Mesoblast Limited

Thank you, Operator. Good afternoon and good morning to our financial results and operational update for the year ended June 30th. On the call with me today, our Chief Medical Officer, Dr. Eric Rose, our Interim Chief Financial Officer, Andrew Chaponelle, and one of our board members, Dr. Philip Krause. Today, we'll be talking about regulatory interactions with the FDA. We will talk about our operational streamlining and our upcoming milestones as we progress our major phase three programs and talk about our cost reduction strategies that we have implemented to ensure that we have significant cost containment and protection of our cash reserves. We can now go to the slide deck. Slide four, please. This slide is a snapshot of our late stage clinical pipeline that is based on two cellular platforms based on stromal cells, remy stem cell and rex lemmy stro cell. Remy stem cell is being developed for both pediatric and adult graft-versus-host disease and other follow-on indications, including inflammatory bowel disease. I'll be talking about our pediatric GVHD regulatory filing and upcoming type A meeting with the FDA shortly. The program is also expanding into the much larger market, adult GVHD, which is five times larger than the pediatric indication. Rexlanistrocell is being developed for chronic inflammatory lower back pain and inflammatory heart failure, and in both of those indications has completed the first of two pivotal phase three programs. We'll be talking about those towards the end of the presentation. Next slide, please. The investment highlights for the company As I mentioned, we're developing products based on our novel allogeneic technology platforms that allows us to, through controlling manufacturing, develop scalable mesenchymal stromal cell products without the need for donor matching or immunosuppression that focus on the core mechanism of action around reduction of significant inflammatory diseases. The lead indication for Remy Stem Cell, our first-generation platform, is pediatric and adult serodefractory acute graft-versus-host disease. We have developed substantial data that has been presented to the FDA. Let me talk about those in a couple of minutes. But we do have a very important Type A meeting with the FDA mid-September, scheduled for mid-September now, to discuss our strategy for product approval. For chronic low back pain, Rexlamy's stroke cell has completed a first phase three trial. It has been granted regenerative medicine advanced therapy designation by the FDA, and we have alignment with the FDA on the primary endpoint of 12 months of pain reduction in a pivotal second phase three trial, which is currently ongoing and underway. We expect to have first-patient recruitment in the next quarter. The program for inflammatory heart disease, Rex-Limistro-Cell, also has completed a first-phase retrial in patients with reduced ejection fraction, has also completed a trial in patients with end-stage heart failure with an LVAD. In that indication, again, the FDA has granted the product RMAT designation. and we will seek to be meeting with the FDA to talk about extending the RMAT designation to patients prior to an LVAD. Finally, the finances of the past 12 months, we've continued to have stable revenues from our royalties in Japan for Temcel from our partner in Japan. We have cash on hand of $71.3 million as of the end of the financial year, and we will have a lot more detail about cost containment strategies that have been implemented and are being put in place in order to preserve cash further. Next slide, please. Slide five. Slide six. This slide summarizes the regulatory status for any stem cell in pediatric patients with GVHD and the upcoming Type A FDA meetings, which is now scheduled for mid-September. During the six-month BLA review, we made substantial progress towards bringing this cutting-edge product to market with having completed a comprehensive FDA inspection of our manufacturing process and the facility where our cells are being manufactured. In August, unfortunately, the FDA provided a complete response to our BLA resubmission for the treatment of pediatric GVHD. The basis for this was a requirement to mesoblast demonstrate that the product used in the Phase III trial, which was completed several years ago, is similar, closely similar, to the product that's intended now for commercial release as measured by a standardized potency assay. We believe that we can link the product that was made in the Phase III trial to the current commercially released product through additional work using potency data. The FDA indicates that an additional trial would be needed to establish this link if the company is not able to do so via the additional potency assay work that is currently expected to be initiated. The type A meeting with the FDA is scheduled to be held in mid-September, and we will be laying out these exact strategies. We propose providing FDA with additional potency assay data to provide the link between phase three product and the current commercial inventory. We also propose providing FDA with new clinical trial data in adults, which could also support the pediatric indication. Next slide. What other new clinical data that we propose generating? In line with our overall commercial strategy to progress to the adult indication, which is approximately five-fold larger than the pediatric indication, We intend to conduct a targeted control study in adults with very high mortality risk. Survival in adults with steroid refractory GVHD who failed at least one additional agent, such as ruxolitinib, remains as low as 20 to 30% by 100 days. In contrast, 100-day survival has been shown to be 63% after remy stem cell treatment is used under an expanded access in 71 patients aged 12 and older with steroid refractory GVHD who failed to respond to at least one additional agent, such as roxalitinib. We are in discussions with world-leading investigators at the Blood and Marrow Clinical Trials Network, the BMCTN, which is a prime body across the U.S. responsible for 80% of all U.S. bone marrow transplants. The discussions with this group is that they will conduct the new clinical trial. As a result, the costs of this targeted study are expected to be covered fully by the planned spending reductions that we will outline below in the financial section. We can go now to slide number eight, which is our financial results section. Andrew, if you could take on the next few slides, please.

