ECC-5004

同写意20周年大会：中国医药创新未来之路！“意”同创新，穿越周期，赢取未来。7月中旬，苏州金鸡湖畔，让我们与“新药写意人”一起为中国医药创新“同写意”！大会设“多肽及减肥药开发论坛”，点击图片查看完整日程。 2026年，诺和诺德在中国和印度的司美格鲁肽专利都将到期，这成为悬在该跨国药企头上的达摩克利斯之剑，却为更多后来者提供了真金白银的机会。 而就在这几天，三家药企几乎同时发布了GLP-1药物的获批进展消息，其中两家来自中国。 6月24日，翰宇药业宣布，公司及Hikma Pharmaceuticals USA联合向FDA申报的利拉鲁肽注射液新药简略申请，已获得FDA暂定批准（Tentative Approval）。 6月25日，中国生物制药下属企业正大天晴开发的“利拉鲁肽”注射液（贝乐林），获得NMPA的上市批准，用于成人2型糖尿病患者控制血糖。同一天，诺和诺德也宣布，司美格鲁肽减重适应症中国获批上市。 减肥与GLP-1，几年间这两个词汇的含金量和关注度毋庸置疑。往后的故事里，中国这一“后来者”能否在专利到期的关键时期走好自己的那步棋，诺和诺德这个老大哥又将如何应对源源不绝的“后浪”们？ 1 一年卖1900亿美元的明星药 这几年爆火全球的大明星司美格鲁肽，属于一种GLP-1受体激动剂（GLP-1RA）。GLP-1是一种肠促胰素，以葡萄糖浓度依赖的方式促进胰岛素分泌，抑制胰高糖素分泌、降低血糖，同时能延缓胃排空从而抑制食欲。 司美格鲁肽注射液目前有两款产品，一款每周1次，每次0.25mg、0.5mg或1mg，为糖尿病治疗药物，2021年4月已在中国上市，半年后即进入国家医保谈判目录。 同时，另一款司美格鲁肽注射液（每周1次，2.4mg）继利拉鲁肽之后，也以“超重或肥胖”为适应症获FDA批准上市，并在同年再获欧盟批准。 数据显示，2023年，诺和诺德司美格鲁肽收入1458.11亿丹麦克朗，约合212亿美元，其中减重版Wegovy暴涨407%，达到46亿美元。 摩根大通去年曾预期，在司美格鲁肽和替尔泊肽双巨头的推动下，2030年GLP-1这类药的年销售额将超1000亿美元。仅仅半年后，BMO Capital Markets就又把预期推到了1500亿美元。 在国内，司美格鲁肽市场同样迅速扩张。数据显示，2023年中国司美格鲁肽市场规模翻倍到了52亿元，分析师预测今年将达到80亿元。 烈火烹油，鲜花着锦。但诺和诺德在稳坐头把交椅的同时，也因专利到期而腹背受敌。机会往往在转瞬间流逝，留给它的时间不多了。 2 中国环伺“减肥蛋糕” 去年10月，是属于GLP-1类新一代降糖减肥药概念股的狂欢。 作为龙头之一的礼来，股价创下629.97美元/股的历史新高，连续三年大涨后，礼来成为全球药企之王，最新市值超过5000亿美元。另一家来自丹麦的药企诺和诺德，股价也在10月13日这一天触及新高，市值突破4400亿美元，超过LVMH集团，跃升为全欧洲市值最高的公司。 两大医药巨头的股价暴涨，都与当下减肥药热潮以及最热门的靶点GLP-1有关。 面对全新的减肥药风口，中国药企也表现出极大的参与热情。公开数据库显示，国内翰宇药业、海正药业、爱美客、恒瑞医药等多家药企已在减肥药领域展开布局。 中国减肥市场一时间轰轰烈烈。 目前，国内制药企业正在研发国产版“减肥神药”，它们要在这个全球最大的抗肥胖药物市场之一与西方制药商展开竞争。 中国是世界上超重和糖尿病人口最多的国家。本土公司希望，在国内市场与诺和诺德的重磅药物展开竞争。如果成功，它们还可能在西方提供更便宜的替代品。 据弗罗斯特沙利文数据，2021年国内减重市场规模为21亿元，2017年至2021年复合增速为71.4%，预计2026年市场规模可达111亿元。 目前，国际市场已获批多种减肥药物，包括奥利司他、芬特明/托吡酯、安非他酮/纳曲酮、利拉鲁肽、司美格鲁肽、替尔泊肽。 而在中国，去年也出现了两款走向商业化的本土GLP-1减肥药，分别是仁会生物的贝那鲁肽注射液，和华东医药的利拉鲁肽生物类似药。 生物类似药在研方面，华东医药、石药集团等多家公司的竞品处于临床Ⅲ期阶段，双鹭药业和万邦医药的利拉鲁肽类似物也已进入临床Ⅲ期。 此外，甘李药业、中国生物制药等药企也在积极开发创新药。根据机构发布的研报，截至2023年8月，共有106个GLP-1类减肥新药的临床试验项目，中国企业有43个，占比约40%。10余家中国企业研发的药物处于临床Ⅲ期阶段，涉及信达生物、派格生物、信立泰等企业。 国内企业减肥药物研发布局以GLP-1单靶点为主，部分在该领域布局深厚的公司开展双靶点，甚至三靶点研发，寻求打造差异化竞争优势。 随着入局企业持续增加，GLP-1赛道竞争越来越激烈，GLP-1药物的研发正朝着长效、多靶点、口服的方向发展，同时不断开拓更多新适应症。目前，国内企业研发的司美格鲁肽类似药至少有10款。 在环伺市场蛋糕的之余，中国企业似乎还想把价格“打下来”。Nature发布评论称，当中国正式开启仿制，像Wegovy这样的重磅减肥药很快就会变得便宜得多，惠及更多的人——价格可能减半，甚至是当前价格的1/10。 有关GLP-1的故事仍然在高潮段落中被描写，种种消息似乎正在将专利到期的时间无限压缩。有关糖尿病和减肥药市场，时间才是实打实的真金白银。风起云涌间，“卷”似乎成了一切的主命题。 中国Biotech的候选药也引起了巨头的兴趣，阿斯利康去年年底宣布通过从中国公司诚益生物引进候选药物ECC5004，进军减肥领域。 另一类的谋局更早，在司美格鲁肽上市之前，诺和诺德还有一款用于糖尿病和减肥的GLP-1多肽药物利拉鲁肽。 2023年年底，利拉鲁肽化合物专利到期。2023年3月，华东医药旗下利拉鲁肽注射液获批2型糖尿病适应症，成为国内首款获批的利拉鲁肽仿制药。同年7月，利拉鲁肽再度获批减肥适应症，成为首个国产GLP-1“减肥针”。 而放眼亚洲，仿制药大国印度同样在竞速。诺和诺德已于2022年在印度推出司美格鲁肽的口服制剂Rybelsus。利拉鲁肽方面，印度本土企业Glenmark Pharmaceuticals、Sun Pharmaceutical Biocon和Virchow Biotech等也有布局。 两年，一切变化均有可能发生。 参考文献： https://wallstreetcn.com/articles/3697652 https://www.21jingji.com/article/20230708/herald/ef5de69c860ac0c182cb484bbeb70b29.html https://news.yaozh.com/archive/40859.html 近期直播推荐:

The mice that were crossed over from semaglutide to Rejuva maintained their weight loss and improved biomarkers, but the real proof of success was in their beta islet cells. GLP-1 drugs like Eli Lilly's Zepbound and Novo Nordisk's Wegovy work to address obesity—as long as a patient keeps taking them.  Harith Rajagopalan, M.D., Ph.D. thinks his company, Fractyl Health, may have the answer: a gene therapy that integrates a GLP-1-secreting transgene directly into the beta islet cells of the pancreas, locking in the mechanism that gives weight loss drugs their benefits. “The dialogue has shifted from what amazing things these drugs can do to how we keep those effects when people stop the drug because the rebound is so violent and significant that it has become the unmet need in obesity,” Fractyl CEO Rajagopalan told Fierce Biotech Research in an interview. “We’ve got great drugs that can lower your weight and cardiovascular risk, but if the majority of people stop taking them within months and everything gets worse right away, how are we going to actually solve the healthcare problem of obesity?” The Fractyl team presented new data June 23 at the American Diabetes Association Scientific Sessions showing that the AAV9-based drug Rejuva is an effective “off-ramp” for weight loss drugs in mice, allowing them to maintain weight loss of 22% post-GLP-1 agonist treatment at eight weeks, the equivalent of about five years in humans.  “Lilly and Novo have fantastic drugs with high potency, and they really prove the GLP-1 mechanism and its benefit, but the product form is limited,” Rajagopalan explained. While other players in the field are trying to develop drugs with longer half-lives, these still don’t dodge the problems of discontinuation and loss of effect, he said.  “I think that we stand alone in trying to develop therapies that address those fundamental limitations in the class,” he said.  Cellular-level differentiation  Fractyl’s ADA conference data comes from a study on 30 mice with obesity. At the start of the experiment, ten were given daily injections of semaglutide, the active ingredient in Wegovy and Ozempic. Another ten received a single administration of Rejuva directly into their pancreas while another ten served as untreated controls.  By four weeks, the cohort that initially received Rejuva had lost 21% of their body fat, while the ones that were given semaglutide lost 16%—results consistent with findings Fractyl shared in October 2023. The weight loss corresponded to improvements in glucose and insulin levels, indicating that the treatments were effective against metabolic disease. The mice given Rejuva also preserved more lean muscle than the ones on semaglutide alone. At that point, the researchers stopped semaglutide injections, randomized the mice in that cohort and gave five of them Rejuva. Four weeks later, they compared those that were treated with the gene therapy to those that weren’t.  