CT-996

//   · 市值超过1,000亿美元的15家大药企中，7家拥有新一代的减重产品资产； · 基于已发布的减重临床试验数据，12周、24周和48周的减重最好的药物分别是：安进的MariTide、罗氏的CT-388和礼来的retatrutide； · 口服小分子药物更适合作为快速减重后的长期维持治疗，正在成为各大药企角逐的又一个战场； · 该领域未来有可能催生大量交易。 随着GLP-1药物的热度不断攀升，越来越多的公司进入这场减肥大战的同时，推高了相关药企在公开市场的市值。两款重磅GLP-1类减重产品的开发商——礼来和诺和诺德的股价也不断走高，超越强生，成为全球市值最高的两家药企。 礼来和诺和诺德在公开市场上的优异表现，在医药行业掀起了一场减重产品大战，大量资本和药企冲进这一领域。据Stifel，2024 年至 2019 年间，针对减重产品的风险投资额增长了 10 倍，今年预计将超过10亿美元。而当前正在开发和已经获批的减重产品有264个。 来源|CompaniesMarketcap.com，Bernstein，研发客分析，截至9月13日收盘 基于9月13日的收盘价，市值超过1,000亿美元的15家大药企中，7家已经通过自研或者交易拥有了新一代的减重产品（见上图），并寄希望于这些产品能帮助公司进一步推高市值。 关于交易及合作的讨论，欢迎关注第八届研发客临床年会(左右滑动查看讨论主题)。 更好的激动剂出现？ 去年，诺和诺德的GLP-1明星产品司美格鲁肽销售额达到了212亿美元，成为全球最畅销的药物之一。公司股价也一路走高，超过100美元。 五年后，礼来GLP-1/GIP受体双重激动剂替尔泊肽上市，并报告了更为强劲的减重数据。今年二季度，替尔泊肽的销售额大幅增长至43亿美元。得益于这款药物的强劲表现，礼来今年两次提高了全年的销售预期，年初至今股价上涨超过50%，成为全球市值最高的药企。 患者接受GLP-1类药物治疗后一年半内的平均体重减轻情况  来源|Epic Research 相比而言，诺和诺德的司美格鲁肽在二季度的销售额仅有59亿美元，其中减重品牌Wegovy销售额比市场预期低了14%，因此引发股价暴跌。尽管如此，凭借这款重磅减重产品，诺和诺德目前仍然稳居药企市值第二位。 据FactSet，分析师预期到2026年，替尔泊肽的销售额将达到300亿美元，司美格鲁肽将超过400亿美元。为了获得销售持续的增长，两家公司正在投入巨资加快生产，解决供应问题。 利润如此丰厚的市场，吸引了更多大玩家进入。 罗氏在9月30日的Roche Pharma Day上，提到了对这个潜在价值高达1,000亿美元的大市场的兴趣。去年，罗氏以27亿美元收购Carmot Therapeutics获得了三款G蛋白偏向的GLP-1受体激动剂——CT-868、CT-388和CT-996。 来源|Roche 当GLP-1和GIP受体激活剂与相关受体结合后，环磷酸腺苷 (cAMP) 信号通路被激活，但同时ß-arrestin也会被募集到受体上，然后部分通过受体运输减弱 G 蛋白信号传导，导致受体内化（receptor internalization）和脱敏（desensitization），削弱了药物疗效。 为了最大限度扩大GLP-1和GIP受体激活剂的治疗窗口，Carmot 将产品设计成具有信号传导偏向性，以优先激活 cAMP，同时很少甚至没有 ß-arrestin募集，从而减少受体内化和脱敏，以延长药理活性。 5月16日，罗氏披露了CT-388（GLP-1/GIP受体双重激动剂）的1期临床研究数据。结果显示，24周时最高剂量组安慰剂调整后的体重减轻达到18.8%，当天公司股价上涨超过4%。这一数据也超过了6月恒瑞ADA上发布的同类药物HRS9531的2期24周减重数据（16.7%），以及已上市产品替尔泊肽（11.9%）和司美格鲁肽（8.0%），成为已发布24周数据中减重最多的产品。 未来的市场领导者 在新竞品出现的同时，减重市场领军公司也对正在研发的下一代GLP-1产品寄予厚望。 在3月的资本市场日上，诺和诺德透露，在研新药CagriSema正在开展的3期减重研究包括五个子研究，计划招募1.3万名参与者，今年晚些时候将报告第一个研究的数据。此前发布的 20 周的 1 期减重试验结果显示，CagriSema可减重 17.1%，超过了司美格鲁肽的 9.8%。 CagriSema是cagrilintide（胰淀素和降钙素双重受体激动剂）和已上市药物司美格鲁肽的组合制剂。诺和诺德希望胰淀素（amylin）类似物和 GLP-1 受体激动剂的互补的机制能增强食欲抑制，实现更好的减重效果。 礼来同样在做加法。 去年的ADA（美国糖尿病协会）年会上，礼来发布了同时靶向GLP-1、GIP和GCG（glucagon）的新药retatrutide的2期减重研究结果。最高剂量下，48周安慰剂调整后减重22.1%，是已发布48周数据中减重最大的药物。此外，24周的安慰剂调整后减重也达到16%。 安进的高管及其投资者对他们的减重药物MariTide（maridebart cafraglutide，AMG133）寄予厚望，期望MariTide能挑战两巨头的霸主地位。在5月的一季度业绩会上，公司CEO Bob Bradway暗示2期数据很好，“我们对 MariTide 这款差异化产品很有信心”。随后股价飙升了15%。 在已发布12周减重数据的药物中， MariTide减重幅度最大，最高剂量组达到了16%，优于在2a期研究中表现出色的GLP-1/GIP受体双重激动剂VK2735的13周数据（13.1%）。安进目前正在开展MariTide针对超重和肥胖人群的2期研究，预计年底将发布结果。 MariTide拥有独特的机制，是一款同时靶向两个靶点的抗体-肽共轭物，抗体部分抑制GIP受体，而与抗体结合的两个GLP-1类似物可激活GLP-1受体。 来源|Véniant, M.M., et al. Nat Metab 6, 290–303 (2024). 安进的机制研究表明，MariTide 能同时与 GIP 和 GLP-1的受体结合，从而触发 GLP-1受体 的早期受体内化（receptor internalization），增强 GLP-1 特异性血浆和胞内体膜 cAMP 的生成，从而导致快速、显著和持续的体重减轻，且不易出现体重反弹。 口服制剂：又一个战场 尽管减重效果不如肽类注射剂，但口服小分子制剂生产成本低，且使用方便，更适合作为快速减重后的长期维持治疗，因此成为各大药企角逐的又一个战场。 诺和诺德已经成功完成了司美格鲁肽的口服制剂的减重3期研究，但该公司更在意的是新的候选药物。其中，GLP-1/amylin受体双重激动剂amycretin（NN6487）的口服制剂。3月发布的1期研究初步结果显示，用药12周后，安慰剂调整后减重12.0%，诺和诺德股价应声大涨9%。 年初，礼来的CEO David Ricks在投资者会议上提到了口服非肽类GLP-1受体激动剂orforglipron。根据去年ADA上发布的2期数据，最高剂量组下26周和36周安慰剂调整后减重分别可达到10.6%和12.4%。 辉瑞的口服GLP-1受体激动剂danuglipron（PF-06882961）则命运多舛。在放弃开发代谢功能障碍相关性脂肪肝（MASH）适应症后，去年底又因为退出率超过50%而放弃了每日两次的剂型。不过，今年7月辉瑞表示，将继续开发剂量优化后的danuglipron每日一次的剂型。