Brexanolone

异基因造血干细胞移植（allo-HSCT）是血液系统恶性肿瘤的有效治疗方法，但移植后血小板植入延迟是影响患者长期生存的危险因素1，因此，促进移植后血小板植入，对于降低患者出血风险以及改善预后尤为重要。在2024年第66届美国血液学会（ASH）年会上，一项评估海曲泊帕对allo-HSCT后血小板植入有效性和安全性的临床研究（摘要号：3504）公布2，值此契机，医脉通特邀中国科学技术大学附属第一医院朱小玉教授解读该研究，并就移植后血小板植入延迟现状发表真知灼见，以期惠及更多移植后血小板植入延迟患者。 海曲泊帕促进异基因造血干细胞移植后血小板植入的有效性和安全性：一项前瞻性、单臂临床试验 研究背景 血小板植入延迟是allo-HSCT后常见并发症，导致患者移植相关死亡率增加。目前，血小板生成素受体激动剂（TPO-RA）是血小板减少患者重要的治疗选择。海曲泊帕是一种可与血小板生成素受体跨膜结构域结合的小分子TPO-RA，在中国已被批准用于治疗慢性原发免疫性血小板减少症（ITP）及重型再生障碍性贫血（SAA）。然而，关于海曲泊帕治疗移植后血小板植入延迟的报道很少，因此，本研究旨在评估海曲泊帕促进allo-HSCT后血小板植入的有效性和安全性。 研究方法 本项研究纳入48例年龄≥18岁、allo-HSCT后血小板植入不良[血小板植入不良：移植后（≥28天）血小板计数连续7天<20×109/L或依赖血小板输注；血小板植入：连续7天血小板计数≥20×109/L，且脱离血小板输注]的患者。患者在移植后+28d起接受海曲泊帕治疗（初始剂量为5mg/天，最大剂量为10mg/天），直至血小板植入或血小板计数≥100×109/L或用药＞8周后仍持续血小板减少。研究将这些患者的治疗结果与65例历史对照组患者进行了比较。 研究结果 入组患者中位年龄为40岁。末次随访时间为2024年7月23日，中位随访时间为201天（范围36天~773天）。纳入患者中20例为急性髓系白血病，16例为急性淋巴细胞白血病，11例为骨髓增生异常综合征，1例为慢性粒单核细胞白血病。48例患者中2例接受外周血造血干细胞移植，46例接受非血缘脐血移植。其中42例患者在脐血移植后+14天~+28天接受重组人血小板生成素（rhTPO）治疗，随后接受海曲泊帕治疗。48例患者的中性粒细胞的中位植入时间为移植后+17天（范围11天~36天）。 海曲泊帕可促进血小板植入或恢复：移植后+60天血小板累积植入率为91.3%（95% CI：78.5%~96.6%），移植后+120天血小板累积恢复率为88.4%（95%CI：74.3%~95.0%），入组后8周内血小板中位输注量为1U（范围0U~23U）。 序贯治疗临床获益更显著：进一步比较rhTPO和海曲泊帕序贯治疗组（n=42）与历史对照组[移植后+14天~+28天仅接受rhTPO治疗（n=33）和移植后未接受rhTPO或TPO-RA治疗的患者（n=32）]的疗效发现，序贯治疗组移植后+60天血小板累积植入率显著高于仅接受rhTPO组和对照组（90.0% vs. 75.8% vs. 53.1%，P<0.001），同时，在移植后+120天血小板恢复到50×109/L的累积发生率也呈现类似趋势（86.8% vs. 72.7% vs. 53.1%，P<0.001）。 安全性：研究期间，1例患者出现海曲泊帕相关的肝损伤，1例患者出现海曲泊帕相关的肾损伤，其余患者均未发现异常。 研究结论 结果表明，与单独使用rhTPO治疗相比，rhTPO和海曲泊帕序贯治疗可快速促进移植后血小板恢复，特别是在接受脐血移植的患者中。 朱小玉教授 造血干细胞移植是治疗多种恶性血液疾病的重要手段，其中，非血缘脐血移植因原发疾病复发率低、慢性移植物抗宿主病发生率低等优点3，已成为其他移植类型的有效替代方案。但与成人供体外周血干细胞移植相比，非血缘脐血移植后血小板植入明显延迟，而移植后+60天血小板未植入或未恢复与患者移植相关死亡密切相关4。 对于移植后血小板植入延迟，目前尚无推荐的标准治疗方案5，因此，探索促进血小板植入的有效策略成为研究热点。我们团队既往研究发现，在脐血移植后+14天～+28天使用rhTPO可改善+60天血小板累积植入率和+120天血小板累积恢复率6。但仍有部分患者在移植后+60天血小板未成功植入。 作为我国自主研发的新一代TPO-RA，海曲泊帕可有效促进移植后血小板植入或恢复、减少血小板输注量、降低患者出血风险，最终达到改善生活质量的目的7-9。本研究中，我们在移植后+28天给予海曲泊帕治疗（初始剂量为5mg/天，最大剂量为10mg/天），促进了移植后+60天血小板植入及移植后+120天血小板恢复；而rhTPO和海曲泊帕序贯治疗可使移植后+60天血小板累积植入率达90.0%，移植后+120天血小板恢复到50×109/L的累积发生率也可达到86.8%2。由此可见，rhTPO和海曲泊帕序贯治疗可进一步促进移植后血小板植入及恢复。 作为一种新型升板药物，海曲泊帕为促进移植后血小板顺利植入创造条件；而作为一种口服制剂，海曲泊帕亦为移植患者出仓以及出院后的管理提供便利，从而提高患者依从性。相信未来随着更多关于海曲泊帕临床研究的陆续公布，移植后血小板植入延迟患者的生活质量和长期生存将会得到更大改善。 专家简介 朱小玉 教授 医学博士，主任医师，博士生（博士后）导师 中国科学技术大学附属第一医院（安徽省立医院）血液科行政主任，中科大血液和细胞治疗研究所副所长，国家临床重点专科建设项目学科带头人 安徽省血液内科质控中心主任 安徽省学术技术带头人后备人选 安徽省杰出青年基金获得者 安徽省第九批“特支计划”卫生创新领军人才 安徽省“恶性血液病脐血移植治疗”优秀科研创新团队带头人 中国医师协会血液科医师分会第五届委员会委员 中国血液病专科联盟再障协作组副组长 中华医学会血液学分会造血干细胞移植学组委员 安徽省血液学分会第八届委员会副主任委员 中华医学会血液学分会第九届、第十届青年委员会委员 主持区域联合重点项目等国家自然科学基金4项，省部级项目4项。近年来以通讯作者（含共同）在Blood, Blood Advances, Bioactive Materials, Am J Hematol等发表SCI论文近20篇。 参考文献： 1.王静,等.中华血液学杂志,2020,41(02):160-163. 2.Huang A,et al.2024ASH #P3504. 3.Wu Y,et al.Hematol Oncol.2022 Feb;40(1):82-91. 4.李淑钰,等.实用医学杂志,2022,38(03):344-349. 5.刘福佳,等.国际输血及血液学杂志,2020,43(5):383-390. 6.Tang B,et al.Blood Adv.2020 Aug 25;4(16):3829-3839. 7.Zheng X,et al.Eur J Haematol.2023 May;110(5):527-533. 8.Li G,et al.Blood(2023)142(Supplement 1):6965. 9.Liu H,et al.Blood(2023)142(Supplement 1):6967. END 医脉通是专业的在线医生平台，“感知世界医学脉搏，助力中国临床决策”是平台的使命。医脉通旗下拥有「临床指南」「用药参考」「医学文献王」「医知源」「e研通」「e脉播」等系列产品，全面满足医学工作者临床决策、获取新知及提升科研效率等方面的需求。

BOSTON--( BUSINESS WIRE )-- PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) ("PureTech" or the "Company"), a clinical-stage biotherapeutics company, noted that its Founded Entity, Seaport Therapeutics , (“Seaport”) a clinical-stage biopharmaceutical company that is advancing novel neuropsychiatric medicines with a proven strategy and team, today announced the presentation of additional data from its first-in-human, multi-part Phase 1 study of SPT-300 in healthy volunteers at the American College of Neuropsychopharmacology (ACNP) Annual Meeting, held December 8-11, 2024 in Phoenix, Arizona. SPT-300 is an oral prodrug of allopregnanolone that is designed to retain the pharmacological activity of allopregnanolone, an endogenous neurosteroid. Allopregnanolone has been clinically validated in third-party trials as a rapidly acting antidepressant with anxiolytic effects. New