A Phase IIIb Randomised, Parallel-Group, Double-Blind, Placebo-Controlled, Two-Arm Study to Evaluate the Effect of Elafibranor 80 mg on Normalisation of Alkaline Phosphatase in Adult Participants With Primary Biliary Cholangitis (PBC) and Inadequate Response or Intolerance to Ursodeoxycholic Acid.

The participants in this study will have confirmed PBC with inadequate response or intolerance to Ursodeoxycholic acid (UDCA), which is a medication used in the management and treatment of cholestatic liver disease.
Primary biliary cholangitis is a slowly progressive disease characterised by damage of the bile ducts in the liver, leading to a build-up of bile acids which causes further damage. The liver damage in PBC may lead to scarring (cirrhosis). PBC may also be associated with multiple symptoms.
Many patients with PBC may require a liver transplant or may die if the disease progresses and a liver transplant is not done. This study will compare a daily dose of elafibranor (the study drug) to a daily dose of placebo (a dummy treatment).
The main aim of this study is to determine if elafibranor is better than placebo in reducing ALP levels to a normal value. High ALP levels in the blood can indicate liver disease.
There will be three periods in this study: A screening period (up to 8 weeks) to assess whether the participant can take part; a treatment period (up to 52 weeks) where eligible participants will be grouped as per their blood ALP levels and randomly assigned to either receive elafibranor or placebo, and a follow-up period (4 weeks) where participants' health will be monitored.
Participants will be twice as likely to receive elafibranor than placebo (2:1 ratio).
Participants will undergo blood sampling, urine collections, physical examinations, clinical evaluations, electrocardiograms (ECG: recording of the electrical activity of heart), ultrasound examinations (a noninvasive test that passes a probe over skin to look at the bladder, urinary tract, and liver), and Fibroscan® examinations (a noninvasive test that passes a probe on skin to measure stiffness of the liver).
They will also be asked to fill in questionnaires. Each participant will be in this study for up to 64 weeks (15 months).

开始日期2024-07-01

申办/合作机构

Ipsen SA

NCT06016842 / Recruiting临床3期

A Phase III Randomised, Parallel-Group, Double-Blind, Placebo-Controlled, Two-Arm Study to Evaluate the Efficacy and Safety of Elafibranor 80 mg on Long-Term Clinical Outcomes in Adult Participants With Primary Biliary Cholangitis (PBC)

The participants of this study will have confirmed Primary Biliary Cholangitis (PBC).
Participants will also have inadequate response or intolerance to ursodeoxycholic acid (UDCA) a drug used to treat PBC.
PBC is a disease that progresses slowly. It causes damage to the bile ducts in the liver, leading to a build-up of bile acids which causes further damage.
The liver damage in PBC may lead to scarring (cirrhosis). PBC may also be associated with multiple symptoms. Many people with PBC may require liver transplant or may die if the disease progresses and a liver transplant is not done.
This study will compare a daily dose of elafibranor (the study drug) to a daily dose of placebo (a dummy treatment). Each participant will be in the study up to about 7 years.
The main aim of this study is to determine if elafibranor is better than placebo in preventing clinical outcome events showing disease worsening (including progression of disease leading to liver transplant or death).
This study will also study the safety of long-term treatment with elafibranor, as well as the impact on symptoms such as itching and tiredness.

开始日期2023-08-31

申办/合作机构

Ipsen SA

EUCTR2022-002695-37-ES / Unknown status临床2期

A Phase II, Multicenter, Double-Blind, Randomised, Placebo-Controlled Study and Open-Label Long Term Extension to Evaluate the Safety and Efficacy of Elafibranor in Adult Participants with Primary Sclerosing Cholangitis (PSC)

开始日期2023-02-13

申办/合作机构

Ipsen Bioscience, Inc.

