A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2a Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy as Well as in Combination With TERN-101 in Noncirrhotic Adults With Presumed Non-Alcoholic Steatohepatitis (NASH)

This is a Phase 2a Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Orally Administered TERN-501 as Monotherapy as well as in Combination with TERN-101 in Noncirrhotic Adults with Presumed Non-Alcoholic Steatohepatitis (NASH)

开始日期2022-06-28

申办/合作机构

Terns, Inc.

NCT04328077

/ Completed临床2期

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 2a Clinical Trial to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetics of Orally Administered TERN-101 Tablets in Adult Patients With Presumed Non-Cirrhotic Non-Alcoholic Steatohepatitis (NASH)

This is a Phase 2, randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, efficacy, and pharmacokinetics (PK) of TERN-101 in non-cirrhotic NASH patients.

开始日期2020-06-18

申办/合作机构

Terns, Inc.

NL-OMON32962

/ CompletedN/A

A MULTIPLE ASCENDING DOSE PHARMACOLOGY, FOOD EFFECT AND DRUG INTERACTION STUDY OF LY2562175 IN HEALTHY ADULT SUBJECTS - LY2562175 MAD/DDI/FE study

开始日期2009-08-06

申办/合作机构

Lilly Research Laboratories

100 项与 LY-2562175 相关的临床结果

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100 项与 LY-2562175 相关的转化医学

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100 项与 LY-2562175 相关的专利（医药）

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468

项与 LY-2562175 相关的文献（医药）

2025-07-01·JOURNAL OF ETHNOPHARMACOLOGY

Sub-chronic realgar exposure causes liver inflammatory injury in mice by inducing bile acid-mediated NLRP3 inflammasome activation through down-regulation of ileal FXR

Article

作者: Wang, Tongshu ; Xie, Yixuan ; Huo, Taoguang ; Jiang, Hong ; Liu, Huan ; Chen, Hongying ; Li, Guangyan ; He, Lu

ETHNOPHARMACOLOGICAL RELEVANCE:

Realgar is extensively utilized in both modern medicine and traditional Chinese medicine. Although it has therapeutic uses, realgar exhibits hepatotoxicity, and improper use can result in liver inflammation and injury. The disruption of bile acid (BA) homeostasis, identified as an initiating event in liver injury, has been observed in the livers of realgar-exposed mice. However, the relationship between realgar-induced BA homeostasis imbalance and liver inflammation remains to be elucidated.

AIM OF THE STUDY:

To investigate the relationship between hepatic BA homeostasis disorder and liver inflammation caused by realgar exposure in mice, as well as the role and potential mechanism of intestinal farnesoid X receptor (FXR) in realgar-induced liver inflammation.

METHODS:

A sub-chronic realgar exposure mouse model was established and subjected to interventions with an intestinal-restricted FXR agonist or inhibitor. Plasma hepatic enzyme activities and total bile acid (TBA) levels were quantified using spectrophotometry. Hepatic inflammatory cytokine levels were analyzed by ELISA or RT-qPCR. Histopathological evaluation of liver injury was performed using HE staining. F4/80 expression was assessed via immunohistochemistry (IHC). Western blot (WB) and IHC were employed to examine the expression of proteins involved in the FXR-FGF15 axis, and plasma FGF15 concentrations were determined by ELISA. The expression of proteins related to enterohepatic circulation and the NLRP3 inflammasome pathway were evaluated using WB. Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-TOF-MS) was utilized to analyze BA profiles in both ileal and hepatic tissues.

RESULTS:

Our findings demonstrate that realgar exposure induces changes in ileal BA composition and subsequent suppression of the FXR-FGF15 signaling axis in mice. This axis suppression promotes hepatic BA overproduction and disrupts BA homeostasis in the livers of realgar-exposed mice, particularly elevates the levels of taurochenodeoxycholic acid (TCDCA) and taurolithocholic acid (TLCA). In vitro studies revealed that both TCDCA and TLCA can directly activate the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in AML-12 cells, triggering pro-inflammatory cascades. Pharmacological activation of intestinal FXR effectively ameliorated realgar-induced hepatic inflammatory damage via restoring BA homeostasis and suppressing NLRP3 inflammasome activation.

CONCLUSION:

Realgar exposure causes liver inflammatory injury by inducing BA-mediated NLRP3 inflammasome activation through down-regulating ileal FXR. Pharmacological activation of intestinal FXR alleviates realgar-induced liver inflammatory injury by restoring BA homeostasis and inhibiting BA-mediated NLRP3 inflammasome activation. These findings suggest that intestinal FXR may serve as a potential target for the prevention and treatment of realgar-induced liver injury.

2025-05-01·PHYTOMEDICINE

Liang-Ge-San attenuates virus-induced acute lung injury by targeting FXR-mediated ACE2 downregulation to modulate the formation of the cytokine storm

Article

作者: Yu, Linzhong ; Tan, Weifu ; Li, Wei ; He, Jiayang ; Yang, Guangli ; Yang, Liling ; Yu, Jingtao ; Liu, Junshan ; Zhou, Xiangjun ; Ma, Qinhai ; Lu, Zibin ; Fang, Xiaochuan

BACKGROUND:

Traditional Chinese medicine has been recognized for its significant role in treating acute lung injury (ALI) due to its distinct therapeutic advantages. Liang-Ge-San (LGS), a formulation from the ancient "Taiping Huimin Hejiju Fang", is believed to possess beneficial effects for treating ALI. However, LGS's precise mechanisms and efficacy in addressing viral ALI remain inadequately explored.

