Abelacimab

西地那非（伟哥）是最广为人知的男性疾病治疗药物，它诞生于治疗心脏疾病试验的意外。随着它的机理被探明，科学家又发现了它的其他适应症，如肺动脉高压。而近期，多项研究显示西地那非可以降低患阿尔茨海默病的风险，它真的可以防治这种影响人类认知功能的疾病吗？要想知道它究竟能否成功，我们还需要进行怎样的试验？图1  西地那非（Sildenafil ，Viagra®） 图片来源：网络西地那非（Sildenafil ，Viagra®），你一定听过它另一个更为人知的名字：伟哥。它是由美国辉瑞公司研发的用于治疗男性勃起功能障碍（Erectile Dysfunction，ED）的一款畅销药物。除了可以治疗ED之外，近期的多项研究表明，西地那非与降低阿尔茨海默病的风险相关。这篇文章将会为大家介绍西地那非略显传奇的研发历程，同时为大家介绍目前的研究进展——距离治疗阿尔茨海默病，西地那非还有多远的路要走？治疗ED：失之东隅收之桑榆西地那非被开发出治疗ED起源于一场意外。作为一款五型磷酸二酯酶抑制剂（PDE5-I），西地那非可以通过抑制PDE5分解环鸟苷酸 (cyclic guanosine monophosphate，cGMP)，使得血管扩张，从而降低血压，因此在研发之初，科研人员试图用它来治疗心绞痛和高血压等心血管疾病[1]。图2 西地那非的作用机制[2]1991年4月，由于对心血管疾病的治疗效果不理想，早期的临床实验宣告失败。在临床研究的过程中，科研人员意外地发现了西地那非的副作用：在一些口服剂量相对较高的男性志愿者中，出现了阴茎勃起频率增加和勃起时间延长的现象。护士们也时常会观察到男性患者捂住腹部以掩饰窘况。但在临床实验失败之后，受试者们拒绝将剩下的药物返还，研究人员们觉得奇怪，一经追查才发现，原来西地那非改善了他们的性生活[1]。这个发现引发了科学家们的兴趣，他们开始研究西地那非在治疗勃起功能障碍方面的潜力。经过大量的临床试验和研究，1998年，美国食品药品监督管理局（FDA）批准了西地那非作为一种治疗男性勃起功能障碍的药物[3]。这一批准开启了一种全新的治疗方式，为患有ED的男性带来了福音。西地那非治疗ED的作用机制也随之被阐明，和之前得到的结论一致，西地那非可以高选择性地抑制人体内PDE5的活性，而PDE5在阴茎海绵体内表达水平极高，在人体其他组织和器官中则表达较低，因此对于心血管疾病的治疗效果不够理想，却恰好适应于ED治疗[4]。在服用西地那非后，男性阴茎海绵体血管平滑肌在药物的作用下舒张，血液流量增加，海绵体充血，阴茎勃起，从而起到治疗作用[2]。在1998年被FDA批准成功上市之后，西地那非在美国第一个季度的市场销售额就达到了四亿美元之多，仅在 1998 年 5 月的一周以内，就有 30 多万张处方被开出。辉瑞公司对此也功不可没，他们派出了大批销售代表，指导医生如何提起阳痿这个当时还很敏感的话题，并分发药片样品，以治疗这种自古以来就困扰男性的疾病。在随后的时间里，西地那非的影响力持续扩大，在全球范围内带来了一股性医学的革命，每年都会在全球范围内为辉瑞公司带来超过十亿美元的收入[1]。Viagra®在美国境外的专利于2012年后相继到期，在美国境内则于2020年到期，在专利保护期后，抗ED的仿制药掀起了一波新的市场浪潮。在国内，西地那非依然每年在化学药物的销量榜单上遥遥领先，2021年，我国西地那非的总销售额至少在40亿元以上。值得一提的是，在2021年中国网上药店终端化学药TOP20产品中，枸橼酸西地那非片（万艾可）以61.04%的高增长率位列第一[5]。西地那非的上市和畅销，标志着性医学迈向了一个崭新的医疗时代。它的意义更在于为男性打开了一扇门，让他们可以开口讨论那些曾经羞于启齿的挫折，而这些曾经对医生说不出口的问题可能是其他更加严重健康问题（包括心脏病）的征兆。老树开花：预防阿尔茨海默病的新用途近些年来，老药新用屡见不鲜，“老药新用“指的是对已上市或正在进行临床试验的药物进行研究，发现它的新适应症并将其用于疾病治疗[6]。对于新药研发存在的研发成本高昂，研发周期长，研发风险高的一些特点，对已经经过层层考验的老药进行新用途的开发，无疑可以大大加快研发进度。有很多广为人知的案例，例如作为解热镇痛药物的百年老药阿司匹林，近期被发现在心血管疾病预防和治疗中具有相当好的作用[7]；从1957年问世以来，被广泛使用的口服降糖药二甲双胍，也被发现在心脑血管保护方面独到的优势；近期研究还表明二甲双胍的治疗与肺癌、前列腺癌、直肠癌、乳腺癌等癌症风险降低相关[8]。本文主角西地那非最知名的用途是治疗ED，其成功上市后，它的其他适应症的研究仍未停止。肺动脉高压就是其中一种，作为致命性的心血管疾病，患者在严重时会心力衰竭而导致最终死亡，而在随后的研究中发现，西地那非对于肺动脉高压有很好的治疗作用。在多年的临床实验之后，FDA于2005年批准了西地那非作为治疗肺动脉高压的药物上市，商品名为“Revatio”。Revatio的上市一度改变了肺动脉高压治疗药物价格高昂的格局，减轻了患者的经济负担。如今，西地那非逐渐被发现还存在新的用途，多篇文献报道，伟哥可能有降低阿尔茨海默症患病风险的效果。2021年，发表在《自然-衰老》（Nature Aging）杂志上的一项研究表明，服用西地那非的人群相较于未服用人群，阿尔茨海默氏症风险降低69%。这项研究涵盖了了美国平均年龄在 71 岁左右的 700 多万人，其中有 11.6万人服用了西地那非[9]。2024年2月7日发表在《神经病学》（Neurology）杂志上的一项针对英国近67万名男性的新研究显示，服用PDE5I的人群相较于不服用的人群，患阿尔茨海默病的概率更低。其中与未服用西地那非或类似药物的男性相比，服用该类药物的男性，患阿尔茨海默病的风险可降低18%。而更频繁使用的人（开出21-50张处方），患阿尔茨海默氏症的风险降低44%[10]。图3 2月7日发表在《神经病学》（Neurology）杂志上的研究[10]3月19日发表在《阿尔茨海默病杂志》（Journal of Alzheimer's Disease）上的另一项研究发现，与不服用西地那非的人相比，服用西地那非的人被诊断为阿尔茨海默病的几率可以降低30%至54%，进一步证实了《神经病学》文章的观点[11]。图4  3月9日发表在《阿尔茨海默病杂志》上的研究[11]但这并不是这类药物第一次与降低阿尔茨海默病的风险联系在一起——自上世纪90年代末以来，在动物实验层面的研究就表明，PDE5I类药物能对认知能力产生积极的影响[12]。如上文所说，西地那非治疗ED的机制已经被研究得相当透彻，但这种药物是如何影响阿尔茨海默氏症等脑部疾病还不得而知。科学家们提出了几种潜在的机制。比如说，PDE5这类靶标同样存在于人体内的其他部位，包括大脑，因此，增加大脑中的血流量可能会在某种程度上降低阿尔茨海默氏症的患病可能性[13]。在2021年的《自然-衰老》研究中，克利夫兰诊所（Cleveland Clinic）的首席研究员程飞雄（Feixiong Cheng）及其同事在数据分析得出西地那非的使用与阿尔茨海默病的风险率降低有关的结论之外，还进一步对西地那非影响阿尔茨海默病的机制进行了探索。