Bucindolol hydrochloride

在心血管介入治疗技术飞速发展的当下，导管消融在疗效提升、能量优化、技术革新及术者操作水平精进等方面均取得了显著进展。即便如此，抗心律失常药物治疗在临床实践中依然占据至关重要的地位。第36届长城心脏病学大会暨亚洲心脏大会2025期间，中国人民解放军总医院国建萍教授围绕抗心律失常药物的过去、现在与未来展开了深度分享，为参会者梳理了该领域的发展脉络与前沿方向。 抗心律失常药物的过去 20世纪70年代，来自英国牛津大学的Vaughan Williams教授首次对抗心律失常药物进行了分类（即Vaughan Williams分类法）： Ⅰ类，钠通道阻滞剂：主要作用是降低心肌兴奋性，当时对其认识较为局限，仅知晓其作用于钠离子通道。 Ⅱ类，G蛋白信号调节剂（β受体阻滞剂）：核心功能是降低交感神经兴奋性，最初被简单地归为β受体抑制剂。 Ⅲ类，钾通道阻滞剂：能够延长复极时间，早期已知的代表药物有胺碘酮、决奈达隆，但对其作用机制的认知较为浅显。 Ⅳ类，钙通道阻滞剂：通过影响钙离子发挥作用，当时并未对其进行更细致的分类研究。 当时，电生理刚刚起步，心电图为主要诊断手段，受标测条件和对心脏认知的限制，人们对这四类抗心律失常药物的认识有限。在1975年之后的半个世纪里，随着医学技术的不断进步和对心脏生理机制研究的深入，学者们逐渐发现这四类抗心律失常药物存在诸多亚型，它们分别作用于不同的心脏离子通道、G蛋白偶联的不同受体以及钙离子相关通路，抗心律失常药物分类也随之不断扩展。 抗心律失常药物的现在 1.抗心律失常药物使用框架 《2025欧洲心律协会（EHRA）抗心律失常药物实用纲要》指出，抗心律失常药物治疗依然占据至关重要的地位，并给出了在不同场景下进行抗心律失常药物使用的框架（ABC指示）： A - Appropriate（适当治疗）：对于部分患者，药物治疗仍是最佳治疗方案；对于部分因经济条件受限或无法接受消融治疗的患者，药物治疗或为唯一选择。 B - Backup（备用治疗）：当导管消融失败或不可行时，抗心律失常药物治疗可作为后备治疗策略。 C - Complementary（互补治疗）：药物治疗可与导管消融/器械等治疗手段协同应用，具有“1 + 1＞2”的效果。 2.抗心律失常药物分类拓展与特点 表1：《2025 EHRA抗心律失常药物实用纲要》给出的简化抗心律失常药物新分类 随着研究的不断深入，抗心律失常药物分类逐渐扩展，目前已有8类： 【0类】HCN通道阻滞剂 作用机制：制窦房结（SAN）自律性，阻断超极化激活的环核苷门控通道（HCN）If电流，对心室肌没有影响。 代表药物：伊伐布雷定。 【Ⅰ类】电压门控钠离子通道阻断剂 既往仅知道Ⅰ类抗心律失常药物作用于钠离子通道，近年来随着对钠离子通道结合和解离动力学等的了解，明确了不同药物对钠离子的解离速度不同，从而产生了不同的抗心律失常效果；并将Ⅰ类抗心律失常药物分为不同亚类。 Ⅰa类： 机制：降低异位心房、心室自律性，减慢旁路传导，延长有效不应期，减少折返倾向。 代表药物：奎尼丁、阿义马林、丙吡胺。 Ⅰb类： 机制：降低异位心房、心室自律性；减低DAD诱导触发活动；单向和双向阻滞减少折返。 代表药物：利多卡因、美西律。 Ⅰc类： 机制：降低异位心房、心室自律性；减低DAD诱导触发活动；单向和双向阻滞减少折返，快速心室率时降低传导和兴奋性，阻断折返旁路。 代表药物：普鲁帕酮、氟卡胺。 Ⅰd类： 机制：减少动作电位恢复时间，减少早后除极和延迟后除极的触发活动。 代表药物：雷诺嗪。 【Ⅱ类】自主神经抑制剂和激动剂  既往仅知道Ⅱ类抗心律失常药物是β受体抑制剂，现在已明确其可作用于G蛋白偶联的β受体、M受体及腺苷受体。 Ⅱa类：β肾上腺素受体阻滞剂，如阿替洛尔、比索洛尔、美托洛尔。  Ⅱb类：β肾上腺素能受体激动剂，如异丙肾上腺素。 Ⅱc类：毒蕈碱型M2受体抑制剂，如阿托品 。 Ⅱd类：毒蕈碱型M2受体激动剂，如地高辛、洋地黄毒苷。 Ⅱe类：腺甘A1受体激动剂，如腺苷。 【Ⅲ类】钾离子通道阻滞与开放剂  既往仅知道Ⅲ类抗心律失常药物为钾离子通道阻滞剂，包括胺碘酮、决奈达隆等药物，随着研究的深入，目前明确其可作用于多靶点，不仅作用于钾离子，还可作用于钠离子和钙离子等。 Ⅲa类： 非选择性钾通道阻滞剂，如胺碘酮。 HERG通道介导的快速钾离子电流阻滞剂，如多非利特、伊布利特、索他洛尔。 IKur钾离子通道阻滞剂，如维纳卡兰（Vernakalant）。 Ⅲb类：KATP钾离子通道开放剂，如尼可地平。 Ⅲc类：GIRK1和GIRK4阻滞剂，尚无获批药物。 【Ⅳ类】钙离子触控调节剂 Ⅳa：表面膜非选择性及Cav1.2和Cav1.3通道介导的L型钙通道阻滞剂，如维拉帕米、地尔硫䓬。 Ⅳb：细胞内钙通道阻滞剂，无批准药物。 【Ⅴ类】机械敏感性通道阻滞剂 无获批药物，正在研发中。 【Ⅵ类】缝隙连接通道阻滞剂 无获批药物，正在研发中。 【Ⅶ类】上游靶向调节剂 代表药物包括血管紧张素转换酶抑制剂（ACEI）、血管紧张素受体脑啡肽酶抑制剂（ARNI）、盐皮质激素受体拮抗剂、钠-葡萄糖共转运蛋白-2（SGLT-2）抑制剂、他汀类药物等。 图1. 抗心律失常药物的作用靶点 相较于1975年发表的Vaughan Williams分类，抗心律失常药物新分类呈现出诸多新特点： 从“单一靶点” 到 “多靶点协同” 以胺碘酮、决奈达隆为代表，既往人们对这类药物的作用靶点认知较为单一，如今发现其可作用于多靶点，不仅影响钾离子通道，还对钠离子、钙离子通道等产生作用，通过多靶点协同发挥抗心律失常效果。 从 “下游干预” 到 “上游预防” 除针对心律失常发作本身进行治疗外，一些既往用于其他疾病治疗的药物也被发现具有抗心律失常的上游预防作用，如SGLT2抑制剂（既往用于降糖）、ACEI/ARB类药物（既往用于降压）、他汀类药物（既往用于调脂、抗炎）等，能够抑制炎症，抑制心肌纤维化，从源头减少心律失常的发生风险。 从“电生理主导”到“结构代谢-信号整合” 心律失常药物分类中预留了第Ⅴ类和第Ⅵ类药物的席位，分别针对机械敏感通道（结构-电耦合）和缝隙连接通道（细胞间通讯）。目前这两类药物仍处于研发阶段，尚未应用于临床。 从“药物研发”到“药物再定位” 即“老药新用”，一些原本用于其他疾病治疗的药物，在临床应用中被发现具有抗心律失常作用，如雷诺嗪最初用于抗心绞痛治疗，如今发现其可用于治疗心律失常。 抗心律失常药物的发展 1.心房选择性机制药物研发 选择性作用于心房，对心室没有影响或影响非常小，从而避免了抗心律失常药物导致的心律失常副作用，如AP30663和Doxapram。 (1) 小电导钙激活钾通道抑制剂（AP30663） 其作用机制为抑制参与心房复极的通道，延长心房不应期。在实验模型中，该药物能够终止对维那卡兰抵抗的房颤，核心优势在于安全性高（对心室影响小）且具有心房选择性，主要应用于房颤转复。 (2) 多沙普仑 多沙普仑是“老药新用”的代表药物之一，其为一种心房选择性药物，可通过抑制在房颤中表达上调的TASK1钾通道，延长心房不应期，减少房颤负荷，目前处于Ⅱ期临床试验阶段，主要用于房颤复律。 2.多离子通道组织剂探索 临床医生一直期待能研发出一种 “胺碘酮升级版” 的多离子通道阻滞剂。这主要是因为胺碘酮的作用非常强大，疗效显著，但副作用限制了其临床应用。 (1) Sulcardine Sulcardine是一种多离子通道阻滞剂，能够抑制钠离子、钾离子等多个离子通道，作用类似雷诺嗪。可以缩短J点至T波峰的间隔，抑制早后除极（EADs）。 Sulcardine主要用于室性心律失常和房颤治疗，可通过静脉输注用于房颤终止。 目前正在进行剂量探索研究，评估其终止房颤的疗效和安全性，且研究显示其可能降低尖端扭转型室性心动过速（TdP）风险（不显著延长QT间期）。 