中证报中证网讯(王珞)11月27日，甘李药业（603087）宣布，其自主研发的胰高血糖素样肽-1受体激动 剂(GLP-1RA)博凡格鲁肽注射液正式启动中国首个"每月一次"给药的减重III期临床研究(GRADUAL- 3)。 该研究标志着中国首个启动III期的GLP-1RA月制剂进入关键阶段，有望显著提升患者用药依从性，为 长期体重管理提供更优解决方案。 据了解，甘李药业此次启动的GRADUAL-3研究是一项旨在评估每月一次皮下注射博凡格鲁肽的减重疗 效和安全性的随机对照试验。该研究已在药物临床试验登记与信息公示平台登记(登记号： CTR20254659)，由北京大学人民医院纪立农教授牵头，主要终点为治疗24周后体重较基线的变化值和 变化百分比。 与当前市场上周制剂GLP-1药物相比，博凡格鲁肽月制剂方案有望将每年注射次数从52次大幅减少至12 次，注射频次降低近80%，并显著改善患者治疗体验和长期用药依从性。在需要长期维持的体重管理领 域，用药依从性已成为影响临床结果的关键因素。月制剂GLP-1方案直击这一临床痛点，通过减少注射 频率，可降低治疗负担，提高患者生活质量。 GRADUAL系列研究是博凡格鲁肽注射 ...

Core Viewpoint - The article discusses the significant advancements in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases (CVD) through the use of semaglutide, particularly its weight management version, highlighting its dual benefits in liver health and cardiovascular risk reduction [5][8][11]. Group 1: MASLD and CVD Connection - Approximately one-third of the global population is affected by MASLD, which is closely linked to obesity and type 2 diabetes mellitus (T2DM) [5][6]. - The SELECT study has established a strong correlation between MASLD and CVD, emphasizing the need for comprehensive management strategies for patients with these metabolic disorders [6][13]. Group 2: Semaglutide's Clinical Benefits - Semaglutide has been recognized as a "star drug" in the treatment of metabolic diseases due to its proven efficacy in blood sugar control, weight management, and overall metabolic improvement [6][8]. - The SELECT study included 17,604 overweight or obese participants, demonstrating that semaglutide significantly reduces the risk of major adverse cardiovascular events (MACE) by 20% compared to placebo [8][13]. - The drug also shows a 15% reduction in cardiovascular death risk and an 18% decrease in heart failure composite endpoint risk [8][11]. Group 3: Liver Health Improvements - Semaglutide's weight management version exhibits dual liver protective effects, particularly beneficial for overweight or obese patients with CVD [11][12]. - Key findings from the SELECT study indicate rapid improvement in liver enzyme levels (ALT, AST, GGT) and a significant reduction in the fatty liver index by 16.1% after 104 weeks of treatment [12][14]. Group 4: Future Implications - The findings from the SELECT study suggest that semaglutide could pave the way for a comprehensive protective strategy against cardiovascular and liver diseases in overweight and obese populations [14]. - The 2024 Obesity Treatment Guidelines emphasize the importance of focusing on metabolic health beyond mere weight loss, indicating a shift in treatment paradigms [14].

Core Viewpoint - Wave Life Sciences Ltd. presents promising preclinical data for its candidate drug WVE-007, which targets INHBE mRNA to reduce fat mass without compromising muscle quality, potentially lowering the risk of metabolic diseases such as type 2 diabetes and coronary artery disease [1][7]. Group 1: Mechanism and Efficacy - WVE-007 is a GalNAc-modified siRNA that significantly downregulates INHBE mRNA and its product Activin E protein, which inhibits fat breakdown in obesity [2]. - A single administration of WVE-007 results in weight loss comparable to the widely used GLP-1 receptor agonist semaglutide [3]. - The drug effectively reduces visceral fat, decreases adipocyte size, and preserves muscle mass, supporting weight loss through the restoration of adipose tissue function [4]. Group 2: Inflammatory Response - WVE-007 significantly inhibits the recruitment of pro-inflammatory M1 macrophages while maintaining levels of anti-inflammatory M2 macrophages, demonstrating strong anti-inflammatory potential [5]. Group 3: Combination and Maintenance Therapy - When used in conjunction with semaglutide, INHBE-siRNA can double the weight loss effect, indicating a synergistic therapeutic potential [6]. - After discontinuation of semaglutide, INHBE-siRNA significantly slows weight regain, suggesting it could serve as a maintenance or transitional therapy for GLP-1 treatments [7]. Group 4: Genetic Insights and Future Prospects - Individuals carrying INHBE gene loss-of-function variants often exhibit healthier metabolic profiles, including reduced abdominal fat, lower triglyceride levels, and decreased risks of type 2 diabetes and cardiovascular diseases [7]. - The Chief Scientific Officer of Wave emphasizes that if clinical trials confirm these mechanisms, WVE-007 could revolutionize obesity treatment by offering a new pathway that requires only one to two injections per year for healthy weight loss while preserving muscle mass [7].

Core Viewpoint - CureGene's CG-0416 demonstrates significant potential as a dual mechanism candidate drug for treating Metabolic Dysfunction-Associated Steatotic Liver Disease (MASH) and obesity, showing a 58% reduction in liver lipid accumulation, a 66% improvement in weight loss, and a 50% decrease in muscle loss compared to standard therapies [2][4]. Group 1: Breakthroughs in Treatment - CG-0416 overcomes limitations of current GLP-1 receptor agonists by precisely targeting complementary metabolic pathways, enhancing weight control and muscle preservation [3]. - The liver-specific activation of CG-0416 results in a 20-fold higher concentration of active metabolites in the liver compared to peripheral tissues, maximizing safety [4]. - In a 26-week diet-induced obesity mouse model, CG-0416 combined with low-dose semaglutide showed a 66% reduction in fat mass and a muscle fat reduction ratio of 0.18 kg/kg, compared to existing therapies which range from 0.35 to 0.63 kg/kg [4]. Group 2: Clinical Translation Advantages - CG-0416 enhances GLP-1-mediated liver lipid oxidation while activating the IGF-1/Akt/FOXO3a axis to inhibit muscle catabolism, showcasing a dual pathway synergistic effect [4]. - With an oral bioavailability of 92%, CG-0416 is expected to be the first oral therapy used in conjunction with GLP-1 agonists, significantly higher than previously approved THR-β therapies [5]. Group 3: About CG-0416 - CG-0416 is a novel liver-targeted THR-β prodrug under development for treating MASH and obesity-related complications, demonstrating superior metabolic control compared to Resmetirom and VK-2809 in preclinical studies [6]. - As a potential oral adjunct to GLP-1 therapy, CG-0416 combines rapid fat loss with muscle preservation, positioning it as a next-generation metabolic modulator [6]. Group 4: About CureGene - Founded in 2018, CureGene is a biotechnology company based in China with a global focus, specializing in innovative platforms for cardiovascular and antiviral diseases [8]. - The company has successfully transitioned from a research-stage startup to a clinical-stage biotech firm, with a pipeline of drugs showing significant market potential and complete global intellectual property rights [8].