Indapamide

Phase III trial results of novel triple combination pill for hypertension published in The Lancet Novel combination pill significantly reduced blood pressure and improved control rates vs dual therapy, with good tolerability and no increase in adverse event related withdrawalsTriple combination approach aligns with latest European Society of Cardiology hypertension guidelines recommending increased use of combination therapies Subject to regulatory review, following New Drug Application (NDA) filed with FDA in August, GMRx2 would be the first triple combination approved for initial treatment of hypertension London, UK, 18 October 2024 – George Medicines, a late-stage biopharmaceutical company focused on addressing significant unmet needs in cardiometabolic disease treatment, today announced that The Lancet has published results from its pivotal Phase III clinical trial of GMRx2. A proprietary combination of three best-in-class medicines, telmisartan, amlodipine and indapamide, developed in an ultra-low dose (triple quarter-dose), low-dose (triple half-dose), and triple standard-dose options, GMRx2 was compared with dual combinations, for the treatment of hypertension (high blood pressure), including initiation of treatment. The triple combination’s multi-mechanism approach is designed to deliver optimal efficacy and safety while promoting patient adherence. The research, “Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial”, is published in the 19 October issue of The Lancet. The international trial, conducted in seven countries, met all primary efficacy and safety endpoints: GMRx2 was more effective than each dual therapy, significantly reducing both home- and clinic-measured blood pressure (BP) and improving BP control rates, with both standard- and half-dose forms.GMRx2 half-dose achieved 63% clinic BP control <140/90 mmHg, which rose to 74% at the end of follow-up on GMRx2 standard-dose – superior to all three dual combinations at standard-dose (53-61%).Assessed against more stringent BP control rates of <130/80 mmHg, GMRx2 standard dose achieved 56% control rates, again clinically and statistically superior to all three dual combinations (33-44%).Tolerability was good, with no increase in withdrawal from treatment due to adverse events. This treatment approach aligns with recently updated European Society of Cardiology (ESC) guidelines for hypertension management1, which recommend lower blood pressure levels to begin treatment among those at raised risk and greater use of combination therapy, starting off with dual low-dose followed by a triple low -dose therapy. Chair of the trial’s steering committee, Dr. Paul Whelton, Show Chwan Chair of Global Public Health at Tulane University, New Orleans, Louisiana, and President of the World Hypertension League, commented: “This trial, conducted across seven countries and diverse populations, demonstrates that GMRx2 provides significantly better blood pressure control compared to dual combinations, while maintaining an excellent safety profile. The findings are particularly noteworthy as they show efficacy at lower blood pressure levels, aligning with the latest guideline recommendations. This new single-pill combination has the potential to address the critical need for more effective and tolerable treatment options to achieve and maintain blood pressure control in the many patients who remain uncontrolled on current therapies.” Dr. Anthony Rodgers, Chief Medical Officer of George Medicines, and Professorial Fellow at The George Institute for Global Health, said: “These findings, now published in The Lancet, provide robust evidence for the potential of GMRx2 to transform hypertension management. The superior efficacy of this triple combination therapy compared to dual combinations, coupled with its good tolerability, addresses key challenges in current hypertension treatment approaches and directly supports recent guideline recommendations. Subject to regulatory approval, we believe GMRx2 could play a crucial role in addressing the global burden of hypertension and improving patient outcomes.” These results, along with data from other recent trials, including the VERONICA trial in Nigeria, funded by the National Health and Medical Research Council (NHMRC) of Australia, supported by The George Institute for Global Health and recently published in JAMA, and a placebo-controlled Phase III study recently published in the Journal of the American College of Cardiology, provide a comprehensive body of evidence supporting the efficacy and safety of GMRx2 across various patient populations and dosing regimens. In August 2024 George Medicines announced its submission to the US Food and Drug Administration (FDA) of a New Drug Application (NDA) for GMRx2. Data from GMRx2’s clinical development program will support additional global regulatory filings. George Medicines is an independent spin-out company from The George Institute for Global Health, one of the world’s leading medical research institutes with a focus on addressing global health inequity. The Company is backed by George