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Mesoblast Resubmits Biologics License Application (BLA) With United States Food & Drug Administration (FDA) for Approval of Ryoncil in Children With Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD)

Mesoblast Resubmits Biologics License Application (BLA) With United States Food & Drug Administration (FDA) for Approval of Ryoncil in Children With Steroid-Refractory Acute Graft-Versus-Host Disease (SR-aGVHD)

Mesoblast向美國食品藥品監督管理局（FDA）重新提交了生物製品許可申請（BLA），以獲得Ryoncil用於激素難治性急性移植物抗宿主病（SR-aGVHD）兒童的批准。
GlobeNewswire ·  07/08 20:37

NEW YORK, July  08, 2024  (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in allogeneic cellular medicines for inflammatory diseases, announced today it has resubmitted its BLA for approval of Ryoncil (remestemcel-L) in the treatment of children with SR-aGVHD.

2024年7月8日，納斯達克上市公司Mesoblast Limited（股票代碼：MESO；澳交所代碼：MSB）是治療炎症性疾病的異基因細胞藥物全球領袖，今天宣佈已重新提交BLA申請，以獲得在治療兒童SR-aGVHD（嚴重急性移植物抗宿主病）中批准Ryoncil（remestemcel-L）的許可。

The filing comes after Mesoblast was informed by FDA at the end of March that, following additional consideration, the available clinical data from the Phase 3 study MSB-GVHD001 appears sufficient to support submission of the proposed BLA for remestemcel-L for treatment of pediatric patients with SR-aGVHD. As a result, the filing addresses remaining CMC (Chemistry, Manufacturing, and Control) items.

此次提交是在Mesoblast於三月底得知FDA經過額外考慮後認爲，來自第三階段研究MSb-GVHD001的可用臨床數據足以支持提交擬議的BLA文件以治療SR-aGVHD的小兒後。因此，提交主要解決了剩餘的CMC（化學、製造和控制）問題。

"We have worked closely with the agency and thank them for their ongoing guidance, facilitating the potential approval of RYONCIL and addressing the urgent need for a therapy that improves the dismal survival outcome in children with SR-aGVHD," said Mesoblast CEO Dr. Silviu Itescu.

“我們一直與該機構保持密切合作，並感謝他們的指導，以便批准RYONCIL並滿足改善SR-aGVHD患兒預後的迫切需求，”Mesoblast首席執行官Dr. Silviu Itescu表示。

FDA granted remestemcel-L Fast Track designation, a process to facilitate the development and expedited review of therapies for serious conditions that fill unmet medical needs, and Priority Review designation, which is given to drugs that treat a serious condition and provide a significant improvement in safety or effectiveness over existing treatments.

FDA授予remestemcel-L 快速通道設計，以便促進治療嚴重疾病且填補未滿足醫療需求的藥物開發和加快審查，並授予優先審查資格，該資格頒發給治療嚴重疾病並比現有治療提供顯著安全或有效改進的藥物。

The BLA resubmission upon acceptance is expected to have a review period of between two and six months from receipt.

接受後BLA重新提交的審查期望爲2至6個月。

About Ryoncil (remestemcel-L)
Mesoblast's lead product candidate, Ryoncil (remestemcel-L), is an investigational therapy comprising culture expanded mesenchymal stromal cells derived from the bone marrow of an unrelated donor. It is administered to patients in a series of intravenous infusions. RYONCIL has immunomodulatory properties which counteract the inflammatory processes that are implicated in SR-aGVHD by inhibiting activation and proliferation of effector T cells, down-regulating the production of pro-inflammatory cytokines, and enabling recruitment of anti-inflammatory cells to involved tissues.