data presented at the conference include further safety analyses and pharmacokinetic and pharmacodynamic data. Based on the Phase 1 study results, the profile of SPT-300 is suitable for chronic dosing and oral administration at night in the planned Phase 2b placebo-controlled study. The full text of the announcement from Seaport is as follows: Seaport Therapeutics Presents Additional Data from Phase 1 Study of SPT-300 at ACNP Annual Meeting 2024 Multiple well-tolerated doses with pharmacodynamic activity were identified and will be included in a planned Phase 2b study in major depressive disorder BOSTON , December 11, 2024 – Seaport Therapeutics (“Seaport” or the “Company”), a clinical-stage biopharmaceutical company that is advancing novel neuropsychiatric medicines with a proven strategy and team, today announced the presentation of additional data from its first-in-human, multi-part Phase 1 study of SPT-300 in healthy volunteers at the American College of Neuropsychopharmacology (ACNP) Annual Meeting, held December 8-11, 2024 in Phoenix, Arizona. SPT-300 is an oral prodrug of allopregnanolone that is designed to retain the pharmacological activity of allopregnanolone, an endogenous neurosteroid. Allopregnanolone has been clinically validated in third-party trials as a rapidly acting antidepressant with anxiolytic effects. The Phase 1 study enrolled 99 participants (in three parts: double-blind single ascending dose, multiple ascending dose, and open-label food effect) and evaluated oral bioavailability, safety, tolerability, pharmacokinetics and GABA A target engagement. Pharmacodynamic assessments included quantitative electroencephalography (EEG) analyses of brain function and video-oculography (VOG) assessments of eye movement. SPT-300 was well-tolerated, with all adverse events (AE) being mild or moderate, transient and dose-dependent. The most common AE was somnolence, which was mild and transient in all cases. The study showed that SPT-300 had therapeutically relevant blood levels that were up to approximately nine times greater than published data on orally administered unmodified allopregnanolone, which has minimal bioavailability. New data in the poster presented at the conference include further safety analyses and pharmacokinetic and pharmacodynamic data. In the Phase 1 study, increases in EEG beta frequency power and reduction in saccadic eye velocity were observed at approximately 4 hours post-dose. Somnolence peaked in this same timeframe and diminished by 6 to 8 hours post-dose, consistent with both pharmacodynamic markers and blood levels of allopregnanolone. Based on the Phase 1 study results, the profile of SPT-300 is suitable for chronic dosing and oral administration at night in the planned Phase 2b placebo-controlled study in major depressive disorder with or without anxious distress. “ Together with previous clinical efficacy data, the further analyses of the Phase 1 study demonstrate that these doses of SPT-300 are well-tolerated and have rapidly acting pharmacodynamic activity. This reinforces our confidence in SPT-300 as an oral modulator of GABA A receptors and as a potential rapidly acting antidepressant and anxiolytic agent,” said Tony Loebel, M.D., Chief Medical Officer and President of Clinical Development of Seaport Therapeutics. “ There is a great need for innovative neuropsychiatric medicines, and an oral form of allopregnanolone has the potential to provide important advantages that we believe will allow for once-daily use on a chronic basis. We look forward to the next phase of our clinical development plan for SPT-300.” About SPT-300 SPT-300 (Glyph allopregnanolone), an oral prodrug of allopregnanolone, an endogenous neurosteroid, is in clinical stage development for the treatment of major depressive disorder (MDD) with or without anxious distress. Allopregnanolone has demonstrated therapeutic benefit in a range of neuropsychiatric conditions, but is currently only approved as an intravenous infusion, which has limited the scope of its clinical