PURPOSE:

To evaluate LGS's therapeutic effects and underlying mechanisms in treating viral-induced ALI.

METHODS:

The protective effects of LGS were examined in a Polyinosinic-polycytidylic acid [Poly(I:C)]-induced ALI model using real-time quantitative PCR, enzyme-linked immunosorbent assay, and histopathological analysis. A bioinformatics approach combined with network pharmacology was utilized to ascertain the key targets of LGS in viral pneumonia. The pharmacodynamic mechanisms of LGS in viral ALI were further validated through immunofluorescence, overexpression, short hairpin RNA, chromatin immunoprecipitation, and target agonist assays.

RESULTS:

LGS administration resulted in a reduction of IL-1β, IL-6, and TNF-α levels, along with a decrease in macrophage infiltration, pulmonary damage, and pneumonedema following the Poly(I:C) challenge. Bioinformatics and network pharmacology analyses suggested that Farnesyl X receptor (FXR) and angiotensin converting enzyme 2 (ACE2) are potential therapeutic targets for LGS in viral pneumonia. Further experiments revealed that LGS suppressed the expression of FXR, ACE2, and NF-κB-p65 in Poly(I:C)-infected cells. Notably, overexpression of FXR counteracted the repressive effects of LGS, while ACE2 expression remained unchanged in FXR-knockdown RAW264.7 cells upon treatment with Poly(I:C) or LGS. Additionally, LGS inhibited the interaction between FXR and ACE2 transcriptional promoters. In vivo, LGS attenuated the Poly(I:C)-induced upregulation of FXR, ACE2, IL-1β, IL-6, and TNF-α in ALI zebrafish and mice models, effects that could be reversed by chenodeoxycholic acid (CDCA), an FXR agonist. Moreover, LGS markedly alleviated weight loss, improved survival rates, reduced lung index, diminished viral load, and inhibited lung pathological changes in H1N1-PR8-induced ALI mice. IL-1β, IL-6, TNF-α, INF-γ, FXR, ACE2, small heterodimer partner, and NF-κB-p65 levels were markedly reduced by LGS, with these effects being reversed by CDCA.

CONCLUSION:

This investigation provides the first evidence that FXR/ACE2 signaling is pivotal in acute respiratory viral infections, while LGS demonstrates antiviral activity against viral-induced ALI. LGS inhibits ACE2 expression induced by viral infection via FXR inhibition and modulates the cytokine storm, thus alleviating viral ALI. These findings suggest that LGS may be a promising treatment strategy for treating viral ALI.

2025-05-01·JHEP Reports

A novel in vitro system for simultaneous infections with hepatitis B, C, D and E viruses

Article

作者: Diaz, Olivier ; Meuleman, Philip ; Michelet, Maud ; Wedemeyer, Heiner ; Salvetti, Anna ; Durantel, David ; Passot, Guillaume ; Verrier, Eloi R ; Verhoye, Lieven ; Doceul, Virginie ; Pons, Caroline ; De Meyer, Amse ; Fouillé, Roxanne ; Rivoire, Michel ; Pavio, Nicole ; Steinmann, Eike ; Lucifora, Julie ; Darteil, Raphaël ; Barnault, Romain

Background & Aims:

The liver, and more precisely hepatocytes, can be infected by several hepatotropic viruses, including HBV, HDV, HCV and HEV, with chronic infection leading to end-stage liver diseases. Since no in vitro model allowing multi-infections with the four viruses is reported, limited data are available on their interplay as well as on the potential cross-reactivity of antivirals in multi-infection cases. The aim of our study was to set up such a model.

Methods:

HuH7.5-NTCP cells were cultured with 2% DMSO (dimethyl sulfoxide) for 1 week to allow partial differentiation into hepatocytes (dHuH7.5-NTCP) before infection with the different viruses and treatment with known antiviral molecules.

Results:

We observed increased expression of liver specific transcripts and production of ApoB containing VLDL in dHuH7.5-NTCP cells and replication of HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. We recapitulated the known antiviral effect of sofosbuvir on HCV and HEV (>90% reduction in the levels of intracellular viral RNAs, p <0.0005) and of IFN-α on HCV, HEV and HDV (80% reduction in the levels of intracellular viral RNAs, p <0.0005). Besides its already described antiviral effect on HBV and HDV, we observed that GW4064, a farnesoid X receptor (FXR) agonist, also strongly inhibited HEV replication (85 to 95% reduction in the levels of intracellular HEV RNAs, p <0.0005). Using HEV-infected HuHep mice, we confirmed the antiviral effect of vonafexor, an FXR agonist, that is currently being tested clinically against HBV/HDV.

