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FDA designation provides potentially seven years of market exclusivity after approval and expanded partnering opportunities for tecarfarin PONTE VEDRA, Fla., April 9, 2024 /PRNewswire/ -- Cadrenal Therapeutics, Inc. (Nasdaq: CVKD), a biopharmaceutical company developing tecarfarin, a late-stage novel oral and reversible anticoagulant (blood thinner) designed to prevent heart attacks, strokes, and deaths due to blood clots in patients with rare cardiovascular conditions, announced today that the United States Food and Drug Administration (FDA) has granted tecarfarin Orphan Drug Designation (ODD) for the prevention of thromboembolism and thrombosis in patients with an implanted mechanical circulatory support device (left ventricular assist device (LVAD), right ventricular assist device (RVAD), collectively known as ventricular assist devices (VADs), biventricular assist device, and total artificial heart). "This second orphan drug designation highlights the expanded need for tecarfarin where existing anticoagulation therapies are inadequate," said Quang Pham, Founder, Chairman and Chief Executive Officer of Cadrenal Therapeutics. "We are dedicated to advancing tecarfarin through clinical development options as swiftly as possible." The FDA's ODD program provides incentives to sponsor organizations for the development of innovative treatments for rare diseases that affect fewer than 200,000 people in the U.S. Since its adoption in 1983, the Orphan Drug Act has helped countless individuals living with these conditions gain access to life-enhancing and life-saving therapies. ODD also provides certain benefits to drug developers, including assistance in the drug development process, tax credits for certain clinical research, and a waiver of the New Drug Application user fee. The designation is made to promote safe and efficacious products for the treatment of rare conditions. All patients with VADs require chronic anticoagulation to prevent the formation of thrombus (clot) which can cause the device to fail or can result in a clot breaking off (embolizing), resulting in a stroke or other vascular catastrophe. The current market-leading direct oral anticoagulants (DOACs), such as Eliquis, are not indicated for patients with VADs due to a lack of evidence of benefit. Moreover, a recent study revealed that the level of anticoagulation achieved with warfarin, the only currently available Vitamin K Antagonist (VKA), is maintained in the target range only 56% of the time which has been shown to increase the risk of clotting and bleeding complications. ABOUT CADRENAL THERAPEUTICS, INC. Cadrenal Therapeutics is developing tecarfarin for unmet needs in anticoagulation therapy. Tecarfarin is a late-stage novel oral and reversible anticoagulant (blood thinner) to prevent heart attacks, strokes, and deaths due to blood clots in patients with rare cardiovascular conditions. Tecarfarin has orphan drug and fast-track designations from the FDA for the prevention of systemic thromboembolism (blood clots) of cardiac origin in patients with end-stage kidney disease (ESKD) and atrial fibrillation (AFib) and just received orphan drug designation for the prevention of thrombosis and thromboembolism in patients with ventricular assist devices (VADs). Cadrenal is also pursuing additional regulatory strategies for unmet needs in anticoagulation therapy for patients with thrombotic antiphospholipid syndrome (APS). Tecarfarin is specifically designed to leverage a different metabolism pathway than the oldest and most commonly prescribed Vitamin K Antagonist (warfarin). Tecarfarin has been evaluated in eleven (11) human clinical trials and more than 1,000 individuals. In Phase 1, Phase 2, and Phase 2/3 clinical trials, tecarfarin has generally been well-tolerated in both healthy adult subjects and patients with chronic kidney disease. For more information, please visit . Safe Harbor Statement Any statements contained in this press release about future expectations, plans, and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements." These statements include statements regarding tecarfarin addressing unmet needs in anticoagulation therapy and the ability to derive the anticipated and potential benefits from the recent Orphan Drug Designation for tecarfarin, including seven years of market exclusivity, and the expanded development and commercial partnering for tecarfarin as a result of the Orphan Drug Designation. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the Company's ability to derive the anticipated benefits from the recent Orphan Drug Designation for tecarfarin and the other risk factors described in the Company's Annual Report on Form 10-K for the year ended December 31, 2023, and the Company's filings with the Securities and Exchange Commission, including periodic reports on Quarterly Reports on Form 10-Q and Current Reports on Form 8-K. Any forward-looking statements contained in this press release speak only as of the date hereof and, except as required by federal securities laws, the Company specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events, or otherwise. For more information, please contact: Cadrenal Therapeutics: Matthew Szot, CFO 858-337-0766 [email protected] Investors: Lytham Partners, LLC Robert Blum, Managing Partner 602-889-9700 [email protected] SOURCE Cadrenal Therapeutics, Inc.