100 项与 Elafibranor 相关的临床结果

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100 项与 Elafibranor 相关的转化医学

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100 项与 Elafibranor 相关的专利（医药）

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项与 Elafibranor 相关的文献（医药）

2024-01-01·Nature reviews. Gastroenterology & hepatology

Elafibranor in primary biliary cholangitis

Article

作者: Kotsiliti, Eleni

2023-11-01·Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Elafibranor upregulates the EMT-inducer S100A4 via PPARβ/δ

Article

作者: Ruart, Maria ; Montori-Grau, Marta ; Peña, Lucía ; Rada, Patricia ; Peyman, Mona ; Balsinde, Jesús ; Valverde, Ángela M ; Cugat, Clara ; Aguilar-Recarte, David ; Camins, Antoni ; Wahli, Walter ; Vázquez-Carrera, Manuel ; Zarei, Mohammad ; Jurado-Aguilar, Javier ; Palomer, Xavier ; Zhang, Meijian ; Montironi, Carla ; Barroso, Emma

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and β/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARβ/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.

2023-10-01·JHEP reports : innovation in hepatology

A new NRF2 activator for the treatment of human metabolic dysfunction-associated fatty liver disease

Article

作者: Colnot, Nathalie ; Delerive, Philippe ; Albuquerque, Miguel ; Paradis, Valérie ; Brzustowski, Angélique ; Provost, Nicolas ; Laouirem, Samira ; Valla, Dominique ; Hammoutene, Adel

Background & Aims:

Oxidative stress triggers metabolic-associated fatty liver disease (MAFLD) and fibrosis. Previous animal studies demonstrated that the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2), the master regulator of antioxidant response, protects against MAFLD and fibrosis. S217879, a next generation NRF2 activator has been recently shown to trigger diet-induced steatohepatitis resolution and to reduce established fibrosis in rodents. Our aim was to evaluate the therapeutic potential of S217879 in human MAFLD and its underlying mechanisms using the relevant experimental 3D model of patient-derived precision cut liver slices (PCLS).

Methods:

We treated PCLS from 12 patients with varying stages of MAFLD with S217879 or elafibranor (peroxisome proliferator-activated receptor [PPAR]α/δ agonist used as a referent molecule) for 2 days. Safety and efficacy profiles, steatosis, liver injury, inflammation, and fibrosis were assessed as well as mechanisms involved in MAFLD pathophysiology, namely antioxidant response, autophagy, and endoplasmic reticulum-stress.

Results:

Neither elafibranor nor S217879 had toxic effects at the tested concentrations on human PCLS with MAFLD. PPARα/δ and NRF2 target genes (pyruvate dehydrogenase kinase 4 [PDK4], fibroblast growth factor 21 [FGF21], and NAD(P)H quinone dehydrogenase 1 [NQO1], heme oxygenase 1 [HMOX1], respectively) were strongly upregulated in PCLS in response to elafibranor and S217879, respectively. Compared with untreated PCLS, elafibranor and S217879-treated slices displayed lower triglycerides and reduced inflammation (IL-1β, IL-6, chemokine (C-C motif) ligand 2 [CCL2]). Additional inflammatory markers (chemokine (C-C motif) ligand 5 [CCL5], stimulator of interferon genes [STING], intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]) were downregulated by S217879. S217879 but not elafibranor lowered DNA damage (phospho-Histone H2A.X [p-H2A.X], RAD51, X-ray repair cross complementing 1 [XRCC1]) and apoptosis (cleaved caspase-3), and inhibited fibrogenesis markers expression (alpha smooth muscle actin [α-SMA], collagen 1 alpha 1 [COL1A1], collagen 1 alpha 2 [COL1A2]). Such effects were mediated through an improvement of lipid metabolism, activated antioxidant response and enhanced autophagy, without effect on endoplasmic reticulum-stress.

Conclusions:

This study highlights the therapeutic potential of a new NRF2 activator for MAFLD using patient-derived PCLS supporting the evaluation of NRF2 activating strategies in clinical trials.