值得一提的是，由于在相关研究报告中Sulcardine具有一些安全事件，因此之后未在更新Sulcardine相关研究报道。 (2) 布尼达隆（Budiodarone） 布尼达隆是胺碘酮的改良版，其半衰期短，累积毒性相对较小，主要用于房颤预防。近期，该药物再次引起了研究人员的关注，计划开展更多临床研究，其快速清除的特性使其安全性优于胺碘酮。 3.快速起效药物开发 快速起效药物对于新发心律失常的转复具有重要意义，能够及时缓解患者症状，为治疗争取时间。 (1) 依曲帕米（Etripamil） 依曲帕米是一种新型L型钙通道阻滞剂，具有快速起效（Tmax≤7 min）和半衰期短的特点，可通过鼻喷雾给药，方便患者院外使用，有望成为“口袋药物”，但其具有局部鼻刺激等缺点。 值得一提的是，依曲帕米除可转复房室结折返性心动过速外，对于新发房颤也有转复作用，目前仍在进行Ⅲ期临床试验，我们拭目以待。 (2) 吸入型氟卡尼 吸入型氟卡尼可用于房颤转复，其可通过肺部快速吸收，能够显著缩短房颤转复时间，中位转复时间约12.8 min，优于口服制剂。然而，其或存在房扑转换伴1:1房室传导等潜在风险。该药物或可避免首过代谢，提高生物利用度，目前仍处于Ⅲ期临床试验阶段，结果如何我们拭目以待。 4.基因指导的个性化治疗推进 精准医疗是未来医学发展的重要趋势，在抗心律失常药物领域，基因指导的个性化治疗（即精准治疗）能够根据患者的基因类型选择合适的药物，提高治疗效果，减少不良反应。 (1) 布新洛尔（Bucindolol） 布新洛尔是一种非选择性β受体阻滞剂，可同时抑制α1肾上腺素能受体，引起血管舒张。研究发现，其可减少特定基因型（ADRB1 Arg/Arg）患者的新发房颤风险，主要用于心衰伴房颤患者的房颤预防。 目前，该药物在特定人群（如心衰患者）中已显示出有效性，但尚未获得广泛批准，未来有望在基因检测指导下实现更精准的临床应用。 5.重新利用现有药物 进一步挖掘现有药物的抗心律失常潜力，探索 “老药新用”的可能性。在临床实践中，密切关注药物使用过程中出现的意外治疗效果，及时开展相关研究，为抗心律失常治疗提供更多选择（如如Doxapram）。 总体而言，关于新型抗心律失常药物的未来发展，可从优化现有药物、深化精准医疗和验证新型疗法三个方向努力，迈向更快速、更精准、更安全、更便捷的新时代。 （特别鸣谢媒体合作伙伴：医脉通） GW-ICC/AHS 2025 点击阅读原文 关注最新资讯

WESTMINSTER, Colo., Aug. 01, 2024 (GLOBE NEWSWIRE) -- ARCA biopharma, Inc. (Nasdaq: ABIO), (the “Company”) a biopharmaceutical company applying a precision medicine approach to developing genetically targeted therapies for cardiovascular diseases, today reported second quarter 2024 financial results and provided a corporate update. In April 2022, ARCA established a Special Committee of the board of directors (the “Board”) of ARCA to conduct a comprehensive review of strategic alternatives. As part of the strategic review process, the Company explored potential strategic alternatives that included, without limitation, an acquisition, merger, business combination or other transactions. The Company has and is continuing to explore strategic alternatives related to its product candidates and related assets, including, without limitation, licensing transactions and asset sales. On April 3, 2024, following a comprehensive review of strategic alternatives, the Company, Atlas Merger Sub Corp., a Delaware corporation and a wholly-owned subsidiary of ARCA (“Merger Sub I”), Atlas Merger Sub II LLC, a Delaware limited liability company and a wholly-owned subsidiary of ARCA (“Merger Sub II”) and Oruka Therapeutics, Inc., a Delaware corporation (“Oruka”), entered into an Agreement and Plan of Merger and Reorganization (the “Merger Agreement”), pursuant to which, among other matters, and subject to the satisfaction or waiver of the conditions set forth in the Merger Agreement, Merger Sub I will merge with and into Oruka, with Oruka continuing as a wholly owned subsidiary of ARCA and the surviving corporation of such merger (the “First Merger”) and as part of the same overall transaction, the surviving corporation in the First Merger will merge with and into Merger Sub II with Merger Sub II continuing as a wholly owned subsidiary of ARCA and the surviving entity of such merger (the “Second Merger” and together with the First Merger, the “Merger”). The Merger is intended to qualify for federal income tax purposes as a tax-free reorganization under the provisions of Section 368(a) of the Internal Revenue Code of 1986, as amended. Additional descriptions about the Merger Agreement and related agreements were previously disclosed on a Current Report on Form 8-K filed with