CT-996

近日，诺和诺德的CagriSema的III期试验REDEFINE 1的减重数据不如预期，这使得该公司的股价大幅下跌。诺和诺德引领了GLP-1革命，但现在却面临着被其他新产品迭代的危险——甚至更糟糕的是，被现有产品所取代。 REDEFINE 1是一项为期68周的疗效和安全性试验，旨在进行皮下注射CagriSema（cagrilintide2.4mg和司美格鲁肽2.4mg的固定剂量复方制剂）与cagrilintide2.4mg、司美格鲁肽2.4mg和安慰剂（均每周给药一次）的比较。该试验随机纳入了3417名肥胖或超重患者，他们都患有一种或多种并发症（无2型糖尿病），平均基线体重为106.9kg。 在上周公布的读数中，诺和诺德的胰岛淀粉样肽-GLP-1组合药物在使用符合方案集（PPS）分析的情况下，使肥胖患者减重22.7%。该分析排除了未按计划接受试验药物的患者。而在更保守的意向治疗（ITT）分析中，将这些患者视为无应答者，这也是最终会出现在药物说明书上的数据，减重比例为20.4%。 这些数据虽然不错，但诺和诺德需要更好的结果。其既定目标是减重25%，未能达标使其付出了沉重的代价——上周五收盘时股价下跌17%。这些数据给诺和诺德以及所有活跃在肥胖治疗领域的公司留下了多个待解的问题。 01 与礼来的Zepbound相比，诺和诺德的CagriSema有何优势？ 在使用意向治疗（ITT）分析的情况下，CagriSema的安慰剂校正减重效果与其竞争对手礼来的第一代产品Zepbound在关键试验中观察到的几乎相同。尽管Zepbound达到这一效果所需的时间更长，但CagriSema也有其劣势，作为两种分子的组合，CagriSema的生产比Zepbound更复杂、成本更高，其潜在利润也可能更低。此外，CagriSema还被证明具有更差的安全性。而迄今为止，诺和诺德在这一方面一直保持沉默。 CagriSema与Zepbound在约800名非糖尿病肥胖患者中的头对头III期试验正在进行中，预计将于2025年底前得出数据。如果诺和诺德的产品数据在这一试验中落后于Zepbound的，那么诺和诺德的股价可能会进一步下跌。同样，产品的安全性数据也将是关键所在。 图1：诺和诺德的CagriSema与其他肥胖症药物的比较 02 GLP-1药物是否已触及天花板？ CagriSema的失败引发了这样一种可能性：基于肠促胰素的药物所能实现的减重效果可能存在上限。正在研发中的一些第二代产品或许能为解答这一问题提供特别有力的帮助。 即使具有相同机制的药物，其疗效也表现出很大的差异。诺和诺德的早期GLP-1药物Saxenda已上市十年被用于治疗肥胖症，但其疗效从未接近Wegovy及其后续药物。尽管它们具有共同的机制，但正在研发中的新型产品可能会更有效。 例如，礼来的三重激动剂retatrutide在II期试验中的42周时取得了惊人的结果——优于Zepbound和CagriSema。罗氏通过27亿美元收购Carmot获得的GLP-1/GIP激动剂CT-388在六个月时，经安慰剂校正后的减重率更高，约为19%。然而，这些数据来自一项小型的Ib期试验，还需要更大规模、更后期的试验来支持。 此外，Viking Therapeutics的GLP-1/GIP激动剂VK2735也备受期待，它让肥胖患者在仅三个月的治疗后减重近15%。这大致与诺和诺德的第一代产品Wegovy在大约一年四个月时达到的减重效果相当。使用这些产品减重通常在60个月左右趋于平稳，之后患者的减重效果微乎其微。 这三种实验性注射药物中的任何一种，都有可能在数月治疗后实现减重方面的突破性进展，打破迄今为止所见的减重天花板。 03 当市场转向口服药物时，谁将胜出？ 诺和诺德和礼来大幅提升的生产能力，意味着注射型肠促胰岛素终于开始覆盖所有需要它们的新患者。但是，当患者接受注射治疗数月或数年后会发生什么呢？下一个战场将是维持治疗，这意味着口服药物将成为主角。 口服药物为了达到与皮下注射制剂相同的效果，需要更高的剂量和新的生产工艺，因此当市场转向口服药物时，生产能力将再次成为问题。但在此之前，这些药物必须在临床上证明自己的效果。 去年，诺和诺德的口服型Wegovy在III期试验报告中显示，其效果与注射型Wegovy大致相当。然而，在监管方面进展甚微——诺和诺德没有公开表示是否已提交该产品进行审批。 礼来没有试验口服型Zepbound，而是转向了另一种GLP-1/GIP激动剂orforglipron。该口服药物在II期试验的36周后减重近15%，这比诺和诺德的口服药物减重更明显。目前，该药物正在进行III期试验。 至于一些其他的知名公司，也在试图直接进军口服药物市场，但并非都取得了成功： 2023年12月，辉瑞搁置了其口服GLP-1激动剂danuglipron的每周两次服用版本。2024年7月11日，辉瑞宣布基于目前正在进行的1期药代动力学研究结果，确定推进其剂型改良版danuglipron（一日一次）。该研究旨在探索原剂型danuglipron与三种改良剂型danuglipron（不同剂量/释放速率）单次给药后的PK和安全性。该数据可能会在2025年公布，届时将决定是否进行III期试验。 罗氏也在努力研发口服药物——CT-996。该药物是一种口服、每日一次的实验性肥胖药，可激活GLP-1受体，从而促进胰腺分泌胰岛素。其最初由Carmot Therapeutics公司开发，罗氏于2023年12月以27亿美元收购了该公司。2024年7月，该公司发布了CT-996的初步数据，在仅一个月的时间内实现了7.3%的减重，在当时是所有早期口服药物中效果最好的。然而，这一记录在11月被Viking的VK2735口服药物所超越，该药在28天时以100mg的剂量实现了8.2%的减重。但是，这些数据来自小规模的I期试验，因此说服力不强。 参考资料： [1]CagriSema’s weight loss data disappointed. What does Novo do next?.Elizabeth Cairns.December 23, 2024 11:24 AM EST. [2]68周减重22.7%！诺和诺德CagriSema III期减重数据公布.医药魔方Info.2024年12月20日. [3]再试一次！辉瑞“复活”其口服GLP-1RA.药时代.2024年07月12日. [4]罗氏口服减肥药CT-996疗效数据强劲，但面临安全性问题（附PPT）.星药.2024年09月13日. 识别微信二维码，可添加药时空小编 请注明：姓名+研究方向！

On December 20, Novo Nordisk announced the primary results of its Phase 3 REDEFINE-1 clinical trial for the next-generation weight-loss drug CagriSema. The 68-week trial involved 3,417 participants with a baseline weight of 106.9 kg. The results showed that patients receiving subcutaneous injections of CagriSema achieved an average weight reduction of 22.7% (based on trial product estimates) or 20.4% (based on treatment policy estimates). CagriSema is a combination drug composed of semaglutide and a long-acting amylin analog, cagrilintide. Given Novo Nordisk's success with semaglutide in diabetes and weight loss, CagriSema was highly anticipated as the next-generation product. However, following the announcement of the REDEFINE-1 trial results, Novo Nordisk's stock plummeted by 28% in pre-market trading, closing at $85, with a market value loss exceeding $82.1 billion. Although CagriSema’s weight-loss efficacy over 68 weeks was comparable to the already marketed tirzepatide, the market's elevated expectations led to the sharp stock decline. From a data perspective, CagriSema’s weight-loss effect failed to meet the company's