31% in those who received best available therapy. So across all of these studies, there's evidence of an early day 100 survival benefit using remy stem cell. If we go to the next slide, in newer data that's now before the FDA, analysis of survival through day 180, six months, in the pivotal phase three trial in patients with the highest risk for mortality, those with biomarkers, the MAP biomarker scores above 0.29, demonstrated a significant survival benefit compared to a propensity-matched control cohort, the so-called MAGIC cohort. And you can see that in the control children treated with best available therapy, only 10% were alive beyond three months compared to 67% alive in those who received remy stem cell. Next slide, please. Slide 14. So what is the status of our BLA for remy stem cell in pediatric patients with serotrophic acute GVHD? The new data under review by the FDA are outlined on this slide. The BLA was resubmitted in January 30th. The BLA file was considered by the FDA to be a complete response, was accepted for review, and we were given a PDUFA goal date of August 2, 2023. The new data under review shows durable long-term survival of patients in the Phase III trial, increased survival in high-risk patients compared with propensity-matched controls and a positive correlation between in vitro potency assay and survival. Additional data that the FDA is reviewing shows that the validated potency assay has low variability and can adequately demonstrate manufacturing consistency and reproducibility. Next slide, please. In addition, today we announced that the manufacturing inspection of the remy stem cell process has been conducted by the FDA. The FDA inspection did not result in the issuance of any form 483. Form 483 is always provided at the conclusion of an inspection if investigators have observed any conditions that in their judgment may constitute violations of the FDA cosmetic act and related acts. So we were very pleased. that no issuance of a Form 483 was provided. The Establishment Inspection Report, or the EIR, is expected to be issued by the FDA in the coming weeks, which will provide a detailed summary and a final assessment of the inspection. Next slide, please. Slide 16. Liseblast provided new results from a four-year observational survival study performed by the Center for International Blood and Bone Marrow Transplant Research, CIBMTR, on 51 valuable patients with acute GVHD who were enrolled in our Phase III clinical trial of remy stem cell. These data provide a cornerstone of our BLA resubmission. Overall survival in the remy stem cell cohort was 63% in one year, 51% in two years, and remained roughly at that level through at least four years and beyond. In other words, approximately 50% of children with this very fatal disease, of whom almost 90% were grade CD disease, are alive, not just at two years, but for as long as the follow-up has allowed us to evaluate the outcomes. These data provide assurance that the short-term responses and early survival through 180 days previously shown to the FDA in the BLA submitted previously are unlikely to have arisen by chance. These long-term survival outcomes really are a cornerstone of our BLA resubmission. Next slide, slide 17. This slide shows a comparison between two-year outcomes on the right with remy stem cell from our phase three trial, 51% survival, against the largest pediatric cohort study published to date which is the Macmillan study on the left from the University of Minnesota showing just 35% survival in children with steroid refractory disease. And it's important to point out that in the Macmillan study on the left, children treated with best available therapy, only 22% had grade 3, 4 disease, whereas 89% of our study on the right had grade CD disease, the same level of So very different patient populations, much more severe in the Rumi stem cell treatment, and yet survival through 24 months substantially improved. We can go to the next slide, please, slide 18. This summarizes, again, the long-term survival data in the column with dark blue over four years against four studies that have been recently published between 2020 and 2022. The McMillan study I've already described. But in addition, there are four other studies that relate to adults with steroid refractory acute graft as a host disease. And whilst they all have lower levels of severity in terms of patients with grade 3, 4 disease in comparison to our phase 3 trial, the Relative two-year survival in each of these studies is of the order of between 25% and 38%, comparing to 51% of two-year outcomes in our Phase III trial. So we believe that the long-term survival that we're seeing in GVHD001 treated patients with Remy stem cell provides a durable long-term outcome that is not comparable with any of the recently proven performed studies, including those with ruxolitinib. Next slide, please. Slide 19. And moving from new clinical data to new data around potency, which is part of the BLA submission, it's important to note that the primary mechanism by which GVHD progresses is due to alloreactive T cell activation, T cell proliferation, and orchestrations I mentioned earlier of inflammatory cytokine production by these activated T cells. An in vitro assay measuring inhibition of T cell activation was established during development of remy stem cell prior to the phase three trial as a potential measure of product