Arrowhead Pharmaceuticals, Inc.

Appointment of Sohanya Cheng Resignation of Michael Torok PHILADELPHIA, Oct. 30, 2024 /PRNewswire/ -- Carisma Therapeutics Inc. (Nasdaq: CARM) ("Carisma" or the "Company"), a clinical-stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, today announced the appointment of Sohanya Cheng, MBA to the Company's Board of Directors, effective October 31, 2024. Additionally, Michael Torok has informed the Board of his intention to step down as a member, effective October 31, 2024, due to other professional commitments. "It's a pleasure to welcome Sohanya to our Board," said Sanford Zweifach, Chair of the Carisma Board. "Her broad experience in oncology, alongside her skills in leadership, strategic planning, and commercialization, will be instrumental as we continue to advance our portfolio and strengthen our foundation. We are also thankful to Michael for his valuable service and wish him all the best in his next chapter." "I am excited to join Carisma's Board and collaborate with the management team as the Company advances its mission to deliver innovative immunotherapies to patients facing serious diseases," said Ms. Cheng. "I look forward to sharing my insights and supporting the Company's strategic goals as it solidifies its position as a leader in engineered macrophages within oncology and beyond." About Sohanya Cheng, MBA Ms. Cheng brings over 20 years of experience in biopharmaceutical commercialization and research, with a strong focus on oncology. She currently serves as the EVP, Chief Commercial Officer, and Head of Business Development at Karyopharm Therapeutics. Prior to this, she was Vice President, Head of Marketing and Corporate Affairs at Arrowhead Pharmaceuticals. Ms. Cheng also spent over a decade at Amgen in various leadership roles, including Executive Director, Head of Marketing & Sales for multiple myeloma and Head of Oncology National Sales, contributing to the commercialization of key oncology brands. She holds an MBA from the MIT Sloan School of Management and both a BSc and MA from the University of Cambridge, UK. About Carisma Carisma Therapeutics Inc. is a clinical-stage biopharmaceutical company focused on utilizing our proprietary macrophage and monocyte cell engineering platform to develop transformative immunotherapies to treat cancer and other serious diseases. We have created a comprehensive, differentiated proprietary cell therapy platform focused on engineered macrophages and monocytes, cells that play a crucial role in both the innate and adaptive immune response. Carisma is headquartered in Philadelphia, PA. For more information, please visit . Investors: Shveta Dighe Head of Investor Relations [email protected] Media Contact: Julia Stern (763) 350-5223 [email protected] SOURCE Carisma Therapeutics Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Adapted from iStock, Drypsiak Vertex may have pivoted away from the space, but candidates in development by Arrowhead/Takeda, Wave, Korro and others could address the damage underlying alpha-1 antitrypsin deficiency and make today’s treatments a thing of the past. Alpha-1 antitrypsin deficiency is a genetic disorder that affects the liver and/or lungs. Approximately 1 in 3,500 people have two abnormal SERPINA1 genes for the alpha-1 antitrypsin (AAT) protein and are at