Conclusions:

We set-up the first in vitro model allowing multi-infections with hepatitis viruses that can be used for broad drug screening and highlighted FXR ligands as potential broad-acting antivirals.

Impact and implications:

Hepatitis virus infections caused by HBV, HCV, HDV, and HEV represent a global health threat. Treatment options remain limited, notably due to the lack of knowledge about molecular virus-host interactions. Moreover, the interplay between these four viruses in the context of co-infections remains unknown. In this study, we report the first in vitro system that allows for mono and multi-infections with these four viruses and characterize the broad antiviral activity of farnesoid X receptor agonists, paving the way for the development of new strategies for viral cure.

164

项与 LY-2562175 相关的新闻（医药）

2025-06-20

·生物探索

Nature Medicine | 告别“油腻肝”！12周见证肝脏“瘦身”奇迹，TERN-501或将改写MASH治疗格局

引言在我们的身体里，肝脏是一个重要的“化工厂”，默默执行着上百种关键任务。然而，现代生活方式正让这个勤劳的器官不堪重负。脂肪肝，正以前所未有的速度席卷全球。当脂肪在肝脏中过度堆积，并引发炎症和损伤时，它就演变成一种更具威胁性的疾病——代谢功能障碍相关脂肪性肝炎 (Metabolic Dysfunction-Associated Steatohepatitis, MASH)。MASH不仅是肝硬化和肝癌的“温床”，更是心血管疾病风险的“放大器”。长期以来，面对这个棘手的健康难题，我们缺乏有效的药物武器。近日，《Nature Medicine》发表了一项备受瞩目的研究 “TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial”。这项研究评估了一款名为TERN-501的新型口服药物，为攻克MASH带来了全新的曙光。沉默的“肝”扰：为何我们急需新疗法？在我们深入了解这项新研究之前，先认识一下我们的“敌人”——MASH。它隶属于一个更广泛的疾病范畴，即代谢功能障碍相关脂肪性肝病 (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD)。简单来说，MASLD就是肝脏里堆积了太多脂肪。而MASH，则是这个过程的“恶化升级版”，它不仅有脂肪堆积（steatosis），还伴随着肝细胞的炎症（hepatitis）和损伤，如同在“油腻”的肝脏上点了一把火。这把“火”的破坏力不容小觑。长期的炎症会刺激肝脏产生疤痕组织，即肝纤维化 (liver fibrosis)。纤维化不断加重，最终可能导致肝硬化 (cirrhosis)，此时肝脏功能已严重受损。更糟糕的是，MASH患者罹患肝细胞癌 (hepatocellular carcinoma) 的风险也显著增高。研究数据显示，全球高达 5% 的人口可能患有MASH，而在超重或肥胖人群中，这一比例飙升至惊人的三分之一。在美国，由MASH引发的肝硬化已成为女性和65岁以上人群肝移植的首要原因。面对如此严峻的形势，医学界一直在寻找能够有效逆转MASH进程的“钥匙”。其中一个被寄予厚望的靶点是甲状腺激素受体-β (Thyroid Hormone Receptor-β, THRβ)。这个受体在肝细胞中高度表达，可以被看作是肝脏代谢的“总开关”之一。激活它，就等于给肝脏下达了“燃烧脂肪”的指令，能够促进脂肪分解、增加线粒体功能，从而减少肝脏的脂肪负担。然而，甲状腺激素受体还有一个“兄弟”——甲状腺激素受体-α (THRa)，它主要分布在心脏和骨骼等组织。传统的甲状腺激素药物会同时激活这两个受体，可能导致心率加快等副作用。因此，开发一种能够选择性激活肝脏中THRβ，而对THRa影响甚微的药物，便成了MASH治疗领域的核心策略。TERN-501正是这样一款被寄予厚望的高选择性THRβ激动剂。DUET双重奏：一项巧妙的临床试验设计为了验证TERN-501的真实效力与安全性，研究人员设计了名为DUET的临床试验。这是一项随机、双盲、安慰剂对照 (randomized, double-blind, placebo-controlled) 的IIa期研究——这是评估新药有效性的“金标准”设计，能最大程度地排除主观偏见和偶然因素。该研究在美国的27个临床中心招募了162名被诊断为MASH的非肝硬化患者。