Thanks Sylvia. Please turn to the financial highlights for the year on slide nine. Revenue from royalties were 7.5 million US dollars for the year. On a constant currency basis, royalties on sales of Tencel in Japan by our licensee were 8.1 million dollars compared with 8.7 million dollars for the prior year. Net cash usage for operating activities for the year was $63.3 million. This represented a 37% reduction on FY 2021 and a 4% reduction on FY 2022. At June 30th, 2023, cash on hand was $71.3 million, with up to an additional $40 million from our existing financing facilities subject to both certain milestones and the extension of availability. Turn to slide 10 please. There you'll see we are reporting a reduction in expenditure and an improved loss before tax for the year ended June 2023. Our revenue of $7.5 million is predominantly from royalties on sales of stem cell in Japan. Our R&D expenditure was reduced by 17% from the prior year. Our R&D spend in the year was primarily to support the Remy Stem Cell L BLA resubmission and preparations for pivotal studies for Eurex and Estrocell. Our manufacturing expenditure reduced by 10% from the prior year. And our finance costs for the year ending in 2023 include $15 million of non-cash accrued interest and borrowing costs. Now turning to slide 11, I'll take you through the cost containment plan for the next 12 months. It's important to note that our net operating cash usage in FY2023 was a 37% reduction compared with 2021. and 4% reduction compared with 2022. But we are targeting a further 23% reduction of approximately $15 million in our projected FY 2024 annual net operating cash spend through reduced spend across research, sales and marketing, commercial inventory and payroll. This targeted reduction will be partially offset as we invest in our phase three programs for steroid refractory acute GVHD and CLBP. We are targeting a 40% annual reduction in payroll by February 2024. This reduction is coming from reductions in base salaries, short-term incentive payments and contractor fees in the coming year. Our CEO and CMO have deferred their entire FY 2023 short-term incentives and have voluntarily their base salaries for FY2024 by 30% to preserve cash. Instead, they will receive long-term, non-cash incentives to further align with shareholders. Any grants of equity-based LTIs will be for shareholder approval. FY2023 short-term incentives have been entirely deferred for all employees. Management are eligible to receive LTIs in lieu of a 30% reduction in salary. And non-executive directors have voluntarily deferred 100% of the cash payment of their director fees and agreed to receive 50% of their fees in LTIs. Again, any grants of equity-based LTIs will be subject to shareholder approval. And for the coming year, We are shifting from quarterly to half-yearly reporting of financial statements. The next financial statements we will report will be for the half-year ended December 31, 2023. We will continue to report our quarterly cash burn via Appendix 4C and include a report on operational activities. This process is in line with the requirements for ASX listed entities. Now I'll hand the call back to Sylvie for the remainder of the presentation.