然而，此前每日两次剂型的2b期研究中，最高剂量组32周安慰剂调整后减重10%，相对于礼来的orforglipron并无优势。 罗氏从Carmot获得的CT-996是一款小分子的GLP-1受体激动剂，根据7月发布的初步结果，这款每日一次的药物能在四周内达到安慰剂调整后6.1%。受此消息影响，罗氏股价一度上涨7%，竞争对手诺和诺德和礼来的股价则分别下跌了5%和近4%。 阿斯利康同样选择从外部购入口服资产。去年11月，该公司花费1.85亿美元首付款从中国公司诚益生物获得了每日一次口服GLP-1受体激动剂ECC5004（AZD5004），目前正在开展2期研究，尚未公布数据。 潜在买家有哪些 为了尽快获得具有竞争力的产品，除了自主开发以外，大药企还积极开展交易。前文提到的罗氏和阿斯利康都是通过外部购买获得了减重候选药物。 不过，仍有不少大药企迄今为止尚无新一代的减重产品，如强生、艾伯维、诺华、赛诺菲和BMS等。此外，默沙东的GLP-1和GCG受体双重抑制剂efinopegdutide（MK-6024）当前仅进行MASH适应症的开发，这些公司不可能放弃减重领域这个大市场，未来很可能会通过购买有竞争力的资产进入该领域。 而已有资产的公司也不会停止交易。 9月初，礼来与Haya Therapeutics达成多年期合作，探索使用Haya的专有技术平台，寻找暗基因组中的长链非编码RNA（lncRNA）靶点，开发减重和代谢新药物。去年该公司还斥资19.3亿美元收购了Versanis，获得myostatin单抗bimagrumab，开发减重适应症。 诺和诺德在今年1月以2.35亿欧元获得了EraCal的临床前食欲抑制剂Era-379等多款口服创新机制的口服小分子减重药物。去年8月，该公司11亿美元收购Inversago，获得的大麻素1型受体（CB1）逆激动剂monlunabant（INV-202）。 另一方面，一些拥有不错数据的在研减重药物及其开发商很有可能是大药企未来的收购目标。例如，Viking的GLP-1/GIP受体双重激动剂VK2735，以及Altimmune 的 GLP-1/GCG受体双重抑制剂pemvidutide等。 可喜的是，多家中国公司在今年的ADA等会议上发布的减重在研产品数据也相当不错，如甘李药业的GZR-18、恒瑞的HRS9531、先为达的伊诺格鲁肽（Ecnoglutide，XW003）等，受到海外关注。未来，或许会有大药企与中国药企的减重资产交易出现。 编辑 | 姚嘉 yao.jia@PharmaDJ.com  总第2228期 访问研发客网站，深度报道和每日新闻抢鲜看 www.PharmaDJ.com

Within the pharmaceutical industry, a multibillion-dollar race is underway to top Novo Nordisks and Eli Lillys in-demand obesity drugs.Dozens of companies, large and small, have set out to test experimental medicines they claim could be more potent, convenient or have fewer side effects than Novos Wegovy and Lillys Zepbound. But those two companies are already hard at work with successors of their own.The next six months figure to be an important preview. Data are expected for a number of drugs that are already, or are shaping up to be, contenders in this high-stakes competition. The readouts will be closely watched, as they will set expectations for how the obesity drug market currently a duopoly between Lilly and Novo will look in the future. Heres what to expect:Zepbound versus WegovyHead-to-head trials always carry high risk. Any company that sponsors one is doing so with the knowledge testing could reveal its drug is equivalent to a competitor or, worse, less effective.With Zepbound, Eli Lilly appears to believe its a risk worth taking. In a trial called SURMOUNT-5, Lilly enrolled 700 people in an attempt to prove Zepbound is better than Wegovy at reducing the body mass of people with obesity or who are overweight, and have another weight-related complication like heart disease or high blood pressure.It expects to have results by the end of the year, and the findings could impact physician and patient perception of which drug offers greater weight loss benefits..So far, Zepbound has seemed superior, as testing showed treatment helped people with obesity lose up to 21% of their body weight. The comparative figure for Wegovy was 16% in the Phase 3 trials Novo used to gain Food and Drug Administration approval. Based on this, Leerink Partners analyst David Risinger expects Zepbound to show a statistically significant advantage in the head-to-head trial.A resoundingly positive outcome could help push Lilly past $1 trillion in market valuation, a milestone that would be