PONTE VEDRA, Fla., Dec. 12, 2023 /PRNewswire/ -- Cadrenal Therapeutics, Inc., (Nasdaq: CVKD) a biopharmaceutical company developing tecarfarin, a late-stage, novel, oral and reversible anticoagulant (blood thinner) designed to prevent heart attacks, strokes and deaths (due to blood clots in patients with certain orphan diseases), today announced an engagement with The Sage Group () to assist the company in exploring strategic partnerships, co-development and licensing agreements for tecarfarin. The Sage Group is a leader in providing strategic and transactional advice to healthcare and life science companies in the pharmaceutical, diagnostics, medical devices, biotech, regenerative medicine, and cell and gene therapy fields. This partnership will give Cadrenal access to The Sage Group's clinical and regulatory expertise, capital resources, and network of contacts, including innovators and large pharma companies. Tecarfarin is a novel chemical entity that provides stable anticoagulation to patients with certain orphan diseases, including End-Stage Kidney Disease (ESKD) with Atrial Fibrillation (AFib); Left Ventricular Assist Devices (LVADs); and Antiphospholipid Syndrome (APS). The currently available blood thinners, including warfarin, Pradaxa, Xarelto, Eliquis, and Savaysa, fail to achieve sufficiently stable anticoagulation in these patients and are not widely prescribed for these rare medical conditions. In recent advertisements for Eliquis, the narration specifically states, 'Don't take Eliquis if you have an artificial heart valve…' and 'Eliquis is not for patients who have antiphospholipid syndrome (APS).' Tecarfarin was designed to solve one of warfarin's major problems, namely warfarin's unreliable pharmacokinetic (PK) profile, due to its metabolism via the cytochrome P450 pathway. This pathway is responsible for the metabolism of many other drugs, resulting in drug-drug interactions that can lead to unstable anticoagulation. Tecarfarin was specifically designed to be metabolized via an alternate pathway, resulting in a more reliable, stable PK and anticoagulation, as evidenced in clinical trials in over 1,000 patients. "Patients with certain orphan diseases, including ESKD with AFib, LVADs, and APS, suffer from a lack of options to achieve sufficiently stable anticoagulation," said Quang Pham, CEO of Cadrenal. "With The Sage Group's support, we look forward to identifying the right partner to help us advance clinical development globally in an effort to bring a much-needed blood thinner solution to the market for these underserved patients." Tecarfarin has been evaluated in eleven (11) human clinical trials and more than 1,000 individuals. In Phase 1, Phase 2, and Phase 2/3 clinical trials, tecarfarin has generally been well-tolerated in both healthy adult subjects and patients with chronic kidney disease. The FDA has granted tecarfarin orphan drug and fast-track designations for ESKD with AFib. Cadrenal is also developing expanded regulatory strategies for LVAD and APS. Cadrenal estimates that in the treatment of these orphan diseases, the combined addressable market opportunity is in excess of US $2 billion per year in the U.S. ABOUT CADRENAL THERAPEUTICS, INC. Cadrenal Therapeutics is developing tecarfarin, a late-stage novel oral and reversible anticoagulant (blood thinner), to prevent heart attacks, strokes, and deaths due to blood clots in patients with certain rare medical conditions. Tecarfarin has orphan drug and fast-track designations for the prevention of systemic thromboembolism (blood clots) of cardiac origin in patients with end-stage kidney disease, or ESKD, and atrial fibrillation, or AFib. Tecarfarin has been specifically and deliberately designed to leverage a different metabolism pathway than the oldest and most commonly prescribed Vitamin K antagonist (warfarin). Tecarfarin has been evaluated in eleven (11) human clinical trials and more than 1,000 individuals. In Phase 1, Phase 2, and Phase 2/3 clinical