让我们来看看这些参与者的“画像”：他们的平均年龄为53.3岁，其中女性占54.9%。他们的平均身体质量指数 (Body Mass Index, BMI) 高达 37.8 kg/m²，远超肥胖标准。更重要的是，他们是典型的MASH患者，常常伴有多种代谢性疾病：42.0% 的患者患有2型糖尿病 (Type 2 Diabetes, T2D)，61.1% 患有高血压 (hypertension)，54.3% 患有血脂异常 (dyslipidemia)，并且57.4% 的人正在使用他汀类药物控制血脂。这充分说明，DUET试验的受试者群体，恰恰是现实世界中最需要MASH新疗法的高危人群。研究人员巧妙地将这162名患者分成了7个组，进行为期12周的治疗：第一组：安慰剂组 (Placebo)，服用不含有效成分的模拟药片。第二组： TERN-501单药低剂量组，每日1毫克。第三组： TERN-501单药中剂量组，每日3毫克。第四组： TERN-501单药高剂量组，每日6毫克。第五组： TERN-101单药组，TERN-101是另一款靶向法尼醇X受体 (Farnesoid X Receptor, FXR) 的药物。第六组： TERN-501 (3mg) + TERN-101 联合治疗组。第七组： TERN-501 (6mg) + TERN-101 联合治疗组。这样的设计可谓一石多鸟：不仅能评估TERN-501不同剂量的效果，还能与安慰剂进行严格对比，同时探索了与另一种机制药物联合使用的可能性。那么，如何衡量治疗效果呢？研究人员使用了两种无创检测技术：磁共振成像质子密度脂肪分数 (Magnetic Resonance Imaging Proton Density Fat Fraction, MRI-PDFF)，它可以像一台超高精度的“秤”，精确测量出肝脏中的脂肪含量百分比，这是本次研究的主要终点 (primary endpoint)。以及校正T1弛豫时间 (corrected T1 relaxation time, cT1)，这项技术能够反映肝脏的纤维化炎症 (fibroinflammation) 活动水平。cT1值越高，通常意味着肝脏的炎症和损伤越严重。核心发现：TERN-501如何给肝脏“减负”？经过12周的治疗，激动人心的结果出炉了。TERN-501不负众望，展现了强大且剂量依赖的“减脂”效果。我们首先来看最核心的指标——肝脏脂肪含量的变化。在12周时，服用安慰剂的患者，其肝脏脂肪含量平均仅下降了 4.0%。而TERN-501单药治疗组则取得了显著的成果：● 1毫克剂量组：肝脏脂肪含量相对基线平均下降了 15.4%。● 3毫克剂量组：肝脏脂肪含量相对基线平均下降了 27.5%，与安慰剂组相比具有统计学上的显著差异 (P = 0.0036)。● 6毫克剂量组：效果最为惊人，肝脏脂肪含量相对基线平均大幅下降了 44.8%，与安慰剂组的差异达到了极显著水平 (P < 0.0001)。这些平均数据背后，是更多个体患者的显著改善。在临床上，肝脏脂肪含量相对减少30%以上，通常被认为与肝脏组织学的改善密切相关。那么，有多少患者达到了这个“有效”标准呢？在安慰剂组，只有 4.2% 的患者（24人中的1人）达到了这一标准。而在3毫克TERN-501组，有 39.1% 的患者（23人中的9人）达标。在6毫克TERN-501组，这一比例更是高达 63.6%（22人中的14人）！这意味着，服用最高剂量TERN-501的患者中，超过六成的人获得了临床意义上的显著“减脂”效果。更令人振奋的是，研究人员还考察了肝脏脂肪“正常化”的比例，即肝脏脂肪含量降至5%以下的健康水平。在12周的治疗后，安慰剂组无一人实现这一目标。然而，在6毫克TERN-501组中，有 22.7% 的患者（22人中的5人）的肝脏脂肪含量恢复到了正常范围。这无疑是一个巨大的成功，表明TERN-501有潜力彻底逆转部分患者的肝脏脂肪变性。不止是减脂：多维度改善肝脏健康MASH的治疗目标绝不仅仅是“减油”，更要“灭火”。那么，TERN-501在对抗肝脏炎症方面的表现如何呢？通过cT1检测，研究人员得到了肯定的答案。12周后，安慰剂组的cT1值平均还略微上升了3.6毫秒 (ms)，意味着炎症水平没有改善。相比之下，6毫克TERN-501组的cT1值平均下降了 72.0毫秒，差异非常显著 (P = 0.0008)。cT1值的显著降低，有力地证明了TERN-501在缓解肝脏纤维化炎症方面同样具有强大的潜力。除了直接作用于肝脏，研究人员还通过血液中的生物标志物，来观察TERN-501是否准确“击中”了靶点。性激素结合球蛋白 (Sex Hormone-Binding Globulin, SHBG) 是一个关键指标，它由肝脏产生，其水平的升高是THRβ激动剂在肝脏中发挥作用的直接证据。数据显示，12周后，6毫克TERN-501组患者的SHBG水平平均飙升了 127.4%，而安慰剂组仅为4.4%。在其他大型研究中，SHBG增加120%以上与MASH组织学改善高度相关。TERN-501轻松超越了这一阈值，再次印证了其强大的靶点活性。此外，由于MASH患者常伴有心血管风险，改善血脂状况同样至关重要。TERN-501在这方面也交出了一份优异的答卷。它不仅显著降低了总胆固醇 (Total Cholesterol, TC) 和甘油三酯 (Triglycerides, TG)，还显著降低了两种“坏血脂”的代表：载脂蛋白B (Apolipoprotein B, ApoB) 和脂蛋白(a) [Lipoprotein(a), Lp(a)]。