Impact and implications:

Oxidative stress is a major driver of metabolic-associated fatty liver disease (MAFLD) development and progression. Nuclear factor (erythroid-derived 2)-like 2, the master regulator of the antioxidative stress response, is an attractive therapeutic target for the treatment of MAFLD. This study demonstrates that S217879, a new potent and selective nuclear factor (erythroid-derived 2)-like 2 activator, displays antisteatotic effects, lowers DNA damage, apoptosis, and inflammation and inhibits fibrogenesis in human PCLS in patients with MAFLD.

143

项与 Elafibranor 相关的新闻（医药）

2024-06-25

·赛柏蓝

2024上半年FDA批准新药（附名单）

编者按：本文来自药智网，作者九思；赛柏蓝授权转载，编辑凯西上半年，FDA批准多款具有里程碑意义药物，看点颇多。 01 2024年上半年 FDA批准新药 40年来首款非酒精性脂肪性肝炎药物Rezdiffra获批上市；时隔32年，又一款应用于肿瘤免疫治疗的细胞因子药物Anktiva获批上市等等。截至目前，2024年上半年CDER批准了18个新分子实体，其中包括13款化药新药和5款生物药新药。值得一提的是，今年上半年的新药获批数量明显少于去年，2023年同期已有20多款新分子实体获批，主要是化药新药上市数量减少（去年同期有17款化药新药上市）。表1 2024上半年，CDER批准的化药新药从审批方式看，获批的13款新化药中Iqirvo、Xolremdi、Ojemda等8款药物是通过优先审评上市，与NDA标准审批需要10个月相比，优先审评需在6个月内完成，节省了企业的时间成本，同时优先审评的药物具有更高的治疗价值。从适应症上来看，代谢类疾病治疗领域有4款，肿瘤领域有3款，免疫治疗领域有2款，抗感染领域有2款，神经系统和其他领域各1款。在获批的化药新药中孤儿药有6款，占比接近一半，可见罕见病研发领域依旧火热。 02 这些化药新药值得关注下面简要介绍几款获批上市的新化药。 Iqirvo（Elafibranor） 6月10日，益普生宣布美国FDA已加速批准Iqirvo，Iqirvo是同类首创的口服、每日一次的过氧化物酶体增殖激活受体(PPAR)激动剂，用于治疗对UDCA应答不足的成人原发性胆汁性胆管炎（PBC），或作为单药疗法治疗对UDCA不耐受的患者。这是近十年来首个获批治疗罕见肝病原发性胆汁性胆管炎的新药。 PBC是因为胆管的慢性损伤，导致清除毒素的能力下降，引发肝硬化和肝功能衰竭。根据关键性3期试验ELATIVE结果显示只有接受elafibranor治疗的患者在第52周碱性磷酸酶（ALP）达到正常值，与对照组相比降低幅度达到41%。目前治疗罕见自身免疫性PBC患者、治疗PBC的炎症、胆汁淤积和纤维化等研究正在进行。值得一提的是，同靶点药物Seladelpar，已获得FDA优先审评资格，预计8月份公布审评结果。 Rytelo（Imetelstat） 6月6日，Geron Corporation的Rytelo被FDA批准上市，用于治疗低危骨髓增生异常综合征（LR-MDS）患者的输血性依赖性贫血。MDS指阻碍血液（造血）干细胞成熟为健康血细胞的一组癌症，是一种罕见的血癌。如果患者体内没有足够的健康血细胞，可能会出现贫血、频繁感染和失控出血等严重疾病。 Rytelo是一款first in class端粒酶抑制剂，Imetelstat通过结合并抑制端粒酶，从而调控恶性造血干细胞的凋亡。1990年Geron成立，从开始研发端粒酶抑制剂到Rytelo上市，Geron花了30多年，在经历一系列的失败之后，Imetelstat终于在MDS上有了用武之地；3期IMerge研究显示Imetelstat治疗后无需输血的比例显著高于安慰剂组。 