MMONARCh-1: Study of MSDC-0602K, a Modulator of the Mitochondrial Pyruvate Carrier for Outcomes in Patients With Pre Type 2 Diabetes (T2D) or T2D and NAFLD/NASH, Assessed for ImpRoved Glycemic Control and Cardiovascular Outcomes-1

This is a randomized, double-blind study of MSDC-0602K or placebo in subjects with pre-T2D or T2D and evidence of NAFLD/NASH.

开始日期2022-06-01

申办/合作机构

Cirius Therapeutics, Inc.初创企业

NCT02784444 / Completed临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 12-Month, Multiple-Dose Study to Evaluate the Safety, Tolerability and Efficacy of Three Dose Levels of MSDC-0602K in Patients With NASH (EMMINENCE™)

This is a randomized, double-blinded study of three doses of MSDC-0602K or placebo given orally once daily to subjects with biopsy proven NASH with fibrosis and no cirrhosis.

开始日期2016-09-14

申办/合作机构

Cirius Therapeutics, Inc.初创企业

[+1]

NCT01280695 / Completed临床2期

A Phase 2a, Randomized, Double-Blind, Comparator- and Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, Tolerability and Efficacy of Three Dose Levels of MSCD-0602 in Type 2 Diabetic Patients

The purpose of this study is to assess the safety and tolerability of MSDC-0602 and to evaluate the reduction in fasting plasma glucose in patients with Type 2 diabetes.

开始日期2011-02-01

申办/合作机构

Metabolic Solutions Development Co. LLC

100 项与 MSDC-0602K 相关的临床结果

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100 项与 MSDC-0602K 相关的转化医学

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100 项与 MSDC-0602K 相关的专利（医药）

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项与 MSDC-0602K 相关的文献（医药）

2023-04-14·Science immunology

Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19

Article

作者: Mann, Barbara J. ; Sturek, Jeffrey M. ; Wu, Yue ; Vassallo, Robert A. ; Zhang, Ruixuan ; Jackson, Patrick E. H. ; Krawczyk, Connie M. ; Braciale, Thomas J. ; Li, Chaofan ; Zhu, Bibo ; Colca, Jerry R. ; Sun, Jie ; Jones, Russell G. ; Wei, Xiaoqin ; Narasimhan, Harish ; Pandey, Akhilesh ; Cheon, In Su ; Somerville, Lindsay ; Qian, Wei ; Kaplan, Mark H.

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

2023-04-01·Molecular metabolism

Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism

Article

作者: Ferguson, Daniel ; Lutkewitte, Andrew J ; Patti, Gary J ; Yiew, Nicole K H ; Shew, Trevor M ; Niemi, Natalie M ; Mukherjee, Sandip ; Eichler, Sophie J ; Cho, Kevin ; McCommis, Kyle S ; Finck, Brian N ; Colca, Jerry R

OBJECTIVE:

The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH.

METHODS:

Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines and mouse primary hepatocytes were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA metabolism in the liver of obese mice and MSDC-0602K treatment of Zucker diabetic fatty (ZDF) rats.

RESULTS:

In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, had decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades in vitro. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. Finally, while MSDC-0602K treatment improved glucose homeostasis and increased the concentrations of some BCAA metabolites in ZDF rats, it did not lower plasma BCAA concentrations.

CONCLUSIONS:

These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations.

2023-01-01·European journal of gastroenterology & hepatology

Side effect profile of pharmacologic therapies for liver fibrosis in nonalcoholic fatty liver disease: a systematic review and network meta-analysis

Review

作者: Li, Yilin ; Xiong, Qin ; Lei, Honglin ; Lei, Rong ; Feng, Peimin ; Yao, Chengjiao ; Xie, Fengjiao

