Retatrutide

For years, drug developers working to treat an advanced form of fatty liver disease known as MASH were chasing wide-open terrain. There were no products on the market, millions of potential patients and a high bar on the science to get a successful drug. Then, in June, Eli Lilly reported that its blockbuster weight loss drug tirzepatide might be an effective treatment for the condition. Last week, Novo Nordisk released a study showing that its weight loss drug semaglutide also improved MASH in patients . It’s planning to apply for an FDA approval next year. MASH (metabolic dysfunction-associated steatohepatitis) is often associated with obesity, and the apparent success of the widely available (and cheaper) GLP-1 drugs has raised the question about how much room there will be for MASH-targeting drugs. The answer, however, appears to be that there’s still an opportunity. Last week, the first company to bring a MASH drug to market reported third-quarter sales of $62.2 million, well above Wall Street expectations. It’s a fraction of what the weight loss products are selling, but it was enough to send the company’s stock up by almost half. On a call with investors Thursday, Madrigal Pharmaceuticals executives said many of their patients are also on weight loss drugs, and they don’t expect patients to have to try a GLP-1 before moving to a MASH therapy. “We’ve had ongoing dialogue with payers now for well over a year,” Madrigal CEO Bill Sibold said. “They understand the profile of the product and what it can offer.” At the same time, biotechs developing the MASH drugs have begun to tweak their development strategies to prove that their liver-targeting candidates work in conjunction with the weight loss drugs, especially as more patients show up in trials already on the therapies. And early batches of data released by biotechs in the space suggest there are benefits to combining the treatments. Sagimet Biosciences, for example, has a once-daily, oral MASH drug named denifanstat that’s set to enter Phase 3 before the end of the year . In the company’s Phase 2b study that read out this year, about 10% of patients were on a GLP-1 receptor agonist. CEO David Happel estimates that rate could jump to as much as 50% in a Phase 3 trial, and a survey of clinicians published by Cantor Fitzgerald in late June found that about a third of patients with advanced MASH are already on GLP-1s. “We were able to show a highly statistically significant improvement in fibrosis in those patients that frankly exceeded what either molecule alone could achieve,” Happel said in an interview with Endpoints News . None of the four patients on a GLP-1 who were given placebo demonstrated an improvement in either resolution of MASH without worsening of fibrosis or improvement in fibrosis without worsening of MASH. Five of 12 patients that were given the study drug showed MASH resolution and fibrosis improvement, respectively, though the MASH resolution results weren’t statistically significant. Those sorts of data are just beginning to emerge, now that companies developing MASH drugs are starting to study what happens when patients are on GLP-1s — and whether some patients might benefit more than others. “Until now, we have put all these patients in one population