potency. This assay was used to measure the ability of individual remy stem cell lots to inhibit T cell activation prior to their use in both the expanded access protocol 275 and prior to the phase three trial GVHD001. We therefore evaluated and established correlations between survival outcomes in these two pediatric studies with potency of the lots that the children received as measured by inhibition of T cell activation. And these correlative analyses have been presented to the FDA. Slide 20, next slide is representation of some of these potency data, which were presented earlier this year at the tandem meetings of the bone marrow transplant society. Firstly, as can be seen in the capitalized line on the right, there was an association between higher levels of inhibition of T cell activation by product loss received and day 180 survival, such that those patients who got product above the median had 85% survival versus those who got product below the median. This establishes that the greater the potency of products received in the phase three, the greater the survival outcome. In further subgroup analyses, looking at patients by higher risk severity, including the Minnesota high-risk category, the MAGIC algorithm score above 0.29, and grade D disease, in all of these subgroup analyses, product lots with potency above the median were associated with higher survival than product lots with potency below the median. I think it's important, however, to also note that particularly with grade D disease, even products with lower levels of potency gave survival outcomes of 50%, which is substantially higher than the expected survival for grade D disease in the CIBMTR registry using best available therapy where that survival outcome is only 30%. So even a lower potency product has substantially higher survival than best available therapy. And of course, the relationship between potency and survival is now established through the phase three trial. If we go to slide 21, the next slide, we then reevaluated survival outcomes in the EAP study, one single study, by the presence of our newly established improved manufacturing product that is now called Rioncil, with the product produced prior to 2008 that was called Prochymal. That product had a lower potency as measured by our current potency assay than the new product, Rioncil. So what you see here on this slide, on the left-hand side, is survival through 100 days in those children who had failed all other therapies in our EAP program by prokymal versus rionsal treatment. And as you can see, a significantly higher survival, 74%, was achieved with rionsal than was achieved with prokymal, 56%. Even more important, if you can look on the figure on the right, this survival benefit with the improved manufactured product Rionsel is even more significant in those patients at highest risk of mortality, those with grade D disease. In 106 patients with grade D disease, Rionsel achieved a 72% survival, whereas Prochymal, the lower potency product, achieved only 44% survival. So these studies, these analyses within a single protocol, the expanded access protocol, is able to establish not only that we have a potency assay that predicts survival at the level mechanistically of T cell activation, the primary mechanism of action, the GVHD, but it is able to also delineate higher potency products from lower potency products and their relationship to improve survival. Next slide, please. Slide 22. So those having... summarize those data, the new data that form part of the BLA. Let's talk now about our go-to-market strategy with the assumption, hopefully, that a PDUFA after August gives us a positive outcome. The pre-launch activities that are active and ongoing are engagement of the highest transplant volume centers with experience using Rionsel. Non-promotional activities include profiling of the centre's education on disease awareness, unmet needs and support for payer engagement. We are currently hiring select positions to build out a small commercial team. The key activities of this team are market access to initiate payer outreach, medical, providing education to payers, corporate leadership initiating engagement with the top 15 centres and regional sales directors leading centre profiling. Importantly, manufacturing preparation has been ongoing throughout, with 31 million of Remy Stem Cell pre-launch inventory in hand. Slide 23. The post-approval launch activities are intended to be a staged approach, initially targeting the highest transplant volume centers. Those centers are those not only with highest volume, but also with experience with our product. plan is to build out an efficient targeted sales force with understanding the 15 highest volume transplant centers account for about 50% of all patients. The key activities post-approval will be to initiate commercial onboarding and logistics, MSLs engaging the centers around medical and scientific needs, logistical and reimbursement support offered as needed, and center certification on a on a center-by-center basis for remy stem cell administration. Having now covered where we are with remy stem cell, let's move to RexLemyStroCell, our next-generation product for chronic low back pain and for inflammatory heart disease. By 25. We've said previously, of course, that discogenic back pain impacts large numbers of patients, both in the US and in the EU. In the US alone, it