Pegozafermin

Pictured: A fatty liver over a cell/Taylor Tieden for BioSpace You would be forgiven if, with all the cancer news from ASCO24 in Chicago this week, you missed the hepatology data dump at the 2024 Congress of the European Association for the Study of the Liver in Milan, Italy. However, there’s a battle brewing between Eli Lilly and the partnered companies Boehringer Ingelheim and Zealand Pharma in metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH). The drugs being tested in MASH belong to the now-blockbuster class of therapies known as glucagon-like peptide-1 receptor agonists (GLP-1s). Lilly’s tirzepatide is already approved for type 2 diabetes (marketed as Mounjaro) and weight loss (marketed as Zepbound), spaces it shares with Novo Nordisk’s semaglutide products Ozempic and Wegovy—a duopoly that has led to skyrocketing revenue for both companies, which continue to seek additional indications. Meanwhile, Boehringer and Zealand are looking to leap into the space with its own GLP-1 agonist, survodutide, which is under investigation for obesity and other indications. What was interesting this week at EASL24 was the GLP-1 clash between Lilly and Boehringer/Zealand in the MASH space, with both sides providing readouts on their latest Phase II data and each declaring victory. MASH is a potentially deadly fatty liver disease that affects more than 115 million people globally and is expected to increase to 357 million by 2030. In March, the FDA approved Madrigal Pharmaceuticals’ Rezdiffra, a liver-directed thyroid hormone receptor (THR)-β agonist, as the first-ever treatment for the disease. On Wednesday, Lilly’s Phase II data was presented at the European Association for the Study of the Liver (EASL24), showing that 54.9% of MASH patients treated with a 5-mg dose of tirzepatide saw at least a one-stage improvement in fibrosis. In the study of MASH patients with F2 and F3 fibrosis, tirzepatide treatment was found to be more effective than placebo in achieving MASH resolution without worsening of fibrosis. Just two days later, following a data leak snafu at EASL24 on Thursday, Boehringer and Zealand announced that survodutide demonstrated “breakthrough improvement” in liver fibrosis with no worsening of MASH in 64.5% of patients with F2 and F3 fibrosis. The companies said the new data also revealed up to 52.3% of adults with fibrosis stages F1, F2 and F3 had improvement in fibrosis without worsening of MASH. Survodutide, which is licensed to Boehringer from Zealand, is moving into a Phase III study. While GLP-1 drugs may have beneficial effects on MASH by improving insulin sensitivity, reducing liver fat accumulation and reversing fibrosis, Jefferies analysts said in a note to investors this week that they “don’t think GLP-1s will eliminate the market opportunity” for Madrigal in MASH. Likewise, Evercore ISI analysts opined, “there is room for different treatment options for patients with different needs, including daily oral pills and injectable products.” Evercore estimated a potential U.S. market opportunity for Madrigal’s Rezdiffra of $4 billion, while Jefferies’ estimate was considerably lower, pegging peak U.S. sales for Rezdiffra at $2.3 billion. Of course, there are a host of other promising MASH candidates, including Akero Therapeutics. Also at EASL24 this week, Viking Therapeutics announced its candidate VK2809—a thyroid hormone beta receptor agonist—significantly improved secondary histologic endpoints at 52 weeks with no worsening of fibrosis, as assessed by hepatic biopsy. And tomorrow, 89bio will be presenting Phase IIb data for pegozafermin, a specifically engineered glycoPEGylated analog of fibroblast growth factor 21. Meanwhile, new data from Altimmune and a preclinical poster presentation from Aligos Therapeutics also hint at promise in the treatment of MASH. Still, MASH is a complex and confounding disease that has caused many once-promising programs to be discontinued. However, with a projected $25.7 billion total market by 2032 in the U.S., France, Germany, Italy, Spain, the U.K. and Japan, competitors will continue to be in hot pursuit of Madrigal, which has set the standard. Let the clash of the MASH titans begin! Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

▎药明康德内容团队编辑 礼来公司（Eli Lilly and Company）在今年欧洲肝病学会（EASL）年会当中，公布其重磅GLP-1类药物tirzepatide用以治疗代谢功能障碍相关脂肪性肝炎（MASH）患者的2期临床试验SYNERGY-NASH的积极结果。分析显示，与安慰剂相比，73.3%接受最高剂量tirzepatide治疗患者实现MASH消退且肝纤维化未恶化此一主要终点，且过半患者产生≥1级肝纤维化显著改善。 MASH前名为非酒精性脂肪性肝炎（NASH），是非酒精性脂肪性肝病（NAFLD）的晚期形式。MASH是导致肝脏相关死亡的主要原因，对全球卫生系统造成日益加重的负担。此外，MASH患者，特别是那些具有更多代谢风险因素（高血压、合并2型糖尿病）的患者，心血管不良事件的风险增加，发病率和死亡率也相应提高。 SYNERGY-NASH是一项多中心、双盲、随机、安慰剂对照的2期剂量探索试验，共有190名经活检确认的MASH患者入组，这些患者伴有2级或3级肝纤维化且非酒精性脂肪性肝病活动评分（NAS）≥4。受试者以1：1：1：1的比例随机分配接受每周一次皮下注射tirzepatide（5 mg、10 mg或15 mg）或安慰剂治疗，共持续52周。主要终点是52周时MASH缓解且肝纤维化没有恶化。次要终点包括纤维化改善≥1级且MASH没有恶化，以及NAS减少≥2分且至少2个NAS指标减少≥1分。 图片来源：123RF 分析显示，在完成治疗并进行可评估活检的155名受试者中，接受5 mg、10 mg、15 mg tirzepatide治疗受试者分别有51.8%、62.8%和73.3%达到主要终点，而此数值在安慰剂组仅为13.2%（所有剂量p<0.001）。 此外，接受5 mg、10 mg、15 mg tirzepatide治疗患者达到MASH未恶化且具有≥1级纤维化改善的比例分别为54.9%、51.3%、51.0%，与安慰剂组（29.7%）患者相比的差异为21.3-25.2%（所有剂量p<0.05）。在三个tirzepatide剂量组中，71.7-78.3%患者的NAS降低了≥2分，此数值在安慰剂组为36.7%（所有剂量p<0.001）。 患者在使用tirzepatide后，体重减轻可达17.3%。此外，与安慰剂组相比，tirzepatide组的肝酶和肝脏脂肪减少，以及肝脏炎症和纤维化的血清和影像生物标志物亦显著改善（p<0.01）。 Tirzepatide的不良事件主要是胃肠道不良事件，严重程度为轻度至中度。 图片来源：123RF Tirzepatide是一款葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素样肽-1（GLP-1）受体双重激动剂，可同时激活GLP-1受体和GIP受体介导的信号通路。GIP和GLP-1是调控血糖的天然的肠促胰岛素激素。Tirzepatide于2022年5月获得美国FDA批准（商品名：Mounjaro），用于与控制饮食和锻炼联用，改善成人2型糖尿病患者的血糖控制。去年11月，tirzepatide再获FDA批准（商品名：Zepbound），用以使肥胖或超重成年患者减轻体重并保持体重稳定。 根据礼来公司官网和ClinicalTrials.gov的信息，tirzepatide目前正在进行多项3期临床试验，研究范围包括评估该药物治疗阻塞性睡眠呼吸暂停（OSA）、射血分数保留型心力衰竭（HFpEF）、降低肥胖症的发病率及死亡率，以及减少2型糖尿病患者的不良心血管后果等。同时，礼来也在进行多项2期临床试验，这些试验分别探究更高剂量的tirzepatide对肥胖和2型糖尿病患者的作用，以及tirzepatide在治疗MASH和1型Wolfram综合征中的效果。此外，近期还启动了tirzepatide治疗中重度化脓性汗腺炎的临床试验。今年4月，礼来公布两项3期试验结果显示，tirzepatide可显著改善中重度OSA肥胖患者的打呼情况，无论患者是否佩戴通气装置治疗。根据此积极结果，礼来计划递交相关监管申请。 图片来源：123RF MASH疗法的开发是近年来产业关注的领域。今年3月，美国FDA加速批准Madrigal Pharmaceuticals药品Rezdiffra（resmetirom）联合饮食和运动，治疗患有中重度肝纤维化（F2至F3期）的MASH成人患者。根据新闻稿，这是获得FDA批准的首款MASH疗法，标志着该领域的一项重要里程碑。 同样专注于MASH的还有89bio公司。去年9月，其所开发的成纤维细胞生长因子21（FGF21）类似物pegozafermin用于治疗MASH的2b期试验结果登上《新英格兰医学杂志》，分析显示，有37%的15 mg pegozafermin治疗组患者的MASH得到缓解，此数值在安慰剂组仅有2%，该疗法用于治疗MASH的3期试验已经启动。Sagimet Biosciences则在今年1月宣布其在研口服FASN小分子抑制剂denifanstat用于治疗MASH的临床2b期试验达成主要终点和多个次要终点，该公司预计于今年下半年启动3期试验。而Akero Therapeutics的在研药品efruxifermin（EFX）用于治疗MASH的3期试验也已经开展。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Tirzepatide for the treatment of metabolic dysfunction-associated steatohepatitis with liver fibrosis: results of the SYNERGY-NASH phase 2 trial. Retrieved June 5, 2024 from https://events-distribution.easl.eu/from.storage?image=mIoM6rsplpmkPbT9D4cRMhCdB962jqqPLI0ekg3BGloLb0klBbYoN9dNVhvU-7Oz0 [2] Updated: Lilly details mid-stage win for tirzepatide in MASH with fibrosis data. Retrieved June 5, 2024 from https://endpts.com/lilly-details-mid-stage-win-for-tirzepatide-in-mash-with-fibrosis-data/ 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新