a first among pharmaceutical firms. Lilly is currently worth nearly $900 billion.Yet Lilly has yet to prove Zepbound can prevent cardiovascular complications in people with obesity or who are overweight and already have heart disease, as Novo has with Wegovy. That study result helped Novo gain limited Medicare coverage for people with existing heart disease. Lilly has an outcomes trial called SURPASS-CVOT underway, but doesnt expect to have data until next year.Novos dual agonistWegovy works by stimulating a metabolic hormone called GLP-1, while Zepbound targets GLP-1 and a second one called GIP. The biology behind the dueling approaches is still being sorted, but Zepbounds dual agonism has set a model for others to follow, including Novo.The Danish company is now in late-stage testing with a dual-acting experimental drug it calls cagrisema. The drug combines semaglutide, the active ingredient in Wegovy, with another compound that mimics a metabolic hormone called amylin.Cagrisemas Phase 3 trial, called REDEFINE1, is due to wrap up and generate data in the fourth quarter. The results could help Novo fight off Lillys commercial challenge should SURMOUNT-5 favor Zepbound over Wegovy.REDEFINE1 tests cagrisema against a placebo and Wegovy, measuring weight loss over 68 weeks in about 3,400 people. Cagrisemas performance against Wegovy should give analysts a sense of how well it might also measure up against Zepbound, once the SURMOUNT-5 data are available.Novo is also testing cagrisema directly against Zepbound, but that trial isnt due to generate data for another year.Amgens contenderAmgen isnt known for cardiometabolic drugs, but it has one, called maridebart cafraglutide or maritide, thats among the most closely-watched obesity medicines not owned by either Lilly or Novo.Maritide targets the same two gut hormones, GLP-1 and GIP, that Zepbound does. But, somewhat controversially, it is designed to inhibit rather than stimulate GIP. It is also a monthly shot, compared with the weekly injections used for Wegovy and Zepbound.Phase 2 results for maritide are due by the end of the year. Enthusiasm for the experimental drugs potential has driven Amgens shares higher this year sometimes dramatically so. Phase 1 data Amgen disclosed in February suggested it might drive the most weight loss among tested drugs over 12 weeks, according to Stifel analysts.The Phase 2 trial enrolled nearly 600 people with obesity, some of whom also have diabetes, and randomized them to receive one of several doses of maritide or a placebo. Researchers will measure weight loss over 52 weeks.An obesity pillNovo has advanced an oral version of Wegovy and Lilly has pushed its pill oforgliproninto Phase 3 trials. But there are many rivals staking their competitive future on the idea that people with obesity will prefer a pill over a shot. Roche is one such company, having acquired Carmot Therapeutics for $2.7 billion in late 2023 to gain access to three obesity drugs.A Phase 1 dosing trial of the GLP-1 pill CT-996 is due to wrap up by November, which will give Roche and its investors an idea of the drugs biological activity, safety