Thanks, Andrew. If we go to slide 13, please. This is a mechanistic slide, which I've addressed many times in the past. But I think just to summarize for those who don't know the disease, the devastating complication of a bone marrow transplant is acute graft-versus-host disease. It's mediated by the graft immune system attacking the gut and the liver in particular, as well as the skin of the recipient. And the immune cells create a cytokine storm that results in organ destruction and ultimately death. What we aim to do with our mesenchymal stromal cell product is to target the precise mechanisms of the immune disactivation and turn off the immune cells and turn off the destructive cytokines. Next slide, please. Slide 14. This slide addresses the market size and the opportunity for the company. There are more than 30,000 allogeneic bone marrow transplants performed globally, and about 10,000 of those are performed annually in the United States, whilst approximately 1,500 are in children. The remainder are in adults, indicating that the adult GBSD market is about five times the size of the pediatric market. In Japan, we already have a product that is generating revenues for us. It's the only product that has been approved in Japan through our licensee, JCR Pharma. In the U.S., no products are approved for steroid-affected graftless host disease in children. In adults, the only product that is approved is roxalitinib. Next slide, please, slide 15. This slide is a summary of the short-term survival results across three distinct trials in pediatric GVHD with children having been treated through any stem cell. In each of these trials, you see short-term survival outcomes that are significantly higher than those survival outcomes at three and six months that have been reported in matched contemporaneous or historical controlled cohorts. These results have been extensively provided to the FDA as part of our BLA resubmissions. Next slide, please. Slide 16 now shows the long-term survival outcomes of the children in our pivotal phase three trial through to at least four years. And you can see that whilst one-year survival is 63%, by two, three, and four years, survival is of the order of 50% and remains stable thereafter. In contrast, you see the results of five published contemporaneous studies in children and adults where survival at one and two years is abysmally low and substantially different from what we've seen in our phase three trial. And there are no reports of survival outcomes in these high-risk patient populations beyond two years. These results also were provided to the FDA. Next slide, please. Slide 17. We are now focusing, in addition to the pediatric population, on adults with steroid refractory GVHD. As I mentioned earlier, this is a much larger market opportunity. And the only drug that is approved in this patient population is roxalitinib after steroid failure. However, 45% of roxalitinib-treated patients continue to be non-responders. And survival in these patients is 20 to 30% by 100 days, an abysmal outcome. In contrast, across 71 patients, under expanded access that have been treated with ruxolitinib, patients who are 12 and older, who are considered adolescent or adults, and have failed to respond to at least one additional agent such as ruxolitinib, we have seen a 63% survival. A terrific outcome. And this is very similar to the type of survival that we see in similar high-risk pediatric patients. As a result of these very promising data, we are in late-stage discussions with the Blood and Bone Marrow Clinical Trials Network across the U.S., body responsible for 80% of all U.S. bone marrow transplants, to have them conduct the new clinical trial, which will target patients who have failed steroids and at least one additional agent, such as ruxolitinib, with a primary endpoint designed to either to improve early day 28 responses or to demonstrate a survival benefit at 100 days. Importantly, the costs of this targeted study are expected to be entirely covered by the planned spending reductions as outlined earlier in the financial section. Move to the next few slides, which focus on the opportunities with Rexlamy-Strosel. our second-generation stromal cell collagenate product. Slide number 19, please. The market opportunity for inflammatory low back pain is huge, both in the US and in the dominant European markets. Over 7 million patients in each of these jurisdictions are estimated to suffer from chronic low back pain due to degenerative disc disease, which is an inflammatory condition. And despite non-steroidal anti-inflammatory drugs or opioids none of there are no other treatments that have an impact on either the disease symptoms or disease progression in this large patient population in fact 50% of opioid prescriptions in the United States are precisely for this indication and this represents a a real major cause of the opioid epidemic that continues to be a major source of poor healthcare outcomes. Slide 20 provides a summary of where our program is at. We have regulatory alignment with the FDA on the appropriate pivotal phase three study to confirm the results on the first phase three trial. which showed a significant reduction in pain at 12 and 24 months of follow-up. The phase three protocol for this pivotal trial design has been agreed to with the FDA