Several studies have found that antifibrosis treatment for nonalcoholic fatty liver disease (NAFLD) can cause a variety of side effects. No network meta-analysis (NMA) analyzes the adverse events of antifibrotic drugs for NAFLD. This NMA aimed to systematically compare the drug-related side effects when using different pharmacological agents for the treatment of liver fibrosis in NAFLD. PubMed, EMBASE, Web of Science and Cochrane Library were systematically searched to select related studies published in English from the database inception until 30 June 2022. We conducted Bayesian fixed-effects NMA using data from randomized controlled trials (RCTs) to derive relative risks (RRs). The surface under the cumulative ranking (SUCRA) probabilities was used to assess ranking. A total of 26 RCTs with 19 interventions met the inclusion criteria. SUCRA analysis suggested that the lanifibranor group had the highest risk of diarrhea (SUCRA, 94), whereas the liraglutide group had the highest risk of constipation (SUCRA, 92.9). The semaglutide group showed the highest incidence of nausea (SUCRA, 81.2) and abdominal pain (SUCRA, 90.5), respectively. The cenicriviroc group showed the highest risk in the incidence of fatigue (SUCRA, 82.4). The MSDC-0602K group had the highest risk of headache (SUCRA, 76.4), whereas the obeticholic acid group had the highest risk of pruritus (SUCRA, 80.1). The risk of side effects significantly varied among different pharmacologic regimens, and evidence showed that lanifibranor, liraglutide, semaglutide, cenicriviroc, MSDC-0602K and obeticholic acid were the pharmacological interventions with the highest risk in patients with NAFLD. This study may guide clinicians and support further research.

项与 MSDC-0602K 相关的新闻（医药）

2024-06-05

·GlobeNewswire-Health Care

Late Breaking Poster Shows a Novel Oral Insulin Sensitizer Azemiglitazone (MSDC-0602K) Could Substantially Preserve Lean Muscle in Combination with Weight-Loss GLP1s