Health, the commercial arm of The George Institute, and Brandon Capital, Australia’s leading life sciences venture capital firm. The Company’s GMRx2 development program built on earlier research by The George Institute, including the 700-patient TRIUMPH trial undertaken in Sri Lanka in 2016/17, which found that among patients with mild to moderate hypertension, treatment with a low-dose triple combination pill led to an increased proportion of patients achieving their target blood pressure goal versus usual care. Ends About the clinical trialA Phase III trial among 1,385 patients in Australia, Czech Republic, New Zealand, Poland, Sri Lanka, UK and the US, standard- and half-dose forms of GMRx2 were tested against dual combinations of its component drugs. The trial’s primary efficacy outcome was the difference between GMRx2 and its comparators in home blood pressure change from randomization to week 12. The head-to-head trial provides the first large scale comparison of a low- and standard-dose triple combination pill and its dual combinations at the same doses. It assessed the safety and efficacy of the triple combination among patients with starting blood pressure levels that were considerably lower than those in previous trials. About hypertension (high blood pressure)Globally, more than one billion adults have hypertension2. Many diagnosed patients aren’t achieving sufficient blood pressure control because they are on inadequate therapy, aren’t receiving the right combination of medicines at the right doses or aren’t taking their treatment as prescribed or continuing their treatment in the long term. The major, globally recognized treatment guidelines3 recommend the use of fixed dose combination therapy for most patients with hypertension, including for first-line treatment and yet, in practice, newly diagnosed patients will often still be prescribed monotherapy treatment. This is despite a broad evidence base indicating that, individually, blood pressure medicines are only modestly effective at reducing blood pressure, even at high doses, and most patients will require two or more medicines to achieve control. As dosage of hypertension drugs is increased, so too are side effects, which can preclude the use of high doses for many patients. These side effect challenges, alongside the management of multiple hypertension medicines being taken together with treatments for other conditions, can significantly impact treatment compliance and adherence, including failure to take medications as prescribed and to persist on long-term therapy. About George Medicines George Medicines is a late-stage biopharmaceutical company addressing significant unmet need in the treatment of cardiometabolic diseases with innovative combinations of best-in-class existing treatments, designed for optimal efficacy and safety. Combining best-in-class molecules from existing medicines in novel low-dose formulations, George Medicines is developing innovative and proprietary treatments to be more efficacious, safer and accessible than currently available treatment options. These multi-mechanism, single-pill combinations offer the potential to bring significant improvements in clinical outcomes and therapy adherence in patients with cardiometabolic disorders, including hypertension and diabetes, each of which remain the leading causes of premature death and disability worldwide. The Company’s lead candidate, GMRx2, has completed a Phase III development program for the treatment of hypertension, including first-line therapy, and a global trial focused on the prevention of recurrent intracerebral hemorrhage (the most severe type of stroke) is underway. George Medicines is an independent spin-out company from The George Institute for Global Health, one of the world’s leading medical research institutes with a focus on addressing global health inequity. The Company is backed by George Health, the commercial arm of The George Institute, and Brandon Capital, Australia’s leading life sciences venture capital firm. For more information, please visit www.george-medicines.com. References 2024 ESC Guidelines for the management of elevated blood pressure and hypertension https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Elevated-Blood-Pressure-and-HypertensionWorld Health Organization Hypertension factsheet https://www-who-int.libproxy1.nus.edu.sg/news-room/fact-sheets/detail/hypertension2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines https://www-ahajournals-org.libproxy1.nus.edu.sg/doi/10.1161/HYP.0000000000000065; WHO Guideline for the pharmacological treatment of hypertension in adults https://iris-who-int.libproxy1.nus.edu.sg/bitstream/handle/10665/344424/9789240033986-eng.pdf; 2024 ESC Guidelines for the management of elevated blood pressure and hypertension https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines/Elevated-Blood-Pressure-and-Hypertension Media contacts ICR Consilium David Daley, Lindsey Neville, Isabelle Abdou georgemedicines@consilium-comms.com; Tel: +44 (0) 203 709 5700

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