use. Using the Glyph™ platform, SPT-300 is designed to retain the activity, potency and the breadth of the natural biological response of endogenous allopregnanolone in an oral form, which has the potential to capture clinically important antidepressant and anxiolytic effects. In a Phase 2a clinical study, SPT-300 demonstrated initial proof-of-concept in a validated clinical model of anxiety in healthy volunteers. SPT-300 also demonstrated oral bioavailability, tolerability and γ-aminobutyric-acid type A (GABA A ) receptor target engagement in healthy volunteers in a Phase 1 clinical study. About Seaport Therapeutics Seaport Therapeutics is a clinical-stage biopharmaceutical company advancing the development of novel neuropsychiatric medicines in areas of high unmet patient needs. The Company has a proven strategy of advancing clinically validated mechanisms previously held back by limitations that are overcome with its proprietary Glyph technology platform. All the therapeutic candidates in its pipeline of potentially first and best-in-class medicines are based on the Glyph platform, which is uniquely designed to enable oral bioavailability, bypass first-pass metabolism and reduce liver enzyme elevations or hepatotoxicity and other side effects. Seaport is led by an experienced team that invented and advanced important neuropsychiatric medicines and is guided by an extensive network of renowned scientists, clinicians and key opinion leaders. For more information, please visit www.seaporttx.com . About PureTech Health PureTech is a clinical-stage biotherapeutics company dedicated to giving life to new classes of medicine to change the lives of patients with devastating diseases. The Company has created a broad and deep pipeline through its experienced research and development team and its extensive network of scientists, clinicians and industry leaders that is being advanced both internally and through its Founded Entities. PureTech's R&D engine has resulted in the development of 29 therapeutics and therapeutic candidates, including three that have been approved by the U.S. Food and Drug Administration. A number of these programs are being advanced by PureTech or its Founded Entities in various indications and stages of clinical development, including registration enabling studies. All of the underlying programs and platforms that resulted in this pipeline of therapeutic candidates were initially identified or discovered and then advanced by the PureTech team through key validation points. For more information, visit www.puretechhealth.com or connect with us on X (formerly Twitter) @puretechh. Cautionary Note Regarding Forward-Looking Statements This press release contains statements that are or may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation those related to Seaport’s development plans for its pipeline of therapeutics for the treatment of depression, anxiety and other neuropsychiatric disorders, potential benefits to patients, and Seaport’s and our future prospects, developments and strategies. The forward-looking statements are based on current expectations and are subject to known and unknown risks, uncertainties and other important factors that could cause actual results, performance and achievements to differ materially from current expectations, including, but not limited to, those risks, uncertainties and other important factors described under the caption "Risk Factors" in our Annual Report on Form 20-F for the year ended December 31, 2023, filed with the SEC and in our other regulatory filings. These forward-looking statements are based on assumptions regarding the present and future business strategies of the Company and the environment in which it will operate in the future. Each forward-looking statement speaks only as at the date of this press release. Except as required by law and regulatory requirements, we disclaim any obligation to update or revise these forward-looking statements, whether as a result of new information, future events or otherwise.