Azemiglitazone (MSDC-0602K) working through a newly identified mitochondrial target adds cardiometabolic benefit to GLP-1 receptor agonists Benefit includes preservation of lean muscle, which could expand the usefulness of the new class of GLP-1 weight loss drugs Recent paper in press in Hepatology emphasizes the important effect of reducing fasting insulin and posters at ADA in Orlando later in June KALAMAZOO, Mich., June 05, 2024 (GLOBE NEWSWIRE) -- Cirius Therapeutics, a privately-held clinical stage biopharmaceutical company, is presenting new data demonstrating the unique potential of combining their second-generation insulin sensitizer azemiglitazone (MSDC-0602K) with GLP-1 receptor agonists (GLP-1s). Cirius Therapeutics together with the Dr. Kyle McCommis lab of St. Louis University are presenting a late breaking poster at the European Association for the Study of Liver Disease (EASL) annual meeting, June 5-8 in Milan, Italy, that describes how the second generation insulin sensitizer azemiglitazone may address body composition issues caused by GLP-1s. The poster presents both a post-hoc analysis of the 23 patients with biopsy-proven MASH in the 52-week Phase 2B EMMINENCE trial who also had concomitant type 2 diabetes and were already on a stable dose of a GLP-1, and data from a pre-clinical study in diabetic db/db mice with GLP-1 liraglutide. These data show: The addition of any dose of azemiglitazone to patients on a GLP-1 improved all circulating parameters, especially HbA1c and liver histology.In the accompanying preclinical study in diabetic db/db mice: The combination of azemiglitazone and the GLP-1 liraglutide, new body composition measurements demonstrated a significant preservation of lean body mass (or muscle) in the combined presence of azemiglitazone, whereas liraglutide alone decreased lean body mass.Together, the combination also produced a synergistic improvement in glucose tolerance that occurred with less elevation of circulating insulin and an increase in pancreatic insulin content.Azemiglitazone also increased the amount of brown adipose tissue (BAT) alone and in combination with liraglutide. BAT is known for its ability to burn calories and store energy. GLP-1s are highly effective weight loss drugs, but they do not directly affect the underlying insulin resistance, are usually used for finite periods of time, and cause loss of both adipose and lean mass, which may limit their use in certain patient populations. Together these new data suggest this combination could optimize metabolic control and produce healthier weight loss and weight maintenance. Dr. Jerry Colca, Chief Scientific Officer of Cirius Therapeutics, said, “This second-generation insulin sensitizer was designed to take advantage of the newly discovered mitochondrial target of the thiazolidinediones (TZDs), which is the mitochondrial pyruvate carrier (MPC). Azemiglitazone avoids the direct activation of PPAR-γ, which has resulted in a significantly improved safety profile versus the first-generation insulin sensitizers. The aha realization here is that this novel identified mechanism of action of TZDs could provide a differentiated solution to the limitations with GLP-1 receptor agonists. Based on these new preclinical results, azemiglitazone could allow patients to lose fat without having to lose muscle. This finding together with the additive benefit on all other parameters could make azemiglitazone the optimal partner for the GLP-1s.” Dr. Kyle McCommis, Assistant Professor in Biochemistry and Molecular Biology at St. Louis University, said, “Our lab has been interested in the implications of this newly identified MPC target, which sits at the crossroads of regulating metabolism in many cell types. We have only recently recognized the positive effects on skeletal muscle and body composition, and we look forward to more detailed studies into the potential of this newly identified mechanism of action.” EASL Annual Meeting Title: Azemiglitazone in Combination with GLP1 Agonists Increases Benefit and Could Preserve Lean MassLate Breaking Poster LB-10, June 5-9 2024Discussions Late Breaking poster allows for discussions throughout the meetingPresenting author: Jerry R. Colca, PhD Additional New Publication and Posters at American Diabetes Association Meeting in Orlanda, Florida: Harrison SA, Dubourg J, Knott M, Colca J. Hyperinsulinemia, an overlooked clue and potential way forward in metabolic dysfunction-associated steatotic liver disease. Hepatology, online and in press. 2024-1582-P Fasting Insulin as an Independent Predictor of Metabolic Dysfunction–Associated Steatohepatitis (MASH) Severity. Authors: Stephen A. Harrison, Julie Dubourg, Sophie Jeannin, Jerry R. Colca, and Vlad Ratzu.2024-892-P: Potential for New Oral Insulin Sensitizers in Combination with GLP-1 Agonists. Author: Jerry R. Colca About Azemiglitazone Azemiglitazone is a novel once-daily, oral second-generation insulin sensitizer that was designed to exert pharmacology similar to pioglitazone without directly activating the transcription factor PPAR-γ. This allows dosing to full effect on the recently identified mitochondrial target, the mitochondrial pyruvate carrier (MPC), and directly impacts the underlying dysmetabolism of chronic metabolic disease. Azemiglitazone has completed all preclinical studies including 2-year carcinogenicity studies and 7 US clinical trials, including a 52-week dose-ranging study in subjects with MASH with and without type 2 diabetes (and mostly overweight and obese). Phase 3 clinical development will examine the potential of azemiglitazone to fulfill the original promise of insulin sensitizing pharmacology, which is the underlying pathophysiology of chronic metabolic disease. Of particular interest will be the ability to work in combination with weight loss approaches such as the GLP-1s. About Cirius Therapeutics Cirius is a clinical-stage biopharma company focused on the development and commercialization of innovative therapies for the treatment of metabolic diseases. Its lead product candidate, azemiglitazone (MSDC-0602K), is a potential best-in-class small molecule being developed as a once-daily oral therapy, selectively designed to modulate the mitochondrial target MPC, which mediates at the cellular level the effects of overnutrition, a major cause of Type 2 Diabetes, Obesity, MASH, and other metabolic disorders. Contacts: Jerry R. Colca, PhD; jcolca@ciriustx.comMina Sooch, MBA, msooch@ciriustx.com Forward looking Statements: This press release contains "forward-looking statements" within the meaning of the federal securities laws. These forward looking statements are not facts, but rather are based on current expectations. Forward-looking statements can be identified by words such as: "could", "believe," "project," and similar references to future results. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements.