the U.S. Securities and Exchange Commission (the “SEC”) on April 3, 2024. In connection with the proposed Merger, the Company has filed relevant materials with the SEC, including a registration statement on Form S-4 that contains a definitive proxy statement and prospectus of the Company. In connection with the Merger, the Company will dispose of (or is in the process of disposing of) its legacy technology and intellectual property, including those related to Gencaro™ (bucindolol hydrochloride) and Recombinant Nematode Anticoagulant Protein c2 (“rNAPc2”). Any such disposal of legacy technology and intellectual property will be contingent upon obtaining stockholder approval for the Merger and is expected to occur immediately prior to or concurrently with the closing of the Merger. In the event that the Company shall enter into an agreement for any such sale or other disposition of its legacy assets at or prior to the closing of the Merger, the net proceeds received at or prior to the closing of the Merger will be included in the calculation of the net cash of the Company as of the closing. The Company’s future operations are highly dependent on the success of the Merger and there can be no assurances that the Merger will be successfully consummated. In the event that the Company does not complete the Merger, the Company may explore strategic alternatives, including, without limitation, another strategic transaction and/or pursue a dissolution and liquidation of the Company. Second Quarter 2024 Summary Financial Results Cash and cash equivalents were $33.3 million as of June 30, 2024, compared to $37.4 million as of December 31, 2023. ARCA believes that its current cash and cash equivalents, consisting primarily of money market funds, will be sufficient to fund its operations through the end of 2025. Our future viability beyond that point is dependent on the results of the strategic review process and our ability to raise additional capital to fund our operations. We expect to continue to incur costs and expenditures in connection with the process of evaluating strategic alternatives. There can be no assurance, however, that we will be able to successfully consummate any particular strategic transaction, including the Merger. The process of continuing to evaluate these strategic options may be very costly, time-consuming and complex and we have incurred, and may in the future incur, significant costs related to this continued evaluation, such as legal, accounting and advisory fees and expenses and other related charges. General and administrative (G&A) expenses were $3.0 million for the quarter ended June 30, 2024, compared to $1.7 million for the corresponding period in 2023, an increase of approximately $1.3 million. During the three months ended June 30, 2024, we recorded $370,000 for one-time termination benefits related to the separation of Dr. Michael Bristow, the former Chief Executive Officer of ARCA, effective April 3, 2024. The increase for the three month period was primarily the result of a $0.9 million increase in professional fees primarily related to the Merger Agreement discussed above and $0.4 million higher one-time termination benefits from the termination discussed above in 2024. G&A expenses in 2024 are expected to be higher than