作者: Roth, Christian L ; Chichura, Kylie S ; Doyle, Robert P ; den Hartigh, Laura J ; Ashlaw, Emily F ; Liu, Yongjun ; Mullins, Ginger ; Chepurny, Oleg G ; Holz, George G ; Elfers, Clinton T ; McGivney, Aelish ; Miranda, Isabella Chavez

Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.

2025-11-19·BIOCONJUGATE CHEMISTRY

Developing ⁶⁸ Ga-Labeled Exendin(9–39) Derivatives for PET Imaging of Insulinomas

Article

作者: Luo, Yaping ; Li, Tuo ; Li, Linlin

Glucagon-like peptide-1 receptor (GLP-1R) is overexpressed in >90% of insulinomas, making it an optimal target for imaging. However, current GLP-1R agonist tracers may induce side effects including hypoglycemia and nausea, particularly in pediatric patients. In this study, we employed a rational design approach combining molecular dynamics (MD) simulations with experimental validation to develop three ⁶⁸Ga-labeled NOTA-conjugated exendin(9-39) derivatives featuring antagonist activity for safer imaging. MD simulations predicted differential binding affinities based on conjugation sites at Asp⁰⁹ (E09), Lys¹² (E12), and Lys²⁷ (E27), with MM/GBSA calculations ranking E09 (-216.06 kcal/mol) > E12 (-200.01 kcal/mol) > E27 (-117.08 kcal/mol). Experimental validation through surface plasmon resonance confirmed these computational predictions, showing binding affinities consistent with the computational predictions. All radiotracers achieved radiochemical yields (>95%) and plasma stability (>91% intact after 120 min). In vivo PET imaging validated the computational hierarchy, with [⁶⁸Ga]Ga-E09 demonstrating superior tumor uptake (SUV_max: 3.99 at 60 min) compared with E12 (SUV_max: 0.75 at 60 min) or E27 (undetectable). These findings highlight the power of combining computational screening with systematic experimental validation. In conclusion, [⁶⁸Ga]Ga-E09 demonstrates superior binding affinity, cellular uptake, and imaging performance, suggesting its potential as a promising agent warranting further studies.

2025-10-01·INTERNATIONAL JOURNAL OF OBESITY

Visual demonstration of weight loss and health risk improvement with a dual GIP and GLP-1 receptor agonist

Article

作者: Kennedy, Samantha ; Ramirez, Sophia ; Shepherd, John A ; Habibovic, Muhammed ; Bennett, Jonathan P ; Yang, Ryan ; Heymsfield, Steven B ; Thomas, Diana M

BACKGROUND:

Body weight and health-outcome results of highly effective new GLP-1R agonist medicine trials are usually presented in scientific reports in the form of standard graphs and tables. These representations are not easily translated to what the average participant looked like or their health risks at the outset of the study and how improvements in adiposity and clinical measures changed with treatment. Two recently developed methods for visually presenting complex weight and health-risk information that encapsulate substantial amounts of clinical trial observations were recently developed that can potentially supplement and give new insights into conventional GLP-1R agonist scientific reports. The current study aim was to put these visual presentations into a demonstration format to explore if and to what extent they convey new or useful information beyond traditional graphical and tabular approaches.

METHODS:

The first developed approach was the capability of generating, with manifold regression, humanoid avatars with accurate anthropometric dimensions. The second developed approach, body roundness index (BRI), associates a person's shape phenotype with high-risk adiposity components and multiple health outcomes; BRI can be displayed in a visual format. These two approaches were applied to produce visual representations of body size and shape in Surmount 1 average male and female participants (maximal-tolerated dose group) at baseline and after 72-weeks of tirzepatide treatment.

RESULTS:

Developed images revealed clear excess adiposity and high health-risk (BRI) at baseline with marked improvements, although not to within the healthy BMI (<25 kg/m²) and BRI ranges at 72 weeks, observations not evident in the published report. Avatar analyses revealed sexual dimorphism in regional shape (volume) changes with weight loss.

CONCLUSIONS:

Visual presentation of new weight loss medicine trial results can supplement standard published reports by condensing substantial amounts of complex technical information in an easily understood format that can potentially yield new study insights.