他们发现西地那非可以促进神经元的生长，并减少来自AD患者诱导多能干细胞神经元模型中磷酸化-tau的表达，而磷酸化的tau蛋白正是与阿尔茨海默病患病密切相关的一类蛋白——会在阿尔茨海默病患者脑内蓄积，这从机理上支持了西地那非对AD的潜在益处。但作者也表明，使用西地那非与降低AD发病率之间的联系并不能确定因果关系，这需要进行更多的实验进行验证[14]。还有一些研究人员认为，PDE5I类药物可以加强大脑神经元及突触之间的连接，因为这一过程部分依赖于cGMP，大脑通过加强突触连接来储存记忆，帮助相连的神经元相互“对话”。这可以解释PDE5I药物与降低阿尔茨海默氏症风险之间的联系，因为阿尔茨海默氏症的症状之一就是记忆丧失[13]。此外，2019年《美国人类遗传学杂志》（American Journal of Human Genetics）上的一项研究揭示，具有2型糖尿病遗传风险因素的人群比没有这些风险因素的人更容易出现勃起功能障碍（ED）[14]。而高血压或2型糖尿病又与罹患阿尔茨海默氏症的风险有关。不过，PDE5I这类药物对改善认知的帮助是否通过控制这些疾病有关，还不得而知[15]。目前这些理论都没有得到明确的证实，PDE5I 药物对阿尔茨海默症的影响仍需要继续探究。也有研究给出了与上述不同的结论，例如，2022 年一项针对肺动脉高压患者的研究（肺动脉高压可以用 PDE5I 药物治疗）发现，这种药物与阿尔茨海默氏症风险的降低无关[16]。图5 针对肺动脉高压患者的研究表明，PDE5I与阿尔茨海默氏症风险的降低无关[16]。上述研究均存在同样的局限性：虽然调查涵盖了非常大规模的人群，但是这些研究都是观察性的；也就是说，这些研究只是追溯性地比较了不同人群的患病率，而没有深入探究可能影响阿尔茨海默氏症风险的其他因素。因此无法给出肯定的结论来说明PDE5I类药物会影响AD患病风险。例如，2024 年《阿尔茨海默病杂志》的研究结果被人指出，作者在分析中没有考虑到遗传或社会经济因素，以及他们在实验中使用的药物剂量的影响。治疗AD，路在何方在过往的大数据追溯性研究中，涵盖的人群常常是认知功能良好，可以进行性生活并且有服用药物需求的人，尤其西地那非大部分的使用者为男性，西地那非是否能改善女性的认知能力并未被纳入考虑，这些都会对研究结果出现偏差。想要证明西地那非确实有预防阿尔茨海默病的效果，甚至是想要将它用到临床上给需要的人群提供帮助，科学家们需要按照严格的标准去进行临床实验，而非仅仅是上述证明关联性的大数据。更加严格的临床试验标准可以包括：招揽符合标准的受试者，平行设置对照组和给药组，并让两组的人群在年龄与性别方面与今后要进行治疗的人群相匹配，这些都有助于得到更加准确的实验结果。目前已经有几项临床试验评估了 PDE5I 药物对人类认知的潜在影响。不过，这些试验的规模有限；例如，一项试验只包括 10 名。有些试验只测试了治疗的短期影响——在一天的时间里测量单剂量的认知影响[17]。要想更进一步证明西地亚非这类药物有助于预防阿尔茨海默氏症，未来的试验可能还需要进行更长的周期，比如三到五年，并纳入临床确诊为阿尔茨海默氏症的患者，这些结果会比先前的研究更加具有说服力。同时，在临床试验的过程中寻找阿尔茨海默症治疗机制的蛛丝马迹也很重要，目前阿尔茨海默病的发病机制说法众多，病理复杂，如果在治疗过程中利用一些新的技术去探索治疗过程中病人指标的变化，比如利用脑成像技术测量患者服用PDE5I药物后血流的变化等，这些数据也许可以为今后治疗阿尔茨海默病提供帮助。长期试验还有利于科学家们观察长期服用该类药物的副作用。如果这类药物真的有效，后续还有更好的改进方案，比如对于阿尔茨海默病这类脑部疾病来说，药物透过血脑屏障的能力很重要，药物分子只有在脑部有足够的蓄积量，才能发挥更好的效果，因此在后续的研究中，科学家们也许可以在这个方面进行优化，以达到更好的治疗效果[13]。如果这些药物最终被证明可以有效预防阿尔茨海默病，那么与其他被发现新用途的老药一样，由于已经在人体层面上获得了安全性的数据，它推向临床使用的速度会大大加快，更多的患者会因此受益。对于这类蓝色小药丸来说，要成为真正可以预防阿尔茨海默病的处方药物，它还有很长的路要走。参考文献[1] Scherzer ND, Le TV, Hellstrom WJG. Sildenafil's impact on male infertility: what has changed in 20 years? Int J Impot Res. 2019 Mar;31(2):71-73. doi: 10.1038/s41443-018-0067-x. Epub 2019 Mar 5. PMID: 30837720.[2] Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov. 2006;5(8):689-702. doi:10.1038/nrd2030[3] https://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20895ltr.pdf[4] Lin CS, Lin G, Xin ZC, Lue TF. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des. 2006;12(27):3439-3457. doi:10.2174/138161206778343064[5] https://mp.weixin.qq.com/s/cIn2cxyf0QVOS5d45nlytw[6] Nosengo N. Can you teach old drugs new tricks? Nature. 2016;534(7607):314-316. doi:10.1038/534314a[7] Younis N, Williams S, Ammori B, Soran H. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother. 2010;11(9):1459-1466. doi:10.1517/14656561003792538[8] Ahn HK, Lee YH, Koo KC. Current Status and Application of Metformin for Prostate Cancer: A Comprehensive Review. Int J Mol Sci. 2020;21(22):8540. Published 2020 Nov 12. doi:10.3390/ijms21228540[9] Fang, J., Zhang, P., Zhou, Y. et al. Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease. Nat Aging 1, 1175–1188 (2021). https://doi-org.libproxy1.nus.edu.sg/10.1038/s43587-021-00138-z[10] Adesuyan M, Jani YH, Alsugeir D, et al. Phosphodiesterase Type 5 Inhibitors in Men With Erectile Dysfunction and the Risk of Alzheimer Disease: A Cohort Study. Neurology. 2024;102(4):e209131. doi:10.1212/WNL.0000000000209131[11] Gohel D, Zhang P, Gupta AK, et al. Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons. J Alzheimers Dis. 2024;98(2):643-657. doi:10.3233/JAD-231391[12] Rutten K, Vente JD, Sik A, Ittersum MM, Prickaerts J, Blokland A. The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP levels in hippocampal slices. Behav Brain Res. 2005;164(1):11-16. doi:10.1016/j.bbr.2005.04.021[13] https://www.livescience.com/health/medicine-drugs/does-viagra-reduce-the-risk-of-alzheimers-heres-what-we-know[14] Bovijn J, Jackson L, Censin J, et al. GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology. Am J Hum Genet. 2019;104(1):157-163. doi:10.1016/j.ajhg.2018.11.004[15] Sierra C. Hypertension and the Risk of Dementia. Front Cardiovasc Med. 2020;7:5. Published 2020 Jan 31. doi:10.3389/fcvm.2020.00005[16] Desai RJ, Mahesri M, Lee SB, et al. No association between initiation of phosphodiesterase-5 inhibitors and risk of incident Alzheimer's disease and related dementia: results from the Drug Repurposing for Effective Alzheimer's Medicines study. Brain Commun. 2022;4(5):fcac247. Published 2022 Oct 4. doi:10.1093/braincomms/fcac247[17] Samudra N, Motes M, Lu H, et al. A Pilot Study of Changes in Medial Temporal Lobe Fractional Amplitude of Low Frequency Fluctuations after Sildenafil Administration in Patients with Alzheimer's Disease. J Alzheimers Dis. 2019;70(1):163-170. doi:10.3233/JAD-190128封面图来源：pixabay版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn揭秘2024Q1全球药品销售额TOP10！替尔泊肽如榜，修美乐跌出前五Q1财报之后，减肥药格局再变！2024年至今：24笔并购（M&A）交易，总金额520.2亿美元，单笔金额都远低于2023年点击阅读原文，了解更多！

Treatment with abelacimab could result in potential cost-savings of $50,000 over a lifetime per patient basis and higher quality-adjusted life years in atrial fibrillation patients at a high risk of stroke versus rivaroxaban Cost-effectiveness analysis based upon the results from the landmark AZALEA-TIMI 71 study which was stopped early by the Data Monitoring Committee (DMC) due to a substantially greater than anticipated reduction in major and clinically relevant non-major bleeds in the abelacimab arms compared to rivaroxaban Abelacimab is an investigational, once-monthly, highly selective, fully human monoclonal antibody that achieves a near complete 99% Inhibition of Factor XI CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Results of the first-ever cost-effectiveness study of a Factor XI inhibitor were presented today during sessions of the Professional Society for Health Economics and Outcomes Research (ISPOR) annual meeting. The analysis indicates that abelacimab could offer a potential cost-savings of $50,000 USD and improvements of 1.5 quality-adjusted life years (QALY’s) per person over