CT-388

近期，罗氏在2024年医药日活动中阐述了最新药物研发进展以及未来研发的战略方向。值得注意的是，除了肿瘤、自身免疫、神经系统、眼科等传统优势业务，心血管、肾脏及代谢领域（CVRM）成为罗氏新押注的疾病领域，罗氏认为，在下一个增长周期中，CVRM将成为业绩增长的重要引擎。 图1.罗氏CVRM领域在研产品管线情况 资料来源：Roche Pharma Day 2024 1 Zilebesiran：长效高血压RNA干扰药物 Zilebesiran是由罗氏与Alnylam Pharmaceuticals公司共同开发的靶向血管紧张素原（AGT）的在研RNAi疗法，用于治疗未受控高血压。肾素-血管紧张素-醛固酮系统（RAAS）是高血压疾病发展的重要作用机制之一，AGT是血管紧张素的唯一前体蛋白。 Zilebesiran是由一个小干扰RNA（siRNA）与N-乙酰半乳糖胺（GalNac）配体共价链接组成。siRNA通过与靶标AGT mRNA结合，形成RNA干扰沉默复合体（RISC），肝细胞内的核酸酶能够选择性地降解RISC中的AGT mRNA，从而大幅抑制肝脏中血管紧张素原的合成，并最终导致血管紧张素的减少，同时经RISC反复循环利用而达到长效的作用。 今年4月，Alnylam Pharmaceuticals公司公布了Zilebesiran在治疗轻度至中度高血压的2期临床试验KARDIA-2中取得的积极结果：将Zilebesiran与抗高血压药物联合使用，在接受治疗的第三个月，与安慰剂组相比，通过动态血压监测测量的24小时收缩压显示出具有临床意义的降低，吲达帕胺治疗组24小时动态收缩压多降低12.1mmHg。 图2. Zilebesiran 2期临床试验结果 资料来源：Roche Pharma Day 2024 此外，部分接受Zilebesiran治疗的患者在6个月后，在无需使用其它补救疗法的情况下，仍能维持降压效果，在吲达帕胺和氨氯地平治疗组中尤为明显。 图3. Zilebesiran 2期临床试验结果 资料来源：Alnylam公司官网 后期，Alnylam将开展临床3期研究CVOT，旨在探索Zilebesiran治疗高血压不受控制的高危患者，研究的主要终点为主要不良心脏事件的复合终点，并探索Zilebesiran扩展其他心血管适应症的可能性。预计将于2025年下半年完成首例患者入组。 2 代谢领域：寻求差异化定位 罗氏的GLP-1管线来自于收购Carmot Therapeutics公司获得。2023年12月，罗氏以27亿美金首付款和4亿美金的潜在里程碑付款收购Carmot Therapeutics公司，获得Carmot Therapeutics公司旗下3个早期肥胖症和糖尿病候选药物，分别为：一周一次皮下注射的GLP-1R/GIPR双靶激动剂CT-388；一天一次皮下注射的GLP-1R/GIPR双靶激动剂CT-868；一天一次口服给药的小分子GLP-1R激动剂CT-996。 罗氏在降糖减重领域的研发进展已远远落后于两大巨头诺和诺德与礼来，珠玉在前，后入局者想要弯道超车，在激烈的市场竞争中突围，关键在于以临床未满足需求为切入点，进行差异化定位。 3 药物差异化设计：偏向性激动剂 罗氏的3款GLP-1系列在研药物CT-388、CT-868、CT-996均为偏向性激动剂，即其在激活cAMP信号传导的同时，减少β-抑制蛋白（β-arrestin）活性，从而减少β-抑制蛋白介导的内吞和脱敏。根据临床前研究结果显示，减少β-抑制蛋白活性，可以延长降糖和减重疗效。 图4.罗氏3款GLP-1药物的差异化设计 资料来源：EASD 2024 罗氏在今年的EASD会议上公布了GLP-1/GIPR双靶点激动剂CT-388用于治疗肥胖和2型糖尿病的临床1期试验结果，数据显示，每周一次22mg的CT-388皮下注射，在治疗达到第24周时，患者体重降幅达18.9%。在第24周时，100%接受治疗的患者实现了超过5%的体重减轻，85%的患者体重降幅超过10%，70%的患者体重降幅超过15%，45%的患者体重降幅超过20%。 图5. CT-388疗效数据 资料来源：EASD 2024 CT-388用于治疗肥胖和2型糖尿病的2期临床试验也已开展，2024年Q3完成首例患者入组。 罗氏的另一款小分子口服GLP-1受体激动剂CT-996也取得了积极的疗效数据。1期临床试验结果显示，肥胖且无2型糖尿病的患者，在接受治疗4周后，体重降幅达7.3%，安慰剂组体重降幅仅为1.2%（差异值6.1%，P＜0.001）。 图6. CT-996疗效数据 资料来源：EASD 2024 目前，CT-996正在进行1b期研究的第三部分研究（针对肥胖且患有2型糖尿病患者队列），2期临床试验预计将在2025年启动。 4 联合疗法应对减重“平台期”：CT-173+CT-388 减重过程中通常会遇到停滞期，罗氏希望通过CT-173与CT-388联合疗法以应对减重平台期的问题。 CT-173是一款肽YY（Peptide YY，PYY）类似物，PYY是一种由肠道内分泌细胞所产生的激素，能够起到控制食欲的作用。 根据临床前研究结果显示，相较于单独使用CT-388或CT-173，CT-173和CT-388的联合治疗可以显著降低小鼠体重，在停止治疗后，联合疗法下的体重反弹速度更慢。在单独使用CT-388体重下降达到平台期后，加入CT-173，在协同作用下，体重仍能持续显著下降。 罗氏预计将于2025年启动CT-388+CT-173联合疗法用于应对减重平台期的临床1期试验。 图7. CT-388+CT-173临床前研究相关数据 资料来源：Roche Pharma Day 2024 5 肌肉保护：GYM329 相关研究显示，使用GLP-1R药物会显著降低去脂体重，其主要成分为骨骼和肌肉。因此，能够同时实现减重效果并避免肌肉流失的新药将拥有更大的市场价值。 罗氏的GYM329是一款与肌肉生长抑制素前体蛋白结合的单克隆抗体。肌肉生长抑制素是一种骨骼肌生长和强度的关键负调节因子，GYM329与肌肉生长抑制素前体蛋白的结合能够抑制它被蛋白酶激活。在临床前研究中，GYM329表现出提高肌肉大小和强度的活性。 目前GYM329治疗面肩肱型肌营养不良症、脊髓性肌萎缩症的临床试验分别处于2期、2/3期阶段，治疗肥胖症的临床1期试验已启动。 图8. GYM329在研项目情况 资料来源：罗氏2024年H1报告 近年来，罗氏的业绩表现并不乐观，传统优势领域肿瘤业务板块增长有限，老牌明星产品贝伐珠单抗、曲妥珠单抗年收入下滑幅度达两位数，罗氏的业绩支撑主要来源于创新药，例如，治疗多发性硬化的Ocrevus、治疗血友病的双抗Hemlibra等。罗氏求变，此次挺进CVRM领域，体现了罗氏将在自身的多元化布局上再下一城，以及为寻找“第二增长曲线”作战略性准备。 参考资料 罗氏2024年H1报告 EASD 2024 Roche Pharma Day 2024