risk of serious organ damage due to AATD. While M-AAT is produced in healthy humans to inhibit neutrophil elastase in the lungs, AATD patients produce Z-AAT, which does not inhibit neutrophil elastase as effectively. If too much neutrophil elastase builds up in the lungs or liver, the result is inflammation which, untreated, can lead to lifelong complications. The only currently approved treatment option for AATD is augmentation therapy , which entails delivering normal alpha-1 antitrypsin collected and purified from blood donors through weekly intravenous administration. But this treatment does not reverse pulmonary damage or stop the progression of liver damage. Multiple companies are developing candidates that would prevent or reverse this damage, and despite some setbacks in the field, in the next 5 to 10 years we could see augmentation therapy become a thing of the past. In August 2024 , Vertex Pharmaceuticals announced that the company would cease research into both of its investigational small molecules for AATD. While Vertex had hoped that VX-634 and VX-668 would treat the disease by correcting the AAT protein, the efficacy was not transformative enough. Along with Vertex’s November 2023 discontinuation of the development of VX-864 for AATD due to reports of rashes and elevated liver enzymes, these setbacks highlight some of the challenges associated with researching new treatments for AATD. Meanwhile, Arrowhead Pharmaceuticals and Takeda are recruiting for three Phase III trials for fazirsiran, an investigational subcutaneous first-in-class investigational RNA interference (RNAi) therapy for AATD-associated liver disease. While Phase II AROAAT-2002 results indicated that fazirsiran led to significant reductions in Z-AAT, the evidence for pulmonary efficacy and improvement is murky because the Phase II trial did not have a placebo arm and the median FEV1 and mean DLCOhbg—markers of pulmonary function—were stable over time in all subjects receiving experimental treatment compared to baseline. While these data do not show any signs of pulmonary decline, there is no sign of overall pulmonary improvement either. In addition, Sanofi is working on SAR447537, an AATD asset acquired from Inhibrx. Formerly known as INBRX-101 , SAR447537 is a fusion protein currently in the recruitment stage for Phase II trials involving AATD emphysema. In Phase I results, safety and pharmacokinetic data supported the intravenous use of SAR447537 every three or four weeks. However, efficacy data related to the liver are not available. In the in vivo base editing space, Beam Therapeutics is investigating the use of BEAM-302 to treat AATD. BEAM-302 is a liver-targeting lipid nanoparticle formulation that is currently undergoing Phase I/II trials and is formulated to be a one-time intravenous injection of an adenine base editor. When tested in rat and mouse models , toxic liver protein levels decreased. Finally, Wave Life Sciences, AIRNA and Korro Bio are competing in the early phases of preclinical/clinical research to develop AATD-targeting subcutaneous RNA-editing oligonucleotides. On Oct. 16, Wave reported positive proof-of-mechanism data from a Phase Ib/IIa trial of WVE-006 in AATD, while Korro Bio released preclinical data this month for its AATD investigational treatment, KRRO-110 . AIRNA had