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].

整理 | GLP1减重宝典内容团队 事实证明，身体会在肠道中产生这些药物的天然版本 - 也称为肠促胰岛素激素。食物中的营养素有助于调节这些激素，肠道中的数万亿微生物 是协调这一过程的关键。 司美格鲁肽和替尔泊肽是减肥和治疗糖尿病的药物，它们针对肥胖和糖尿病的调节途径，被广泛认为是减肥和血糖控制方面的突破。 但这些药 物是否指向代谢疾病的根本原因？是什么首先激发了它们的开发？ ▍ 肠道受损 下肠道中的特殊细菌会吸收无法消化的食物成分，如纤维和多酚（许多加工食品中去除的植物元素），并将它们转化为刺激激素控制食欲和新 陈代谢的分子。这些包括 GLP-1，司美格鲁肽的天然版本。 GLP-1 和其他激素（如 PYY）有助于通过胰腺调节血糖。它们还会告诉大脑已经吃饱了，并告诉胃和肠减缓食物沿消化道的移动以便消化。 这个系统甚至有一个名字：结肠制动器。 在现代加工食品出现之前，代谢调节途径由多样化的健康肠道微生物群指导，这些微生物群使用这些激素自然调节新陈代谢和食欲。然而， 旨 在提高保质期和增强口感的食品加工会去除有助于调节该系统的生物活性分子，如纤维和多酚 。 ▍ 天然GLP-1由下肠道产生，可以抑制食欲，减缓胃排空 ...

整理 | GLP1减重宝典内容团队 CG-0416 的肝脏特异性激活使肝内活性代谢物浓度比外周组织高 20 倍，从而最大限度地降低全身 THR-β 激活，并提高长期安全性。 2. 肌肉保存突破 在26周饮食诱导肥胖 (DIO) 小鼠模型中，CG-0416 与低剂量 司美格鲁肽联合使用表现出： 脂肪量减少 66%（与司美格鲁肽 单药治疗相比） 肌肉脂肪减少比为 0.18 kg/kg（现有疗法为 0.35-0.63 kg/kg） 临床转化优势 在欧洲肝病研究协会 (EASL) 年会上，柯君医药 公布了其在研的肝脏靶向甲状腺激素β受体 (THR-β) 前药 CG-0416 的最新临床前研究结果。 该研究数据在"最新海报"环节中展示，突显了 CG-0416 在代谢功能障碍相关脂肪性肝炎 (MASH) 和体重管理方面的三重治疗潜力：与标准疗 法相比，肝脏脂质蓄积减少 58%；减重效果提高 66%；肌肉流失率降低 50%。这些研究结果使 CG-0416 成为同时治疗 MASH 和肥胖症的新 型双机制候选药物。 突破当前治疗局限性 GLP-1 受体激动剂（例如司美格鲁肽、替泽帕肽）在持续控制体重和保持肌肉质量方面面临挑战， ...

Financial Data and Key Metrics Changes - The company reported net product sales of $75.9 million for Q1 2025, representing a 90% increase year-over-year and continued sequential growth [27] - Net sales for VILSPARI grew 182% year-over-year and 13% compared to the previous quarter, reflecting strong demand and uptake [6][20] - The net loss for Q1 2025 was $41.2 million, or $0.47 per basic share, compared to a net loss of $136.1 million, or $1.76 per basic share, for the same period in 2024 [32] Business Line Data and Key Metrics Changes - VILSPARI maintained strong momentum with $55.9 million in net product sales for Q1 2025, despite higher gross-to-net discounts due to insurance coverage changes [27][28] - Thiola and Thiola EC contributed $20 million in net product sales for the first quarter [28] - The company expects to receive a $17.5 million milestone payment from CSL V4 due to the conversion of VILSPARI's conditional approval to full approval in Europe [32] Market Data and Key Metrics Changes - The European Commission and MHRA in the UK converted FILSPARI's conditional approvals to full approvals for the treatment of adults with IgA nephropathy, enabling broader access across Europe and the UK [7] - Approximately 75% of nephrologists are now targeting proteinuria below 0.5 grams per gram, with nearly a third targeting even more ambitious goals of 0.3 grams [25] Company Strategy and Development Direction - The company aims to solidify VILSPARI's foundational positioning in IgA nephropathy and unlock additional growth through a potential new indication in FSGS [5] - The company is preparing for a potential launch of VILSPARI for FSGS, which is expected to be a significant opportunity, potentially larger than in IgA nephropathy [10][26] - The company is committed to advancing its investigational therapy PEG T for classical homocystinuria (HCU) and plans to restart patient enrollment in the Phase III HARMONY study next year [10][19] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the strategy with strong fundamentals and a clear focus on executing key priorities [11] - The company anticipates continued strong demand for FILSPARI and IgA nephropathy, projecting meaningful growth in net product sales throughout the year [33] - Management is monitoring legislative developments and geopolitical uncertainties but believes that potential tariffs on pharmaceutical products would not have a material impact on VILSPARI [33] Other Important Information - The company reported a decrease in R&D expenses to $46.9 million for Q1 2025, down from $49.4 million in the same period in 2024 [29] - Selling, general, and administrative expenses increased to $72.8 million for Q1 2025, compared to $64.2 million for the same period in 2024, largely due to increased investment in the FILSPARI launch [30] Q&A Session Summary Question: Can you elaborate on any interactions with the agency regarding the sNDA for FSGS? - Management indicated that interactions with the FDA have been consistent and progressing as expected, similar to previous experiences with the IGAN indication [36][38] Question: What do you think the label for FSGS will look like? - The expectation is that the indication will be for the treatment of FSGS in patients ages eight and up, based on the broad inclusion criteria of the duplex study [42][45] Question: How is the recent approval of Novartis' therapy impacting your sales reps in the field? - Management noted that it is early to assess the impact, but continued demand for FILSPARI has been observed, indicating confidence in its efficacy profile [50][52] Question: What is the impact of the removal of the REMS program on new patient starts in IGAN? - Management stated that REMS has not been an obstacle to performance and anticipates that modifications will enhance convenience for patients and physicians [76][78] Question: What is the split between new versus repeat prescribers for FILSPARI? - The split is slightly skewed towards experienced prescribers, with a healthy continuation of new prescribers as well [86]