临床2期临床3期临床结果

2024-01-21

·同写意

十年面壁图破壁，非酒精性脂肪性肝炎历史性突破的前夕

写意精品课 | 方法与工具—快速打造生物药供应链企业的独特品牌价值，欢迎报名！1从非酒精性脂肪性肝炎更名说起作为一种尚未有FDA疗法获批的适应症，非酒精性脂肪性肝炎领域最近酝酿着变化。首先是NASH的易名，从非酒精性脂肪性肝炎（Nonalcoholic Steatohepatitis）更改为代谢功能障碍相关脂肪性肝炎（MASH，Metabolic dysfunction-associated steatohepatitis）。其实这个更名在去年夏天就已经发生了，这是根据德尔菲共识命名法（Delphi Consensus Nomenclature）做出的，目的是呼吁人们认识到精确疗法和以患者为中心的护理在治疗MASH中的重要性。2020年，全球肝脏协会和患者权益团体召集了一个小组，审查脂肪肝疾病各阶段的命名和定义选项。2023年夏天采用的名称强调了肝脏疾病的代谢基础，使其与肥胖或糖尿病等根本原因更加紧密地联系在一起。随着研究的进展，尤其是GLP-1糖尿病药物在肥胖症领域取得的突破，大多数被归类为非酒精性脂肪性肝病的疾病与肥胖、胰岛素抵抗、高胆固醇或高血脂等代谢因素产生了关联。全球肝脏协会建议更名的原因之一，是通过删除“脂肪”和“酒精”的表述来减少耻辱（NASH本身并不含有fatty描述，但NFALD中包含，见下文）。但实际上，有些患者似乎更喜欢“非酒精性”的定语，这样可以向家人传达一个信息：酒精不是他们肝病的罪魁祸首，他们就不会对自己的饮酒习惯感到愧疚（当然这个逻辑是完全错误的）。•　脂肪肝病 (SLD，Steatotic liver disease)：涵盖脂肪变性的肝病总体术语。•　代谢功能障碍相关脂肪肝病（MASLD，metabolic dysfunction-associated steatotic liver disease）：对应以前的非酒精性脂肪肝病（NAFLD，Nonalcoholic fatty liver disease），包括患有肝脂肪变性并且至少具有五种心脏代谢危险因素之一的疾病。•　MetALD：新类别疾病，针对患有MASLD并且每周饮酒量超过140克的女性，以及每周饮酒量超过超过210克男性。•　代谢功能障碍相关脂肪性肝炎（MASH，Metabolic dysfunction-associated steatohepatitis）：取代类此前的“非酒精性脂肪性肝炎”（NASH，Nonalcoholic Steatohepatitis），指一种严重的脂肪肝疾病，由于肝脏中的脂肪沉积，导致肝脏肿胀并受损。MASH是一种晚期形式的脂肪肝，其特征是器官炎症，主要由肥胖引起，2 型糖尿病也是已知的危险因素。这种疾病很难诊断，被称为“沉默的疾病”，因为 MASH 几乎没有任何症状，直到发展到后期，这可能会对肝脏造成更严重的损害和疤痕。•　隐源性 SLD（Cryptogenic SLD）：专指脂肪肝病症的术语，其致病因素仍然难以捉摸，特别是在不存在代谢危险因素的情况下。2MASH疗法巨大的未满足度MASH的特殊性，在于它直到今天仍然没有一款获得FDA批准的疗法。其巨大的未满足需求营造出“十年面壁图破壁”的紧迫感。预计从2022年到2032年的十年间，七个主要市场（7MM，美国、法国、德国、意大利、西班牙、英国和日本）的MASH确诊病例数将增长450万例，从2022年的2204万人增加到2032 年的2655万人。美国将成为最大市场，预测美国到2032年将有1045万确诊病例。MASH在日本和英国增长最快，预计2032年这两个国家的确诊病例将在2022至2032的十年间分别增长32%和71%。美国的同期增长率将为12%。MASH疗法的开发相当艰巨，自从Intercept Pharmaceuticals的二期MASH数据让投资者陷入疯狂以来，已经过去近10年了。当时的数据曾经推动其股价上涨超过500%，但这一切的雕栏玉砌最终却成为了一场黄粱美梦。FDA在去年6月份（第二次）拒绝了Intercept Pharmaceuticals的法尼醇X受体激动剂奥贝胆酸（obeticholic acid，商品名Ocaliva）片剂用于治疗非酒精性脂肪性肝炎导致的肝硬化前期肝纤维化患者。曾被寄以厚望的Intercept在第二天就决绝地做出了放弃他们的所有MASH项目，并且解雇三分之一员工的决定。Intercept表示，将放弃对MASH的执念，转向奥贝胆酸与bezafibrate的联合疗法针对原发性胆汁性胆管炎的开发。Intercept只是MASH光环下的一个缩影，自从MASH适应症吸引制药商投入研发的黄金时代以来，许多试图治疗MASH的制药公司前赴后继，但始终未能攻克这个艰巨的阵地。之前的领跑者Intercept和Genfit已经选择激流勇退。阿斯利康也从其2期产品线中清除了GLP-1/Glucagon双受体共激动剂cotadutide。