and weight loss. Roche already reported data from earlier stages of the trial, which tested single and increasing doses in trial volunteers who are overweight or have obesity. The third part will test the pill in 60 people who have diabetes in addition to obesity or being overweight.Roche has already said CT-996 will advance into Phase 2 clinical development based on the Phase 1 data. Its already touting the drugs best-in-class potential, although Phase 2 data will be a better test of that claim. Others are already in Phase 2, including Pfizer with its drug danuglipron and Structure Therapeutics with GSBR-1290. They could soon be joined by Terns Pharmaceuticals TERN-601 and Viking Therapeuticsoral version of VK2735.Preserving muscle massThe rapid weight loss stimulated by GLP-1 agonists melts away muscle as well as fat. That worries some experts, who note how people who discontinue treatment tend to regain weight in the form of fat. Muscle cells also have a higher resting metabolic rate, which results in higher caloric burn.In response, some drugmakers are exploring ways to preserve lean muscle mass. An early test could come in the form of results for Verus enobosarm, a type of drug that stimulates muscle-building hormones. Previously sold under the name Ostarine, it has been tested clinically in people with cancer whose muscles have shrunk, as well as those with muscular dystrophy.In obesity, a Phase 2 test of enobosarm together with Wegovy is underway in people 60 and over who are overweight or have obesity and have lost muscle mass. The trial will measure how much trial volunteers muscle mass changes over 16 weeks, and will compare results in people who receive the two drugs to those who were given only Wegovy. Another endpoint will assess physical function by evaluating how participants climb stairs.Veru expects results by the end of the year. The data could help analysts parse how important lean mass might be in future obesity treatment.A new drug targetOutside of targeting GLP-1, GIP, amylin and other gut hormones, there are a range of other treatment approaches under evaluation. One involves blocking a cannabinoid receptor called CB1 that is known for regulating an appetite-modulating hormone called leptin. CB1 is known to have effects on other biological functions such as inflammation, too.So far, theres been at least one disappointing data point on CB1 inhibition. Phase 2 data for a Novo drug called monlunabant didnt meet expectations for weight loss, leading Novo to state that further work is needed to determine the optimal dosing.The next shot for CB1 may be Skye Biosciences nimacimab, which is due to have interim Phase 2 results by mid-2025. The trial, called CBEYOND, tests nimacimab against placebo, as well as a combination of Wegovy and nimacimab against Wegovy alone. The study will measure weight loss over 26 weeks. Enrolling 120 volunteers, the study should be large enough to detect at least an 8% difference between the experimental drug and placebo, according to the trials plan.Skye shares fell by more than 40% the same day Novo reported its data for monlunabant. '