Rejuva effectively kept the grams off in the absence of semaglutide. Mice in the crossover arm maintained a 17% fat loss and a 22% total weight loss, while the ones in the discontinuation group regained all but 1% of their baseline weight. The difference extended to their biomarkers, too: Mice that didn’t cross over to Rejuva lost all improvements in their insulin and glucose levels, while they continued to get better in the mice that did.  But the real proof was in the beta islet cells of the Rejuva-treated mice. When the researchers isolated the cells and treated them with various amounts of glucose, they found that they secreted GLP-1 according to how much glucose was present.  “The reason that matters is because it's the first demonstration that our construct, which uses the insulin promoter, is truly nutrient-responsive in how it secretes GLP-1,” Rajagopalan said. “We think that that is an incredible differentiator of this approach.”  If Rejuva reaches the clinic, it will be administered directly into the pancreas using a special device. The approach may solve a couple of key problems that have come up with gene therapies in the past, the first of which is permanence. Given that beta islet cells don’t divide, one treatment may be enough for long-term efficacy. Second, because the treatment isn’t administered systemically and will likely be effective at relatively low doses, it’s less prone to toxicity than other gene therapies delivered via AAV9, which is already widely considered to be safe, Rajagopalan explained.  He compared Fractyl’s gene therapy to Zolgensma, Novartis’ gene therapy for spinal muscular atrophy. Zolgensma also works on non-dividing cells—neurons—and, like Rejuva, uses an AAV9 vector.  “If you're using a capsid where there's a ton of experience with it already, and you have two to three orders of magnitude less of a dose than what is being used in an approved product, we believe that reduces the risk of AAV-associated toxicity,” he said. That said, whether Fractyl’s therapy will be less effective in people who have antibodies to the adenovirus—an old challenge for gene therapies—is an open question that will require clinical studies to answer, he said.  For the company’s diabetes program, such studies are anticipated for the first half of 2025. Fractyl has already nominated a candidate, Rejuva 001, and is in the process of completing investigational new drug-enabling studies. It will nominate an obesity candidate by the end of 2024, Rajagopalan said.  While it’s too early to talk about price, Rajagopalan acknowledged that gene therapies are expensive. But because Rejuva is delivered locally, it might be less costly than systemic treatments because many fewer particles are needed for it to be effective, he said.