Eli Lilly showed a drug that goes after two metabolic targets to treat obesity can successfully shed weight and become a revenue-generating heavyweight. Other companies aspire to improve on the Lilly drug’s approach and Kailera Therapeutics is the newest of them, backed by $400 million to support a pipeline of obesity drug candidates. Kailera, which splits its operations between San Diego and Waltham, Massachusetts, is joining a growing field of companies developing drugs that mimic peptides in the body, binding to and activating receptors to spark metabolic effects. The company’s lead program goes after GLP-1 and GIP, targets addressed by Lilly’s blockbuster drug Zepbound, which won FDA approval for chronic weight management last November. Kailera’s portfolio of four metabolic disorder dugs comes from China-based Jiangsu Hengrui Pharmaceuticals. In May, Kailera licensed exclusive rights to develop those molecules globally, except for greater China where Hengrui retails rights. The most advanced program is KAI-9531, a once-weekly injectable dual agonist of the GLP-1 and GIP receptors. Under Hengrui, Kailera said this drug showed “compelling results” in obesity and type 2 diabetes from Phase 2 tests conducted in China. presented by Sponsored Post The Promise of Value-Based Care and MedTech Innovation Monica Vajani, Executive Director for mHUB’s MedTech Accelerator, discusses how mHUB is helping innovators transition healthcare towards value-based care. By Monica Vajani - mHUB The Phase 2 test in obesity enrolled 249 participants randomly assigned one of four doses of the once-weekly injectable study drug or a placebo. The double-blind treatment period was 24 weeks. Hengrui presented Phase 2 results in obesity in June, during the American Diabetes Association Scientific Sessions meeting. These results showed a dose-dependent increase in weight loss during the treatment period. At the 6 mg dose — the highest one tested — 53.1% of patients lost 15% or more of their body weight compared to baseline. Adverse events reported from the study included nausea, diarrhea, decreased appetite, and vomiting. Gastrointestinal problems are consistent with other weight management drugs and Hengrui classified the side effects in its study as mild to moderate in severity. It’s difficult to make cross-trial comparisons, but