CYP2C19

导致人类死亡最多的疾病是什么？提到这个问题，“癌症”也许是许多人脑海里想到的第一个答案。事实上，癌症并非致死率最高的疾病，人类健康的“头号杀手”其实“另有其病”，那就是——心血管疾病。过去20多年来，心脑血管疾病一直是全球疾病死亡的首要原因。根据WHO发布的《2019全球健康预测》报告，2019年，在全球5540万死亡病例中，其中，有近900万死于缺血性心脏病，与2000年相比，心脏病死亡人数增加了200多万。此外，中风患者死亡人数高达655万，包括缺血性心脏病和中风在内的心血管疾病成为全球疾病死亡的最主要原因。目前，市场上也已研发出多款治疗药物，例如氯吡格雷、坎格雷洛、替格瑞洛等抗血小板药物，以及华法林、肝素等抗凝血药物。尽管已有众多治疗药物，但由于药物副作用以及不同个体对抗血小板药物的反应性不同，目前仍有患者对抗血小板药物存在抵抗，即治疗反应不足，其他替代药物又可能伴随着较高的出血风险。药物抵抗问题摆在了科研、产业界的人士面前，如何为患者提供疗效更好、安全性更高的治疗药物成为当下的重点。上海柯君医药科技有限公司（以下简称“柯君医药”）便是一家致力于研发新一代抗血小板药物，以解决药物抵抗问题的创新药企。柯君医药于2018年在上海创立，是一家聚焦于心脑血管和抗病毒领域治疗药物研发的初创企业，在研产品包括抗血小板、抗凝血、抗呼吸道病毒感染、抗乙肝药物等。成立至今，柯君医药自主构建了两大核心技术平台——靶向前药技术平台和核酸药物技术平台。依托团队优势和核心技术，公司在心脑血管和抗病毒领域布局了多条创新管线。值得一提的是，公司自主研发的抗血小板药物CG-0255已完成1期临床试验，目前正在推进关键注册临床研究，未来有望通过快速审评流程实现上市。核心团队从吉利德走出，平均具有15年医药行业经验在短短5年时间里，柯君医药完成了团队组建、平台搭建、管线推进等重要事项，并且核心管线即将进入注册临床试验阶段，不日将迈入产品化阶段。公司快速且顺利的发展过程离不开一位核心人物的执掌——柯君医药创始人兼首席执行官何公欣博士。何博士是一位深耕生物医药行业30年的科学家兼创业者。正式进入医药领域前，何博士在日本九州大学获得了合成化学博士学位，并在美国加州大学完成了博士后研究。1992年，何博士进入美国吉利德科学公司，先后担任吉利德美国总部科学家和研发高级总监等职位。在吉利德任职期间，何博士曾参与并主导了多个国际best-in-class新药的研发工作，值得关注的是，他还是目前世界广泛使用的抗乙肝病毒药物替诺福韦新一代前药替诺福韦艾拉酚胺 (TAF) 的主要发明人和研发项目负责人。此外，何博士也是多个抗病毒疗法的共同发明人，在心脑血管、核酸药物和多种抗病毒治疗领域具有丰富研发经验。2008年，何博士回国出任吉利德中国区首席代表及首任总经理，负责吉利德在国内搭建区域分部工作。在此期间，何博士从一位药物研发者逐渐成为一位负责生产运营、供应链管理以及企业发展的管理者。2018年，何博士担任吉利德中国区负责人已整整10年，工作期间，对国内整体医药运行体系建立了深刻理解并积累了广泛资源。也正是在这个时候，“参与到中国生物医药领域的发展中，促进国内医药健康行业发展”的想法再次在何博士心里涌现。“创办一家公司，将科学理论真正转化实际成果，为患者带来更好原研新药”怀着这样的愿景，2018年，何博士选择离开工作了26年的吉利德，在国内创立了柯君医药，并将研发重点聚焦在致死率最高的心血管疾病和抗病毒领域。而后，何博士快速组建了一个具有相同价值理念、高度凝聚力以及专业实力的团队，团队成员超半数为何博士在吉利德的前同事们，其中包括首席运营官陈佳琳以及财务副总裁姚莉，他们共同见证了吉利德从一个小型公司发展成为一个跨国药企的过程，并且拥有低调务实的特性和专业认真的执行能力。除此之外，公司的科学家团队也“众星云集”，包含多位药物研发领域的资深科学家。其中，化学研发副总裁陈小五博士拥有超25年的创新药研发经验，在吉利德参与了流感口服药达菲（奥司他韦）的后期研发，并在多个后来成为“重磅炸弹产品”的艾滋病和丙肝药物研发过程中做出了重要贡献．同时，柯君医药还吸引了病毒学领域资深科学家聂玉春博士担任生物研发副总裁。聂博士深耕核酸药物抗病毒领域10余年，此前曾任罗氏研发中心和斯隆-凯特琳癌症中心担任高级研发职位。此外，医学方面的资深科学家严桦女士担任公司临床项目管理高级总监，她拥有近40年药物研发管理经验，曾先后在上海徐汇区中心医院、中美上海施贵宝、上海新生源医药负责临床、注册申报、药理毒理及新药研发管理等工作。至此，柯君医药打造了一个在药物研发领域平均具有15年以上经验的专业化团队，核心成员的专业知识和经验覆盖新药研发的整个流程，为公司的运营发展和在研管线推进提供了充足动力。两大核心技术平台，加速科研成果落地转化基于核心团队的丰富经验和对临床需求的综合判断，柯君医药决定布局心脑血管疾病领域和抗病毒领域，并根据市场需求，重点研发新一代抗血小板药物以及广谱呼吸道抗病毒药物。明确发展规划和研发领域后，柯君医药迅速搭建了两大核心技术平台——靶向前药技术平台和核酸药物技术平台。其中，靶向前药技术平台率先在2020年完成建构。简单而言，“前药”是一种需要经过体内的酶或非酶转化才能释放出活性药物、从而发挥药效的治疗药物。值得关注的一点是，吉利德拥有成熟的前药技术，而何博士在吉利德工作期间就曾主导过替诺福韦前药TAF的研究。在何博士的带领以及团队的努力下，柯君医药在2年内搭建起了一个专有的靶向前药技术平台。“靶向”是该平台的突出优势之一，它能够修饰改善药物的理化特性、递送转运效率、酶选择性、化合物稳定性等成药特性，从而实现针对不同疾病器官的靶向递送，即将有效成分更加高效地递送到特定治疗位置，从而在最小安全剂量下达到最佳药效。此外，该平台能够基于已验证活性物质靶点快速形成具有重大药代/药效或安全性改进的新型靶向前药，高效产生具有临床开发价值且成药性明确的候选化合物。而核酸药物技术平台则由聂博士主导开发。该平台具备小核酸药物和信使RNA药物的序列设计和修饰标记能力，以及多元化先进的药物递送技术，能够针对肝靶向和肝外器官选择性使用药物递送平台，开发针对全身给药或局部给药等不同机制的临床候选产品。有效克服氯吡格雷抵抗、20分钟内起效，核心管线临床效果显著在核心技术平台和团队两大“引擎”推动下，柯君医药目前在心脑血管和抗病毒领域共布局了4条在研管线。其中，核心管线抗血小板药物CG-0255进展最快。CG-0255是新一代P2Y12类抗血小板药物，被开发用于心脑血管疾病的抗板治疗。值得注意的是，CG-0255采用的是水解前药设计，基于深厚的前药技术功底做出了科学上的突破，设计出世界第一款硫醇前药，通过羧酸酯酶转化生成有抗血小板作用的活性代谢产物H4，完全绕过了抗板药物普遍依赖的氧化代谢途径。因此，它在体内可通过水解酶的作用快速产生活性代谢物，且由于水解酶的广泛分布几乎不存在个体代谢差异。另外，CG-0255也是世界上目前第一个既可以口服，也可以注射的P2Y12抑制剂，填补了国内注射针剂的空白。氯吡格雷是目前最为常用的抗血小板药物之一，它是一种无活性前体药物，主要依赖细胞色素P450酶系统（CYP）中的酶，其中最主要的是CYP2C19，才能够被激活，从而转化为有抗血小板作用的活性代谢产物H4，进而发挥治疗作用。但是，世界上很大一部分人口携带的是CYP2C19功能丧失的等位基因，这意味着，氯吡格雷在该类人群中代谢缺失或者代谢极其缓慢，继而导致服药后所产生的抗血小板作用弱，发生“氯吡格雷抵抗”。正因如此，FDA在批准的说明书上对氯吡格雷添加了黑框警告。现有研究显示，CYP2C19等位基因功能丧失在所有族裔的患者中都十分常见。