those in 2023 as we incur professional fees related to the Merger Agreement discussed above and maintain administrative activities to support our ongoing operations. We expect to incur significant costs related to our exploration of strategic alternatives and the Merger, including legal, accounting and advisory expenses and other related charges. Research and development (R&D) expenses were $0.1 million for the quarter ended June 30, 2024, compared to $0.3 million for the corresponding period in 2023. Of the $0.2 million decrease in R&D expenses in the second quarter of 2024 as compared to the second quarter of 2023, $0.1 million was primarily related to decreased headcount and $0.1 million was primarily related to the unrestricted research grants with ARCA’s former President and Chief Executive Officer’s academic research laboratory at the University of Colorado. There was no expense under these arrangements for the three months ended June 30, 2024. Total expense under these arrangements for the three months ended June 30, 2023 was $0.1 million. In December 2023, the Company made a payment of $125,000 for the grant period July 2022 through December 2023 under these arrangements. As discussed above, the former President and Chief Executive Officer resigned in April 2024. R&D expense in 2024 is expected to be lower than 2023 while we explore strategic alternatives. Should we resume clinical trials of product candidates, we expect research and development costs to increase significantly for the foreseeable future as our product candidate development programs progress. Total operating expenses for the quarter ended June 30, 2024 were $3.1 million compared to $2.0 million for the second quarter of 2023. Net loss for the quarter ended June 30, 2024 was $2.7 million, or $0.18 per basic and diluted share, compared to $1.5 million, or $0.10 per basic and diluted share in the second quarter of 2023. About ARCA biopharmaARCA biopharma is dedicated to developing genetically and other targeted therapies for cardiovascular diseases through a precision medicine approach to drug development. For more information, please visit www.arcabio.com or follow the Company on LinkedIn. Safe Harbor Statement This press release contains "forward-looking statements" for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995 concerning ARCA, Oruka, the proposed pre-closing financing and the proposed merger between ARCA and Oruka (collectively, the “Proposed Transactions”) and other matters. These statements include, but are not limited to, express or implied statements relating to ARCA’s or Oruka’s management team’s expectations, hopes, beliefs, intentions or strategies regarding the future including, without limitation, statements regarding: the Proposed Transactions and the expected effects, perceived benefits or opportunities, including investment amounts from investors and expected proceeds, and related timing with respect thereto, expectations regarding or plans for discovery, preclinical studies, clinical trials and research and development programs, in particular with respect to ORKA-001 and ORKA-002, and any developments or results in connection therewith, including the target product profile of each of ORKA-001 and ORKA-002; the anticipated timing of the commencement of and