PXS-4728

12月19日，Madrigal Pharmaceuticals, Inc宣布了该公司非酒精性脂肪肝（NASH）药物resmetirom在III期MAESTRO-NASH的肝活检临床中到达了主要临床终点和一项次要临床终点。受此消息影响，截止19日收盘为止，该公司的股价因此暴涨了268.07%，事实上，这种级别的涨幅放在整个制药历史中都是极为罕见的。该公司还表明，2023年上半年Madrigal会提交新药上市申请（NDA），那么此次发布的resmetirom的临床数据为何如此受到市场待见？NASH的现状和FDA的临床数据评价指标非酒精性脂肪肝病（NAFLD）是一种与胰岛素抵抗和遗传易感密切相关的代谢应激性肝损伤。非酒精性脂肪肝起病隐匿，危害不容小觑，普通人群非酒精性脂肪性肝病的患病率在10%到30%之间，其中10%到20%为非酒精性脂肪性肝炎；而非酒精性脂肪性肝炎的患者十年之内肝硬化的发生率是比较高的，高达25%，最终甚至可能发展为肝细胞癌（HCC）。虽然常常是建议患者去通过改变生活方式来逆转疾病，但许多患者无法通过改变生活方式来成功实现显著和持续的体重减轻，因此该组患者对药物治疗的需求很高。据弗若斯特沙利文报告，中国非酒精性脂肪肝病患病人数呈上升趋势，2020年已接近2亿人，2016-2020年复合增长率为2.9%；在人口老龄化及肥胖、糖尿病等疾病因素的作用下，未来中国非酒精性脂肪肝病患病率会以更快的速度增长，将于2022年达到2.07亿人。图片来源：中商产业研究院然而，可惜的是NASH目前为止尚未有一款药物在中美获批，一些曾经被寄予厚望的药物如Ocaliva，Emricasan（VAY785），MSDC-0602K，BI 1467335接连失败，这一蕴含了潜在的百亿市场尚未得到开发这是相当可惜的。其中原因常常被认为是有两点：其一，NASH的致病机理本身就很复杂，涉及多因素的致病机理；其二，FDA还严格规定了NASH药物III期临床试验的替代终点，FDA指出NASH的可靠诊断和对于NASH发展阶段的判断，只能通过肝活检标本的组织病理学检查来进行。因为NASH和肝硬化是一种弥散性的病变， 采用快速穿刺方法，从肝内抽取少量的肝组织，直接在显微镜下观察其组织形态的改变，能比较准确地反映出病变的性质和程度。（下图为FDA关于肝纤维化的药物开发指南）然而，肝活检是一种侵入性手术，会产生一些副作用有关，在极少数情况下，甚至会导致患者死亡。在临床试验中使用肝活检带来了重大的后勤挑战(例如，成本，具有NASH特定专业知识的病理学家的可用性)；此外，患者是否愿意也成为了一个挑战，一些患者不愿意进行活检。因此，FDA认为需要非侵入性生物标志物(包括成像生物标志物)来取代肝活检，并提供相当或更好的能力来准确诊断和评估各种级别的NASH和肝纤维化分期。FDA虽然鼓励这些申请的公司考虑生物标志物的开发，但肝活检标本仍然是最优的金标准……而此次resmetirom的临床结果则完全采用了肝活检的金标准，在MAESTRO-NASH为期52周的连续肝活检3期研究（NCT03900429）中，950多名晚期肝纤维化（F2期和F3期）NASH患者接受了resmetirom治疗，与安慰剂相比，每日口服80 mg和100 mg剂量的resmetirom既达到了治疗一年后NASH的缓解的主要终点，也达到了降低低密度脂蛋白胆固醇的次要终点。（如下图所示）resmetirom的机制机理及同类竞品resmetirom是一种甲状腺激素受体β（THR-β）激动剂，甲状腺激素通过激活肝细胞中的β受体，在肝功能中发挥重要作用，影响一系列健康参数，从血清胆固醇和甘油三酯水平到肝脏中脂肪的病理堆积。THR-β作用是正常肝功能的关键，包括线粒体活性的调节，如肝脂肪的分解和正常、健康线粒体水平的控制，而在NASH患者的肝脏THR-β受体活性水平降低，因此THR-β激动剂是治疗NASH的潜在治疗手段之一。（机制见下图所示）为了优化用于肝病治疗目的的THR-β途径的有效性，重要的是避免THR-α受体的活性，该受体是甲状腺激素的主要全身性受体，负责肝脏外包括心脏和骨骼中的活性。resmetirom则被证明能够避免产生THR-α受体的活性，并能够特异性靶向肝脏避免脱靶效应而靶向身体其他组织。除了Madrigal的resmetirom，THR-β激动剂的同类型竞品在国内还有拓臻生物的TERN-501，歌礼制药的ASC41，歌礼制药和拓臻生物都采取THR-β+FXR双激动的两项临床。歌礼为ASC43F复方制剂（NCT05118516），拓臻生物为TERN-501+TERN-101的联合治疗（NCT05415722）。而除了THR-β同靶点竞品外，PPAR，FXR，GLP-1等靶点也是NASH的有力竞争者，而从国内管线竞争形势来看，根据湘财证券研究所的不完全统计，目前国内共有89个在研项目，大部分项目尚处于早期阶段。从开展项目数量来看正大天晴、歌礼及众生药业等公司布局项目较多。小编总结Madrigal的此次成功为NASH疾病领域开了个好头，而目前已经手握THR-β选择性激动剂管线的国内公司可能将因此收益，特别是国内公司如歌礼和拓臻的双激动剂临床则有可能展现出更优异的疗效。参考来源：https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-announces-positive-topline-results-pivotal-phase-3湘财证券 肝病创新疗法破局在即，掘金巨大 Unmet 蓝海市场中商产业研究院 2022年中国非酒精性脂肪肝市场数据及其药物研发趋势预测分析注：本文不构成任何投资建议和医学建议

NGM Biopharmaceuticals’ aldafermin failed to hit its primary endpoint in the company’s Phase IIb ALPINE 2/3 trial for non-alcoholic steatohepatitis (NASH) with stage 2 or 3 liver fibrosis. NASH, a form of fatty liver disease in people who drink little or no alcohol, has been a tough nut to crack, with several high-pro in recent years. The ALPINE 2/3 study evaluated 171 patients with biopsy-confirmed NASH with stage 2 or 3 liver fibrosis (F2/F3). Patients received either 0.3 mg, 1 mg or 3 mg doses of aldafermin once a day via subcutaneous injections and were compared to placebo. The trial failed to hit the primary endpoint of a dose response showing improvement in liver fibrosis by greater