25%-30%的白人人群存在CYP2C19功能缺失等位基因，而这个比例在东亚人群中更是高达59%1。并且多项临床研究表明，氯吡格雷的疗效确实在这些患者中存在降低或丧失。这也意味着，“氯吡格雷抵抗”问题在国内心脑血管患者身上更加明显。另外，氯吡格雷仅可口服给药，无法静脉注射，起效时间约为2～8小时，限制了其在紧急状况下的临床应用。与氯吡格雷不同的是，CG-0255可以完全绕过与其相关的CYP代谢问题。并且在靶向前药技术的支持下，CG-0255给药更加精准，能够以最小剂量达到更大效果。此外，CG-0255生物利用度高、起效快，可通过静脉注射和口服给药，有望作为氯吡格雷的替代药，全面解决患者潜在的药物抵抗问题，同时扩大了临床应用场景。此前，陈小五博士在2023年度美国心脏协会（2023 AHA）年会的特色科学专场发表了CG-0255的1期临床研究结果。这是一项开放标签、阳性对照、剂量递增、1期临床试验，5个队列（每组6名参与者）通过推注或输注不同剂量的方式给予CG-0255，以坎格雷洛为阳性对照组，旨在评估健康受试者经静脉注射CG-0255的安全性、耐受性、药效学和药代动力学。研究结果显示，CG-0255具备良好的安全性和耐受性，可快速、稳定转化为活性代谢产物H4，并且血小板聚集抑制效果呈明确剂量依赖关系且作用迅速，给药20分钟内血小板聚集抑制率超过90%。此外，CG-0255不可逆地结合P2Y12受体，抗血小板作用持久，给药24小时后IPA仍在持续。重要的是，CG-0255 的血小板聚集抑制作用无显著个体差异。抗病毒管线即将申请IND，布局广谱呼吸道抗病毒药物空白市场作为一家核心团队皆从吉利德走出的初创企业，柯君医药同样布局了抗病毒领域，但并非模仿复刻吉利德，而是在形成核心技术的基础上，希望像吉利德研发出治疗丙肝的“神药”索磷布韦一样，在抗病毒领域有所建树。因此，柯君医药专注于广谱呼吸道和乙肝抗病毒药物领域的研发。其中，RNA聚合酶抑制剂CG-0980是公司针对广谱呼吸道RNA病毒感染适应症研发，它是一款具有广谱抗病毒活性的小分子直接抗病毒药物，与仅针对某一特定感染源的药物不同的是，它对于多种常见呼吸道RNA病毒，如呼吸道合胞病毒（RSV）、偏肺病毒（hMPV）、副流感病毒、普通冠状病毒、鼻病毒等均有明确的抗病毒活性，适用于大部分人群对于呼吸道病毒感染的治疗及密接暴露后预防的临床潜在需求。其临床前研究显示，CG-0980具有良好的安全性特征，有潜力覆盖最广泛的患者群体，填补广谱呼吸道抗病毒药物这一空白市场。目前，CG-0980正处于临床前研究阶段，预计将在今年年底申请IND。完成亿元B轮融资，探索中国生物医药发展新模式在柯君医药公布CG-0255的1期临床试验的积极数据后不久，在今年年初，公司再次宣布，顺利完成亿元B轮融资。本轮融资由泰珑投资旗下泰鲲基金领投，其他主要投资方包括骊宸投资、泰煜投资等，原有投资方宏海创健、汉康资本等也持续加持。新的资金加持也进一步支持了持续推进中的CG-0255关键注册临床研究，同时推动其他核心在研管线加速向临床阶段推进。快速推进CG-0255的临床开发和商业化进程成为柯君医药短期内的重要目标。“今年将快速完成CG-0255的关键注册临床研究工作，后续有望通过快速审评流程实现上市，届时，也期待能够为国内外患者提供更好的治疗选择。”陈小五博士说道。“柯君医药希望探索中国生物医药发展的新模式”怀着这个伟大愿景，陈小五博士表示，尽管目前柯君医药是一家小型初创公司，但在未来，柯君医药将继续研发针对心脑血管疾病的联合疗法，同时，推进抗病毒领域管线的进一步研发，并实现候选产品的商业化，为患者提供更多有效的治疗药物，为社会创造广泛的价值，这也是柯君团队大多数科学家踏入生物医药行业的初心。* 参考资料：1. Ellithi M, Baye J, Wilke RA. CYP2C19 genotype-guided antiplatelet therapy: promises and pitfalls. Pharmacogenomics. 2020 Aug;21(12):889-897. doi: 10.2217/pgs-2020-0046. Epub 2020 Jul 29. PMID: 32723143; PMCID: PMC7444625.近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

2024美国癌症研究协会（AACR）年会将于当地时间4月5日至10日在美国圣地亚哥举行。作为肿瘤领域最受关注的国际学术会议之一，AACR年会聚焦肿瘤早期研究和创新进展，更新发布肿瘤领域前沿的研究成果。日前，AACR官网公布了大会标题，恒瑞医药已有卡瑞利珠单抗、阿帕替尼、SHR-4602等创新药在内的9项抗肿瘤研究成果入围 1-9 。本文特做梳理，一同浏览。 01产品：卡瑞利珠单抗+阿帕替尼 英文标题：Camrelizumab combined with apatinib and hepatic artery infusion chemotherapy (HAIC) as conversion therapy for patients with unresectable hepatocellular carcinoma(HCC): A single-arm exploratory clinical study 中文标题：卡瑞利珠单抗联合阿帕替尼和肝动脉灌注化疗(HAIC)作为不可切除肝细胞癌(HCC)患者的转化治疗：一项单臂探索性临床研究 作者：赵磊等 山东省肿瘤医院 02产品：卡瑞利珠单抗 英文标题：Camrelizumab plus chemotherapy as neoadjuvant treatment for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC): A single-center, randomized, phase II trial 中文标题：卡瑞利珠单抗联合化疗用于可切除局部晚期食管鳞状细胞癌(LA-ESCC)新辅助治疗的单中心、随机、II期试验 作者：沈琳、董晓凤等 北京大学肿瘤医院 03产品：阿帕替尼 英文标题：Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates 中文标题：200mg每日1次给药阿帕替尼对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4底物的药代动力学的影响 作者：S. Jang Elevar Therapeutics, Fort Lee, NJ 04产品：SHR-4602 英文标题：SHR-4602, next generation of HER2-targeting ADC with potent anti-tumor efficacy overcoming the resistance of HER2 ADC with Topo I inhibitor payload in xenograft models 中文标题：SHR-4602：一种具有强大的抗肿瘤疗效的新一代HER2靶向ADC药物，在异种移植模型中克服了Topo I抑制剂负载的HER2 ADC耐药性 作者：田宇楠等 江苏恒瑞医药股份有限公司 05产品：SHR1127 英文题目：Discovery of SHR1127, an orally bioavailable, highly potent and selective KRAS G12D inhibitor 