Xolremdi（Mavorixafor） 4月26日，X4 Pharmaceuticals公司宣布美国FDA批准Xolremdi（mavorixafor）胶囊上市，用于治疗12岁及以上患有WHIM综合征的患者，以增加血液循环中成熟中性粒细胞和淋巴细胞的数量。这是首款获批针对WHIM综合征患者的小分子疗法。WHIM综合征是一种罕见的原发性免疫缺陷和慢性中性粒细胞减少症，由CXC趋化因子受体4（CXCR4）信号通路障碍引起。 Xolremdi是一种选择性CXCR4拮抗剂，关键3期临床4WHIM研究结果显示，与安慰剂相比，Xolremdi治疗显著增加了中性粒细胞计数（ANC）水平超过阈值（≥500细胞/微升）和绝对淋巴细胞计数（ALC）水平超过阈值（≥1000细胞/微升）的持续时间，安全性良好。此前，Xolremdi已经被FDA授予突破性疗法认定。 Ojemda（Tovorafenib） 4月23日，FDA加速批准Day One Biopharmaceuticals开发的泛RAF激酶抑制剂Ojemda（tovorafenib）上市，用于治疗6个月及以上的复发或难治性儿童低级别胶质瘤（pLGG）患者，这些患者存在BRAF融合或重排，或BRAF V600突变。Ojemda是用于治疗该疾病的全身疗法，它能够抑制携带BRAF融合或BRAF V600突变的肿瘤的生长，并且具有大脑渗透性。先前被FDA授予突破性疗法和罕见儿科疾病资格，这也是基于FIREFLY-1临床2期试验数据获批的原因之一。儿科低级别胶质瘤是儿童中最常见的脑瘤，在美国，儿童LGG年发病率为每十万人1.3~2.1例，预计每年有1000-1600例新发病例。2023年3月16日，FDA批准了诺华的BRAF/MEK组合即Tafinlar（dabrafenib，达拉非尼）联合Mekinist（trametinib，曲美替尼），这是pLGG的首个靶向疗法。 Rezdiffra（Resmetirom） 3月14日，MASH治疗领域迎来重大进展，FDA批准Madrigal的口服小分子药物Rezdiffra用于治疗伴有中度至晚期肝瘢痕形成（纤维化）的代谢功能障碍相关脂肪性肝炎成人患者，配合饮食、运动一起使用。这是40年来首款获批上市的MASH药物。 Resmetirom是一款甲状腺激素受体（THR）-β口服选择性激动剂。THR-β在人体肝脏中高表达，能够调节脂代谢，降低LDL-C、甘油三酯和致动脉粥样硬化性脂蛋白，THR-β还可以通过促进脂肪酸的分解和刺激线粒体的生物发生来减少脂肪毒性并改善肝功能，进而减少肝脏脂肪。 03 这些生物药新药值得关注表2 2024上半年，CDER批准的生物药新药截至目前，2024年上半年CDER共批准了5款生物药新药，1款双抗（Imdelltra），1款细胞因子药物（Anktiva），1款融合蛋白（Winrevair），1款单克隆抗体（Tevimbra），1款神经毒素（Letybo）。从治疗领域来看，在获批的5款生物药新药中，占比最多是癌症治疗领域，有Imdelltra、Anktiva、Tevimbra 3款新药上市，值得注意的是国产创新药企百济神州的Tevimbra（替雷利珠单抗）成功登陆美国市场成为第二款在美上市的PD-1药物；代谢领域有一款Winrevair，另外还有一款医美药物Letybo上市。 Anktiva 4月22日，ImmunityBio公司宣布FDA已经批准Anktiva联合卡介苗（BCG），用于治疗卡介苗不响应的非肌层浸润性膀胱癌(NMIBC)伴原位癌(CIS)，伴或不伴乳头状瘤患者，成为全球首个获批的白细胞介素-15（IL-15）药物，这是美国FDA时隔32年后批准的又一款应用于肿瘤免疫治疗的细胞因子药物，也是历史上的第三款。 Anktiva是一种IL-15超激动剂复合物，由IL-15突变体与IL-15Rαsushi结构域以及IgG1 Fc融合蛋白结合而成，IL-15Rαsushi结构域使其无需像天然IL-15通过反式呈递就可以激活下游信号通路，且IgG1-Fc片段极大延长了药物半衰期。 Winrevair 3月26日，FDA批准了默沙东Winrevair治疗肺动脉高压（PAH）的上市申请，PAH是由于促进和抑制增生信号的不平衡导致肺动脉壁的血管增厚，限制血流，使得心脏右侧负担日渐加重，最终导致心力衰竭。 Winrevair是首个获批的PAH的激活素信号抑制剂疗法，该药物全年费用高达24.2万美元，据有关机构估计年销售峰值可达75亿美元。表3 2024年上半年，CBER批准的生物制品数据来源：FDA、药智数据截至目前，CBER批准了9款生物制品，其中包括一款RSV疫苗（Mresvia）,一款基因疗法（Beqvez），一款细胞疗法（Amtagvi），还有多款疾病诊断技术和血液制品。 