项与 GLP-1R Agonist (Biomea Fusion) 相关的新闻（医药）

2025-12-10

·PRNewswire

Ascletis Announces China National Medical Products Administration Acceptance of New Drug Application for Denifanstat (ASC40), a First-in-Class FASN Inhibitor for Acne Treatment

-Denifanstat (ASC40) met all primary, key secondary and secondary efficacy endpoints (ITT analysis) and significantly improved moderate-to-severe acne vulgaris compared with placebo in a randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial. HONG KONG, Dec. 10, 2025 /PRNewswire/ -- Ascletis Pharma Inc. (HKEX: 1672, "Ascletis") announces today that its New Drug Application (NDA) for denifanstat (ASC40), a first-in-class, once-daily oral small molecule fatty acid synthase (FASN) inhibitor for the treatment of moderate-to-severe acne vulgaris, has been accepted by the China National Medical Products Administration (NMPA). "Acceptance of this NDA is an important milestone in our efforts to provide a potentially groundbreaking therapeutic approach for the treatment of moderate-to-severe acne," said Jinzi Jason Wu, Ph.D., Founder, Chairman and CEO of Ascletis, "We are excited denifanstat (ASC40) is only one step away from the commercialization." Ascletis has completed Phase II (NCT05104125) and Phase III (NCT06192264) studies of denifanstat (ASC40) for the treatment of moderate-to-severe acne vulgaris. In the Phase III study, denifanstat (ASC40) met all primary, key secondary and secondary efficacy endpoints (ITT analysis) and significantly improved moderate-to-severe acne vulgaris compared with placebo. Denifanstat (ASC40) demonstrated a favorable safety and tolerability profile. All denifanstat (ASC40)-related treatment-emergent adverse events (TEAEs) were mild (Grade 1) or moderate (Grade 2). There were no denifanstat (ASC40)-related Grade 3 or 4 TEAEs and no denifanstat (ASC40)-related serious adverse events (SAEs). There were no denifanstat (ASC40)-related permanent treatment discontinuations or withdrawals observed. The Phase III study results were presented as an oral presentation at the European Academy of Dermatology and Venereology (EADV) Congress 2025 in Paris, France on September 17, 2025 (link). The Company recently completed the pre-NDA consultation with the China NMPA for denifanstat (ASC40) for the treatment of moderate-to-severe acne vulgaris and received positive feedback from NMPA. Ascletis licensed denifanstat (ASC40) from Sagimet Biosciences Inc. (Nasdaq: SGMT) for exclusive rights in Greater China. About Ascletis Pharma Inc. Ascletis Pharma Inc. is a fully integrated biotechnology company focused on the development and commercialization of potential best-in-class and first-in-class therapeutics to treat metabolic diseases. Utilizing its proprietary Artificial Intelligence-Assisted Structure-Based Drug Discovery (AISBDD) and Ultra-Long-Acting Platform (ULAP) technologies as well as Peptide Oral Transport ENhancement Technology (POTENT), Ascletis has developed multiple drug candidates in-house, including both small molecules and peptides, such as its lead program, ASC30, a small molecule GLP-1R agonist designed to be administered once daily orally and once monthly to once quarterly subcutaneously as a treatment therapy and a maintenance therapy for chronic weight management; ASC36, a once-monthly subcutaneously administered amylin receptor peptide agonist, ASC35, a once-monthly subcutaneously administered GLP-1R/GIPR dual peptide agonist and ASC37, an oral GLP-1R/GIPR/GCGR triple peptide agonist for chronic weight management. Ascletis is listed on the Hong Kong Stock Exchange (1672.HK). For more information, please visit . Contact： Peter Vozzo ICR Healthcare 443-231-0505 (U.S.) [email protected] Ascletis Pharma Inc. PR and IR teams +86-181-0650-9129 (China) [email protected] [email protected] SOURCE Ascletis Pharma Inc. 21% more press release views with Request a Demo