TERN-501能够全面改善血脂谱，为MASH患者带来了降低心血管疾病风险的额外益处。安全性与耐受性：新药必须跨过的“坎”一款新药，即使效果再好，如果副作用巨大，也难以在临床上广泛应用。特别是对于需要长期服药的MASH患者，良好的安全性和耐受性至关重要。那么，TERN-501的表现如何？总体来看，TERN-501的安全性记录非常出色。在整个研究期间，所有TERN-501单药治疗组的不良事件发生率与安慰剂组基本持平。例如，6毫克组有 50.0% 的患者报告了不良事件，而安慰剂组为 45.8%。绝大多数不良事件都是轻度至中度的（1级或2级）。尤其值得关注的是胃肠道反应。在一些其他的THRβ激动剂临床试验中，腹泻和恶心是较为常见的副作用，有时甚至会影响患者的持续用药。然而，在DUET试验中，TERN-501展现了极佳的胃肠道耐受性。例如，在6毫克组，腹泻的发生率为 4.5%，与安慰剂组的 4.2% 几乎没有差别。整个单药治疗组中，恶心的发生率也很低。这可能成为TERN-501相比同类药物的一个巨大优势，意味着患者能更好地坚持治疗，从而获得长期的健康益处。此外，研究人员还密切监测了药物是否存在“脱靶”效应，即对心脏或甲状腺轴的潜在影响。结果显示，所有TERN-501治疗组患者的心率、心电图（ECG）以及血液中的甲状腺激素水平（如TSH、fT3）在12周内均保持稳定。这再次证实了TERN-501的高度肝脏选择性，它能精准地在肝脏中“工作”，而不会干扰身体其他器官的正常功能。强强联手还是画蛇添足？探索联合疗法MASH的发病机制非常复杂，涉及多条信号通路。因此，研究人员推测，同时从不同角度攻击MASH，即采用联合疗法 (combination therapy)，或许能产生“1+1>2”的效果。DUET试验就大胆地探索了TERN-501与另一款靶向FXR受体的药物TERN-101的联用方案。结果显示，联合用药同样非常有效。例如，6毫克TERN-501与TERN-101联用，可使肝脏脂肪含量相对下降 47.7%，与6毫克TERN-501单药治疗的 44.8% 降幅相当。在cT1的改善方面，联合用药也表现出色。然而，在这项为期12周的研究中，联合疗法相比于高剂量的TERN-501单药疗法，并未显示出压倒性的额外优势。但这并不意味着联合疗法没有意义。首先，这项研究证明了两种不同机制的药物可以安全地联合使用，没有出现新的安全警示，这为未来的治疗策略铺平了道路。其次，FXR激动剂类药物有时会引起血脂升高，而TERN-501强大的降脂作用恰好可以抵消这一潜在副作用。或许在更长时间的治疗中，联合疗法的优势（尤其是在抗纤维化方面）才会更加凸显。迈向肝脏健康的下一站DUET试验的结果无疑是振奋人心的。它清晰地告诉我们，口服药物TERN-501：1.疗效显著且剂量依赖：它能强效降低MASH患者的肝脏脂肪含量和纤维化炎症标志物，且剂量越高，效果越好。2.安全性极佳：其总体不良事件发生率与安慰剂相当，特别是胃肠道副作用非常轻微，显示出优越的耐受性。3.靶向性精准：它能有效激活肝脏中的THRβ靶点，而没有对心脏或甲状腺轴产生不良影响。当然，我们需要保持科学的严谨态度。DUET是一项IIa期研究，其持续时间较短（12周），且主要依赖于影像学和生物标志物作为终点。尽管这些指标与肝脏的真实病理状况高度相关，但TERN-501的最终价值，还需要通过更大规模、更长周期的III期临床试验来验证。未来的研究将直接通过肝穿刺活检，来观察它是否能真正逆转肝脏的纤维化——这才是MASH治疗的“终极目标”。尽管如此，DUET试验的成功，为全球数以亿计的MASH患者带来了坚实的希望。它不仅证明了TERN-501作为一款潜力巨大的候选药物，更以其出色的安全性，为MASH的长期、安全管理提供了一种极具吸引力的新可能。我们有理由相信，在不远的未来，像TERN-501这样的创新药物，将成为医生手中对抗MASH这一“沉默杀手”的有力武器，帮助无数患者重获肝脏健康。参考文献Noureddin M, Alkhouri N, Lawitz EJ, Kowdley KV, Loomba R, Lee L, Jones C, Schlegel A, Marmon T, Anderson K, Li Y, Quirk E, Harrison SA. TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial. Nat Med. 2025 Jun 11. doi: 10.1038/s41591-025-03722-7. Epub ahead of print. PMID: 40500414.声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！往期热文：Nature Methods | 长读长测序“去伪存真”：SAVANA如何颠覆癌症基因组分析的传统认知？Nature | 基因治疗的“新大陆”：新生儿体内基因治疗的“黄金窗口”Nature Genetics | 颠覆认知！KDM4C另辟蹊径，竟通过“组蛋白剪辑”扼杀乳腺癌！Cell | 告别“一刀切”：骨骼肌深层分子图谱，开启糖尿病精准医疗新篇章！Nature Methods | 打破传统瓶颈：InterpolAI以光流魔法，重塑高精度3D组织重建新范式Cell | 万物可控：机器学习如何解锁蛋白质“开关”，开启活体按需功能调控新时代？