關於Ryoncil（remestemcel-L）
Mesoblast的領先產品候選人Ryoncil（remestemcel-L），是一種由無關獻血者骨髓中細胞培養擴增的間充質幹細胞製成的研究性治療方案。Ryoncil通過抑制效應T細胞的激活和增殖，調控針對SR-aGVHD涉及的炎症過程，降低促炎性細胞因子的產生，以及促進抗炎細胞向涉及的組織內部的轉移來發揮免疫調節作用。

About the Phase 3 Trial of Ryoncil (remestemcel-L) in Children with Steroid-Refractory Acute Graft Versus Host Disease
The Phase 3 Study GVHD001/002 was conducted in 54 children (89% Grade C/D) across 20 centers in the US where RYONCIL was used as the first line of treatment for children who failed to respond to steroids for acute GVHD.1 The trial met its pre-specified primary endpoint, Day 28 Overall Response (OR), 70.4% versus 45%, p=0.0003. An overall response at day 28 was highly predictive of improved survival through day 100 (87% compared to 47% in patients that did not achieve day 28 OR p= 0.0001).

關於Ryoncil（remestemcel-L）用於兒童患有激素難治性急性移植物抗宿主病的第三期試驗
第三期研究GVHD001/002分別在美國的20箇中心進行，共有54名兒童參加（89%爲C/D級），RYONCIL是作爲兒童的一線療法，應對激素治療無效的激素難治性急性移植物抗宿主病。試驗達到了預先確定的主要終點，即28天總體反應（OR），爲70.4%與45%，P=0.0003。28天總反應通常高度預測了在100天內的生存（87%比沒有達到28天OR的患者的47%，P=0.0001）。

Compared with a matched control group of pediatric subjects from the contemporaneous database of the Mount Sinai Acute GVHD International Consortium (MAGIC) treated with best available therapy, treatment with Ryoncil achieved higher Day 28 OR (70% vs 43%) and higher Day 100 survival (74% vs 57%). A propensity-matched study of outcomes in 25 children from Mesoblast's Phase 3 trial and 27 control children who received best available treatment, including ruxolitinib, from the MAGIC database showed that 67% of high-risk children (MAP scores >0.29) who received Ryoncil achieved a Day 28 overall response and were alive after 180 days compared to just 10% in both categories in the MAGIC group.

與MAGIC數據庫（Mount Sinai急性移植物抗宿主病國際聯合會）中接受最佳治療的符合青少年被匹配對照組相比，接受Ryoncil治療的患者在第28天總響應（70% vs 43%）和第100天的生存（74% vs 57%）方面都表現更優。Mesoblast 的第三期試驗和27名接受最佳可用治療（包括ruxolitinib）的對照組兒童成對匹配的趨勢研究顯示，在最高風險的兒童中（MAP得分高於0.29），接受Ryoncil的兒童在第28天總反應後180天存活率達67%，而MAGIC組別中兩個組別都僅爲10%。

In addition, results of a 4-year survival study performed by the Center for International Blood and Marrow Transplant Research (CIBMTR) on 51 evaluable patients with SR-aGVHD who were enrolled in the Phase 3 trial, demonstrated durability of the survival benefits, with 67% survival at 6 months, 63% survival at 1 year, 51% at 2 years, and 49% survival through 4 years in children with expected 2 year survival of just 25-38% using best available therapy.2-4

此外，由國際血液和骨髓移植研究中心（CIBMTR）進行的SR-aGVHD人群的4年生存研究結果顯示，該研究入組51名受試兒童，在RYONCIL的預期2年生存率僅爲25-38%的已最佳可用治療治療的情況下表現高效，生存率爲6個月的67%，1年的63%，2年的51%，4年的存活率達49%。

About Steroid-Refractory Acute Graft Versus Host Disease
Acute GVHD occurs in approximately 50% of patients who receive an allogeneic bone marrow transplant (BMT). Over 30,000 patients worldwide undergo an allogeneic BMT annually, primarily during treatment for blood cancers, including about 20% in pediatric patients.5,6 SR-aGVHD is associated with mortality as high as 90% and significant extended hospital stay costs.7,8 There are currently no FDA-approved treatments in the US for children under 12 with SR-aGVHD.