trials, tecarfarin has generally been well-tolerated in both healthy adult subjects and patients with chronic kidney disease. For more information, please visit: . ABOUT THE SAGE GROUP, INC. The Sage Group Inc. is a leader in the provision of strategic and transactional advice to health care companies in the pharmaceutical, diagnostics, medical device, biotechnology and life science fields. Sage currently maintains offices in USA, Europe, Israel and Japan. Since its founding in 1994, The Sage Group has served more than 200 clients in the US, Europe and Asia, and completed numerous transactions including alliances, acquisitions, divestitures, and financings with values ranging from $5 million to $500 million. The Sage Group is an organization of experienced and successful executives who are committed to the service of the very vital and dynamic health care industry and its investors. The range of services offered includes: * Strategic alliances and licensing/partnering * M&A, divestment, buy- and sell- side * Global product and technology acquisition searches * Strategic assessment and planning * Due diligence, technology and molecule assessment, valuation * New ventures, interim management * Facilitating investment in R&D and/or company equity through introductions, network and brokering The Sage Group's Principals, each an Executive Director, have been Founders, Chairmen, Presidents, CEO's and COO's of a number of emerging health care companies. These Principals have also held senior level management positions in large multi-national organizations. In addition to their management backgrounds, The Sage Group's Principals also have extensive experience in providing professional management consulting services to healthcare industry clients. All these experiences are being applied by The Sage Group to assist industry participants. For more information, please visit: . Safe Harbor Statement Any statements contained in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements." These statements include statements regarding the partnership with The Sage Group giving Cadrenal access to its clinical and regulatory expertise, capital resources, and network of contacts, including innovators and large pharma companies, the belief that tecarfarin will provide LVAD and APS patients with stable anticoagulation, identifying a partner to help Cadrenal advance clinical development globally with The Sage Group's support, developing expanded regulatory strategies for LVAD and APS, and the estimated addressable market opportunity in excess of $2 billion per year in the U.S. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the ability to advance tecarfarin within patients with implanted medical devices for heart diseases, the ability to penetrate the U.S. market for patients with LVADs who struggle with stable anticoagulation with warfarin, the ability to advance patient care in cardiorenal diseases and the other risk factors described in the Company's Annual Report on Form 10-K for the year ended December 31, 2022, and the Company's subsequent filings with the SEC, including subsequent periodic reports on Quarterly Reports on Form 10-Q and Current Reports on Form 8-K. Any forward-looking statements contained in this press release speak only as of the date hereof and, except as required by federal securities laws, the Company specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. For more information, please contact: Cadrenal Therapeutics: Matthew Szot, CFO 858-337-0766 [email protected] Investors: Lytham Partners, LLC Robert Blum, Managing Partner 602-889-9700 [email protected] For more information about Cadrenal and partnering opportunities for tecarfarin, please contact: Dr. Bill Mason The Sage Group Inc The Stockyard Creake Road, Syderstone PE31 8SG UK Tel: +44 (0) 7785 950134 [email protected] Or Wayne Pambianchi The Sage Group Inc. 24 E. Main Street, Box 5365 Clinton, New Jersey 08809 Phone: +1 908 2306170 [email protected] SOURCE Cadrenal Therapeutics, Inc.