2025-06-16

·医学新视点

每天一次，64%患者肝脏脂肪含量减少超30%！《自然-医学》：脂肪肝新药6周就起效

代谢相关脂肪性肝炎（MASH）是常见的慢性肝病之一，目前其治疗选择比较有限。多项研究均证实，以甲状腺激素受体（THR）β为靶点的甲状腺激素及THRβ激动剂在调节肝脏脂质代谢及炎症中发挥着重要作用，成为治疗MASH极具潜力的治疗药物。TERN-501是一种在研的口服THRβ激动剂，既往针对健康人群开展的1期研究表明，其耐受性良好，可剂量依赖性增加一种肝脏分泌的特异性糖蛋白-睾酮-雌二醇结合球蛋白（SHBG），这种蛋白与THRβ活性水平正相关。TERN-101是一种在研的法尼醇Ｘ受体（FXR）激动剂，具有降低丙氨酸氨基转移酶和肝脏脂肪含量的作用。近日，《自然-医学》（Nature Medicine）发表DUET试验2a期研究结果，表明治疗第12周时，TERN-501组肝脏脂肪含量较基线显著降低15.4%~44.8%，且呈剂量依赖性降低，高于安慰剂组（降低4.0%）；肝脏脂肪含量减少≥30%的患者比例在26.1%~63.6%。此外，TERN-501联合TERN-101也展现出治疗潜力。截图来源：Nature MedicineDUET试验是一项为期12周的随机、双盲、安慰剂对照、多中心2a期临床试验，旨在评估每日1次口服TERN-501单药（1 mg/3 mg/6 mg）或联合TERN-101（10 mg）的疗效与安全性。研究纳入年龄18~75岁、无肝硬化的MASH患者162例。基线时，所有患者经MRI-PDFF测量的肝脏脂肪含量平均值为17.7%（符合高危MASH人群特征）。MRI-PDFF（磁共振质子密度脂肪分数）：运用磁共振技术对整个肝脏中的脂肪进行定量评估的生物标志物，反映肝脏脂肪含量，范围0%~100%。研究人员以1:1:1:1:1:1:1的比例将患者随机分配至下列7个治疗组接受治疗，均为口服给药，每日一次，持续治疗12周，再额外随访4周。1 mg TERN-501单药治疗组（23例）；3 mg TERN-501单药治疗组（23例）；6 mg TERN-501单药治疗组（22例）；10 mg TERN-101单药治疗组（24例）；3 mg TERN-501联合10 mg TERN-101治疗组（23例）；6 mg TERN-501联合10 mg TERN-101治疗组（23例）；安慰剂组（24例）。主要研究终点为TERN-501单药治疗组较安慰剂组的肝脏脂肪含量（MRI-PDFF评估）相对基线变化。结果显示，治疗第12周时，不同剂量的TERN-501单药治疗组MRI-PDFF较基线的变化均优于安慰剂组，TERN-501单药治疗组肝脏脂肪含量下降更多，其中1 mg TERN-501单药治疗组、3 mg TERN-501单药治疗组和6 mg TERN-501单药治疗组MRI-PDFF测量的肝脏脂肪含量分别降低15.4%、27.5%和44.8%，而安慰剂组仅降低4.0%。▲不同剂量TERN-501单药治疗组和安慰剂组治疗12周时，相较于基线时MRI-PDFF测量的肝脏脂肪含量变化情况（图片来源：参考文献[1]）此外，治疗第12周时，所有剂量TERN-501单药治疗组肝脏脂肪含量减少≥30%的患者比例也显著更高，其中1 mg TERN-501单药治疗组、3 mg TERN-501单药治疗组和6 mg TERN-501单药治疗组达标患者比例分别为26.1%、39.1%和63.6%，优于安慰剂组（降低4.2%）。▲不同剂量TERN-501单药治疗组和安慰剂组治疗12周时，相较于基线时MRI-PDFF测量的肝脏脂肪含量减少≥30%的患者比例对比（图片来源：参考文献[1]）6 mg TERN-501单药治疗组中有22.7%的患者实现肝脏脂肪含量正常（肝脏脂肪含量＜5%），而安慰剂组无患者达到这一目标。值得关注的是，所有剂量的TERN-501单药治疗组在治疗第6周时就能观察到肝脏脂肪含量的显著降低。TERN-501联合TERN-101也展现出治疗潜力。治疗第12周时，3 mg TERN-501联合10 mg TERN-101治疗组和6 mg TERN-501联合10 mg TERN-101治疗组肝脏脂肪含量较基线分别显著降低20.8%和47.7%，优于安慰剂组（降低4.0%）。安全性方面，50.6%的患者报告了至少一起不良事件，多数为1~2级，主要为瘙痒、头痛等。未观察到任何治疗组有心血管安全性信号或生命体征数据显著变化，整体安全性良好。总之，本次研究结果表明，每日一次的TERN-501单药治疗，可显著降低MASH患者肝脏脂肪含量，6 mg剂量即可实现近45%的脂肪含量下降，且安全性可控。研究结果支持将TERN-501单药或联合治疗用于MASH治疗。点击文末“阅读原文/Read more”，即可访问Nature Medicine官网阅读完整论文。推荐阅读《柳叶刀》子刊：每周一次，近90%患者肝脏脂肪减少至少30%！常见降糖药让53%患者脂肪肝好转！南医大张惠杰团队领衔中国研究登BMJNEJM： “三重获益”！司美格鲁肽改善肝炎，获益患者比例近乎翻倍49.2%患者肝纤维化改善！新药有望为脂肪肝治疗添新选择欢迎投稿：学术成果、前沿进展、临床干货等主题均可，点此了解投稿详情。参考资料[1] Noureddin, M., Alkhouri, N., Lawitz, E.J. et al. TERN-501 monotherapy and combination therapy with TERN-101 in metabolic dysfunction-associated steatohepatitis: the randomized phase 2a DUET trial. Nat Med (2025). https://doi.org/10.1038/s41591-025-03722-7免责声明：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：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「医学新视点」微信公众号留言联系。如有其他合作需求，请联系wuxi_media@wuxiapptec.com分享，点赞，在看，传递医学新知

