Mesoblast Ltd (MESO) 2024 Q4 法說會逐字稿

Thank you, Operator. And I'm very pleased to welcome everybody to the financial results and operational update for the year ended June 30, 2024. With me today, Chief Financial Officer, Andrew Chaponnel and one of our members of the Board, Dr. r. Philip Krause, formerly Deputy Director of the Vaccine Division of FDA's CBER.

謝謝你，接線生。我非常高興地歡迎大家了解截至 2024 年 6 月 30 日的年度財務表現和營運更新。今天與我在一起的有財務長 Andrew Chaponnel 和我們的董事會成員之一 r. r. 博士。Philip Krause，FDA CBER 疫苗部門前副主任。

I'm very pleased to report that in the past six months, Mesoblast has made tremendous progress and we've built great momentum in our relationships with the FDA on each of our three lead products. We are now in a strong position to have our first potential product approved by the FDA and planning for a go-to-market strategy for our first commercial launch.

我很高興地向大家報告，在過去的六個月中，Mesoblast 取得了巨大的進步，我們與 FDA 就我們的三種主導產品中的每種產品建立了巨大的合作關係。我們現在處於有利地位，可以讓我們的第一個潛在產品獲得 FDA 批准，並為我們的首次商業發布製定進入市場策略。

If we could go now to the slide deck, please, starting with slide four. We're a global leader in allogeneic cellular medicines for inflammatory diseases and have established a leading position with intellectual capital with over a thousand patents granted or filed across all the major jurisdictions. Slide five. Our platform technology demonstrates a shared mechanism of action across all of our products.

如果我們現在可以轉到投影片，請從第四張投影片開始。我們是治療發炎性疾病的同種異體細胞藥物領域的全球領導者，並在智力資本方面確立了領先地位，在所有主要司法管轄區已授予或申請了一千多項專利。幻燈片五。我們的平台技術展示了我們所有產品的共享行動機制。

The mesenchymal precursor and stromal cells that we are working with respond to and are activated by multiple inflammatory cytokines through surface receptors, resulting in orchestration of an anti-inflammatory cascade, all of which is central to the mechanism by which these cells turn off damaging inflammation in each of the diseases that we are aiming to get products approved for.

我們正在研究的間質前體細胞和基質細胞透過表面受體對多種發炎細胞因子做出反應並被多種發炎細胞因子激活，從而協調抗發炎級聯反應，所有這些都是這些細胞關閉破壞性發炎的機制的核心我們的目標是讓產品獲得批准用於治療每種疾病。

Next slide, please. Slide six. (technical difficulty)US patent exclusivity for these cells, termed composition of matter, method of treatment patents have been granted for RYONCIL as well as for our other stromal cell products up to at least 2037 and beyond in certain indications. Methods of treatment and manufacturing go out to as far as 2043, and they include mesenchymal cells from different sources, including iPS for a range of indications that we'll be talking about in the next few slides.

請下一張投影片。幻燈片六。（技術難題）這些細胞的美國專利獨佔權（稱為物質組合物）、治療方法專利已授予 RYONCIL 以及我們的其他基質細胞產品，至少在 2037 年及以後的某些適應症中。治療和製造方法可追溯到 2043 年，其中包括來自不同來源的間質細胞，其中包括用於一系列適應症的 iPS，我們將在接下來的幾張幻燈片中討論這些適應症。

Slide number seven is a snapshot of the late-stage clinical pipeline of our proprietary allogeneic cell therapy platform. And you can see in blue the products that are being developed using the remestemcel platform. The branded name is RYONCIL. And in green, the products being developed through our second-generation pipeline product called rexlemestrocel, which is a STRO3+ cell line generated through immunoselection with monoclonal antibodies.

第七張幻燈片是我們專有的同種異體細胞治療平台的後期臨床管道的快照。您可以看到藍色的產品是使用 remestemcel 平台開發的。品牌名稱為 RYONCIL。綠色的是透過我們的第二代管道產品 rexlemestrocel 開發的產品，該產品是透過單株抗體免疫選擇產生的 STRO3+ 細胞系。

The remestemcel cell platform is the more advanced. Our lead product is RYONCIL for pediatric steroid-refractory graft-versus-host disease. It's currently under review by the FDA for potential BLA approval. The adult indication will be a label extension for the product, and it's also being developed for inflammatory bowel disease.

remestemcel細胞平台更為先進。我們的主導產品是 RYONCIL，用於治療兒科類固醇難治性移植物抗宿主疾病。目前 FDA 正在審查該藥物是否可能獲得 BLA 批准。成人適應症將是該產品的標籤延伸，它也正在開發用於發炎性腸道疾病。

Rexlemestrocel for cardiovascular disease is being developed for pediatric congenital heart disease, for adult patients with end-stage heart failure with low ejection fraction, and for adults with class two to four heart failure with low ejection fraction. And finally, Rexlemestrocel is also being developed for inflammatory lower back pain, currently in the midst of the final Phase 3 program.

用於心血管疾病的 Rexlemestrocel 正在開發用於兒童先天性心臟病、患有低射血分數的終末期心臟衰竭的成人患者以及患有低射血分數的 2 至 4 級心臟衰竭的成人患者。最後，Rexlemestrocel 也正在開發用於治療發炎性腰痛，目前正處於最後的第 3 階段計畫中。

Next slide. In the coming 12 months, we expect to substantially advance our multiple product pipeline toward FDA approvals in the following context. RYONCIL, its BLA has already been resubmitted. We have a PDUFA date, January 7, 2025, and we expect to then initiate a study in adult patients beyond post-approval for label extension.