than or equal to 1 stage with no worsening of NASH at week 24. It did achieve statistical significance compared to placebo on some secondary endpoints, including NASH resolution at the 3 mg dose and multiple non-invasive measures of NASH, including liver fat content reduction at the 1 mg and 3 mg doses. Aldafermin is an engineered analog of the human hormone FGF19. “These results are certainly disappointing, particularly given the dire unmet need in this patient population,” said David J. Woodhouse, chief executive officer of NGM. “The lack of significant fibrosis improvement was unexpected given the consistency of histology findings previously seen with aldafermin in our adaptive four-cohort Phase II study. "However, in line with the data from that study, ALPINE 2/3 achieved statistical significance on multiple non-invasive measures of NASH at the two higher doses," Woodhouse continued. "That said, given the failure to meet the primary endpoint, we have decided to shift resources that had previously been reserved for a Phase III F2/F3 NASH development program toward advancing our other programs.” That pipeline includes NGM621, an anti-complement C3 antibody in Phase II studies for geographic atrophy; NGM120, a GFRAL antagonistic antibody in Phase II for metastatic pancreatic cancer and cancer-related cachexia; and NGM707 and NGM438, anti-ILT2-ILT4 and LAIR1 myeloid checkpoint candidates, respectively. Both of those compounds are expected to start Phase I trials for advanced solid tumors this year. In addition, Merck is progressing its Phase IIb trial of MK-3655, an FGFR1c/KLB agonistic antibody for NASH, which NGM discovered via a collaboration with Merck. Woodhouse added, “NGM is a markedly different company than when we initiated ALPINE 2/3 in May 2019, when our clinical-stage pipeline consisted primarily of liver and metabolic programs. Over the past two years, we have steadily expanded that pipeline with programs generated from our productive in-house discovery engine, and today we are also an ophthalmology and oncology company with four Phase II programs underway. We look forward to advancing our clinical programs and moving additional programs into the clinic, supported by our cash balance that was in excess of $300 million at the end of the first quarter.” In mid-2020, France’s Genfit reported that its drug elafibranor failed a Phase III trial in NASH. The year before, Gilead Sciences’ selonsertib flunked a Phase III trial. Gilead’s firsocostat and cilofexor were also unsuccessful in NASH. Boehringer Ingelheim and Pharmaxis’ BI 1467335 also failed in trials. For quite some time, the leading company in the NASH race was Intercept Pharmaceuticals and its drug obeticholic acid (OCA). In June 2020, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) rejecting their application. The CRL stated that it could not be approved because of uncertainty about the efficacy of the treatment. There were also concerns over the risk-benefit pro the drug. NGM Bio took a hard hit at today’s news, with shares dropping 48.73% in premarket trading.