临床结果临床2期

2025-06-12

·Business Wire

ENYO Pharma Announces Completion of Series C Financing With Vesalius Biocapital and Continued Progress of Its ALPESTRIA-1 Clinical Phase 2 Study in Alport Syndrome Patients

LYON, France--(BUSINESS WIRE)--ENYO Pharma (“ENYO”), a clinical-stage biotechnology company focused on developing FXR agonists for the treatment of severe kidney diseases, today announced the smooth continuation of its Phase 2 ALPESTRIA-1 trial in 26 Alport syndrome patients. The topline results from the trial are on track for the fourth quarter of 2025. In parallel, ENYO has finalized its Series C financing round with a €6 million investment from Vesalius Biocapital IV, bringing the total Series C raise to €32 million. The ongoing ALPESTRIA-1 study evaluates Vonafexor, a highly selective and oral FXR agonist, in patients with Alport syndrome, a rare genetic kidney disease with no approved therapy. The trial involves a 24-week ascending doses regimen followed by a 12-week off-treatment observation period. ALPESTRIA-1 was launched mid 2024 in 4 countries (US, F, SP and D) following Orphan Drug Designation from both the FDA and EMA. The new funding from Vesalius Biocapital IV extends ENYO’s cash runway through the second half of 2026 and enables the initiation of two new clinical programs: A proof-of-concept trial in patients with Chronic Kidney Disease (CKD) grade 3 and concurrent F2/F3 MASH , building on the promising renal results from the previous Phase 2 LIVIFY clinical study ; A PK/PD head-to-head comparison of Vonafexor and its analog EYP651 in healthy subjects. In addition, ENYO will continue to expand its preclinical portfolio, notably in Autosomal Dominant Polycystic Kidney Disease (ADPKD), where the Vonafexor franchise could offer a novel and disease-modifying approach. “We are pleased with the continued progress of ALPESTRIA-1 and honored to welcome Vesalius Biocapital to our investor syndicate and Dr. Jean-Christophe Renondin as new Board member,” said Dr. Jacky Vonderscher, CEO of ENYO. “This additional investment will allow us to accelerate the development of our FXR agonist pipeline in both rare and more prevalent kidney diseases. We share a common belief with Vesalius in the transformative potential of Vonafexor and EYP651 for patients suffering from inflammation- and fibrosis-driven renal conditions.” “Vesalius Biocapital is excited to support ENYO as it progresses into the next phase of clinical development for Vonafexor and its analog EYP651,” commented Dr. Jean-Christophe Renondin, Managing Partner at Vesalius Biocapital IV. “There is an immense need for new treatments in kidney conditions such as Alport Syndrome and CKD. We believe Vonafexor has the potential to help these patients and make a meaningful impact on their lives. I look forward to working with ENYO’s excellent leadership team to advance this promising therapeutic candidate.” About ENYO Pharma: ENYO is a clinical-stage biopharmaceutical company headquartered in Lyon (France) and developing proprietary drug candidates to improve quality of life and avoid end stage renal disease and dialysis/transplantation for patients with rare and common kidney diseases. Since its inception ENYO collected extensive phase I/II clinical data through nine completed clinical studies with ca. 400 subjects. ENYO is supported by a strong syndicate of global investors: OrbiMed, Morningside, AndEra, BPIFrance (InnoBio and Large Venture), Sofinnova Partners and Vesalius). For more information: ENYO Pharma About Vesalius Biocapital: Vesalius is a specialist life sciences venture capital investor, investing in companies in later stage companies in drug development, medical device diagnostic and e-health since 2007. Vesalius Biocapital IV, launched in June 2023, targets first and best-in-class European life science companies in drug development and digital health. Its investment portfolio is well balanced between drug development and non-drug development investments and committed to providing capital to science-backed innovation and ambitious entrepreneurs. The team is based in Europe to explore investment opportunities and valuation potential for the portfolio. Managing Partners include Guy Geldhof, Dr Jean-Christophe Renondin and Stéphane Verdood. https://www.vesaliusbiocapital-4.com/