该产品于2022年进入MASH试验，但因无法招募足够的患者而停止。辉瑞也在 2021年放弃了其2期MASH候选药物。然而在巨大利润的吸引下，大量后来者迎难而上，其中包括Madrigal，Akero Therapeutics、勃林格殷格翰、礼来和辉瑞等。3Madrigal有望开天辟地Madrigal Pharmaceuticals已经提交了他们的MASH疗法Resmetirom（图1）的NDA申请，并且获得了FDA的优先审评和突破性疗法的认定，其PDUFA日期为2024年3月14日。业内众多人士纷纷看好这款小分子药物将实现MASH疗法的历史性突破，加冕FDA批准的首款MASH药物。与奥贝胆酸法尼醇 X 受体激动剂的机制不同，Resmetirom是一款每日一次口服的甲状腺激素β受体（THR）-β选择性激动剂。甲状腺激素（Thyroid hormone）通过激活肝细胞中的 β 受体，在影响一系列健康参数的肝功能中发挥核心作用。在MASH患者中，肝脏中的甲状腺激素β活性受损，导致线粒体功能下降和脂肪酸的氧化，进而导致炎症和肝纤维化。图1. Resmetirom化学结构THR-β激动剂具有减少炎症性肝脏脂肪和纤维化的潜力，同时降低胆固醇和其他致动脉粥样硬化的脂质。Resmetirom关键的3期MAESTRO-NASH中实现了肝脏组织学改善的两个终点：NASH的缓解和肝纤维化的减少。预测显示，到2035年底，MASH治疗市场规模预计将达到483亿美元，在此期间复合年增长率为18%。2022年，MASH治疗的行业规模已超过52亿美元。如果如愿获批，resmetirom无疑将迅速成为一款重磅炸弹药物。尽管尚未获得FDA的监管审批，但临床与经济评估研究所（ICER）已经开始评估resmetirom的成本效益范围。ICER认为，resmetirom每年的价格在39600到50100美元之间是具有恰当的成本效应的。4GLP-1会后发先至吗？GLP-1已经逐渐演变成为代谢病领域内无所不能的角色，除了已获批的2型糖尿病和肥胖症之外，在MASH领域也有望取得建树。相对于小分子口服制剂的resmetirom，GLP-1多肽在业已取得了诸多安全性数据的基础上，能完成在MASH领域的后来居上吗？早在2020年，在semaglutide尚未如此光芒万丈之时，诺和诺德就已经为这款GLP-1多肽获取了NASH突破性疗法的头衔（当时的名称）。四年后，GLP-1 受体激动剂已成为MASH这个“沉默杀手” “最受认可和最受期待”的新疗法之一。诺和诺德仍在招募患有纤维化的NASH患者进行一项1200名患者的IIIa期研究，预计要到2028年才能获得数据。尽管临床试验显示了semaglutide和其他GLP-1激动剂在治疗MASH方面的潜力，但对于这些药物在肝病后期的疗效的局限性仍存在疑问。有专家认为，GLP-1激动剂在MASH的研究中“表现欠佳”。虽然血糖控制和减肥也会缓解肝脏中的脂肪浓度，但目前仍缺乏足够的数据来证明这个机制是否可以直接改善肝脏健康。尽管如此，仍有很多人认为，即使GLP-1激动剂治疗纤维化或肝硬化的效果低于预期，但这些药物仍然有巨大的市场。因为一半的 MASH 患者还患有2型糖尿病，其中约三分之二患有肥胖症，这说明如果获得批准，这些重磅药物的使用范围将会更加广泛。在一项320名患者参与的II期semaglutide研究显示，semaglutide与MASH缓解之间存在正剂量关系，但在改善纤维化方面表现不佳。MASH的缓解可能是由于患者整体代谢健康状况的改善，因此人们对GLP-1激动剂如何直接影响肝脏存在疑问。还有人明心见性地指出，肝脏中并不存在GLP-1受体。然而，GLP-1激动剂仍可能对肝脏产生有价值的间接影响。通过提高胰岛素敏感性，肝脏中的游离脂肪酸 (FFA) 应该会减少。FFA是一种能量来源，但积累过多时会导致脂肪肝。减少FFA可以缓解肝脏炎症，从而下调导致纤维化的过程。但Semaglutide只是第一代GLP-1受体激动剂疗法，它身后的一干多受体共激动剂是否会在MASH领域取得更高成就？礼来的tirzepatide是GLP1/GIP双受体共激动剂，其MASH的II期试验将在2024年读数。勃林格殷格翰与西兰制药的GLP-1/Glucagon双受体共激动剂survodutide（图2）针对MASH的关键II期数据也将与2024年上半年公布。勃林格殷格翰发言人表示，survodutide可能成为第一款减少肝脏能量摄入并增加肝脏能量消耗的抗肥胖药物。图2. Survodutide化学结构默沙东管线中也有一款MASH资产efinopegdutide，同西兰制药/勃林格殷格翰survodutide一样，也是一款GLP-1/Glucagon双受体共激动剂。Efinopegdutide已经被FDA授予快速通道资格，目前处于II期阶段。尽管肝脏中没有GLP-1受体，但却存在GIP和Glucagon受体。