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.
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.
"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.
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.
The BLA resubmission upon acceptance is expected to have a review period of between two and six months from receipt.
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.
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).
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.
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
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.
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.
References / Footnotes
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
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
MacMillan ML et al. Pediatric acute GVHD: clinical phenotype and response to upfront steroids. Bone Marrow Transplant 2020; 55(1): 165-171
Zeiser R et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med 2020;382:1800-10.
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.
HRSA Transplant Activity Report, CIBMTR, 2019
Westin, J., Saliba, RM., Lima, M. (2011) Steroid-refractory acute GVHD: predictors and outcomes. Advances in Hematology.
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.
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
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
2024年7月8日、Mesoblast Limited(Nasdaq:MESO;ASX:MSB)は、炎症性疾患のための異種移植細胞医薬品のグローバルリーダーであると発表し、SR-aGVHDの小児患者の治療におけるRyoncil(remestemcel-L)の承認のためのBLAの再提出を行った。
3相試験MSb-GVHD001から利用可能な臨床データが提出されることに十分であることが判明したため、Mesoblastは3月末にFDAから通知を受けた後、CMC(Chemistry、Manufacturing、およびControl)項目に対応した提出を行った。したがって、この提出は、残りの分野に対処するものである。
「当社は、機関と密接に協力し、RYONCILの承認とSR-aGVHDの児童患者の生存率を改善する治療法の緊急ニーズを対処することを促進する彼らの持続的な指導のために彼らに感謝します」とMesoblast CEOのDr. Silviu Itescuは述べています。
FDAは、リメステムセルLファーストトラック指定と、未治療の医療ニーズを満たす深刻な状況の治療薬の開発と迅速なレビューを促進するプロセスであるプライオリティレビュー指定を付与した。
受け入れ後のBLA再提出は、受領から2〜6ヶ月のレビュー期間を持つことが予想されています。
Ryoncil(remestemcel-L)について
Mesoblastのリード製品候補であるRyoncil(remestemcel-L)は、非関連ドナーの骨髄由来の培養拡大間葉系幹細胞を含む検診療法であり、患者に静脈内投与されます。 RYONCILは、効果細胞の活性化と増殖を抑制し、炎症性サイトカインの産生を低下させ、関与する組織に抗炎症作用を持つ細胞の募集を促します。
ステロイド非応答性急性移植片対宿主病の子供を対象としたRyoncil(remestemcel-L)の第3相試験について
GVHD001 / 002第3相試験は、SR-aGVHDにステロイド治療が効かなかった子供たち(89%がGrade C / D)の54人(20のセンターで)でRYONCILが最初の治療法として使用された場合に実施されました。試験は、前もって指定された主要エンドポイントである28日目の全体的な応答(OR)で70.4%対45%、p = 0.0003を満たしました。 28日目の総合的な反応は、Day 100を通じて生存率の改善を非常に予測するものであった(Day 100での生存率は、Day 28 ORを達成しなかった患者に比べて87%対47%で、p =0.0001)。
Mesoblastの第3相試験の25人と最高の利用可能な治療法、ラクソリチニブを含むMAGICデータベースからの対照的な小児被験者の対照群とのプロペンシティマッチング研究では、Ryoncilを受けた高リスクの子供たちの67%がDay 28の全評価に到達し、MAGICグループの両方のカテゴリにいる10%よりも180日後に生き残った。
さらに、SR-aGVHDに苦しむ51人の患者を対象に行われた4年間の生存率研究の結果、Mesoblastの第3相試験に登録された評価可能な患者では、存続上の利益が継続し、最高利用可能な治療を使用した場合の25〜38%の期待される2年間の生存率を示しました。2-4
ステロイド非応答性急性移植片対宿主病について
移植片対宿主病は、非同種骨髄移植(BMT)を受けた患者の約50%で発生します。世界中で30,000人以上の患者が年間に非同種BMTを受け、主に血液がんの治療中に行われますが、小児患者が約20%を占めます。 SR-aGVHDは、90%の高い死亡率と長期間の入院費用を伴います。 7,8現在、米国では12歳未満の子供たちを対象としたSR-aGVHDの承認された治療法はありません。
最も重度のSR-aGVHDを持つ子供または大人の生存率は過去20年間で改善されておらず、12歳未満の子供たちの承認された治療法がないことは、子供たちの絶望的な生存率の改善を必要とする緊急のニーズであることを意味しています。
参考文献・脚注
Kurtzberg J.らが行った研究では、グルココルチコイド治療で効果を得られなかった小児患者の急性移植片対宿主病治療のための、体外培養拡大した成体人間間葉系幹細胞、レメステムセル-Lの単一腕、前向き研究の第3相が行われ、Biol Blood Marrow Transplant 26 (2020) 845-854 で報告された。
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
MacMillan ML et al. Pediatric acute GVHD: clinical phenotype and response to upfront steroids. Bone Marrow Transplant 2020; 55(1): 165-171
Zeiser R et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med 2020;382:1800-10.
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.
HRSA 移植活動レポート、CIBMTR、2019年
Westin、J.、Saliba、Rm.、Lima万。 (2011) ステロイド耐性急性GVHD:予測因子と結果。ヘマトロジー進歩。
Axt L、Naumann A、Toennies J (2019) グルココルチコイド非感受性移植片対宿主病の結果、リスク要因、および治療の単一施設後ろ向き分析。骨髄移植。
Berger m、Pessolano R、Carraro F、Saglio F、Vassallo E、Fagioli F。小児患者における等級III-IVのステロイド耐性急性移植片対宿主病。長期フォローアップを伴う単一機関の経験。小児移植。2020年; 24(7):e13806
Biavasco F、Ihorst G、Wasch R、Wehr C、Bertz H、Finke J、Zeiser R。下部腸管のグルココルチコイド非感受性急性GVHDの治療反応。骨髄移植。2022