impacts 7 million patients in each of the US and EU5. And that's our target market, very well-defined patients who have underlying degenerative disc disease as the cause of their chronic pain. It's important that 50% of opioid prescriptions after chronic lower back pain due to this condition. So we expect that if we have a successful treatment here, we might have an important impact on the opioid epidemic. Let's go to slide 26. The summary of the program is outlined on this slide. We've gained alignment with the FDA on the appropriate pivotal phase three study, which seeks to replicate the significant reduction in pain that was seen as early as 12 months and through up to 36 months in our first phase three trial. FDA has agreed with our plans for pain reduction through 12 months as the primary endpoint of the pivotal trial and with functional improvement and reduction in opioid use as the key secondary endpoints. The planned phase three program will include additional 20% of patients recruited across the EU to support regulatory submissions simultaneously or in close sequence to both FDA and EMA. We have an RMAP designation for discogenic back pain received from the FDA earlier this year in February, and we expect to commence patient enrollment in the third quarter of this year. Next slide, please, 27. The RMAP designation that we received from FDA provides all the benefits of both breakthrough and fast-track designations, including a rolling review and eligibility for priority review on filing of a BLA. The objective of the pivotal trial is to replicate as closely as possible the data that we obtained from the first phase three trial, which showed that a single injection of Rexalini-Strozole into the lumbar disc resulted in significant reduction in pain, relative to saline controls as early as 12 months, throughout 24 months, and throughout 36 months in a 404-patient study. The pain reduction through 36 months was also seen in the subset of patients who were using opioids at baseline. They were not insignificant, 168 patients. In this group, there was substantially greater reduction at all time points in pain compared with saline controls. And very importantly, at the end of the 36-month follow-up, 28% of patients who had received Rexlimistrocell together with its carrier, HA, were not taking opioids compared with only 8% of saline-treated controls. This is a very important observation that we think is critical to evaluate again prospectively in the pivotal trial. Slide 28 is a snapshot of the reduction in pain that was seen in the first And it was maximal in those patients who had pain with duration below the median for the whole trial, which was approximately 68 months. So therefore, this group of patients is likely to have had the highest levels of inflammation. And so the target in the pivotal trial will be this group of patients with pain for up to five years. The objective is to address as early as possible this very large unmet medical need where we think that the likelihood of treatment response is greatest. Finally, let me move to the last couple of slides that address our cardiac program in inflammatory heart disease. Again, cardiovascular disease remains a leading cause of death in the U.S., particularly those patients with the more advanced forms of heart failure. and hard damage who finally progress either to mortality or an LVAD or a transplant. We have an existing, if we go to slide 31, please, we have an existing regenerative medicine advanced therapy designation to cover the use of our cells in the most severe patients, those who have an LVAD in place. But we really believe that there's a continuum of of disease that Rexlimustrazo is likely to be beneficial in. And the continuum is from patients in class two, three, and four, defined by very high levels of biomarkers of severity, such as NT-proBNP, and markers of inflammation, such as CRP, as well as those patients who then finally move into end-stage disease who have an L-band in place. That's our target market. Slide 32 is a summary of new data that were published this quarter in the premier journal, Cardiovascular Journal, Journal of the American College of Cardiology, data from the 537-patient phase 3 trial called DREAM Heart Failure, which followed severely advanced patients with heart failure for up to 30 months of follow-up. And the key outcomes that were published in this important publication was that left ventricular ejection fraction was significantly improved from baseline through 12 months in those patients, particularly in those with evidence of inflammation. The major complications of heart attacks or stroke were reduced by 57% in all treated patients and by 75% in those with inflammation. And the so-called three-point major adverse cardiac event rate in patients, which includes the endpoint of cardiovascular death reduction, was reduced in those with inflammation by 37%. These results were spectacular. We're very excited about these results and the implication for patients with severe disease. If we go to slide 33, the overall totality of data, 159 patients in LVAD study number two and 537 patients in DREAM heart failure are now being evaluated in totality for a continuum of mechanistic data that may allow us to structure a pivotal trial as we talk to the FDA about pathways towards approval. And on that note, I think I'll stop and open this to questions, please.