因此即便作为GLP-1受体激动剂的semaglutide尚未给出在MASH研究中令人信服的数据，但第二代和第三代资产（GLP-1受体共激动剂）的早期疗效数据已经显露出了相对于单纯GLP-1受体激动剂的优势。但现在下结论尚早，因为这些资产仍然出于中期研究，有些还没有组织学数据。在共激动剂中，对于不同受体的效力也存在差异。例如Efinopegdutide对GLP-1和Glucagon受体的相对效力分别约为 2:1，药物渗透肝脏也对生物学功效产生一定影响。5MASH开发现状尽管semaglutide对MASH的影响仍然有待观察，但诺和诺德对于进军MASH领域的渴望已如司马昭之心。诺和诺德正在寻求与两家生物技术初创公司合作，开发治疗心脏代谢疾病的新药。2024年1月4日，诺和诺德宣布与两家公司Omega Therapeutics和Cellarity分别签署了协议。Omega协议将重点关注治疗肥胖的新方法，而Cellarity合作伙伴关系则针对MASH药物。Cellarity利用人工智能寻找纠正细胞功能障碍的新方法，目标是开发用于MASH的小分子药物。交易的预付款、开发付款和商业里程碑付款的价值可能高达5.32亿美元。目前的MASH管线中包含不同药理学机制的候选药，主要包含以下几大类别：FXR （法尼醇 X 受体）激动剂FGF21 （成纤维细胞生长因子21）受体激动剂FGF19 类似物GLP-1受体激动剂PPAR（过氧化物酶体增殖物活化受体）调节剂甲状腺激素β受体激动剂MASH其它靶点包括G蛋白偶联受体 (GPCR)、雌激素相关受体 α (ERRα)、骨形态发生蛋白 (BMP) 和 KLF（Kruppel-like-factor）。目前处于中后期的MASH研究，除了即将撞线的resmetirom和被寄以厚望的semaglutide，survodutide之外，还包括以下候选药：•　Lanifibranor（IVA337）开发商：Inventiva Pharma阶段：III期图3. Lanifibranor化学结构Lanifibranor（图3）是新一代泛PPAR（过氧化物酶体增殖物活化受体）激动剂，用于治疗纤维化疾病，且依从性更好，是唯一处于临床开发阶段的泛PPAR激动剂，是第一种同时针对PPAR-α、PPAR-β和PPAR-γ的靶向药物。Lanifibranor被视为治疗MASH的潜在重磅药物。Lanifibranor对很多MASH相关肝脏病变取得了积极结果，并分别于2019年9月和2020年10月获得FDA治疗MASH的快速通道和突破性疗法认定。与MASH的其它III期试验药物相比，lanifibranor的优势在于它对脂肪性肝炎和纤维化都有改善作用。Lanifibranor目前正在进行一项关键的III期临床试验NATiV3，用于治疗成年 MASH患者。预计将于2026年在美国上市。2022年9月，Inventiva Pharma与正大天晴药业集团股份有限公司签订独家许可及合作协议，授权后者在中国开发和商业化Lanifibranor。•　Azemiglitazone potassium（MSDC-0602K）开发商：Cirius Therapeutics阶段：III期图4. Azemiglitazone potassium化学结构Azemiglitazone potassium（MSDC-0602K，图4）是第二代胰岛素增敏剂（insulin sensitizer），可以减少第一代胰岛素增敏剂的副作用，如水肿、骨折和低血糖。胰岛素增敏可以改善MASH。在目前对MASH患者的研究中，MSDC-0602K并未显示出对肝脏组织学有显著影响（活检技术）。但它仍然为未来研究的设计获取了有益的探索。MSDC-0602K显著降低了空腹血糖、胰岛素、糖化血红蛋白和肝损伤标志物，并且没有剂量限制性副作用。故而MSDC-0602K仍然有可能成为MASH患者的有效治疗选择。Cirius Therapeutics目前正在对MSDC-0602K进行III期评估，预计可能于2026年在美国上市。•　Vonafexor (EYP001)开发商：Enyo Pharma阶段：II期图5. Vonafexor化学结构Vonafexor（EYP001，图5）由Enyo Pharma开发，是一种口服合成非甾体、非胆汁酸FXR受体激动剂小分子，也在针对MASH 开发。与其他FXR受体激动剂不同的是，Vonafexor对肾功能 (eGFR)、炎症以及肝脏和内脏脂肪纤维化（MASH患者的IIa期LIVIFY研究）以及CKD（慢性肾病）和Alport综合征（临床前研究）具有有益作用。Vonafexor已在MASH 治疗领域取得了可喜的成果。Vonafexor具有快速改善MASH患者肝功能和肝脂肪的潜力。目前正处于针对MASH患者CKD的II期临床阶段，预计将于2027年在美国上市。