results from those studies and trials; expectations regarding the use of proceeds, the sufficiency of post-transaction resources to support the advancement of Oruka’s pipeline through certain milestones and the time period over which Oruka’s post-transaction capital resources will be sufficient to fund its anticipated operations; the cash balance of the combined entity at closing; expectations regarding the treatment of psoriasis and associated diseases; expectations related to ARCA’s contribution and payment of dividends in connection with the Merger, including the timing thereof; the expected trading of the combined company’s stock on Nasdaq under the ticker symbol “ORKA;” potential future development plans for Gencaro, including ARCA’s ability to continue development of Gencaro; ARCA’s ability to secure sufficient financing to support any clinical trials for Gencaro: and the ability of ARCA’s financial resources to support its operations at the current levels through the end of fiscal year 2025, ARCA’s ability to obtain additional funding when needed or enter into a strategic or other transaction, the extent to which ARCA’s issued and pending patents may protect ARCA’s products and technology, the potential of such product candidates to lead to the development of safe or effective therapies, ARCA’s ability to enter into collaborations, or ARCA’s ability to maintain listing of its common stock on a national exchange. These and other factors are identified and described in more detail in ARCA’s filings with the Securities and Exchange Commission, including without limitation ARCA’s annual report on Form 10-K for the year ended December 31, 2023 and the registration statement on Form S-4, as amended, filed with the SEC, and subsequent filings. ARCA disclaims any intent or obligation to update these forward-looking statements. All forward-looking statements in this press release are current only as of the date hereof and, except as required by applicable law, ARCA undertakes no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. All forward-looking statements are qualified in their entirety by this cautionary statement. No Offer or Solicitation This press release and the information contained herein is not intended to and does not constitute (i) a solicitation of a proxy, consent or approval with respect to any securities or in respect of the Proposed Transactions or (ii) an offer to sell or the solicitation of an offer to subscribe for or buy or an invitation to purchase or subscribe for any securities pursuant to the Proposed Transactions or otherwise, nor shall there be any sale, issuance or transfer of securities in any jurisdiction in contravention of applicable law. No offer of securities shall be made except by means of a prospectus meeting the requirements of the Securities Act of 1933, as amended, or an exemption therefrom. Subject to certain exceptions to be approved by the relevant regulators or certain facts to be ascertained, the public offer will not be made directly or indirectly, in or into any jurisdiction where to do so would constitute a violation of the laws of such jurisdiction, or by use of the mails or by any means or instrumentality (including without limitation, facsimile transmission, telephone and the internet) of interstate or