▎药明康德内容团队编辑  p53编码基因是目前研究最为广泛和深入的抑癌基因之一，它对阻止肿瘤形成起着重要作用，在超过50%的肿瘤中会出现p53突变。作为转录因子，p53可以调控众多下游信号通路：其公认地通过促进细胞周期停滞、细胞凋亡和细胞衰老发挥肿瘤抑制作用。但2012年Cell上的一篇文章开启了p53研究的新篇章——美国哥伦比亚大学欧文医学中心癌症遗传研究所顾伟教授课题组首次证实p53在缺失诱导细胞周期停滞、细胞凋亡和细胞衰老功能后仍然能够发挥肿瘤抑制作用，其内在机制是通过调控肿瘤代谢实现的[1]。图片来源：123RF2015年，顾伟课题组在Nature发文证实，促进肿瘤细胞的铁死亡（Ferroptosis）是p53作为“基因卫士”抑制肿瘤的关键[2]。铁死亡是一种铁离子依赖的过量脂质过氧化（Lipid peroxidation）积累导致的细胞膜功能异常及最终完成破裂的程序性死亡方式[3]。决定铁死亡进程的关键因素是细胞内的抗氧化防御系统和代谢稳态。从转录水平上来看，p53可以抑制胱氨酸转运蛋白（SLC7A11）的表达，从而使细胞在p53激活时对活性氧（ROS）或者SLC7A11抑制剂诱导的铁死亡更加敏感。此后，顾伟课题组于2019年在Nature Cell Biology发文提出，p53介导的铁死亡是通过脂质加氧酶ALOX12来实现的。以及在2021年Nature Communications发文揭示p53转录调控磷脂酶iPLA2β独立于GPX4调控铁死亡等[4]，[5]。尽管如此，关于p53是否能够通过独立于胱氨酸-谷胱甘肽（Cystine-GSH）通路发挥促进铁死亡的作用仍然需要进一步的研究。日前，美国哥伦比亚大学欧文医学中心癌症遗传研究所的顾伟团队（杨鑫博士和王哲博士为第一作者）在Cell Metabolism上发表的研究发现，经典维生素K代谢中的还原酶——维生素K环氧还原酶复合物亚基1类1（VKORC1L1），通过催化维生素K还原态的产生来保护细胞抵抗铁死亡。激活关键抑癌因子p53可以通过转录方式抑制VKORC1L1表达，从而激活铁死亡并诱导体内肿瘤抑制。该研究发现抗凝血药物华法林（Warfarin）作为VKORC1L1的抑制剂可以在高表达VKORC1L1的胰腺癌肿瘤中通过促进铁死亡发挥抑癌作用，华法林或许可以“老药新用”，成为潜在的肿瘤治疗策略。作者通过CRISPR-Cas9技术对全基因组以及代谢基因组进行了敲除筛选，他们发现VKORC1L1是一种能够高效抑制铁死亡的代谢酶。敲除VKORC1L1能显著提高铁死亡诱导剂处理下细胞内脂质过氧化的水平和细胞死亡。作者通过质谱技术检测证明VKORC1L1是通过生成还原态维生素K（维生素K对苯二酚）来保护细胞免受铁死亡。基于VKORC1L1调节铁死亡的现象，研究人员想解决一个问题：作为VKORC1L1的代谢底物，维生素K是否能够抑制铁死亡？▲研究借助CRISPR-Cas9技术进行了代谢基因组筛选（图片来源：研究论文）通过GPX4抑制剂处理，GPX4敲除，胱氨酸饥饿以及谷氨酰胺处理等多种诱导细胞铁死亡的模型，作者发现两种活性维生素K（维生素K1和K2）都能够抑制铁死亡，说明维生素K是一种全新的独立于GSH/GPX4轴的方式抑制铁死亡的代谢物。研究人员发现，维生素K抑制铁死亡的内在机制是依赖于VKORC1L1还原酶活性的。Marcus Conard课题组曾在Nature杂志发表研究论文，证实FSP1可以通过非经典的维生素K代谢完成对于维生素K的还原从而抵抗铁死亡。作者进一步的研究发现，VKORC1L1和FSP1在利用维生素K抵抗铁死亡中起到互相独立的作用。值得一提的是，一旦细胞同时缺少VKORC1L1和FSP1，即使是高剂量的维生素K也无法挽救细胞的铁死亡。接下来，作者发现VKORC1L1是p53的直接转录抑制靶标。p53激活后可以在mRNA和蛋白水平抑制VKORC1L1的表达，从而使细胞对铁死亡诱导更易感。p53缺失的细胞表现出VKORC1L1蛋白和mRNA水平的上调，说明野生型p53可以调控其内源的表达水平。▲研究示意图（图片来源：研究论文）另外，通过对TCGA数据库肿瘤样本中VKORC1L1的mRNA水平进行分析，作者发现比起p53野生型，p53突变的肿瘤样本中VKORC1L1的mRNA水平明显上升，说明VKORC1L1很可能参与了p53突变肿瘤的代谢重编程。华法林是一种历史悠久且应用广泛的抗凝血剂，在1954年就被美国FDA批准用于抗凝血治疗。华法林通过抑制维生素K代谢的关键酶VKORC1或VKORC1L1的酶活性来降低具有生物学活性的凝血因子的产生。由于安全性问题，最近发现的抗凝血药物如直接口服抗凝剂（DOACs）和低分子肝素（LMWHs）可以作为华法林的热门替代品，其原理不通过抑制VKORC1或VKORCL1L1而是直接抑制凝血因子发挥作用。但是华法林在胰腺癌、胃癌和结直肠癌中比DOACs和LMWHs表现出明显的总生存期延长的优势，提示华法林很可能是通过某些未知的抗肿瘤途径来延长服用华法林病人的总生存期[7]，[8]。