中文题目：SHR1127：一种口服生物利用度高、选择性强的KRAS G12D抑制剂 作者：李心等 江苏恒瑞医药股份有限公司 06产品：HRA00184-C004 英文标题：HRA00184-C004, preclinical characterization of a novel tissue factor-targeted antibody-drug conjugate 中文标题：HRA00184-C004：一种新型组织因子靶向抗体-药物偶联物的临床前表征 作者：应晗笑等 江苏恒瑞医药股份有限公司 07产品：SDP03923-000-9106 英文标题：SDP03923-000-9106, a novel and optimized LIV-1 ADC with superior anti-tumor efficacy in breast cancer xenograft models 中文标题：SDP03923-000-9106：一种在乳腺癌异种移植模型中具有良好的抗肿瘤效果的新型优化LIV-1 ADC药物 作者：龚彦玲等 江苏恒瑞医药股份有限公司 08产品：HRA00242-C004 英文标题：HRA00242-C004, a novel anti-PSMA ADC with high DAR reveals potent in vitro and in vivo anti-tumor efficacy 中文标题：HRA00242-C004：一种在体外和体内均显示出强大的抗肿瘤作用的具有高DAR的新型抗PSMA ADC药物 作者：林广等 江苏恒瑞医药股份有限公司 09产品：HRA00130-C004 英文标题：HRA00130-C004, a novel anti-DLL3 ADC with bystander effect, high DAR and favorable safety profiles 中文标题：HRA00130-C004：一种具有旁观者效应、高DAR和良好安全性的新型抗DLL3 ADC药物 作者：姚青青等 江苏恒瑞医药股份有限公司 作为中国医药创新代表性企业，恒瑞医药多年来针对高发肿瘤领域持续开展科研攻关。公司累计研发投入近400亿元，已获批上市16款创新药，其中抗肿瘤创新药占比过半，另有80多个自主创新产品正在临床开发，270多项临床试验在国内外开展。未来，恒瑞医药将继续坚持“以患者为中心”的理念，努力研发出更多的新药好药，服务健康中国、造福全球患者。 参考文献： 1.https://www.abstractsonline.com/pp8/#!/20272/presentation/6657 2.https://www.abstractsonline.com/pp8/#!/20272/presentation/11544 3.https://www.abstractsonline.com/pp8/#!/20272/presentation/11498 4.https://www.abstractsonline.com/pp8/#!/20272/presentation/6304 5.https://www.abstractsonline.com/pp8/#!/20272/presentation/8988 6.https://www.abstractsonline.com/pp8/#!/20272/presentation/62857.https://www.abstractsonline.com/pp8/#!/20272/presentation/6839 8.https://www.abstractsonline.com/pp8/#!/20272/presentation/7655 9.https://www.abstractsonline.com/pp8/#!/20272/presentation/7656 声明： 1. 本新闻旨在分享研发前沿资讯，仅供医疗卫生专业人士基于学术目的参阅，非广告用途。 2. 恒瑞医药不推荐任何药品、适应症的使用。

Analysis from a 10-month post-launch evaluation of the REMS Program finds 2.8% incidence of LVEF <50% in over 1500 patients, strengthening the safety pro CAMZYOS® (mavacamten) for NYHA class II-III obstructive hypertrophic cardiomyopathy Real-world data reaffirm therapeutic value and treatment benefit of CAMZYOS in improving cardiac symptoms and NYHA class in patients with obstructive hypertrophic cardiomyopathy PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb Company (NYSE: BMY) today announced the presentation of data at the American College of Cardiology (ACC) Annual Scientific Session & Expo, taking place April 6-8, 2024 in Atlanta, Georgia. “The therapeutic benefit of CAMZYOS in real-world practice, demonstrated by our data at ACC, builds on the well-established clinical program and further underscores the importance of this transformational medicine which is the first and only approved cardiac myosin inhibitor. With thousands of patients around the world treated to date, CAMZYOS is redefining the treatment landscape for this patient population and may offer hope to countless others moving forward,” said Roland Chen, MD, Senior Vice President and Head of Development, Immunology, Cardiovascular & Neurology. “In addition to showcasing our growing body of real-world evidence and safety data for CAMZYOS at ACC, we look forward to highlighting additional data from our cardiovascular portfolio, including an analysis of the real-world clinical impact of ELIQUIS.” Research to be presented at the