a lifetime horizon as compared to rivaroxaban, a commonly used direct oral anticoagulant (DOAC). If approved by US regulatory authorities, abelacimab could be a highly cost-effective anticoagulant option. “The objective of our economic analysis was to explore the potential cost-effectiveness of abelacimab versus rivaroxaban, using the results from the AZALEA-TIMI 71 study that were presented during a late-breaking session at the 2023 American Heart Association Scientific Sessions,” explained Josephine Li-McLeod, RPh, PhD, at Stratevi, an independent health economics and outcomes research consulting firm, who developed the modeling and led the assessment. “The results from this early economic analysis clearly indicate that abelacimab was dominant versus rivaroxaban with significant savings and a greater number of quality-adjusted life years, meaning it could be a very cost-effective anticoagulant option for patients with atrial fibrillation at moderate-to-high risk of stroke.” Despite the effectiveness of current anticoagulants in stroke prevention, concerns about bleeding risk for patients taking anticoagulants persist. So much so that the underuse of anticoagulants in patients with atrial fibrillation (AF) at risk for stroke is one of the greatest public health issues facing cardiovascular patients.1 “The reality is too many patients with atrial fibrillation are either not taking an anticoagulant at all, or are using a sub-therapeutic dose, typically due to the risk or fear of bleeding associated with currently available therapies. The great promise of a factor XI inhibitor such as abelacimab, rests largely with the ability to prevent thrombosis with minimal disruption of hemostasis. In doing so, this class could represent a major paradigm shift in how we best manage patients in the future,” said Dan Bloomfield, MD, Chief Medical Officer at Anthos Therapeutics. “The significantly improved bleeding pro abelacimab as seen in the AZALEA-TIMI 71 study, coupled with the results from this new cost-effectiveness analysis means that, if approved, patients may have a safer, cost-saving treatment alternative as compared to a standard of care direct-oral anticoagulant.” About Abelacimab Abelacimab is a novel, dual-acting, once-monthly-administered fully human investigational monoclonal antibody that binds to FXI preventing its activation and also neutralizes FXIa activity.2 As a monoclonal antibody, abelacimab is not metabolized via the cytochrome P450 system or as a substrate for P-glycoprotein, meaning the risk of drug-drug interactions is very low. There is no need to adjust the dose based on age or renal/hepatic status. Factor XI inhibition offers the promise of hemostasis-sparing anticoagulation for the prevention and treatment of arterial and venous thromboembolic events.3 Abelacimab is the only Factor XI inhibitor being studied for both conditions. In patients with atrial fibrillation, abelacimab is planned to be dosed subcutaneously (SC) monthly to maintain near-complete inhibition in a chronic setting. It is also planned to be administered via an initial intravenous (IV) infusion for acute indications requiring immediate onset of action and then followed by subsequent monthly SC administration. In the AZALEA-TIMI 71 study, abelacimab 150 mg dosed subcutaneously once-monthly, inhibited Factor XI by 99%.3 In a PK / PD study, abelacimab administered IV provided profound suppression of Factor XI within one hour after the start of therapy and maintained near maximal inhibition for up to 30 days.4 In a Phase 2 study published in the New England Journal of Medicine in 2021, a single intravenous dose of abelacimab after knee surgery reduced the rate of venous thromboembolism by 80%, measured 10 days after surgery, compared to enoxaparin.5 Abelacimab received a Fast Track Designation from the FDA in July 2022 for the treatment of thrombosis associated with cancer. In September 2022, abelacimab was also granted a Fast Track Designation for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Abelacimab is an investigational agent and is not approved for any indication in any country. About the Cost-Effectiveness Model A previously developed Markov state-transition cohort model reflecting the clinical pathways typical of people with AF at moderate-to-high risk of stroke was revised to assess the cost-effectiveness of abelacimab versus rivaroxaban from the US payer perspective.6,7 Clinical inputs were derived from prior models and the AZALEA-TIMI 71 trial.6,7,8 In scenario analyses, the value-based price of abelacimab was explored at various willingness-to-pay (WTP) thresholds using the 95% confidence interval (CI) of the primary bleeding endpoint from AZALEA-TIMI 71. Cost and utility estimates were derived from literature and publicly available sources. Because AZALEA-TIMI 71 was a safety study, the model assumed no difference in the risk of stroke or MI between abelacimab and rivaroxaban.8 The model used a 3-month cycle length and a lifetime horizon. All costs were inflation-adjusted to 2023 US dollars (USD). Following economic model guidelines, a 3% annual discount rate was applied to both cost and utilities.9 All model parameters were varied ±20% in one-way sensitivity analyses to evaluate cost-effectiveness sensitivity. About the AZALEA-TIMI 71 Study The AZALEA-TIMI 71 study was an event-driven, randomized, active-controlled, blinded endpoint, parallel-group study with a primary endpoint that evaluated the effect of two blinded doses of abelacimab relative to open-label rivaroxaban in patients with atrial fibrillation (AF) who are at moderate-to-high risk of stroke. The primary endpoint of the AZALEA-TIMI 71 study was the composite of the rate of major or clinically relevant non-major bleeding events. A secondary endpoint was major bleeding on its own. Patients were randomized 1:1:1 and administered subcutaneous (SC) abelacimab 150 mg once-monthly, abelacimab 90 mg once-monthly, or