临床3期申请上市临床结果临床2期

2025-12-07

·新浪财经

生物医药Ⅱ行业周报：新药周观点：商保创新药目录发布支付端新增量值得期待

本周新药行情回顾：　　2025 年12 月1 日-2025 年12 月7 日，新药板块涨幅前5：北海康成（+13.94%）、迈博药业（+11.32%）、嘉和生物（+8.38%）、君圣泰（ +7.14% ）、诺思兰德（ +6.27% ）；跌幅前5 ：圣诺医药（ -15.18%）、首药控股（-9.06%）、博安生物（-8.62%）、腾盛博药（-8.05%）、宜明昂科（-7.72%）。　　本周建议关注标的：　　考虑板块后续仍有多个催化值得期待，包括学术会议、数据读出、多个BD 兑现等，仍建议关注：　　1）已获MNC 认证未来海外放量确定性高的品种：三生制药、联邦制药、科伦博泰等；　　2）存在海外数据催化的品种：贝达药业、和黄医药、映恩生物等；3）下一个可能海外授权MNC 的重磅品种：复宏汉霖、石药集团、益方生物等；　　4）新的创新药技术突破领域：小核酸、体内CAR-T、减脂增肌、自免CAR-T/双抗、基因疗法等。　　本周新药行业重点分析：　　2025 年12 月7 日，国家医保局发布了《商业健康保险创新药品目录（2025 年）》（以下简称商保创新药目录），提出多项利于商保创新药目录内药品放量的措施。本次发布的商保创新药目录共纳入19 款既往价格昂贵的创新药，包括部分受市场关注度高的5 款CAR-T 药物以及2 款针对阿尔茨海默病的新药，我们认为商业健康保险创新药品目录出台后有望改善高价值创新药支付难的问题，有望在基本医保支付之外多一个支付路径，打破既往销售天花板。　　本周新药上市申请获批准&受理情况：　　本周国内有1 个新药或新适应症的上市申请获批准，有16 个新药或新适应症的上市申请获受理。　　本周新药临床申请获批准&受理情况：　　本周国内有44 个新药的临床申请获批准，有40 个新药的临床申请获受理。　　本周国内市场重点关注事件TOP3：　　【歌礼】11 月30 日，歌礼宣布，已选定其首款口服GLP-1R/GIPR/GCGR 三靶点激动剂多肽ASC37 口服片作为临床开发候选药物并将于2026 年Q2 向美国FDA 递交IND。　　【先声药业】12 月3 日，先声药业与旺山旺水公司宣布就氢溴酸氘瑞米德韦订立许可协议,先声药业将获得该药品在大中华区用于抗RSV 感染以及抗HMPV 感染适应症的独家许可权益。　　【信达生物】12 月5 日，信达生物宣布，与武田（Takeda）所达成的全球战略合作已满足所有交割条件，协议已正式生效。　　本周海外市场重点关注事件TOP3：　　【Generate：Biomedicines】12 月2 日，Generate：Biomedicines宣布，计划启动两项全球3 期临床试验，评估约1600 名严重哮喘患者在现有治疗控制不佳情况下使用GB-0895 的疗效。　　【Cosmo Pharmaceuticals】12 月4 日，Cosmo Pharmaceuticals 宣布，其在研疗法clascoterone 5%外用溶液在用于男性雄激素性脱发（AGA）治疗的两项关键3 期试验中取得积极的主要结果。　　【Pharvaris 】12 月4 日， Pharvaris 公布，其在研疗法deucrictibant 在RAPIDe-3 临床3 期关键研究中，用于缓解遗传性血管性水肿（HAE）发作获得积极结果。　　风险提示：　　临床试验进度不及预期的风险，临床试验结果不及预期的风险，医药政策变动的风险，创新药专利纠纷的风险。

临床申请基因疗法临床3期申请上市细胞疗法

2025-10-29

·今日头条

恒瑞医药，吓跑了很多人。。。

后浪森林研究室 | 序夹为编辑 | 许佳维恒瑞三季财报吓跑了很多人。周二，恒瑞成交量1.082亿股，这是恒瑞2022年4月7日以来历史最低出现的第八次大幅下跌成交量超过1亿股记录。外部或市场将此归于一笔6亿美元计入合同负债的问题，且不管恒瑞把这笔钱计入收入还是放进合同负债，这钱终归进入了恒瑞。但投资人对于这个态度却完全不同，相当一部分投资人更多在乎短期财务数据，而忽略的是恒瑞不断强大和核心能力增强的事实。这也对投资人进行了分类。历史最低以来第八次资本出逃周二上午，恒瑞一开市抛盘即巨量涌出。这一天，恒瑞刚披露其2025年第三季度报告，本季度收入74.27亿，归母利润13.01亿，环比Q2收入下降13.20%、利润下降49.50%。不妙。抛盘像止不住的泄口，汹涌而出。盘面始终在-4%以下，且承接无力。最终收入-5.06%，成交量1.082亿股，基于流通股换手率2.78%。恒瑞的香港那边，下跌5.2%。恒瑞A股市值蒸发225亿，H股蒸发10.73亿港元。大抛单集中出现在上午的11点以前，占了83.67%。这是恒瑞股票2022年4月7日以来，第8次下跌时成交量超过1亿股的记录。 2023年7月31日，下跌9.11%，成交量1.359亿股； 2023年8月1日，下跌2.69%，成交量1.344亿股； 2023年8月4日，下跌2.64%，成交量1.065亿股； 2023年8月7日，下跌4.72%，成交量1.348亿股； 2024年12月10日，下跌2.56%，成交量1.022亿股； 2025年4月7日，下跌4.56%，成交量1.155亿股； 2025年9月4日，下跌4.63%，成交量1.103亿股； 2025年10月28日，下跌5.06%，成交量1.082亿股。按成交量排序，这次可排在第6大天量下跌。自然，吓跑了很多人。逃亡与计入合同负债的6亿美元相关吗? 恒瑞医药前三季度实现收入231.88亿元，同比增长14.85%；归母净利润57.51亿元，同比增长24.50%。仅看Q3，恒瑞医药收入74.27亿元，同比增长12.72%，环比下降13.19%；归母净利润13.01亿元，同比增长9.53%，环比下降49.49%。正是这个-13.19%、-49.49%两个数据的环比，吓跑了很多人。市场的预期是，恒瑞在三季度获得的三笔首付款大约6亿美元放在营收里，三季报业绩本应该很亮眼，至少不该比二季度差，那这笔钱去哪了。恒瑞披露的资产负债表显示，其2025年第三季度的流动负债项下的合同负债为39.71亿元，而在2025年第二季度末合同负债为1.61亿元，三季度合同负债多出了约38亿元。这便是那两笔合计约6亿美元首付款收入了。这大约6亿美元款项来自GSK和Braveheart Bio的BD首付款。 1）7月28日，恒瑞与GSK共同开发至多12款涵盖呼吸、自免、炎症与肿瘤创新药物（含HRS-9821大中华区以外授权），潜在总金额约120亿美元选择权行使费和里程碑付款，以及相应的分梯度的销售提成，其中恒瑞获得5亿美元首付款。 2）9月5日，恒瑞将HRS-1893海外权益授权给Braveheart Bio，交易额最高可达10.13亿美元临床开发和销售相关的里程碑付款、及相应的销售提成。其中，首付款含现金及等值股权共6500万美元以及完成技术转移后的1000万美元近期里程碑款。根据《企业会计准则第14号——收入》，BD首付款属于预收对价，企业需在收到时确认为“合同负债”，因尚未履行相关履约义务（如研发、临床推进等）。若首付款与已转让商品直接相关（如预购商品），且无需退回，可部分或全部转为收入。关于履约义务完成时点，则需在客户取得商品控制权（如研发成果交付、里程碑达成）时确认收入，而非收款时点。若首付款对应长期履约义务（如创新药研发），应按履约进度分期确认收入，避免一次性计入当期利润扭曲业绩。