meeting supports the robust safety and clinical pro CAMZYOS® (mavacamten) and compliance with the Risk Evaluation and Mitigation Strategy (REMS) Program. These data include: An analysis of results from the 10-month post-launch evaluation of the CAMZYOS REMS Program in 1,524 patients with patient status forms submitted, which demonstrated that approximately 1% (n=17) of patients reported clinical heart failure requiring hospitalization and 2.8% (n=43) of patients reported a decrease in left ventricular ejection fraction (LVEF) to <50%. These data are consistent with the clinical development program and reinforce the safety pro CAMZYOS in clinical practice. These data (abstract 1075-07) will be featured as a moderated poster on Sunday, April 7 from 1:30 PM – 1:40 PM ET. A single-center real-world experience analysis of 53 patients treated with CAMZYOS which found that at 24 weeks, CAMZYOS led to improvements in cardiovascular symptoms (96%) and improvements in one or more New York Heart Association (NYHA) class (49%). Additionally, resting and Valsalva LVOT gradient decreased during the first four weeks after starting treatment, with statistically significant reductions from baseline at week 24 (P<0.001). No patients required cessation of treatment due to reduction of LVEF to <50% or other side effects, though two patients required temporary drug discontinuation due to Valsalva LVOT gradient less than 20 mmHg during the 24-week treatment period. These data (abstract 1424-134) will be featured as a poster on Sunday, April 7 from 1:15 PM – 2:00 PM ET. The BMS-Pfizer Alliance will also present research at the meeting that adds to the robust body of evidence pertaining to the safety and efficacy pro ELIQUIS® (apixaban). These data include: A real-world evidence study of non-valvular atrial fibrillation (NVAF) patients on Medicare previously treated with warfarin and switched to a direct oral anticoagulant (DOAC: apixaban, dabigatran, or rivaroxaban), which found that those who received ELIQUIS had a statistically significant lower risk of stroke/systemic embolism (S/SE) and major bleeding (MB) than those patients who received rivaroxaban (S/SE HR: 0.91; 95% CI: 0.85-0.97 and MB HR: 0.68; 95% CI: 0.65-0.72) or dabigatran (S/SE HR: 0.83; 95% CI: 0.72-0.96 and MB HR: 0.79; 95% CI: 0.71-0.89). This pairwise comparative analysis provides the rates of S/SE and MB shown in patients with NVAF on Medicare associated with switching from warfarin to different DOACs. This effectiveness and safety information about ELIQUIS use in clinical practice can supplement data from randomized clinical trials. These data (abstract 1306-157) will be featured as a poster on Saturday, April 6 from 2:45 PM – 3:00 PM ET. Select BMS and BMS-Pfizer Alliance-sponsored abstracts to be presented at ACC can be found below. Complete abstracts may be accessed online here. Visit this page on BMS.com for more information on Bristol Myers Squibb’s scientific approach and resources on cardiovascular diseases. Abstract Title Primary Author Type/# Session Title Time (ET) Saturday, April 6, 2024 The experiences, values and goals of people in Australia living with obstructive hypertrophic cardiomyopathy: In-depth patient