rivaroxaban 20 mg daily. With a median follow-up of 21 months, spanning more than 2,000 patient-years, the AZALEA-TIMI 71 study is the largest and longest head-to-head study of a Factor XI inhibitor to provide definitive evidence of a highly significant reduction in bleeding as compared to a standard-of-care anticoagulant. Summary of Results as Presented During the American Heart Association 2023 Scientific Sessions:8 Primary endpoint met with a 67% reduction in major or clinically relevant non-major bleeding (CRNM) with abelacimab 150 mg compared with rivaroxaban 20 mg in patients with atrial fibrillation who are at moderate-to-high risk of stroke (P<0.001, HR 0.33, 95% Cl 0.19–0.55) 74% reduction in major bleeding alone with abelacimab 150 mg vs rivaroxaban 20 mg (P=0.002, HR 0.26, 95% CI 0.11-0.61) 93% reduction in gastrointestinal (GI) bleeding with abelacimab 150 mg vs rivaroxaban 20 mg (P=0.008, HR 0.07, 95% Cl 0.01-0.50) 51% reduction in net clinical outcome with abelacimab 150 mg vs rivaroxaban 20 mg (P<0.001, HR 0.49, 95% CI 0.33-0.71) Factor XI inhibition of ~99% with abelacimab 150 mg dosed once monthly The AZALEA-TIMI 71 study enrolled 1,287 patients across 95 global study sites including the U.S. and Canada, Europe and Asia. The independent data monitoring committee (IDMC) recommended that the study end early because of a substantially greater than anticipated reduction in major and clinically relevant non-major bleeding in the abelacimab arms compared to rivaroxaban and a benefit:risk ratio that favored abelacimab. At the same time, the IDMC also recommend that an optional open-label extension period should be made available. AZALEA-TIMI 71 Open-Label Extension An optional extension period in order to provide longer-term data was included as part of the AZALEA-TIMI 71 study protocol. It could be initiated if the independent data monitoring committee (IDMC) stopped the study early due to an imbalance of bleeding substantially favoring abelacimab over rivaroxaban, and the benefit:risk clearly favored abelacimab. Investigative sites had the option of participating or not participating in the extension period. Patients who completed the end-of-treatment visit on study treatment and met the eligibility criteria for the extension period had the option to participate or not. About Atrial Fibrillation Also known as AF, or AFib, atrial fibrillation is an irregular heartbeat, or arrhythmia that can lead to blood clots, is a preventable cause of stroke, and a leading cause of long-term disability and mortality.10,11 Approximately 37 million people worldwide are currently diagnosed with atrial fibrillation,12 while in the United States, the Centers for Disease Control and Prevention (CDC) estimates that more than 12 million Americans will develop AF by 2030.13 The goal of anticoagulation therapy is to prevent and/or treat thrombosis with minimal disruption of hemostasis. Despite the effectiveness of current anticoagulants in