而在胰腺癌中，VKORC1L1的mRNA水平在肿瘤样本中高表达，且高表达肿瘤患者呈现相对较差的预后。基于以上事实，作者尝试使用VKORC1L1高表达、p53缺失的人类AsPC1细胞和p53突变的小鼠胰腺癌细胞来评估华法林对于肿瘤生长的影响。利用免疫缺失和免疫完整的小鼠异种移植实验，作者证实华法林可以增强小鼠肿瘤内细胞脂质过氧化的水平从而抑制肿瘤生长。考虑到华法林及其衍生物已经在临床上广泛使用，此项研究也提示，患有上述类型癌症的患者持续使用华法林，或者放化疗结合华法林的联合疗法可以成为潜在的治疗策略。综上所述，这项研究对于如何理解、认识维生素K代谢提出了新的见解，也证实p53能通过同时抑制VKORC1L1和SLC7A11的表达，以不依赖GSH和依赖GSH两条平行且独立的通路促进铁死亡的进程，这项研究不仅丰富了p53在代谢领域的功能，也为p53突变肿瘤的治疗提供了新思路。美国哥伦比亚大学顾伟教授为通讯作者，顾伟课题组杨鑫博士和王哲博士为本文第一作者，刘彦卿博士参与此工作。此外，该项工作得到了哥伦比亚大学张志国教授，Brent R. Stockwell教授和纪念斯隆-凯特琳癌症中心姜学军教授等合作者的支持。参考资料：[1] Li, T., Kon, N., Jiang, L., Tan, M., Ludwig, T., Zhao, Y., Baer, R., and Gu, W. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269-1283 (2012).[2] Jiang, L., Kon, N., Li, T., Wang, S.-J., Su, T., Hibshoosh, H., Baer, R., and Gu, W. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57-62 (2015).[3] Dixon, S.J., Lemberg, K.M., Lamprecht, M.R., Skouta, R., Zaitsev, E.M., Gleason, C.E., Patel, D.N., Bauer, A.J., Cantley, A.M., and Yang, W.S. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060-1072 (2012).[4] Chu, B., Kon, N., Chen, D., Li, T., Liu, T., Jiang, L., Song, S., Tavana, O., and Gu, W. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nature cell biology 21, 579-591 (2019).[5] Chen, D., Chu, B., Yang, X., Liu, Z., Jin, Y., Kon, N., Rabadan, R., Jiang, X., Stockwell, B.R., and Gu, W. iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nature Communications 12, 1-15 (2021).[6] Mishima, E., Ito, J., Wu, Z., Nakamura, T., Wahida, A., Doll, S., Tonnus, W., Nepachalovich, P., Eggenhofer, E., and Aldrovandi, M. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778-783 (2022).[7] Chiasakul, T., Redd, R., Patell, R., Khan, A.M., McCarthy, E.P., Neuberg, D., and Zwicker, J.I. Overall survival with warfarin vs. low‐molecular‐weight heparin in cancer‐associated thrombosis. Journal of Thrombosis and Haemostasis 19, 2825-2834 (2021).[8] Chiasakul, T., and Zwicker, J.I. The impact of warfarin on overall survival in cancer patients. Thrombosis Research (2021).本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~