interviews Fifer, S. Poster – 1244-128 1244 - Heart Failure and Cardiomyopathies: Basic and Translational Science 03 11:45 AM – 12:30 PM Effect of mavacamten on health status in Chinese patients with symptomatic obstructive hypertrophic cardiomyopathy: Results from the EXPLORER-CN study Tian, Z. Poster – 1284-132 1284 - Heart Failure and Cardiomyopathies: Pharmacology 05 1:45 PM – 2:30 PM Evaluation of effectiveness and safety outcomes among Medicare patients with non-valvular atrial fibrillation who switched from warfarin to direct oral anticoagulants* Atreja, N. Poster – 1306-157 1306 - Ischemic Heart Disease: Special Populations 06 2:45 PM – 3:30 PM Sunday, April 7, 2024 Greatest absolute benefit of apixaban and limiting aspirin is in those with comorbidity: Results from the AUGUSTUS trial* Krychtiuk, K. Poster – 1065-11 1065 - Vascular Vistas: Tailored Research for Special Populations 12:00 PM – 12:10 PM Real-world experience and 24-week outcomes of patients with symptomatic obstructive hypertrophic cardiomyopathy treated with mavacamten in the US Reza, N. Poster – 1424-134 1424 - Heart Failure and Cardiomyopathies: Special Populations 12 1:15 PM – 2:00 PM The CAMZYOS (mavacamten) risk evaluation and mitigation strategy program: Results from 10 months post-launch Martinez, M. Poster – 1075-07 1075 - Bulking Up: Advances in Hypertrophic Cardiomyopathy 1:30 PM – 1:40 PM Effects of mavacamten on circulating biomarkers in obstructive hypertrophic cardiomyopathy: Insights from the EXPLORER-HCM study using comprehensive proteomics profiling Wang, Z. Poster – 1075-09 1075 - Bulking Up: Advances in Hypertrophic Cardiomyopathy 1:45 PM – 1:55 PM *Sponsored by the Bristol Myers Squibb-Pfizer Alliance About CAMZYOS® (mavacamten) CAMZYOS® (mavacamten) is the first and only cardiac myosin inhibitor approved in the U.S., indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms, and in the European Union, indicated for the treatment of symptomatic (NYHA, class II-III) obstructive HCM in adult patients. It has also received regulatory approvals on five continents including in Argentina, Australia, Brazil, Canada, Great Britain, Hong Kong, Israel, Singapore, South Korea, and Switzerland. CAMZYOS is an allosteric and reversible inhibitor selective for cardiac myosin. CAMZYOS modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. CAMZYOS shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In HCM patients, myosin inhibition with CAMZYOS reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures. IMPORTANT SAFETY INFORMATION WARNING: RISK OF HEART FAILURE CAMZYOS reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction. Echocardiogram assessments of LVEF are required prior to and during treatment with CAMZYOS. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status. Concomitant use of CAMZYOS with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of CAMZYOS is contraindicated with the following: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers Because of the risk of heart failure due to systolic dysfunction, CAMZYOS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CAMZYOS REMS PROGRAM. CONTRAINDICATIONS CAMZYOS is contraindicated with concomitant use of: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers WARNINGS AND PRECAUTIONS Heart Failure CAMZYOS reduces systolic contraction and can cause heart failure or totally block ventricular function. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) are at greater risk of developing systolic dysfunction and heart failure. Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the CAMZYOS dose accordingly. New or worsening arrhythmia, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function. Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional dosing considerations. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. CYP 450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness CAMZYOS is primarily metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant use of CAMZYOS and drugs that interact with these enzymes may lead to life-threatening drug interactions such as heart failure or loss of effectiveness. Advise patients of the potential for drug interactions, including with over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine). Advise patients to inform their healthcare provider of all concomitant products prior to and during CAMZYOS treatment. CAMZYOS Risk Evaluation and Mitigation Strategy (REMS) Program CAMZYOS is only available through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the CAMZYOS REMS Program include the following: Prescribers must be certified by enrolling in the REMS Program. Patients must enroll in the REMS Program and comply with ongoing monitoring requirements. Pharmacies must be certified by enrolling in the REMS Program and must only dispense to patients who are authorized to receive CAMZYOS. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at or by telephone at 1-833-628-7367. Embryo-Fetal Toxicity CAMZYOS may cause fetal toxicity when administered to a pregnant female, based on animal studies. Confirm absence of pregnancy in females of reproductive potential prior to treatment and advise patients to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CAMZYOS may reduce the effectiveness of combined hormonal contraceptives (CHCs). Advise patients using CHCs to use an alternative contraceptive method that is not affected by CYP 450 enzyme induction or to add nonhormonal contraception. Advise females of reproductive potential about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. ADVERSE REACTIONS In the EXPLORER-HCM trial, adverse reactions occurring in >5% of patients and more commonly in the CAMZYOS group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). There were no new adverse reactions identified in VALOR-HCM. Effects on Systolic Function In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS. DRUG INTERACTIONS Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS CAMZYOS is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of CAMZYOS. Impact of Other Drugs on CAMZYOS: Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors: Concomitant use increases CAMZYOS exposure, which may increase the risk of heart failure due to systolic dysfunction. Concomitant use is contraindicated. Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers: Concomitant use decreases CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes. Concomitant use is contraindicated. Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors: Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Initiate CAMZYOS at the recommended starting dose of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available. Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used in combination with CYP3A4, CYP2C19, or CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce their activity. Hormonal Contraceptives: Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of ethinyl estradiol and progestin, which may lead to contraceptive failure or an increase in breakthrough bleeding. Advise patients to use a contraceptive method that is not affected by CYP 450 enzyme induction (e.g., intrauterine system) or add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. Drugs That Reduce Cardiac Contractility Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved. SPECIFIC POPULATIONS Pregnancy CAMZYOS may cause fetal harm when administered to a pregnant female. Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol Myers Squibb at 1-800-721-5072 or . Lactation The presence of CAMZYOS in human or animal milk, the drug’s effects on the breastfed infant, or the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition. Females and Males of Reproductive Potential Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS. Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. Use of CAMZYOS may reduce the effectiveness of CHCs. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception. Please see U.S. Full Prescribing Information, including Boxed WARNING and Medication Guide. About ELIQUIS ® (apixaban) ELIQUIS® is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, ELIQUIS decreases thrombin generation and blood clot formation. ELIQUIS is approved for multiple indications in the U.S. based on efficacy and safety data from multiple Phase 3 clinical trials. ELIQUIS is a prescription medicine indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF); for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE, following initial therapy. ELIQUIS continues to be developed and commercialized by The Bristol Myers Squibb-Pfizer Alliance. ELIQUIS Important Safety Information Indications ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. ELIQUIS is indicated for the treatment of DVT and PE, and to reduce the risk of recurrent DVT and PE following initial therapy. Important Safety Information WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA (A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. (B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of ELIQUIS and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated. CONTRAINDICATIONS Active pathological bleeding Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs. Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage. The anticoagulant effect of apixaban can be expected to persist for at least 24 hours after the last dose (i.e., about two half-lives). An agent to reverse the anti-factor Xa activity of apixaban is available. Please visit for more information on availability of a specific reversal agent. Spinal/Epidural Anesthesia or Puncture: Patients treated with ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours. Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in ELIQUIS patients. Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves and is not recommended in these patients. Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy: Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome (APS): Direct-acting oral anticoagulants (DOACs), including ELIQUIS, are not recommended for use in patients with triple-positive APS. For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. ADVERSE REACTIONS The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding. TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. DRUG INTERACTIONS Combined P-gp and Strong CYP3A4 Inhibitors: Inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) increase exposure to apixaban and increase the risk of bleeding. For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or ritonavir). In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors. Clarithromycin Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS. Combined P-gp and Strong CYP3A4 Inducers: Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban. Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. PREGNANCY The limited available data on ELIQUIS use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes. Treatment may increase the risk of bleeding during pregnancy and delivery, and in the fetus and neonate. Labor or delivery: ELIQUIS use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches. LACTATION Breastfeeding is not recommended during treatment with ELIQUIS. FEMALES AND MALES OF REPRODUCTIVE POTENTIAL Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including ELIQUIS should be assessed in these patients and those with abnormal uterine bleeding. Please see U.S. Full Prescribing Information, including Boxed WARNINGS, available at BMS.com. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. About the Bristol Myers Squibb-Pfizer Collaboration The Bristol Myers Squibb-Pfizer Alliance (the Alliance) is committed to driving education and awareness about atrial fibrillation and deep vein thrombosis (DVT) and/or pulmonary embolism (PE). With long-standing cardiovascular leadership, global scale and expertise in this field, the Alliance strives to implement global, research-driven approaches to illuminate and address the unmet needs around strokes related to non-valvular atrial fibrillation, which are often fatal or debilitating. Through collaborations with non-profit organizations, the Alliance aims to provide patients, healthcare professionals and decision makers with the information they need to understand and take appropriate action on risk factors associated with stroke and other cardiovascular conditions. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that the results of future post-marketing studies will be consistent with the results of these studies, that CAMZYOS (mavacamten) or ELIQUIS (apixaban) may not be commercially successful, any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of such products for such indications may be contingent upon verification and description of clinical benefit in additional confirmatory trials. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news