•　HPG1860开发商：雅创医药阶段：II期图6. HPG1860化学结构雅创医药的资产HPG1860（图6）针对MASH和PBC（原发性胆汁性胆管炎）适应症。HPG1860是一种非胆汁酸口服全FXR受体激动剂。在正在进行的II期RISE研究中，表现出良好耐受性和对肝脏脂肪含量的显著影响，同时也表现出令人满意的安全性。•　VK2809开发商：Viking Therapeutics阶段：II期图7. VK2809化学结构。VK2809 （图7）是Viking Therapeutics开发的一种选择性甲状腺激素β受体 (THR-β) 激动剂，正在研究用于治疗各种代谢和肝脏疾病，包括针对MASH患者的IIb期研究，于2023年5月宣布了积极的顶线结果。有可能于2028年在美国上市。•　BIO89-100（Pegozafermin）开发商：89bio, Inc.阶段：II期Pegozafermin是糖聚乙二醇化的FGF21 （成纤维细胞生长因子21）长效类似物。天然FGF21的半衰期仅为半小时。Pegozafermin在IIb期试验中获得了积极的顶线数据，有潜力成为MASH的治疗选择。预计将于2027年进入美国市场。•　Efruxifermin开发商：Akero Therapeutics, Inc阶段：II期Efruxifermin (EFX) 是Akero Therapeutics, Inc.的主导产品，是一种差异化的Fc-FGF21融合蛋白，经过工程设计可模拟天然FGF21。EFX目前正在两项 IIb期临床试验中对活检确诊的MASH患者进行评估。EMA于2020年10月将 efruxifermin指定为优先药物（PRIME）。次年FDA授予了它快速通道资格。2022年12月，efruxifermin获得FDA治疗MASH的突破性疗法认定。Efruxifermin是目前唯一正在评估用于MASH肝硬化前期和肝硬化患者的药物。如果获得批准，该药物有可能成为一种高度差异化、同类最佳的FGF21类似物，并成为治疗MASH的单一疗法。EFX可以通过单次治疗解决MASH发病机制的所有阶段，包括逆转纤维化、解决脂肪性肝炎以及协助恢复全身健康的新陈代谢。该药预计将于2027年在美国市场上市。参考文献：（上下滑动查看更多）1.Understanding Liver Disease’s New Names—NASH is now MASH. VCU. Aug. 2023.2.Introduction of new terminology for fatty liver diseases. British Liver Trust. 24. 06. 2023.3.Manalac, T. Intercept Cuts All NASH Investments, One-Third of Staff After Second FDA Rejection. BioSpace. 23. 06. 2023.4.Taylor, N. P. NASH market fattening up as wait for liver treatments drags on. FiercePharma. 04. 12. 2023.5.FDA Sets PDUFA Date for Drug to Treat Patients with NASH. Formulary Watch. 14. 09. 2023.6.Shah-Neville, W. Biotech’s battle against NASH: The ongoing pursuit of an effective treatment. Labiotech. 19. 10. 2023.7.DeFeudis, N. Madrigal says it's 'well on the way' to potential NASH launch ahead of FDA decision: #JPM24. Endpoint News. 11. 01. 2024.8.Castaneda, R. Can Novo Nordisk's blockbuster weight loss drug and other 8.GLP-1s also work in NASH? The answer is complicated. Endpoints News. 08. 09. 2023.9.Jensen, K. Novo taps Flagship startups to develop drugs for obesity, MASH. BiopharmaDive. 04. 01. 2024.10.Nonalcoholic Steatohepatitis (NASH) Market to Observe Stunning Growth by 2032 Owing to a Robust Pipeline. BioSpace. 01. 11. 2023.近期直播推荐:

2022-12-21

·生物制药小编

非酒精性脂肪肝“神药”临床数据优异，股价暴涨268%！

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

临床3期ASH会议临床2期申请上市

100 项与 MSDC-0602K 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16028

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
2型糖尿病	临床3期	-	Cirius Therapeutics, Inc.初创企业	2022-06-01
非酒精性脂肪性肝炎	临床3期	-	Cirius Therapeutics, Inc.初创企业	2022-06-01
糖尿病前期	临床3期	-	Cirius Therapeutics, Inc.初创企业	2022-06-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02784444 (EMMINENCE Study \| AIM-NASH \| EMMINENCE, CTgov)	临床2期	非酒精性脂肪性肝炎	392	Placebo (Placebo)	範願糧衊簾齋鹹鑰鹹構(醖遞餘鏇繭遞鏇鬱觸餘) = 範選齋獵製顧鹹膚醖鏇繭壓憲糧築廠製壓壓顧 (構餘憲範壓糧餘築繭齋, 網鬱醖繭顧選餘製獵憲 ~ 醖遞構衊鬱壓餘餘蓋鬱) 更多	-	2020-08-21
				MSDC-0602K (MSDC-0602K 62.5 mg)	範願糧衊簾齋鹹鑰鹹構(醖遞餘鏇繭遞鏇鬱觸餘) = 醖製鑰願淵膚鏇襯鏇範繭壓憲糧築廠製壓壓顧 (構餘憲範壓糧餘築繭齋, 獵範製築網衊範壓膚觸 ~ 鏇壓繭遞鬱膚鹽積衊顧) 更多
NCT02784444 (Pubmed \| J Hepatol)	临床2期	非酒精性脂肪性肝炎	392	Placebo	製壓鏇鹽築壓簾膚鹽窪(鏇簾醖遞選醖夢簾築範) = 廠鹽憲顧醖範獵艱積鹹蓋鹹選簾壓範遞鬱壓衊 (觸積積窪壓醖繭糧夢鑰 )	-	2020-04-01
NCT02784444 (EMMINENCE Study, EASL2019)	临床2期	非酒精性脂肪性肝炎	402	MSDC-0602 K 62.5 mg	願艱窪衊衊築遞膚淵鑰(廠淵鏇鬱餘艱壓齋獵簾) = Overall adverse event rates and rates of peripheral edema were similar across all 4 cohorts 餘醖衊積鹹鹽築淵選簾 (餘壓遞鏇餘憲製艱糧餘 ) 更多	积极	2019-04-12
				MSDC-0602 K 125 mg
NCT01280695 (CTgov)	临床2期	2型糖尿病	129	Placebo (Placebo)	積獵壓衊願齋鹹獵鑰憲(醖襯壓選淵襯淵夢蓋願) = 鏇鬱積壓蓋積淵顧鑰衊窪範壓齋餘簾淵鹹壓鑰 (鬱顧製選窪鹹廠衊鬱製, 餘鹹衊築鑰選簾餘積壓 ~ 積製簾範醖窪襯膚糧醖) 更多	-	2013-12-20
				MSDC-0602 100 mg (MSDC-0602 100 mg)	積獵壓衊願齋鹹獵鑰憲(醖襯壓選淵襯淵夢蓋願) = 範網淵鑰鏇壓鑰築選鬱窪範壓齋餘簾淵鹹壓鑰 (鬱顧製選窪鹹廠衊鬱製, 襯構憲齋鬱齋顧範選淵 ~ 遞製醖築鏇艱構選齋遞) 更多