临床2期孤儿药

100 项与 LY-2562175 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
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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
非酒精性脂肪性肝炎	临床2期	美国	Terns, Inc.	2020-06-18
胆管炎	临床1期	美国	Terns Pharmaceuticals, Inc.	2019-07-17
血脂障碍	临床前	美国	Eli Lilly & Co.	2015-12-24

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临床结果

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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


NCT05415722 (DUET, CTgov)	临床2期	非酒精性脂肪性肝炎	162	TERN-501 (Arm 1: TERN-501 1 mg)	積獵襯憲選窪衊鬱淵襯(願簾範鏇範鏇夢膚膚繭) = 鑰顧糧壓夢選獵憲廠蓋醖鬱膚窪選願構網選觸 (衊膚窪襯遞築廠窪糧憲, 5.186) 更多	-	2025-03-12
NCT05415722 (DUET, CTgov)	临床2期	非酒精性脂肪性肝炎	162	TERN-501 (Arm 2: TERN-501 3 mg)	積獵襯憲選窪衊鬱淵襯(願簾範鏇範鏇夢膚膚繭) = 願衊艱齋觸製構網蓋餘醖鬱膚窪選願構網選觸 (衊膚窪襯遞築廠窪糧憲, 5.740) 更多	-	2025-03-12
NCT04328077 (LIFT, EASL2022)	临床2期	非酒精性脂肪性肝炎	100	TERN-101 15 mg	艱製憲齋膚鬱網夢鹽鏇(糧窪淵艱蓋顧夢範襯蓋) = Pruritus AEs (including pruritic rash) were reported in 11 of 74 (14.8%) patients receiving TERN-101 and none receiving placebo. Onset of pruritus ranged from Day 2 to Day 73. Pruritus resolved with ongoing TERN-101 treatment for 8 of 11 patients. All events were mild or moderate (Grade 1 – 2), with incidence overall balanced across TERN-101 groups. Grade 2 pruritus occurred in two 10 mg patients (generalized pruritus) and one 15 mg patient (pruritus localized to bilateral forearms). No patient discontinued TERN-101 due to pruritus. 願簾壓構膚構糧夢膚淵 (壓窪鑰蓋網壓壓蓋壓遞 )	积极	2022-06-25
NCT04328077 (LIFT, CTgov)	临床2期	非酒精性脂肪性肝炎	101	Placebo	窪鬱獵顧窪齋蓋獵齋築 = 網鹽糧糧顧壓窪積襯網餘選範顧觸顧鹹遞憲壓 (鏇築憲簾構築鑰淵夢廠, 鏇繭網觸醖願鏇窪壓遞 ~ 糧廠壓繭醖糧願構獵膚) 更多	-	2022-06-14
NCT04328077 (LIFT, NASH_TAG2022)	临床2期	非酒精性脂肪性肝炎 MRI-PDFF	100	TERN-101 5 mg	蓋齋網製窪淵積襯艱鏇(鏇壓夢齋網廠齋積鹹衊) = 壓糧選構憲窪憲獵築繭簾窪積廠襯鹽齋獵餘遞 (膚鬱糧鑰構積築積鑰膚 ) 更多	积极	2022-01-06
NCT04328077 (LIFT, NASH_TAG2022)	临床2期	非酒精性脂肪性肝炎 MRI-PDFF	100	TERN-101 10 mg	蓋齋網製窪淵積襯艱鏇(鏇壓夢齋網廠齋積鹹衊) = 餘觸繭獵顧願選獵鏇壓簾窪積廠襯鹽齋獵餘遞 (膚鬱糧鑰構積築積鑰膚 ) 更多	积极	2022-01-06
MET642 (NASH_TAG2021)	临床1期	7Î±-hydroxy-4-cholesten-3-one (C4)	-	MET642	餘壓醖窪蓋遞簾觸窪艱(簾廠淵餘製蓋簾繭鹹廠) = There were no serious adverse events, and all adverse events were mild-moderate in severity. MET642 did not increase serum low-density lipoprotein cholesterol (LDL-C) or cause generalized pruritus 製遞壓衊築顧願廠築鬱 (餘壓醖鹹遞鑰鬱繭餘糧 ) 更多	积极	2021-03-12
NASH_TAG2021	临床2期	非酒精性脂肪性肝炎 7-alpha-hydroxy-4-cholesten-3-one \| FXR pathway genes	-	TERN-101 (10 mg/kg)	糧淵襯製獵鏇壓築繭淵(齋衊築蓋獵鹹蓋膚壓遞) = 顧選糧蓋壓遞餘積鏇壓淵蓋鑰構鑰選願憲簾顧 (襯醖鑰獵醖膚積製鑰鏇, p<0.01) 更多	积极	2021-03-12
NASH_TAG2021	临床2期		-	OCA (30 mg/kg)	糧淵襯製獵鏇壓築繭淵(齋衊築蓋獵鹹蓋膚壓遞) = 積鏇積繭壓齋築遞選網淵蓋鑰構鑰選願憲簾顧 (襯醖鑰獵醖膚積製鑰鏇, p<0.05) 更多	积极	2021-03-12