the results for the drug that is now Kailera’s lead program suggest it’s competitive with others targeting both GLP-1 and GIP. In Zepbound’s pivotal study, patients lost an average 18% of their body weight compared to those who received a placebo. In February, San Diego-based Viking Therapeutics reported Phase 2 data for its once-weekly injectable GLP-1 and GIP agonist, VK2735, showing an average 13.1% placebo-adjusted weight loss after 13 weeks of treatment. A larger and longer Phase 3 study is planned for this molecule. An oral version of the Viking drug is expected to begin a Phase 2 test in obesity by the end of this year. Roche is going after GLP-1 and GIP with CT-388, an injectable peptide from its $2.7 billion acquisition of Carmot Therapeutics last year. In a Phase 1 test, Roche reported the average placebo-adjusted weight loss at 24 weeks was 18.8%. An oral drug included in that M&A deal posted encouraging Phase 1 data over the summer. Kailera’s pipeline also includes oral therapies. The Hengrui deal brought two small molecule programs, KAI7535 and KAI-9531. Kailera’s fourth program is an injectable drug that goes after three targets: GLP-1, GIP, and glucagon receptor. New York-based Metsera has a program that also goes after those three targets. Its most advanced program hits only GLP-1, but with a dosing edge of an injection once a month. Last week, Metsera announced Phase 1 results showing 7.5% reduction in body weight measured at day 36. The company, which launched in April backed by $290 million, expects to begin a Phase 2b test of its lead program by the end of this year; preliminary data are expected in the first half of 2025. presented by Health IT Accelerating Claim Processing: Strategies to Shorten the Life of a Claim These strategies and practices can significantly shorten the life cycle of claims, leading to quicker resolutions and improved financial outcomes. By Greenway Health Kailera’s Series A financing announced Tuesday was co-led by Atlas Venture, Bain Capital Life Sciences, and RTW Investments. Lyra Capital also participated in the round. The company is led by CEO Ron Renaud, who was most recently the chief executive of Cerevel Therapeutics, a neurological diseases drug developer recently acquired by AbbVie. “In this period of rapid innovation in the metabolic space, I believe that Kailera is poised to make an impact beyond the current market leaders,” Renaud said in a prepared statement. “We have an incredible opportunity to develop next-generation treatments for chronic weight management, helping people reclaim their health and live their lives to the fullest.”