to examine, so there is little granularity in the treatment of the patients so far,” said Frank Tacke, director of hepatology at Charité – Universitätsmedizin Berlin, who’s consulted for numerous pharmas, including Novo Nordisk and Madrigal. “If we want to position whatever drug we would like to develop in patients with MASH, it will be in an environment where GLP-1s are one of the main drugs to treat the comorbidities,” Tacke said. Akero Therapeutics has performed similar analyses as Sagimet with its experimental MASH drug efruxifermin, currently in Phase 3. The drug is an analogue of fibroblast growth factor 21 (FGF21), a protein which fights against fat-induced toxicity and its effect on cellular distress. In a Phase 2 trial cohort, Akero studied 31 people on GLP-1s who had type 2 diabetes and MASH, adding either efruxifermin or a placebo. In the group, the majority of patients who added efruxifermin saw significant improvement to key markers of the disease. “The two in combination are really making substantial differences to the liver,” Akero chief development officer Kitty Yale said of the effect of the weight loss drugs and Akero’s experimental medicine. Other results, presented earlier this year, found that efruxifermin improved patients’ fibrosis across two dose levels at the 96-week mark compared to placebo. One reassurance for the companies developing MASH drugs is that the weight loss treatments, while effective in treating obesity, don’t appear to be a cure for the liver disease. Data from Eli Lilly at this year’s European Association for the Study of the Liver annual meeting showed that tirzepatide met the primary endpoint of wiping out fat cells in the liver compared to placebo. The company said the drug demonstrated the potential to be “clinically meaningful” at improving fibrosis, but that the study was not powered for the endpoint. And in a 2021 trial, Novo Nordisk failed to show a significant difference between semaglutide and placebo. “While these medications can be very helpful for the treatment of MASH, they’re not a complete panacea,” said Sidney Barritt, director of hepatology at the University of North Carolina’s liver center. Lilly is still mulling whether to launch a pivotal trial of tirzepatide in MASH, or wait to test a successor weight loss drug — if the better bet is retatrutide — in the disease. A spokesperson for the company said it “plans to continue conversations with the FDA on the next steps for tirzepatide for the treatment of MASH.” As for Novo, investors described the new data as roughly in line with expectations. Analysts at Leerink Partners said the GLP-1s don’t appear to be a ‘silver bullet’ for MASH and believe that combination use will be the standard of care. “For NASH stocks — we believe this outcome removes a potential overhang / worst-case scenario where [semaglutide] showed ‘game-changing’ fibrosis improvement,” the analysts wrote. Investors agreed and Madrigal’s stock climbed after the readout. There could be a handful of reasons for why the obesity drugs don’t solve MASH, Barritt explained, including that GLP-1 receptors aren’t located in the liver. The benefits are indirect, with improvements in weight through decreased appetite that naturally improve MASH — to a point. It’s also possible that a 52-week endpoint that some MASH trials implement may be a bit too soon for GLP-1s to show a full effect. Other trials have a longer, 72-week endpoint. “I think there’s going to be a market for these combination therapies in the future,” said Brian Ting, a transplant surgeon and gastroenterology specialist at the Tulane Transplant Institute. Reynald Castañeda contributed reporting.

礼来减肥药又有新动作。 近日，礼来注册了GLP-1R/GIPR/GCGR三靶点激动剂Retatrutide的第6项用于减重的三期临床试验，与替尔泊肽头对头比较在肥胖成人中的疗效和安全性。 去年11月，替尔泊肽的减重适应症刚刚获批上市，且势头正猛。尽管最新三季报显示，替尔泊肽增速不及市场预期，公司股价也应声大跌，但其前三季度总额依然高达110亿美元，再次缩小与诺和诺德司美格鲁肽的差距。 而在礼来最新的预期中，Retatrutide的疗效将超越替尔泊肽。为此，礼来火力全开，连开5项减重三期临床，拟入组人数超5000人。 那么，这一次，Retatrutide是否能延续礼来在GLP-1减重领域的辉煌？ 01 礼来押注Retatrutide 替尔泊肽是目前已经问世的GLP-1药物中减重效果最好的。 在针对不伴2型糖尿病肥胖受试者的III期SURMOUNT-1研究中，经过72周替尔泊肽治疗后，15mg剂量组的参与者平均体重减轻高达22.5%（24公斤）； 在针对伴2型糖尿病肥胖受试者的III期SURMOUNT-2研究中，经过72周替尔泊肽治疗后，15mg剂量组的参与者平均体重减轻15.7%。 礼来当时表示，这是首个在3期临床试验中平均减重效果超过20%的研究性药物。由于减重效果突出，替尔泊肽上市即大卖。尽管最新三季报增速不及市场预期，但替尔泊肽总销售额依然达到43.7亿美元，前三季度总额高达110亿美元，再次缩小与诺和诺德司美格鲁肽的差距。 而在礼来最新的预期中，Retatrutide的疗效将超越替尔泊肽。 在保证安全性和耐受性的前提下，48周给药最高剂量可减重22%-24%，同时对糖尿病患者可以36周降低2%糖化血红蛋白（HbA1c）。 礼来去年公布了一项Retatrutide减重的II期研究。结果显示，12mg Retatrutide组受试者在接受24周的治疗后体重降低了17.5%，时间拉长至48周时，降幅达到24.2%。并且从减重曲线来看，并未到达平台期。另一项纳入2型糖尿病患者的Ⅱ期试验则显示，24周时12mg剂量组使HbA1降低了2.02%（安慰剂组0.01%）。 如果能够维持这一效果，礼来对Retatrutide的期待并不为过，头对头PK掉替尔泊肽也只是时间问题。 而Retatrutide之所以能够展现出强于替尔泊肽的潜力，核心在于其机制。Retatrutide是目前临床进度最快的同时靶向GLP-1R/GIPR/GCGR的降糖减重药。其在过去降糖减重药所用单一靶点GLP-1和双靶点GLP-1/GIP的基础上再添一个GCG。 三者都是与血糖水平紧密相关的激素。GLP-1和GIP是肠促胰素，促进胰岛素的分泌，同时引起饱腹感，降低食欲，GCG则能够诱导能量消耗，增加脂质的代谢。 过往的研究发现将GLP-1信号与GIP、GCG或两者相结合可增强胰岛素反应，超过单独使用GLP-1产生的胰岛素反应。替尔泊肽已经表现出GLP-1R/GIPR双靶点的极强竞争力，而Retatrutide在其基础上，通过激活GCGR从而增加能量消耗，进而实现超出双靶点的血糖控制和体重减少的效果。 基于对机制的信心及过往临床的数据验证，礼来正在加速推进Retatrutide的临床。在此之前，礼来围绕Retatrutide已经连开8项三期临床，包括5项减重和3项二型糖尿病。其中，仅减重适应症拟临床入组人数就超过5000人。 尽管替尔泊肽的减重适应症，去年11月刚刚获批，势头正猛。但是，对礼来来说，这更像是一场不得不进行的头对头试验。从GLP-1单靶点到双靶点减肥药、GLP-1联用疗法，入局者无数，谁都不愿意错过这一潜力无限的市场。 与其被别人颠覆，不如自我迭代。 02 代谢巨头的自我迭代 礼来在降糖减重领域深耕多年，深谙GLP-1药物发展之势。 从2005年第一个GLP-1药物艾塞那肽被批准用于2型糖尿病，近20年来GLP-1领域内药物更新迭代都有礼来的深入参与。某种程度上，礼来的GLP-1药物管线布局的变化可以被看作GLP-1领域的缩影。 尤其是在和老对头诺和诺德的竞争中，从双方产品的迭代可以窥见GLP-1药物的发展方向：从单靶点到多靶点，从日制剂到周制剂，从注射到口服。 最初礼来成功研发GLP-1的艾塞那肽，作为FIC为糖尿病患者提供了新的选择，但半衰期短，一周需要两次注射给药，给患者依从性带来不小挑战；接着诺和诺德的利拉鲁肽和礼来的度拉糖肽接连上市，分别把给药频率降低到了一天一次和一周一次；直到2017年，诺和诺德推出了鼎鼎大名的司美格鲁肽，一周一次注射给药，同时另辟蹊径推出了口服版本，双方的竞争在不断迭代中，持续升温。 2022年，替尔泊肽上市，是全球首个同时作用于GLP-1R/GIPR两个靶点的新一代药物。虽然与司美格鲁肽头对头的SURMOUNT-5研究还在进行中，但在名为SURPASS-2的大规模研究中，5mg、10mg、15mg剂量的替尔泊肽，在改善成人2型糖尿病患者的血糖水平和体重方面均优于1mg司美格鲁肽。 正如前文所说，替尔泊肽上市即爆卖，但面对前赴后继的竞争者，礼来已经在加速推进三靶点Retatrutide的研发，自我迭代。 说到底，它们都是围绕市场需求——更高效、更安全、更便捷，来引领GLP-1药物的迭代，从单靶点到多靶点以及长效、口服。 除了这两个代谢巨头，国内外还有其余药企也在顺应这一趋势布局减重降糖药。比如VIKING的VK2735，这是一款GLP-1R/GIPR受体激动剂，今年上半年先后公布注射剂型Ⅱ期试验和口服片剂Ⅰ期试验的积极结果；安进将GIPR抗体融合GLP-1，制备的AMG133有成为月制剂潜力。 而国内至少有9款有GLP-1R/GIPR双靶点药物进入临床阶段，众生药业的RAY1225半衰期为替尔泊肽的两倍，有望实现两周给药一次；信达生物的玛仕度肽则将另一靶点设定为GCGR，已经进入上市申请阶段。三靶点方面，联邦制药和康源药业研发的UBT251肥胖适应症正在开展1期临床，韩美制药的efocipegtrutide已进入II期，不过适应症为MASH。 面对诸多竞争，礼来的布局也不只是更领先的三靶点药物，还包括口服小分子Orforglipron，以及收购新的减重增肌药Bimagrumab，单独使用或联合替尔泊肽，以求在保证肌肉质量的前提下安全减重。 从首个推出GLP-1药物，到创新开发双靶点、三靶点，在已登顶降糖减重药后，一边推动GLP-1作用更大化一边迎击GLP-1现存痛点。礼来的布局策略，对其他GLP-1靶点竞争药企乃至整个创新药行业都能带来重要启示。 正是由于不安于现状、思进取，礼来才能一直走在降糖减重的最前方。 来源 | 氨基观察（药智网获取授权转载） 撰稿 | 李灿 责任编辑 | 八角 声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。 商务合作 | 王存星 19922864877（同微信）  阅读原文，是受欢迎的文章哦