下一張投影片。在未來 12 個月中，我們預計在以下情況下將大幅推進我們的多個產品管道以獲得 FDA 批准。RYONCIL，其 BLA 已重新提交。我們的 PDUFA 日期為 2025 年 1 月 7 日，我們預計將在標籤延期批准後啟動一項針對成年患者的研究。

Rexlemestrocel for chronic low back pain has completed one Phase 3 trial, and the second Phase 3 trial to confirm the 12-month pain reduction primary endpoint for potential approval is actively enrolling across multiple sites in the US. And the third product is REVASCOR, which is being developed for heart failure in children with congenital heart disease and adults with low ejection heart failure, is being prepared for potential accelerated approval. More about that in the next few slides.

用於治療慢性下背痛的 Rexlemestrocel 已完成一項 3 期試驗，第二項 3 期試驗正在美國多個地點積極招募，以確認 12 個月減輕疼痛的主要終點，以供潛在批准。第三個產品是 REVASCOR，該產品正在開發用於治療患有先天性心臟病的兒童心臟衰竭和患有低射血性心臟衰竭的成年人，目前正在準備加速批准。接下來的幾張投影片將詳細介紹這一點。

Now I'd like to turn over to Andrew, who will take us through the financial results for the year.

現在我想請安德魯來為我們介紹今年的財務表現。

Thank you, Silviu. Please turn to the financial highlights for the year on slide 10. At June 30, our cash balance was USD63.3 million, with an additional $10 million from an existing facility on FDA approval of RYONCIL. We are pleased to report reductions in our net operating cash usage. There's a 23% reduction of $14.8 million for FY 2024 compared to FY23, and our full year net operating cash usage was $48.5 million for FY 2024 compared to $63.3 million in FY23.

謝謝你，西爾維。請參閱投影片 10 上的本年度財務摘要。截至 6 月 30 日，我們的現金餘額為 6,330 萬美元，在 FDA 批准 RYONCIL 後，我們還從現有設施中額外獲得了 1,000 萬美元。我們很高興地報告我們的淨營運現金使用量有所減少。與 2023 財年相比，2024 財年減少了 23%，即 1,480 萬美元，2024 財年全年淨營運現金使用量為 4,850 萬美元，而 2023 財年為 6,330 萬美元。

And we recorded a 37% reduction of $6.1 million for Q4 in FY 24 compared to the prior comparative quarter. So our Q4 spend was down to $10.2 million compared to $16.3 million in the prior comparative quarter. These impressive reductions in cash usage were predominantly driven by reduced manufacturing activities and lowered payroll, which I'll explain in more detail on the next slide. We will continue our focus on prudent cash management for all operating activities as we undertake targeted commercial rollout and supply chain activities for remestemcel-L.

與上一季相比，24 財年第四季的營收減少了 37%，減少了 610 萬美元。因此，我們第四季的支出降至 1,020 萬美元，而上一季的支出為 1,630 萬美元。現金使用量的大幅減少主要是由於製造活動減少和工資減少所致，我將在下一張投影片中更詳細地解釋這一點。當我們為 remestemcel-L 進行有針對性的商業推廣和供應鏈活動時，我們將繼續專注於所有經營活動的審慎現金管理。

Now turning to slide 11, we can report that we achieved the headcount and payroll cost containment targets we set for FY 2024, and I confirm that these initiatives will continue in FY 2025 as we continue our focus on cost control. Our 23% reduction in net operating cash burn in FY24 was largely in part due to the successful execution of our payroll reduction strategy. The table below outlines the initiatives in more detail.

現在轉向投影片 11，我們可以報告，我們實現了為 2024 財年設定的員工人數和工資成本控制目標，我確認這些措施將在 2025 財年繼續，因為我們將繼續關注成本控制。2024 財年，我們的淨營運現金消耗減少了 23%，這在很大程度上歸功於我們的減薪策略的成功執行。下表更詳細地概述了這些舉措。

So firstly, our CEO and CMO voluntarily reduced their base salaries by 30% in FY24, and this reduction is also in place for FY 2025. They will receive non-cash LTIs in place of the base salary reduction. Additionally, management have also participated in that voluntary base salary reduction program and can continue and will do so in the coming year FY25.

首先，我們的執行長和行銷長自願將 2024 財年的基本薪資削減 30%，而這項削減也將在 2025 財年實施。他們將獲得非現金 LTI 來代替基本工資的減少。此外，管理層還參與了自願基本工資削減計劃，並將在來年 2025 財年繼續這樣做。

Cash payment of STI earned during FY23 and FY24 is deferred until FDA BLA approval for steroid refactoring acute GVHD for all employees. And further to that, management will be offered non-cash LTIs if they'd like to replace the cash payment of the FY23 and FY24 STIs. And we continue to defer 100% of the cash payment of any non-executive director fees until an FDA decision on the BLA.

2023 財政年度和 2024 財政年度賺取的 STI 現金支付將推遲到 FDA BLA 批准用於所有員工的類固醇重建急性 GVHD 為止。除此之外，如果管理階層想取代 2023 財年和 2024 財年 STI 的現金支付，他們將獲得非現金 LTI。我們繼續推遲任何非執行董事費用的 100% 現金支付，直到 FDA 對 BLA 做出決定。

Moving to slide 12. On slide 12, you'll see a summary of the profit and loss statement for FY24. Notably, our manufacturing expenditure reduced by $12 million, a significant 43% due to decreased inventory build and one-off FY23 expenditure on FDA pre-license inspection activities.

轉到投影片 12。在投影片 12 上，您將看到 2024 財年損益表的摘要。值得注意的是，由於庫存建設減少以及 2023 財年 FDA 許可前檢查活動的一次性支出，我們的製造支出減少了 1200 萬美元，大幅減少了 43%。

Our finance cost includes $17.3 million of non-cash expenditure comprising accruing interest and borrowing costs. Notably also, there's been a significant swing in revaluation of contingent consideration between FY23 and FY24. And that's due to the revaluation being updated in FY 2024 for greater probability of GVHD approval compared to the FY23 valuation, which reflected the 2023 CRL.