at 12 months reduction in pain compared with placebo. Secondary endpoints are functional improvement and reduction in opioid usage. Product manufacturing has been completed. for the trial and potency assays are in place for product release. The program has an RMAT designation from the FDA and the pivotal trial startup activities have commenced and recruitment is expected to begin next quarter. Let me just give you a snapshot. of the data that underpinned this pivotal trial and the regular interactions, regulatory interactions with the agency that resulted in the RMAT and the agreement on the pivotal trial and its endpoint. Slide 21, please. The results from the first trial showed that a single injection of Rexlimistro cell delivered together with hyaluronic acid as a carrier into the lumbar disc resulted in significant reduction in pain compared with saline control at 12 and 24 and, in fact, 36 months across all subjects in a 404-patient study. That pain reduction was seen in the subset of patients, in addition, who used opioids at baseline. N equals 168, so a very large subset, but the precise subset that is a greatest risk of opioid overuse and addiction. Among patients on opioids at baseline, despite instructions to maintain existing therapies throughout the trial, by three years, 28% had received the cell product when not taking an opioid compared with just 8% of saline-treated controls. We can go to slide 22, please. This slide is a summary of the effect on pain through 36 months from a single intradiscal lumbar injection. of our cells. And as you can see, the green line on this slide represents the mean change in pain at every time point after a saline placebo injection. In fact, the small reduction in pain that you see with saline approximates that that is typically seen with opioid drugs so that even a saline rehydration of the disc has a small beneficial effect. In contrast, if you look at the red line, the reduction in pain that's observed with a single injection of our cells together with the hyaluronic acid carrier gives a substantial reduction in pain that is maximal at 12 months and is durable through 36 months. And that difference between the red and the green lines is really the difference that we expect to see in the pivotal phase three trial design in patients who are within a five-year period post initiation of pain. In other words, that early five year period when inflammation continues to be at its peak, the disease is still very much active and at a time point when we can have an impact, not on just pain, but also on the natural history of the disease before the disc is ultimately destroyed by the inflammatory process. Let's move to the last indication that I want to focus on and that is our inflammatory heart failure program. also with Rexland estrocell. Slide 24, please. This slide is a snapshot of the current program summary. The significant need is evidence, inflammatory, low ejection fraction heart failure continues to be a very big unmet need with mortality that approaches 50% at five years. The data that we've generated across two large programs is particularly promising, particularly in the DREAM heart failure phase 3 trial, which was recently published in the premier journal in cardiovascular field, Journal of the American College of Cardiology, which demonstrated an improvement in ejection fraction of 12 months preceding a long-term reduction in major adverse cardiovascular events defined by cardiac mortality, heart attacks, and strokes. Potentially, the LDF is an early surrogate endpoint for reduction in these major adverse event outcomes. We believe that we have a good handle on the mechanism of action by which the cells impact both improvement in injection fraction and improvement in MACE outcomes, and that's by reducing the active inflammatory process. We expect to have a meeting with the agency that talks about both the data across the large 500-patient study, Dream Heart Failure, as well as the data that was previously generated in LVAD patients for which the RMAT is already available. And the objective of the study is to show that similar mechanisms exist in the continuum of these two indications to allow us to have a larger RMAT umbrella that covers not just the LVAD patients, but those patients with advanced disease prior to having an LVAD in place. And slide 25 really summarizes, and I won't go into a lot of detail, but summarizes the continuum of this disease And where we think that our mesenchymal stromal cell product can have significant benefit both in advanced heart failure as well as obviously those patients who are end stage and have an LVAD in place. This is the basis of the long-term program that we will be talking to with the agency and are also talking to with potential strategic partners. Finally, slide 26. provides just a pictorial snapshot on the right of some of the data that came out of the DREAM heart failure study. This shows just what an impact a single intramyocardial injection of our cells had on major adverse cardiac events in patients with inflammation. And as you can see here, almost an 80% reduction over a five-year period in patients heart attacks and strokes, the major cardiac events that are affected in this patient population. I think on that note, I might stop and open it up for questions. Thank you very much.