stroke prevention, concerns about bleeding risk persist. The underuse of stroke prevention in patients with AF at risk for stroke is one of the greatest public health issues facing cardiovascular patients.1 About Anthos Therapeutics Anthos Therapeutics was founded by Blackstone Life Sciences in 2019 and obtained from Novartis Pharma AG the exclusive global rights to develop, manufacture, and commercialize abelacimab. Anthos Therapeutics is a clinical-stage biopharmaceutical company focused on the development and commercialization of genetically and pharmacologically validated innovative therapies to advance care for high-risk cardiovascular patients. For more information, visit the Company’s website and follow on Twitter and LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the initiation, and timing, of future clinical trials and its research and development. All statements, other than statements of historical facts, contained in this press release, including statements regarding the company’s strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “become,” “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. Any forward-looking statements are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. In addition, the forward-looking statements included in this press release represent the company’s views as of the date hereof and should not be relied upon as representing the company’s views as of any date subsequent to the date hereof. The company anticipates that subsequent events and developments will cause the company’s views to change. However, while the company may elect to update these forward-looking statements at some point in the future, the company specifically disclaims any obligation to do so. [1] Pokorney SD, et al. Am Heart J. 2019;210:29-38. [2] David Gailani, Andras Gruber. Blood 2024 ( ) [3] Hsu et al. J Am Coll Cardiol. Aug. 2021 ( ) [4] Yi BA et al. J Thromb Haemost. Oct. 2021 ( ) [5] Verhamme P et al. New Engl J Med July 2021 ( ) [6] Sterne JA, et al. Health Technol Assess. 2017;21(9):1-386 [7] Benner J, et al. Value in Health. 2023;26(6):S122. 2 [8] Ruff CT, AZALEA-TIMI 71 Steering Committee & Investigators. AZALEA-TIMI 71. A Multicenter, RandomiZed, Active-ControLled Study to Evaluate the Safety and Tolerability of Two Blinded Doses of Abelacimab Compared with Open-Label Rivaroxaban in Patients with Atrial Fibrillation. Presented at: American Heart Association Scientific Session; November 12, 2023; Philadelphia, PA, USA. [9] Sanders GD, et al. JAMA. 2016;316(10):1093-1103. [10] January CT, et al. J Am Coll Cardiol. 2019;74(1):104-132 [11] Hindricks G, et al. Eur Heart J. 2021;42(5):373-498. [12] Lippi G et al. Int J Stroke 2021;16(2):217-221. [13] Center for Disease Control and Prevention website; Atrial Fibrillation page ( ) View source version on businesswire.com: Contacts Media: Caren Begun TellMed Strategies 908-947-0500 x723 caren.begun@tmstrat.com Source: Anthos Therapeutics View this news release online at: