MB-07811

本次活动以“面向临床 成就产业”为主题，设一场主论坛和四场主题论坛，从技术创新、供应链、临床研究、审评审批、资本推动等多个角度推动细胞药物产品开发，加速细胞制药产业化进程。上个月，Madrigal Pharmaceuticals的Rezdiffra被批准作为首个治疗代谢功能障碍相关脂肪性肝炎（MASH）的药物，专家们盛赞该药物是“important first”。在某种程度上，Rezdiffra开启了MASH疗法的“元年”。MASH是由过量脂肪细胞引起的肝脏炎症，可导致进行性肝纤维化和肝硬化。MASH的患者基数相当庞大，存在巨大的未被满足的临床治疗需求。根据流行病学数据，全球MASH患病人数从2016年的3.1亿上升到2020年的3.5亿，并预计到2030年将达到4.9亿。Evaluate Pharm和弗若斯特沙利文预测，到2025年，全球MASH药物市场规模可达350至400亿美元。Aligos Therapeutics首席执行官Lawrence Blatt表示：“Rezdiffra是第一个在III期临床研究中被证明可以逆转纤维化的口服药物，但还有很大的改进空间。”他指出，在接受Rezdiffra治疗的患者中，约有1/4的纤维化有所改善，“还有75%的患者需要更好的疗法”。该公司也在开发MASH的候选药物。在Rezdiffra获得批准的前一天，Ionis Pharmaceuticals宣布其研发的MASH候选药物在II期试验中达到主要终点，显示出对脂肪性肝炎的显著改善，且纤维化未恶化。BioSpace网站列出了5款处于临床中至晚期的潜在MASH疗法，写意君据此进行了整理。1Ionis ION224一月一针FDA要求MASH药物开发者在III期临床试验中证明，纤维化（从F0或无纤维化到F4，完全型肝硬化）一期改善且MASH无恶化，或者MASH消退且纤维化无恶化。Ionis似乎在实现这一指标方面进展顺利。3月13日，Ionis宣布，其在研反义寡核苷酸药物ION224用于MASH的II期研究达到主要终点，在120mg和90mg两种剂量下均能实现肝脏组织学改善。在II期试验的高剂量组中，32%的患者纤维化至少改善了1个阶段，且活检结果显示脂肪性肝炎未恶化，而安慰剂组的这一比例为12.5%。ION224是一款采用配体偶联反义（LICA）技术开发的反义寡核苷酸药物，旨在抑制二酰基甘油O-酰基转移酶2（DGAT2）的生成，最终达到治疗效果。DGAT2是催化肝脏中甘油三酯合成最后一步的酶，减少DGAT2的产生就会相应减少甘油三酯的合成。此外有证据表明，脂肪酸氧化以及氧化基因表达的增加都和DGAT2的反义抑制有关。Ionis表示，该药物在试验中显示出安全且耐受性良好，与安慰剂相比，ION224研究组的提前终止率较低。ION224旨在减少DGAT2的生成，研究表明DGAT2与脂肪性肝病有关。加州大学圣地亚哥分校的医学教授、胃肠病学和肝病学部门主任Rohit Loomba在公司声明中表示，该II期试验“是第一个证明DGAT2抑制后，肝脏脂肪减少与MASH组织学终点改善相关的临床证据”。2Altimmune Pemvidutide肝脏脂肪降低76.4%Pemvidutide由Altimmune开发，这是一种基于GLP-1/胰高血糖素双受体激动剂，目前正处于IIb期阶段。GLP-1受体的激活导致食欲抑制，而胰高血糖素的激活增加能量消耗，这两者对减轻体重都很重要。据Altimmune介绍，胰高血糖素还被认为对肝脏脂肪代谢有直接影响，导致肝脏脂肪和血脂水平迅速降低。去年11月，Altimmune公布了该产品用于肥胖症为期48周的II期MOMENTUM研究的初步结果。在为期48周的试验中，最高剂量的pemvidutide（2.4mg）可帮助肥胖受试者平均减重15.6%。在肝纤维化临床前模型中，也证明了Pemvidutide的直接抗纤维化作用：使用Pemvidutide治疗14天后，在化学诱导的肝纤维化模型中观察到显著改善；该模型排除了肝脏脂肪减少的影响，为Pemvidutide 减少肝纤维化的直接作用提供了证据。B. Riley Securities医疗保健研究主管Mayank Mamtani，看好以胰高血糖素受体为靶点的疗法。除了pemvidutide，他还提到了礼来的retatrutide和勃林格殷格翰的survodutide。“这些项目或许将成为在MASH中胜出的药物类别。”他表示，除了显著降低肝脏脂肪外，这类药物还有其他好处，包括降低肝酶和胆固醇，“这是Madrigal所没有的”。今年2月，勃林格殷格翰报告了其II期试验的阳性数据。据Altimmune介绍，在迄今的临床试验中，每周一次的pemvidutide显示出“有说服力的体重减轻，甘油三酯、LDL胆固醇、肝脏脂肪含量和血压都显著降低”，并且具有良好的安全性。II期IMPACT试验的24周顶线数据将于2025年第一季度公布。389bio pegozaferminFGF21类似物改善纤维化总部位于旧金山的89bio是少数几家开发FGF21类似物的公司之一，pegozafermin由89bio研发，是一种FGF21类似物。FGF21是一种内源性代谢激素，可调节能量消耗以及葡萄糖和脂质代谢。Pegozafermin采用聚乙二醇化技术，可延长天然FGF21的半衰期和优化生物活性。Mamtani说，MASH未满足的主要需求是在更晚期的疾病中。2023年11月，89bio公布了pegozafermin IIb期试验的阳性顶线数据。48周后，接受候选药物治疗的F2或F3期纤维化的MASH患者在肝脏脂肪和肝损伤/炎症和纤维化的无创检测方面显示出持续、统计学上的显著改善。该公司首席医疗官Hank Mansbach当时在一份声明中指出，pegozafermin是“首个在晚期NASH患者中显示出48周积极、持续益处的FGF21类似物”。F2和F3期纤维化患者进展为肝硬化的风险很高，且发展为肝癌、肝功能失代偿和死亡的风险也会增加。4Viking VK2809肝脏脂肪含量最高降低52%Viking Therapeutics在研的VK2809与Rezdiffra同属于甲状腺激素受体β （THR-β），目前处于IIb期。William Blair分析师Andy Hsieh和lexandra Ramsey在2024年3月的一份报告中写道，这种药物可能会“超过Rezdiffra的临床表现”。2023年5月发布的数据表明，VK2809达到了试验的主要终点，VK2809显著减少了MASH患者的肝脏脂肪。12周后，接受2.5 mg VK2809治疗的患者肝脏脂肪含量降低了45.3%，而安慰剂对照组为3.7%。Viking在2023年11月报告，IIb期研究的最新结果表明，“在患有或未患II型糖尿病的患者，以及F2或F3纤维化的患者中，接受治疗的患者肝脏脂肪显著减少。”此外，与安慰剂组相比，VK2809组患者的低密度脂蛋白胆固醇（LDL-C）、甘油三酯和致动脉粥样硬化的脂蛋白水平亦显著降低。Viking预计今年上半年会有52周的活检结果。5Aligos ALG-055009优于Rezdiffra本月早些时候，Aligos在IIa期HERALD中启动了ALG-055009的研究，安慰剂对照试验将纳入约100例推测有MASH和F1–F3纤维化的患者。ALG-055009也是一种THR β激动剂。Blatt表示，在临床试验中，ALG-055009显示出优于Rezdiffra 100倍的效力。他补充道，与Rezdiffra相比，该药物具有线性和非可变的药代动力学，“所以它非常可控”。使用Rezdiffra时，“患者间的差异很大”。服用Rezdiffra的患者只有大约25%纤维化得到改善，因为“有很多患者没有得到所需的药物量”。预计HERALD试验的安全性和疗效数据将于2024年第四季度公布。目前，全球大约有14款THR-β激动剂正在开发NASH适应症。除了THR-β外，默沙东、礼来、诺和诺德等MNC的GLP-1产品在NASH治疗上也表现出了非常优秀的临床数据，其中个别产品的肝脏脂肪降低数据甚至优于Resmetirom。国内部分，中国生物制药、歌礼制药、众生药业、海思科、石药集团也都积极布局，其中，中国生物制药进展较快，其从Inventia引入的PPAR激动剂Lanifibranor成为国内首个进入III期临床的NASH口服药。参考文章：1、Viking Therapeutics Clears Mid-Stage NASH Trial2、医药魔方更多优质内容，欢迎关注↓↓↓

Pictured: A collage containing a fatty liver over blood vessels/Taylor Tieden for BioSpace When Madrigal Pharmaceuticals’ Rezdiffra was approved last month as the first-ever treatment for metabolic dysfunction-associated steatohepatitis, experts hailed the drug as an “important first.” However, the consensus among experts is that Rezdiffra is just the beginning for a disease that has been notoriously difficult to treat. Metabolic dysfunction-associated steatohepatitis (MASH) is inflammation of the liver caused by excess fat cells, which can lead to progressive fibrosis and cirrhosis of the liver. “[Rezdiffra] is the first oral drug that’s been demonstrated to show reversal of fibrosis in Phase III clinical studies,” said Lawrence Blatt, CEO of Aligos Therapeutics, which is also developing a candidate for MASH. “If you look at the magnitude of the impact of Madrigal’s drug, it’s good for patients,” he told BioSpace. “I don’t want to downplay what they’ve achieved . . . but there’s a lot of room for improvement.” About a quarter of patients treated with Rezdiffra have an improvement in fibrosis, he noted. “That leaves 75% of patients with the need for better therapies.” A day before Rezdiffra’s approval, Ionis Pharmaceuticals announced that its own metabolic dysfunction-associated steatohepatitis (MASH) candidate hit the primary endpoint in a Phase II trial, showing significant improvement in steatohepatitis without worsening fibrosis, according to the company. And this is only the tip of the iceberg. Here, BioSpace looks at five mid- to late-stage investigational MASH drugs. Ionis’s ION224 The FDA asks MASH drug developers to show in Phase III clinical trials a one-stage improvement in fibrosis (ranked on a scale from F0, or the absence of fibrosis, to F4, full-blown cirrhosis) with no worsening of MASH, or the resolution of MASH with no worsening of fibrosis. Ionis appears to be well on its way to this metric, as 32% of people in the high dose arm of its Phase II trial of ION224 had at least a one-stage improvement in fibrosis without worsening of steatohepatitis as measured by biopsy, compared to 12.5% of patients in the placebo cohort. The drug was safe and well-tolerated in the trial, Ionis stated, and there was a lower rate of early termination in the ION224 study arms compared to placebo. ION224 is designed to cut production of DGAT2, an enzyme that studies have linked to fatty liver disease. The Phase II trial “is the first to demonstrate clinical evidence that the reduction of hepatic fat after DGAT2 inhibition correlates with improvements in MASH histological endpoints,” Rohit Loomba, a professor of medicine and chief of the division of gastroenterology and hepatology at the University of California San Diego, said in a company statement. Altimmune’s Pemvidutide Pemvidutide, developed by Altimmune and currently entering Phase IIb trials, is a peptide-based GLP-1/glucagon dual receptor agonist. While activation of the GLP-1 receptors leads to appetite suppression, activation of glucagon increases energy expenditure, both of which are important for weight loss. Glucagon is also believed to have direct effects on hepatic fat metabolism, leading to rapid reductions in levels of liver fat and serum lipids, according to Altimmune. Mayank Mamtani, head of healthcare research at B. Riley Securities, is bullish on therapies targeting the glucagon receptor to treat MASH. In addition to pemvidutide, he cited Eli Lilly’s retatrutide and Boehringer Ingelheim’s survodutide. “If you look at [these programs], they’re telling you that this is the drug class that’s going to win in MASH.” On top of a “profound” lowering of liver fat, he said there are other benefits with this drug class, including lowering of liver enzymes and cholesterol, “that you’re not getting from Madrigal.” Boehringer Ingelheim reported positive data from its own Phase II trial in February. So far in clinical trials, once weekly pemvidutide has shown “compelling weight loss, robust reductions in triglycerides, LDL cholesterol, liver fat content and blood pressure,” and a clean safety profile, according to Altimmune. Topline 24-week data from the Phase II IMPACT trial is due in the first quarter of 2025. 89bio’s Pegozafermin San Francisco–based 89bio is one of a handful of companies developing an analog of FGF21, a hormone that may address underlying metabolic issues that drive liver and cardiometabolic diseases, including MASH. The primary unmet need in MASH is in more advanced disease, Mamtani said. “Something that works in F4 is obviously the holy grail,” he said, adding that analogs of fibroblast growth factor 21 (FGF21) could have potential here. In November 2023, 89bio announced positive topline data from its Phase IIb trial of pegozafermin. After 48 weeks, MASH patients with stage F2 or F3 fibrosis treated with the candidate saw sustained, statistically significant improvements across liver fat and noninvasive tests of liver injury/inflammation and fibrosis. Pegozafermin is “the first FGF21 analog candidate to demonstrate positive, sustained benefits over a 48-week period in patients with advanced NASH,” Hank Mansbach, the company’s chief medical officer, said in a statement at the time. (MASH used to be known by the name nonalcoholic steatohepatitis, or NASH.) Patients with stage F2 and F3 fibrosis are at high risk of progression to cirrhosis and increased risk of liver cancer, liver decompensation and death. Viking Therapeutics’ VK2809 Currently in Phase IIb trials, Viking Therapeutics’ VK2809 belongs to the same thyroid hormone receptor beta (THR-β) class as Rezdiffra. William Blair analysts Andy Hsieh and Alexandra Ramsey wrote in a March 2024 note that the drug could “potentially outshine Rezdiffra’s clinical profile.” Topline data presented in May 2023 showed VK2809 cleared the trial’s primary endpoint, significantly reducing liver fat in patients with biopsy-confirmed MASH. After 12 weeks, patients treated with 2.5 mg of Viking’s candidate saw a 45.3% decrease in liver fat content, compared to 3.7% in placebo comparators. Updated results from the Phase IIb study demonstrated “robust and comparable liver fat reductions among patients with or without type II diabetes, as well as patients with either F2 or F3 fibrosis,” Viking reported in November 2023. Viking expects 52-week biopsy results during the first half of this year. Aligos Therapeutics’ ALG-055009 Earlier this month, Aligos initiated dosing in the Phase IIa HERALD study of ALG-055009, also a THR-ß agonist. The placebo-controlled trial will enroll approximately 100 individuals with presumed MASH and F1–F3 fibrosis. So far in clinical trials, Blatt said ALG-055009 is showing up to 100-fold more potency than Rezdiffra. He added that, in contrast to Rezdiffra, the drug has linear and non-variable pharmacokinetics, “so it’s very well controlled.” With Rezdiffra, “the variation they see among these individuals is highly variable, so some people are getting the optimal dose, some people are getting underdosed [and] some people might be getting overdosed,” Blatt explained, even though they all got the same amount of the drug. He added that only about 25% of patients taking Rezdiffra had improvement in fibrosis because “you have a lot of patients who were underexposed to the drug, and they weren’t receiving the amount of drug that they needed.” Topline safety and efficacy data from the HERALD trial are expected in Q4, 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.