關於激素難治性急性移植物抗宿主病
約有50%接受配型異基因骨髓移植的患者出現急性移植物抗宿主病（aGVHD）。全球範圍內每年約有3萬名患者接受異基因骨髓移植，主要是在治療血液癌症期間，其中約有20%爲兒童患者。激素難治性急性移植物抗宿主病的死亡率高達90%且延長住院費用昂貴。目前，美國尚未批准治療SR-aGVHD的12歲以下兒童的任何治療方法。

Survival outcomes have not improved over the past two decades for children or adults with the most severe forms of SR-aGVHD.2,9-10 The lack of any approved treatments for children under 12 means that there is an urgent need for a therapy that improves the dismal survival outcomes in children.

過去20年來，無論是兒童還是成人，最嚴重的SR-aGVHD形式的存活率都沒有得到改善。由於12歲以下兒童沒有批准的治療方法，因此迫切需要一種改善兒童生存率的治療方法。

References / Footnotes

參考資料/腳註

  1. Kurtzberg J. et al. A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 26 (2020) 845-854

  2. Rashidi A et al. Outcomes and predictors of response in steroid-refractory acute graft-versus-host disease: single-center results from a cohort of 203 patients. Biol Blood Bone Marrow Transplant 2019; 25(11):2297-2302

  3. MacMillan ML et al. Pediatric acute GVHD: clinical phenotype and response to upfront steroids. Bone Marrow Transplant 2020; 55(1): 165-171

  4. Zeiser R et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med 2020;382:1800-10.

  5. Niederwieser D, Baldomero H, Szer J. (2016) Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

  6. HRSA Transplant Activity Report, CIBMTR, 2019

  7. Westin, J., Saliba, RM., Lima, M. (2011) Steroid-refractory acute GVHD: predictors and outcomes. Advances in Hematology.

  8. Axt L, Naumann A, Toennies J (2019) Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation.

  9. Berger M, Pessolano R, Carraro F, Saglio F, Vassallo E, Fagioli F. Steroid-refractory acute graft-versus-host disease graded III-IV in pediatric patients. A mono-institutional experience with a long-term follow-up. Pediatric Transplantation. 2020; 24(7):e13806

  10. Biavasco F, Ihorst G, Wasch R, Wehr C, Bertz H, Finke J, Zeiser R. Therapy response of glucocorticoid-refractory acute GVHD of the lower intestinal tract. Bone Marrow Transplantation. 2022

  1. Kurtzberg J. et al. A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 26 (2020) 845-854

  2. Rashidi A et al. Outcomes and predictors of response in steroid-refractory acute graft-versus-host disease: single-center results from a cohort of 203 patients. Biol Blood Bone Marrow Transplant 2019; 25(11):2297-2302

  3. MacMillan ML et al. Pediatric acute GVHD: clinical phenotype and response to upfront steroids. Bone Marrow Transplant 2020; 55(1): 165-171

  4. Zeiser R et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med 2020;382:1800-10。

  5. Niederwieser D, Baldomero H, Szer J. (2016) Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOt analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

  6. HRSA移植活動報告，CIBMTR，2019年

  7. Westin、Saliba、Lima萬 (2011)：類固醇難治性急性GVHD：預測因素和結果。血液學進展。

  8. Axt L、Naumann A、Toennies J (2019)：同基因造血幹細胞移植後類固醇難治性移植物抗宿主病的預後、危險因素和治療的單中心回顧性分析。骨髓移植。

  9. Berger m、Pessolano R、Carraro F、Saglio F、Vassallo E、Fagioli F。兒童III-IV級類固醇難治性急性移植物抗宿主病。一項長期隨訪的單中心經驗。兒童移植。2020年；24(7)：e13806

  10. Biavasco F、Ihorst G、Wasch R、Wehr C、Bertz H、Finke J、Zeiser R。下消化道糖皮質激素難治性急性移植物抗宿主病的治療反應。骨髓移植。2022年

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