我們的財務成本包括 1,730 萬美元的非現金支出，包括應計利息和借款成本。值得注意的是，2023 財年和 2024 財年之間或有對價的重估出現了重大波動。這是因為與反映 2023 年 CRL 的 2023 財年估值相比，2024 財年更新了重估，以獲得 GVHD 批准的可能性更大。

Our loss after tax for FY24 is $88 million. After adjusting for that revaluation of contingent consideration, given that there was a large swing in that valuation from year to year, our loss after tax for FY24 is $78.3 million, a $12.4 million improvement on FY 2023.

我們 2024 財年的稅後虧損為 8,800 萬美元。在對或有對價重估進行調整後，考慮到該估值每年都有很大波動，我們 2024 財年的稅後虧損為 7830 萬美元，比 2023 財年減少了 1240 萬美元。

I'll now hand the call back to Silviu for the remainder of the presentation.

現在，我將把電話轉回西爾維，以進行剩餘的演示。

Thanks, Andrew. If we can go now to slide number 14. This is a snapshot of the clinical development programs for RYONCIL steroid refractory acute GVHD for children and adults, slide 15. GVHD is a potentially fatal complication of an allogeneic bone marrow transplant. It's essentially a cytokine storm by the T-cells in the donor-graft that attacked the gut, liver, and the skin of the recipient, seeing those tissues as foreign. And the cytokines that are produced result in tissue destruction and ultimately death of the patient.

謝謝，安德魯。我們現在可以轉到第 14 號投影片。這是兒童和成人的 RYONCIL 類固醇難治性急性 GVHD 臨床開發計劃的快照，幻燈片 15。GVHD 是同種異體骨髓移植的潛在致命併發症。它本質上是供體移植物中 T 細胞發起的細胞激素風暴，攻擊受體的腸道、肝臟和皮膚，將這些組織視為外來組織。產生的細胞激素會導致組織破壞並最終導致患者死亡。

Slide 16. The potential unmet need exists in 30,000 patients who undergo allogeneic bone marrow transplants globally, of whom about 20% are pediatric. In the US alone, about 10,000 patients undergo allogeneic bone marrow transplants. And so there continues to be a growing unmet need, given that about 50% of patients will develop graft versus host disease.

幻燈片 16。全球有 30,000 名接受同種異體骨髓移植的患者存在潛在的未滿足需求，其中約 20% 是兒科患者。光是在美國，就有約 1 萬名患者接受同種異體骨髓移植。鑑於約 50% 的患者會出現移植物抗宿主疾病，未滿足的需求仍在增加。

Next slide, slide 17. This slide updates on where we are with potential FDA approval of RYONCIL for pediatric patients with steroid refractory GVHD. We submitted -- we resubmitted our BLA for approval of RYONCIL on July 8 of this year, addressing the remaining CMC items in the August '23 complete response letter.

下一張投影片，投影片 17。這張投影片更新了 FDA 可能批准 RYONCIL 用於類固醇難治性 GVHD 兒科患者的進展。我們於今年 7 月 8 日重新提交了 BLA 供 RYONCIL 批准，解決了 23 年 8 月完整回信中的剩餘 CMC 項目。

FDA, during this year, has informed Mesoblast that the available clinical data from our Phase 3 study appears sufficient to support resubmission of the BLA. Hence, the BLA contains only items relating to the CMC that are new and responsive to the CRL. The FDA accepted the BLA resubmission within two weeks, considering it to be a complete response. We are in ongoing interactions and dialogue with the FDA in relation to the active BLA review. We anticipate a decision prior to or on the FDA's PDUFA goal date of January 7. Our strategy is to first gain pediatric approval for RYONCIL, followed by label extension in the larger adult population.

FDA 今年已通知 Mesoblast，我們 3 期研究的可用臨床數據似乎足以支持重新提交 BLA。因此，BLA 僅包含與 CMC 相關的新項目並回應 CRL。FDA 在兩週內接受了 BLA 重新提交，認為這是一個完整的答案。我們正在與 FDA 就積極的 BLA 審查進行持續的互動和對話。我們預計 FDA 的 PDUFA 目標日期（1 月 7 日）之前或當天會做出決定。我們的策略是先獲得 RYONCIL 的兒科批准，然後在更大的成年人群中擴展標籤。

Next slide, 18. Concurrently with the review process, we have reinstituted pre-launch activities for our go-to-market strategy for RYONCIL and pediatric patients. We've commenced hiring of select senior positions to build out our targeted commercial team. The key activities that were active last year and are now being picked up include market access to initiate payer outreach, medical affairs to provide education, corporate leadership to initiate engagement with the top 15 transplant centers, which perform 50% of the pediatric transplants across the US, and the initiation of sales directors to lead center profiling.

下一張投影片，18。在審查過程的同時，我們為 RYONCIL 和兒科患者的上市策略重新啟動了上市前活動。我們已經開始招募精選的高階職位來建立我們的目標商業團隊。去年活躍且現在正在進行的關鍵活動包括啟動付款人外展的市場准入、提供教育的醫療事務、啟動與排名前15 的移植中心接觸的企業領導力，這些中心承擔了全美50% 的兒科移植手術。

We have ongoing key opinion leader engagement with those KOLs who have the greatest experience with RYONCIL at the centers that have the highest volume of transplants. We've reinitiated non-promotional activities, including profiling the high-volume centers, educational and disease awareness, and payer engagement.

我們與那些在移植量最高的中心擁有 RYONCIL 最豐富經驗的 KOL 保持持續的關鍵意見領袖互動。我們重新啟動了非促銷活動，包括分析大容量中心、教育和疾病意識以及付款人參與。

Next slide, 19. We will plan to have post-launch activities for our go-to-market strategy that will be staged based on onboarding of centers with the highest volume and experience with our product. We will bring on a very targeted sales force with experience in bone marrow transplant centers, as I've mentioned. 15 centers do 50% of the volume.

下一張投影片，19。我們將計劃為我們的上市策略進行啟動後活動，這些活動將根據我們產品數量和經驗最多的中心的入職情況進行。正如我所提到的，我們將引進一支具有骨髓移植中心經驗的非常有針對性的銷售團隊。 15 個中心承擔了 50% 的工作量。

The key activities in the post-launch period will be to initiate commercial onboarding and logistics to have our medical science liaisons engage with the medical and scientific needs of the transplant centers and the leadership at those centers, logistical and reimbursement support offered as needed, and center certification for our remestemcel Administration.

啟動後的關鍵活動將是啟動商業准入和後勤工作，使我們的醫學科學聯絡員能夠滿足移植中心的醫療和科學需求以及這些中心的領導層，根據需要提供後勤和報銷支持，以及我們的remestemcel管理中心認證。

Moving on, slide 20 is our label extension strategy for RYONCIL in adult patients. There is a continued unmet need in adults with steroid refractory GVHD who fail the only approved drug in adults, ruxolitinib, and that accounts for about 40% of ruxolitinib-treated patients. Survival in these patients remains a dismal 20% to 30% by 100 days. This patient population continues to have no approved therapies. In contrast, 100-day survival in these patients treated with RYONCIL is 67% under expanded access. 51 adults and children have been treated in this way.

接下來，投影片 20 是我們 RYONCIL 在成人患者中的標籤延伸策略。患有類固醇難治性GVHD 的成人患者的需求持續未被滿足，這些患者是唯一批准用於成人的藥物魯索替尼（ruxolitinib）失敗的，約佔接受魯索替尼治療的患者的40% 。這些患者的 100 天存活率僅為 20% 至 30%。該患者群體仍然沒有獲得批准的治療方法。相較之下，在擴大使用範圍後，這些接受 RYONCIL 治療的患者的 100 天存活率為 67%。已有51名成人和兒童接受過這種治療。

Following approval in pediatric patients, we intend to commence a Phase 3 trial of RYONCIL in adults and adolescents with this disease who are refractory to a second-line agent such as ruxolitinib. We're collaborating on this trial with the Blood and Marrow Transplant Clinical Trials Network, the BMT CTN, an NIH-funded body responsible for approximately 80% of all US transplants that will be conducting the trial.

在兒科患者獲得批准後，我們打算在對魯索替尼等二線藥物抗藥性的成人和青少年中開展 RYONCIL 的 3 期試驗。我們正在與血液和骨髓移植臨床試驗網絡 (BMT CTN) 合作進行這項試驗，這是一個由 NIH 資助的機構，負責進行這項試驗的美國所有移植手術的大約 80%。

Moving on now to the indications being developed for rexlemestrocel, our second-generation STRO3 selected product. Slide number 22 is a snapshot of the focus on chronic low back pain for this product, and this has completed one Phase 3 and is currently in a second confirmatory Phase 3 trial for the indication.

現在轉向我們的第二代 STRO3 精選產品 rexlemestrocel 正在開發的適應症。第 22 號投影片是該產品關注慢性下背痛的快照，該產品已完成一項 3 期試驗，目前正在進行針對該適應症的第二項確認性 3 期試驗。

Slide 23. The burden of illness is great, and the treatment options are very limited for patients with inflammatory, discogenic, chronic back pain. 50% of opioid prescriptions across the US are for this very indication, and the opioid epidemic continues. Over 7 million patients are estimated to suffer from chronic low back pain due to inflammatory, degenerative disc disease in each of the US as well as the EU5.

幻燈片 23。對於發炎性、椎間盤源性、慢性背痛患者來說，疾病負擔很大，治療選擇非常有限。美國 50% 的鴉片類藥物處方都是針對這種適應症，而且阿片類藥物的流行仍在繼續。據估計，美國和歐盟五國都有超過 700 萬名患者因發炎、退化性椎間盤疾病而患有慢性下背痛。

Go to the next slide, please. Slide 24. This is the patient journey for patients with this debilitating condition. Conservative treatments include, of course, non-steroidal anti-inflammatory drugs, a variety of physical therapy approaches, but really when these modalities fail, the only approaches that are non-interventional, non-surgical are opioids, and there are both weak and strong opioid analgesics, and as I've mentioned, this has fueled the excess opioid usage in the opioid epidemic across Western societies, particularly the US.

請轉到下一張投影片。幻燈片 24。這是患有這種衰弱病症的患者的患者旅程。保守治療當然包括非類固醇抗發炎藥、各種物理治療方法，但實際上，當這些方法失敗時，唯一非介入、非手術的方法就是鴉片類藥物，而且效果既有弱的，也有弱的。

Beyond this, there is spinal cord stimulation and radiofrequency ablation and other end-stage surgical procedures. We intend to be used as early as possible when conservative treatments have failed, and one major objective, of course, is to help avoid opioid analgesics altogether.

除此之外，還有脊髓刺激和射頻消融以及其他末期外科手術。我們打算在保守治療失敗時儘早使用，當然，一個主要目標是幫助完全避免使用鴉片類止痛藥。

Next slide, please. Slide 25. In our first Phase 3 trial of approximately 400 patients randomized to a single injection of rexlemestrocel versus saline injection, what we saw was as early as 12 months after a single injection, there was very significant separation in terms of pain reduction from baseline in those patients who received a single injection of cells together with hyaluronic acid as a carrier, and this separation -- red in this slide versus green, was maintained for at least three years of follow-up, so long, durable, substantial reduction in pain from a single injection of rexlemestrocel.

請下一張投影片。投影片 25。在我們約400 名患者隨機接受單次注射rexlemestrocel 與注射生理食鹽水的第一個3 期試驗中，我們看到，早在單次注射後12 個月，這些患者的疼痛減輕程度就與基線相比有非常顯著的差異他們接受了單次細胞注射以及作為載體的透明質酸，這種分離（這張幻燈片中的紅色與綠色）在至少三年的隨訪中得以維持，如此長時間、持久、大幅減少了因注射而產生的疼痛。

Next slide, please. Slide 26. And so the summary of our ongoing program is that we have regulatory alignment with the FDA on this second Phase 3 trial. The primary endpoint being an approvable endpoint is reduction in pain. These secondary endpoints look at improvement in function and quality of life, measures which were also substantially improved in the first Phase 3 trial, and this program is now underway across multiple sites in the US. It's actively enrolling.

請下一張投影片。幻燈片 26。因此，我們正在進行的計劃的總結是，我們在第二個 3 期試驗中與 FDA 進行了監管協調。作為可批准終點的主要終點是疼痛減輕。這些次要終點著眼於功能和生活品質的改善，這些措施在第一個 3 期試驗中也得到了顯著改善，該計劃目前正在美國多個地點進行。正在積極報名。

Importantly, 40% of the first Phase 3 trial were patients who were on opioids at baseline, and that group of patients demonstrated not only a substantial reduction in pain that was durable for at least three years, but also significant cessation of opioids compared to control patients. Those results are particularly important, and we will be having further discussions with the FDA focusing specifically on the opioid-using population in this program.

重要的是，第一個3 期試驗中有40% 的患者在基線時服用阿片類藥物，該組患者不僅表現出持續至少三年的疼痛大幅減輕，而且與對照組相比，也顯著停止使用阿片類藥物患者。這些結果特別重要，我們將與 FDA 進一步討論，特別關注該計劃中的阿片類藥物使用人群。

Moving forward to the other major indication for the rexlemestrocel product pipeline, heart failure. Slide 28 focuses on a snapshot of the clinical indications being developed for the STRO3+ rexlemestrocel product that has a branded name of REVASCOR, being developed for children with congenital heart disease called hypoplastic left heart syndrome, being developed for adults with end-stage heart failure with low ejection fraction, and it's being developed for adults with ischemic heart failure with low ejection fraction at stages two to four.

接下來討論 rexlemestrocel 產品線的另一個主要適應症：心臟衰竭。投影片28 重點介紹了STRO3+ rexlemestrocel 產品正在開發的臨床適應症，該產品的品牌名稱為REVASCOR，該產品是為患有先天性心臟病（稱為左心發育不全綜合徵）的兒童開發的，是為患有終末期心臟衰竭的成年人開發的低射血分數，它正在為患有第二至第四階段射血分數低的缺血性心臟衰竭的成年人開發。

Next slide. Slide 29. REVASCOR is a potential treatment for severe congenital heart disease as outlined here on this slide. The mechanism of action of REVASCOR is that it has the ability to improve vasculature. It has anti-fibrotic effects and reduces inflammation. These are all features that are critical to the progressive defects in hypoplastic left heart syndrome, a severe congenital heart disease in children where the left side of the heart does not develop appropriately and does not pump oxygenated blood to the rest of the body.

下一張投影片。幻燈片 29。REVASCOR 是治療嚴重先天性心臟病的潛在療法，如本投影片所述。REVASCOR 的作用機制是它具有改善脈管系統的能力。它具有抗纖維化作用並減少發炎。這些都是對左心發育不全症候群的進行性缺陷至關重要的特徵，左心發育不全症候群是一種嚴重的兒童先天性心臟病，患者的左側心臟無法正常發育，不能將含氧血液泵送到身體的其他部位。

The entire circulation is dependent on the right side of the heart, and ultimately, in the absence of surgery, the right side of the heart enlarges, fails, and this is a fatal disease due to right-sided heart failure. We completed a clinical trial, a randomized controlled trial, at Boston Children's Hospital to evaluate whether a single injection of REVASCOR could enhance the left ventricular size of these unfortunate children in order to help the left ventricle support the circulation to the body.

整個循環都依賴右側心臟，最終，在不進行手術的情況下，右側心臟會擴大、衰竭，這是由於右側心臟衰竭而導致的致命疾病。我們在波士頓兒童醫院完成了一項隨機對照臨床試驗，以評估單次注射 REVASCOR 是否可以增加這些不幸兒童的左心室大小，以幫助左心室支持身體的循環。

The results, if we can go to slide 30, the results of that study were published last year in a peer-reviewed publication journal, Thoracic and Cardiovascular Surgery. The results in these 19 patients showed that a single injection into the left ventricle, into the tiny little left ventricle, at the time of stage surgery resulted 12 months later in significantly increased volumes of the left ventricle, both diastolic and systolic, compared with controls.

結果，如果我們可以翻到第 30 張投影片，該研究的結果去年發表在同行評審的出版期刊《胸腔與心血管外科》。這 19 名患者的結果表明，在分期手術時向左心室注射一次，注射到微小的左心室，12 個月後，與對照組相比，左心室舒張期和收縮期的體積顯著增加。

The increase in volumes of the left ventricle enabled surgeons to substantially increase the proportion of children who could then undergo a successful biventricular conversion, meaning that more children that received a REVASCOR injection were able to tolerate definitive surgery where the left side of the heart supported the full body's circulation.

左心室體積的增加使外科醫生能夠大幅增加能夠成功進行雙心室轉換的兒童比例，這意味著更多接受 REVASCOR 注射的兒童能夠耐受左側心臟支撐左心室的確定性手術。

This means that potentially the improvement in left ventricular volumes associated with REVASCOR may result in more widespread use of this type of definitive procedure, which has great implications for these children since all other procedures that maintain a right- sided functioning ventricle ultimately result in right-sided heart failure, liver failure, liver fibrosis, and ultimately mortality.

這意味著與REVASCOR 相關的左心室容量的潛在改善可能會導致這種類型的確定性手術的更廣泛使用，這對這些兒童具有重大影響，因為維持右側心室功能的所有其他手術最終都會導致右心室單側心臟衰竭、肝衰竭、肝纖維化，最終導致死亡。

We could go to slide number 31. Based on the results of this randomized controlled trial, we applied and received from the FDA a rare pediatric disease designation and orphan drug designation. This is in line with both the severe life-threatening disease that hyperplastic left heart syndrome entails, as well as a recognition of the potential benefits that the procedure has resulted in.

我們可以轉到第 31 號投影片。根據這項隨機對照試驗的結果，我們向 FDA 申請並獲得了罕見兒科疾病認定和孤兒藥認定。這既符合左心增生症候群所引起的嚴重危及生命的疾病，也符合對該手術帶來的潛在益處的認識。

It's important to emphasize that if REVASCOR gets FDA approval for this indication, Mesoblast may be eligible to receive a priority review voucher that can be for any subsequent marketing application or may be sold or transferred to a third party. We plan to meet with the FDA to discuss whether the randomized controlled study that I've just outlined can be used to obtain regulatory approval for REVASCOR in children with this life-threatening condition.

需要強調的是，如果 REVASCOR 獲得 FDA 批准適應症，Mesoblast 可能有資格獲得優先審查憑證，該憑證可用於任何後續行銷申請，也可出售或轉讓給第三方。我們計劃與 FDA 會面，討論我剛才概述的隨機對照研究是否可用於獲得監管部門批准 REVASCOR 用於治療患有這種危及生命的疾病的兒童。

Moving on to slide 32 and the program for REVASCOR in adults. This is a program that's aiming to develop a product for heart failure with low ejection fraction and underlying ischemia. Heart failure, as we know, is the number one cause of mortality in the Western world, affecting more than 6.5 million patients in the US alone with an increase in prevalence. Over 60% of heart failure with low ejection fraction have underlying ischemia and it's these patients that are at highest risk of recurrent major adverse cardiac events, including large vessels such as heart attacks, strokes, and ultimately death.

繼續看投影片 32 和成人 REVASCOR 計畫。該計畫旨在開發一種用於治療低射血分數和潛在缺血性心臟衰竭的產品。眾所周知，心臟衰竭是西方世界第一大死因，光在美國就有超過 650 萬名患者受到影響，而且盛行率還在上升。超過 60% 的低射血分數心臟衰竭患者有潛在的缺血，這些患者發生主要不良心臟事件的風險最高，包括心臟病發作、中風等大血管疾病，甚至最終死亡。

The next slide, 33, is a summary of the two large programs we've performed to date. And if you focus on the right-hand side of this slide, two large studies, randomized controlled, one that we call the Dream Heart Failure Trial, 537 patients in class two to four heart failure and patients in end stage heart failure being kept alive with a ventricular assist device, an LVAD, in 159 patients. We focused our program on these two patient populations because they continue to be -- despite all other, all drugs that are currently being used, including SGLT2 inhibitors, including the sacubitril-valsartan combination. Despite all of those drugs, patients progressively and inexorably proceed to class 3, 4, and end stage. And this patient population that we're targeting with a single injection of REVASCOR into the left ventricle.

下一張投影片 33 是​​我們迄今為止執行的兩個大型專案的摘要。如果你關注這張幻燈片的右側，有兩項大型研究，隨機對照，其中一項我們稱之為“夢想心臟衰竭試驗”，537 名二至四級心臟衰竭患者和末期心臟衰竭患者均保持生命159 名患者使用心室輔助裝置 LVAD。我們將計劃重點放在這兩個患者群體上，因為儘管有其他所有藥物，但他們仍然是目前正在使用的所有藥物，包括 SGLT2 抑制劑，包括沙庫巴曲-纈沙坦組合。儘管使用了所有這些藥物，患者仍會不可阻擋地逐漸進入 3 級、4 級和末期。我們向左心室單次注射 REVASCOR 的目標患者群。

Slide 34, in the randomized placebo controlled 537 patient trial, who were followed for a mean follow-up of at least 30 months, we saw an improvement in ejection fraction at 12 months, and we saw a substantial reduction in heart attacks, strokes, cardiovascular death, and 3-point MACE as endpoints in the entire trial. And you can see a picture of the substantial reduction in heart attacks or strokes on the right-hand side from the publication last year in the Journal of American College of Cardiology.

投影片 34，在隨機安慰劑對照 537 名患者試驗中，平均追蹤時間至少 30 個月，我們看到射血分數在 12 個月時有所改善，且心臟病發作、中風、心血管死亡和3 點MACE 作為整個試驗的終點。你可以從去年發表在《美國心臟病學會雜誌》上的文章中看到右側心臟病發作或中風大幅減少的圖片。

Slide 35, we've now got a very clear pathway to accelerate approval for REVASCOR in this adult patient population with low ejection fraction heart data. And that's based on the totality of the data across the two trials I've talked about, where in the DREAM population, in the ischemic patients, there was very significant reduction in 3-point MACE, heart attack, strokes, and mortality.

投影片 35，我們現在已經有了一個非常明確的途徑，可以在具有低射血分數心臟數據的成年患者群體中加速 REVASCOR 的批准。這是基於我所討論的兩項試驗的總體數據，在 DREAM 族群中，缺血性患者的 3 點 MACE、心臟病發作、中風和死亡率顯著降低。

And in the LVAD study, in 70 patients with ischemic end-stage disease, a single injection of REVASCOR successfully weaned patients to a higher degree than placebo, and there was a significant reduction in hospitalizations and mortality.

而在 LVAD 研究中，在 70 名缺血性末期疾病患者中，單次注射 REVASCOR 使患者成功斷奶的程度高於安慰劑，且住院率和死亡率顯著降低。

At the Type B meeting early this year, in the first quarter, FDA informed us that the totality of the trial results across those two studies may support an accelerated approval pathway for RAVASCOR in end-stage ischemic heart-related patients with LVAD. We intend to request a pre-BLA meeting to discuss the totality of the data, the timing, and the FDA expectations for an accelerated approval filing in this patient population.

在今年初第一季的 B 類會議上，FDA 告知我們，這兩項研究的整體試驗結果可能支持 RAVASCOR 在末期缺血性心臟相關 LVAD 患者中的加速核准途徑。我們打算要求召開一次 BLA 前會議，討論數據總量、時間安排以及 FDA 對這群患者加速批准申請的期望。

And with that, I think -- I'll say thank you for listening. This has been a very exciting six months, and we think the excitement will continue as we hopefully get a positive outcome from the FDA. I'd like to open it up to questions. Thank you.

說到這裡，我想──我要感謝你們的聆聽。這是非常令人興奮的六個月，我們認為這種興奮將會持續下去，因為我們希望從 FDA 得到積極的結果。我想開放供大家提問。謝謝。

(Operator Instructions) Louise Chen, Cantor.

（操作員說明）Louise Chen，Cantor。

Hi. Good evening, everyone. This is Carvey Leung for Louise from Cantor. Thank you for taking our questions. First, can you discuss any potential partnerships or cooperation that could accelerate your commercialization effort? And second, how are you planning on tackling reimbursement challenges, assuming you get approval for right on sale? Thank you so much.

你好。大家晚上好。我是 Cantor 的 Louise 的 Carvey Leung。感謝您接受我們的提問。首先，您能否討論任何可以加速您商業化工作的潛在夥伴關係或合作？其次，假設您獲得銷售權的批准，您打算如何應對報銷挑戰？太感謝了。

Thank you. Well, so RYONCIL for pediatric and adults, GVHD, we have a go-to-market strategy on our own because we've already put a lot of effort into doing so. The patient population is relatively targeted and the transplant centers that perform these transplants are relatively small in number.

謝謝。嗯，所以 RYONCIL 對於兒童和成人，GVHD，我們自己有一個進入市場的策略，因為我們已經為此付出了很多努力。患者族群相對有針對性，進行這些移植的移植中心數量也相對較少。

So it's a highly manageable commercialization process. We are in discussions with payers and we have a very good sense of what the reimbursement is likely to be in this space based on two important considerations. One is that the recent approvals of CAR T therapies, particularly in children with leukemia, we represent a similar population as the children we're targeting with GVHD, provides at least a level of basis for comparison.

所以這是一個高度可管理的商業化過程。我們正在與付款人進行討論，基於兩個重要的考慮因素，我們非常了解這個領域可能的報銷內容。一是最近批准的 CAR T 療法，特別是針對患有白血病的兒童，我們代表了與我們針對 GVHD 的目標兒童相似的人群，至少提供了一定程度的比較基礎。

Secondly, we have five year outcomes, which we've talked to and have provided to the FDA last year. Five year outcomes from our Phase 3 trial demonstrating a 50% overall survival for between four to five years, meaning that at least 50% of the children are cured of this disease. That puts the treatment paradigm into the realm of genetic diseases, where again, intense therapy at the front end provides a substantial number of patients with curative outcomes.

其次，我們有五年的成果，我們去年與 FDA 進行了交談並提供給 FDA。我們的 3 期試驗的五年結果表明，四到五年的總體存活率為 50%，這意味著至少 50% 的兒童可以治癒這種疾病。這將治療範式引入了遺傳疾病領域，在該領域，前端的強化治療再次為大量患者提供了治癒結果。

So when one thinks of reimbursement, given the orphan size of the population and given the precedence in both CAR T therapies and gene therapy, we think that the reimbursement is going to fall somewhere between those parameters.

因此，當人們考慮報銷時，考慮到孤兒群體的規模以及 CAR T 療法和基因療法的優先順序，我們認為報銷將落在這些參數之間的某個位置。

The second question I think you asked me was on partnering. And so it really depends on which products we talk about. For our back pain product, we already have a commercialization partner in Europe. That's Grunenthal, which is Europe's number one pharmaceutical company in the pain space. The relationship with Grunenthal is robust on successful completion of this Phase 3 trial. They will take on the responsibility of market access, pricing, and distribution. And we will be eligible for a variety of milestone payments.

我想你問我的第二個問題是關於合作的。所以這實際上取決於我們談論的是哪些產品。對於我們的背痛產品，我們已經在歐洲有了一個商業化合作夥伴。這就是格倫泰（Grunenthal），它是歐洲在疼痛領域中排名第一的製藥公司。在成功完成第三階段試驗後，與格倫泰的關係非常牢固。他們將承擔市場准入、定價和分銷的責任。我們將有資格獲得各種里程碑付款。

In the US, we will be seeking a similar relationship with a commercialization partner, leveraging the existing sales marketing distribution channels, rather than seeking to build those ourselves. And similarly with cardiovascular disease, we have now a pathway to potential approval, both on a first pediatric indication and secondly, an end stage heart disease indication.