恒瑞把约6亿美元计入合同负债在会计原则是没有问题，这与条件已经达成的里程碑付款计入“收入”不同。除此之外，在恒瑞接下来的第四季度里，可能还会出现类似情况。10月17日，恒瑞将瑞康曲妥珠单抗部分国际市场权益授权给Glenmark，将收取1800万美元首付款，另有最高可达10.93亿美元的与注册和销售相关的里程碑付款，以及相应的销售提成。三季度末，恒瑞经营现金流净额91.1亿元，同比增长98.68%，Q3单季度经营现金流净额更是达到48.1亿元，创下历史新高。现金流高速增长反应了一个事实，钱已经到账了，还未确认收入，那么这笔钱应该存放在合同负债里面。全球成长最快药物公司整个三季度，恒瑞共获得48个临床试验批件，平均1.9天获一项，尤其在9月份。加上上半年的62项临床批件，恒瑞前三季度新临床项目已达110项，而2024年全年这个数据是114项。 2025.9.2：HRS-7172片单药在携带RAS突变或扩增的晚期实体瘤获准临床。这是恒瑞自研的新型抗肿瘤小分子抑制剂，全球无同类药物上市。 2025.9.2：注射用SHR-A2009联合抗肿瘤治疗在晚期实体瘤的IB/II期获准临床。SHR-A2009是一款以HER3为靶点的抗体药物偶联物（ADC），全球尚无同类药物上市。 2025.9.4：HRS-4729注射液获批临床，适应症为代谢相关脂肪性肝病/代谢相关脂肪性肝炎。这是恒瑞的首款GLP-1R/GIPR/GCGR三重受体激动剂。同日，子公司瑞石生物医药的RSS0393软膏获准开展临床试验，用于特应性皮炎的治疗。 2025.9.18：SHR-3045注射液获批临床，开展类风湿关节炎临床试验。预期可在类风湿关节炎治疗过程中抑制免疫细胞功能，发挥抑制炎症和改善临床症状的效果。同日，SHR-1139注射液获批临床，预期用于溃疡性结肠炎治疗，国内外尚无同类药物获批上市。 2025.9.23：HRS-3095片获批临床，适应症为用于慢性自发性荨麻疹（CSU）。 2025.9.30：HRS-2329片获批临床，拟用于治疗携带RAS突变或扩增的晚期实体瘤患者同日，SHR-4298注射液获批临床，拟用于治疗晚期实体瘤。目前，恒瑞已在中国获批上市24款1类创新药和5款2类新药，另有100多个自主创新产品正在临床开发，400余项临床试验在国内外开展。三季度，恒瑞有1款新产品获批上市，即T细胞淋巴瘤、中国首个EZH2抑制剂泽美妥司他片。同时，恒瑞还有6款产品上市申请获受理及4款产品纳入突破性治疗品种名单。 1）海曲泊帕用于儿童原发免疫性血小板减少症及成人化疗为主的抗肿瘤治疗所致血小板减少症相关适应症； 2）HRS9531注射液用于成人长期体重管理适应症； 3）瑞康曲妥珠单抗用于局部晚期或转移性HER2阳性成人乳腺癌相关适应症； 4）SHR7280片用于辅助生殖适应症； 5）阿得贝利单抗用于成人非小细胞肺癌相关适应症； 6）卡瑞利珠单抗联合法米替尼用于复发或转移性宫颈癌患者一线治疗适应症。 7）注射用SHR-1501联合卡介苗（BCG）用于BCG无应答的的非肌层浸润性原位癌； 8）HRS-5635注射液治疗慢性乙型肝炎； 9）瑞康曲妥珠单抗联合阿得贝利单抗用于PD-L1阳性（CPS≥1）局部复发不可切除或转移性三阴性乳腺癌的一线治疗。这也是瑞康曲妥珠单抗第9次纳入突破性治疗品种。 2025年10月份以来，恒瑞股价已经累计下跌11.08%，最新市值4223亿元。恒瑞第三季度机构数量无法统计，仅获知香港中央结算有限公司减少了4.10%至7.34%；中国医药投资有限公司减少了6.91%至2.77%；华夏上证50ETF减少了3.55%至1.29%；华泰柏瑞沪深300ETF减少1.45%至1.15%。余下的，则无法知晓了。

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