yet to release its adenosine deaminase acting on RNA (ADAR) preclinical data publicly as of July 2024. With all these investigational treatments aiming to transform the way AATD is treated, augmentation therapy could soon be obsolete. If efficacy data for RNA-based oligonucleotides is significant and points to clinical success, RNA-based oligonucleotides could hit the market as soon as four to five years from now. In the meantime, at the current trajectory, fazirsiran could reach the market as early as two to four years from now if all goes well. Given these developments in the AATD space, competition could heat up within the next decade as more efficacy data are released from therapies currently at earlier stages of development.

来源：药渡 撰文：睿睿李     编辑：维他命 心血管疾病是全球居民死亡的主要原因，有着巨大的未满足需求。开发和商业化可以单独或联合使用的新疗法，对于有效解决已知风险因素并推进患者护理尤为重要，这也是药企研发战略的关键组成部分。 2024年10月7日，阿斯利康宣布与石药集团签订独家许可协议，推进早期新型小分子脂蛋白（a）干扰剂（简称Lp(a)干扰剂）YS2302018的开发。该干扰剂有潜力为血脂异常患者提供更多的获益。根据协议，石药集团将获得阿斯利康的1亿美元首付款，此外还有最高3.7亿美元的潜在开发里程碑付款和最高15.5亿美元的潜在销售里程碑付款，以及根据该产品的年度销售净额计算的分层销售提成。 01 明星靶点孕育潜力疗法 血脂异常的特征是血液中脂质和脂蛋白水平升高，特别是低密度脂蛋白（LDL）胆固醇（也称为“坏胆固醇”）的升高。脂蛋白（a）是低密度脂蛋白（LDL）的一种形式，在血流中对胆固醇的运输起着关键作用。 脂蛋白（a）水平升高以及LDL胆固醇升高是心血管疾病的已知危险因素，包括冠状动脉疾病和中风。据估计，每年在全球范围内血脂异常导致了260万人死亡。 虽然目前已经有心血管疾病相关的治疗方法，但全球血脂异常的疾病负担仍在增加。超过70%的动脉粥样硬化性心血管病（ASCVD）患者仍不能达到LDL胆固醇的控制目标，因此高危患者急需更多样化且更有效的治疗选择。 脂蛋白（a）是血脂异常的一个非常重要的靶点，与多种心脏代谢疾病有关。降低异常的血脂已被证明对心血管疾病的预后有改善作用，并且还可以降低严重心血管事件的风险。 因此，脂蛋白（a）同时也是各大跨国药企竞相布局的靶点。从市场来看，这一靶点的竞争多以小干扰RNA（siRNA）或反义寡核苷酸（ASO）为主。例如： 安进与Arrowhead合作开发的Olpasiran（siRNA）进入了3期临床阶段； 礼来与Dicerna的Lepodisiran（siRNA）在今年启动了3期临床； 诺华与Ionis合作开发的Pelacarsen（ASO）处于3期临床阶段。 而由石药集团发现的YS2302018则是一种小分子候选药物，相比之下可谓另辟蹊径。目前，已有研究证明它能有效防止脂蛋白（a）的形成，展现出极好的临床应用前景。 02 阿斯利康勇闯降脂药赛道 近几个月，阿斯利康已将其AZD0780（一种正在研究的口服小分子PCSK9抑制剂，用于治疗血脂异常）确定为2030年可能推出的一系列关键候选药物之一。该分子可以使90%的胆固醇升高患者达到目标控制水平。基于各种证据，其销售预测非常可观。 图1. 阿斯利康在心血管、肾脏和代谢领域的管线，来源：阿斯利康官网 最近，阿斯利康又买入石药集团的临床前候选小分子YS2302018，目的是将其开发为一种新型降脂疗法，可用于单独或联合治疗一系列心血管疾病适应症，包括与口服小分子PCSK9抑制剂AZD0780联合使用。 这些产品线布局在一定程度上会使阿斯利康与礼来形成竞争。在1期试验中，礼来公司的脂蛋白（a）形成小分子抑制剂将脂蛋白水平降低了65%。礼来公司于今年早些时候完成了muvalaplin（也称为LY3473329）的2期试验，并继续将该分子列入中期研发计划。 这波领先优势暂时被礼来占据。不过，YS2302018可以有效防止脂蛋白（a）形成的临床前证据仍然说服了阿斯利康开展这次与石药集团的合作，侧面反映了阿斯利康对这一新分子的信心和决心。 阿斯利康表示，这款分子的目标人群是近70%的心血管疾病患者。这部分患者虽然服用了高强度他汀类药物，但仍不能达到指南指导的低密度脂蛋白胆固醇目标限度。这是由于依从性差和单药治疗往往不够有效等问题造成的。 阿斯利康在1期试验中将合用口服PCSK9抑制剂与单用标准护理他汀类药物进行了比较，结果发现合用疗法可以把LDL胆固醇水平降低52%。阿斯利康设想，与YS2302018结合使用可以同时降低脂蛋白（a），因此可能会产生进一步的临床益处。 03 阿斯利康与石药强强联合 大药企收购小药企产品来丰富自己管线的操作并不少见，不过像这次阿斯利康与石药集团这样量级的合作，确实是强强联合。 阿斯利康正在投资一系列药物来降低心血管疾病风险因素并减缓慢性心血管疾病的进展，包括AZD0780。对于阿斯利康来说，购入YS2302018进一步强化了公司的心血管产品组合，可以帮助患者更有效地管理他们的血脂异常和相关的心血管代谢疾病。 这次合作石药集团将从阿斯利康获得1亿美元的预付款，还有权获得高达19.2亿美元的进一步开发和商业化里程碑付款，以及分层销售提成。 在其他治疗领域，石药集团和阿斯利康已经取得了丰硕的成果。例如在肺癌治疗领域，石药集团人源化EGFR单克隆抗体联合阿斯利康奥希替尼，在治疗EGFR 20号外显子插入突变（EGFR ex20ins）的非小细胞肺癌方面的出色成果得到了国际学术界的广泛认可。 这样的合作为推动创新药上市注入了强大的动力，一方面它让更多患者能够早日受益于先进的治疗药物，另一方面它让药企能够借助经济获益进一步推动自己的发展。 小 结 根据《中国血脂管理指南（2023年）》，降脂药物联合应用已经成为中国降脂治疗的基本趋势和重要策略。血脂异常可能导致动脉粥样斑块形成，从而引发心脑血管疾病，因此早期干预非常重要。基于这一重要的靶点，阿斯利康通过自研和收购等策略，布局了强劲的产品组合。 降脂药物的发展前景充满挑战与机遇，技术进步、个性化医疗和精准医疗的发展将不断塑造药物市场格局。大大小小的药企合作将不断为新药的研发和商业化推广添砖加瓦。 参考资料： 1. 阿斯利康官网 2. AstraZeneca pays CSPC $100M for preclinical heart disease drug, teeing up combos and Lilly rivalry Oct 7, 2024 6:12am www.fiercebiotech.com *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！ 礼来能否反超诺和诺德？后来者将居上乎？ 药企裁员风波持续 | 九月汇总 礼来多奈单抗日本获批，浅谈：阿尔茨海默病从病理机制到创新药物的探索之路