original target of a 25% reduction, putting it at a disadvantage compared to tirzepatide. Additionally, CagriSema lags behind tirzepatide in clinical and commercialization progress, with the latter expected to launch in 2025. This setback for Novo Nordisk may reshape the global weight-loss drug market. Although CagriSema’s efficacy is comparable to tirzepatide, its market value has significantly diminished due to unmet expectations. In the fiercely competitive weight-loss drug market, Novo Nordisk appears to have little room for error. On one hand, Eli Lilly’s tirzepatide, a dual-target drug, is not even its strongest asset in weight management—its triple-target GLP-1 drug, retatrutide, has shown superior weight-loss results in Phase 2 trials. On the other hand, Novo Nordisk leads in targeting amylin, with both CagriSema (a subcutaneous combination therapy) and Amycretin, an oral dual-target GLP-1 and amylin drug (currently in Phase 1 trials). Additionally, Novo Nordisk has invested heavily in CB1 receptor agonists, though these pipelines are still in early stages. CagriSema’s mechanism relies on semaglutide's ability to boost insulin secretion, while amylin, like insulin, is secreted by pancreatic β-cells. Together, they enhance weight loss by controlling postprandial blood sugar levels and increasing satiety. Amylin also offers better blood-brain barrier permeability and reduced negative impact on muscle. In Phase 2 clinical trials, CagriSema demonstrated remarkable efficacy, with treated patients achieving 15.6% weight loss at week 32, compared to 5.1% in the semaglutide group. However, the incidence of gastrointestinal adverse events with CagriSema was nearly twice that of monotherapy, which may have contributed to the less-than-expected results. Despite lower overall adverse event rates than monotherapy in Phase 2 trials, CagriSema's higher gastrointestinal side effects may impact patient tolerance. Novo Nordisk plans to conduct a low-dose flexibility study next year, but investors remain skeptical of its efficacy. Beyond the REDEFINE-1 trial, Novo Nordisk has multiple ongoing head-to-head clinical trials between CagriSema and Eli Lilly's tirzepatide. Future competition for CagriSema will center not only on weight-loss efficacy but also on other health metrics, such as preservation of lean muscle mass. In the race for oral weight-loss drugs, Novo Nordisk is banking on Amycretin, a dual-action GLP-1 and amylin receptor agonist with long-acting effects, aiming to become a best-in-class (BIC) oral weight-loss medication. Despite the crowded competition, Amycretin has shown potential for rapid and substantial short-term weight loss. Globally, the competition for oral weight-loss drugs is intense. While Pfizer and Eli Lilly are ahead, Pfizer's molecules have faced safety challenges, and Eli Lilly's Orforglipron showed inferior weight-loss efficacy compared to injectable formulations in recent Phase 2 data presented at the 2023 ADA conference. Leading MNCs like Roche, AstraZeneca, and Merck are entering the field, while Chinese biotech firms also benefit from substantial BD investments. Although no small-molecule oral GLP-1 drugs are currently on the market, Eli Lilly's Orforglipron, the closest to commercialization, has shown weak weight-loss results, while Novo Nordisk’s Amycretin and Roche’s CT-996, still in early clinical phases, demonstrate promising efficacy but lack large-scale safety data. Chinese biotech firms may find opportunities in developing small-molecule GLP-1 drugs. As more MNCs join the race and additional GLP-1 pipeline data emerges, the market will rapidly elevate the standards for future GLP-1 data. Novo Nordisk's CagriSema’s underwhelming Phase 3 results may tip the balance of injectable GLP-1 drug competition toward Eli Lilly. However, the most intense and brutal competition for small-molecule oral GLP-1 drugs has only just begun.