在美國，我們將尋求與商業化合作夥伴建立類似的關係，利用現有的銷售行銷通路，而不是尋求自己建立這些管道。與心血管疾病類似，我們現在有一條潛在批准的途徑，無論是第一個兒科適應症還是第二個末期心臟病適應症。

Those are fully manageable by us as a company, given the small patient populations. I think in parallel, as we move the product through the FDA for potential approval in either of those two populations, we will be engaging with -- and are engaging with currently potential commercialization partners who will take on the potential commercial channels for adult patients with class two or class four heart failure.

鑑於患者人數較少，我們作為一家公司完全可以管理這些問題。我認為，與此同時，當我們將該產品通過FDA 以獲得在這兩個人群中的任何一個的潛在批准時，我們將與當前潛在的商業化合作夥伴進行接觸，他們將為成人患者提供潛在的商業管道。

Awesome. Thank you so much and congrats on all the progress. Thank you.

驚人的。非常感謝並祝賀所有的進展。謝謝。

(Operator Instructions) Edward Tenthoff, Piper Sandler..

（操作員說明）Edward Tenthoff、Piper Sandler..

Great. Thank you very much and congrats on all the updates. I'm looking forward to the review for RYONCIL in acute GVHC. I'm wondering, when should we expect an update with respect to REVASCOR and kind of the regulatory filing plan? And how long do you think the Phase 3 for the spinal product will take? Thank you.

偉大的。非常感謝並祝賀所有更新。我期待著 RYONCIL 在急性 GVHC 方面的審查。我想知道，我們什麼時候應該期待 REVASCOR 和監管備案計劃的更新？您認為脊椎產品的第三階段需要多長時間？謝謝。

Sure. Let me take the spinal product question first. The Phase 3now is up and running. You know how enrollment works where you first of all recruit a lot of the centers, contract them, they start to screen their patients, et cetera. And you have a hockey stick kind of enrollment period. And so we're in that early phase right now. We expect that it will ramp up over the coming three months or so.

當然。我先來回答一下脊椎產品的問題。目前三期工程已啟動並投入運作。你知道註冊是如何進行的，首先你招募了很多中心，與他們簽約，他們開始篩檢病人，等等。而且你有一個曲棍球棒式的註冊期。所以我們現在正處於早期階段。我們預計這一數字將在未來三個月左右上升。

Our projection is that it'll take about 12 months to fully enroll. And then the primary endpoint is a 12-month outcome in terms of pain reduction. So we will be updating the market as that program continues to move forward.

我們的預測是大約需要 12 個月才能完全註冊。主要終點是 12 個月的疼痛減輕結果。因此，隨著該計劃的繼續推進，我們將更新市場情況。

I'm sorry, Silviu, how many months to enroll? I apologize.

抱歉，Silviu，入學幾個月？我道歉。

About 12 months.

大約12個月。

Yep. Okay.

是的。好的。

With respect to the regulatory interactions on REVASCOR and cardiac disease, we have two potential early pathways to approvals. One is for the pediatric congenital heart disease. And the other is for in-stage patients on LVADs.

關於 REVASCOR 和心臟病的監管相互作用，我們有兩種潛在的早期批准途徑。一是針對小兒先天性心臟病。另一種是針對接受 LVAD 的階段患者。

The immediate plan for discussion with the agency in the second half of the year is going to be on the pediatric indication because we have a pediatric rare disease voucher designation. And it is important if you know that the first approval is the one that is linked to a pediatric voucher. So that's the first that we need clarity with the FDA, whether the randomized control trial that has already completed and that was the basis of the voucher designation can support a filing for approval process.

今年下半年與該機構討論的直接計劃將是兒科適應症，因為我們有兒科罕見疾病憑證指定。如果您知道第一個批准是與兒科優惠券相關的批准，這一點很重要。因此，這是我們首先需要向 FDA 澄清，已經完成且作為憑證指定基礎的隨機對照試驗是否可以支持申請審批流程。

After that discussion, we will be then also meeting with the agency given the support they've given us to an accelerated approval for the adults based on the totality of the LVAD study and the prior DREAM study. We will be meeting with them to understand exactly what clinical data needs to go into a filing for that patient population.

討論結束後，我們還將與該機構會面，因為他們給予我們支持，根據 LVAD 研究和先前的 DREAM 研究的總體情況，加速批准成人用藥。我們將與他們會面，以準確了解該患者群體需要提交哪些臨床數據。

The confirmatory study that will be required as part of any accelerated approval will be a confirmatory study of the DREAM population in ischemic heart failure patients with class three, four heart failure. So that's a trial that is being designed as we speak and will be obviously presented to the FDA when we meet on a pre-BLA basis.

作為任何加速批准的一部分，所需的驗證性研究將是對患有三、四級心臟衰竭的缺血性心臟衰竭患者的 DREAM 人群進行的驗證性研究。因此，正如我們所說，這是一項正在設計的試驗，當我們在 BLA 之前開會時，顯然將向 FDA 提交該試驗。

Great. Excellent. Thank you.

偉大的。出色的。謝謝。

Thank you. And this concludes our question and answer session. I'd like to turn the conference back over to Dr. Itescu for closing remarks.

謝謝。我們的問答環節到此結束。我想將會議轉回由 Itescu 博士致閉幕詞。

Well, I'm very excited about the progress we've made in the last six months and we look forward to maintaining the momentum and to updating the market in short order on FDA in (technical difficulty)

嗯，我對我們在過去六個月中取得的進展感到非常興奮，我們期待保持這一勢頭並在 FDA 的短時間內更新市場（技術難度）