foreign commerce, or any facility of a national securities exchange, of any such jurisdiction. NEITHER THE SEC NOR ANY STATE SECURITIES COMMISSION HAS APPROVED OR DISAPPROVED OF THE SECURITIES OR DETERMINED IF THIS PRESS RELEASE IS TRUTHFUL OR COMPLETE. Important Additional Information About the Proposed Transactions Will be Filed with the SEC This press release is not a substitute for the registration statement on Form S-4 or any other document that ARCA has filed or may file with the SEC in connection with the Proposed Transactions. In connection with the Proposed Transactions, ARCA has filed with the SEC a registration statement on Form S-4, which contains a proxy statement/prospectus of ARCA. ARCA URGES INVESTORS AND STOCKHOLDERS TO READ THE REGISTRATION STATEMENT ON FORM S-4, PROXY STATEMENT/PROSPECTUS AND ANY OTHER RELEVANT DOCUMENTS THAT ARE OR MAY BE FILED WITH THE SEC, AS WELL AS ANY AMENDMENTS OR SUPPLEMENTS TO THESE DOCUMENTS, CAREFULLY AND IN THEIR ENTIRETY, BECAUSE THEY DO AND WILL CONTAIN IMPORTANT INFORMATION ABOUT ARCA, ORUKA, THE PROPOSED TRANSACTIONS AND RELATED MATTERS. Investors and stockholders can obtain free copies of the proxy statement/prospectus and other documents filed by ARCA with the SEC through the website maintained by the SEC at www.sec.gov. Stockholders are urged to read the proxy statement/prospectus and the other relevant materials filed with the SEC before making any voting or investment decision with respect to the Proposed Transactions. In addition, investors and stockholders should note that ARCA communicates with investors and the public using its website (https://arcabio.com/investors/). Participants in the Solicitation ARCA, Oruka and their respective directors and executive officers may be deemed to be participants in the solicitation of proxies from stockholders in connection with the Proposed Transactions. Information about ARCA’s directors and executive officers including a description of their interests in ARCA is included in ARCA’s most recent Annual Report on Form 10-K, including any information incorporated therein by reference, as filed with the SEC. Information about ARCA’s and Oruka’s respective directors and executive officers and their interests in the Proposed Transactions is included in the proxy statement/prospectus relating to the Proposed Transactions filed with the SEC. Investor & Media Contact:Jeff Dekker720.940.2122ir@arcabio.com ARCA BIOPHARMA, INC.BALANCE SHEET DATA(in thousands)(unaudited) June 30, 2024December 31, 2023Cash and cash equivalents$33,283$37,431Working capital$32,549$36,955Total assets$33,844$37,861Total stockholders’ equity$32,573$37,020 ARCA BIOPHARMA, INC. STATEMENTS OF OPERATIONS(unaudited) Three Months EndedJune 30, Six Months EndedJune 30, 2024 2023 2024 2023 (in thousands, except share and per share amounts) Costs and expenses: General and administrative$2,992 $1,719 $5,309 $3,125 Research and development 130 254 295 644 Total costs and expenses 3,122 1,973 5,604 3,769 Loss from operations (3,122) (1,973) (5,604) (3,769) Interest and other income 444 493 917 943 Net loss$(2,678) $(1,480) $(4,687) $(2,826) Net loss per share: Basic and diluted$(0.18) $(0.10) $(0.32) $(0.20)Weighted average shares outstanding: Basic and diluted 14,506,879 14,410,143 14,504,011 14,410,143