Beqvez(Elaparvovec-Dzkt) 4月26日，辉瑞宣布FDA已批准Beqvez上市，Beqvez是一种基于腺相关病毒（AAV）载体的基因疗法，用于治疗中度至重度血友病B且对AAV血清型Rh74的中和抗体检测为阴性的成年（18岁及以上）患者。据悉Beqvez定价为350万美元，能通过一次性治疗产生自体的凝血因子IX蛋白，目前的标准治疗则需要定期输注凝血因子IX。 Amtagvi(Lifileucel) 2月16日，Iovance Biotherapeutics宣布，FDA已通过加速批准Amtagvi上市，lifileucel是一种肿瘤浸润淋巴细胞（TIL）治疗方案，用于治疗PD-1/PD-L1治疗后进展的晚期黑色素瘤。 Lifileucel是全球首款获批上市的TIL细胞疗法，该疗法从肿瘤细胞中分离浸润的淋巴细胞，在体外扩增后像CAR-T疗法样回输给患者，可以特异性识别患者的肿瘤细胞进行杀伤。根据C-144-01研究已读出的结果，队列4的73名患者中31.5%的患者达到客观缓解。 04 结语今年上半年，美国FDA批准的新药中抗肿瘤、自免、代谢、抗感染和罕见病仍是热点领域，与去年相比肿瘤药物占比明显提高，这表明肿瘤药物仍是药物研发的热点。在获批的化药新药中罕见病药物占比接近一半，在FDA的政策鼓励下，可见药企对罕见病治疗药物的研发热情依然高涨，另外MASH治疗领域的突破和多款FIC药物获批同样令人欣喜。突破还在继续，2024下半年同样不平凡。6月11日，礼来公司的阿尔茨海默病药物donanemab，被药物咨询委员会以11:0的票数一致赞同该药物的有效性，预计不久也将获批上市。除此之外，FDA又会批准哪些药物呢，我们拭目以待！ END 内容沟通：郑瑶（13810174402）医药代表交流群扫描下方二维码加入银发经济市场机遇交流群扫描下方二维码加入左下角「关注账号」，右下角「在看」，防止失联

优先审批上市批准临床3期免疫疗法

2024-06-25

·echemi

Emerging PBC Treatments: The Fourth Novel Therapy Set to Lead the Market

In recent years, the treatment of primary biliary cholangitis (PBC) has seen remarkable progress, with the continuous introduction of new drugs bringing good news to PBC patients worldwide. According to reports from authoritative institutions, the global PBC treatment market is thriving and is expected to experience explosive growth in the coming years. However, despite the fact that three PBC treatment drugs have already been approved, the market still has a significant unmet need, and the industry's expectations for new therapeutic drugs are becoming increasingly urgent. First, let's understand the three PBC treatment drugs currently on the market. Ursodeoxycholic acid (UDCA) is the recognized first-line treatment drug and has been widely used in clinical practice for many years. However, it is regrettable that about 40% of patients do not respond well to this treatment, leaving them in urgent need of more effective treatment options. Against this backdrop, Ocaliva and Elafibranor emerged, being approved as second-line treatment options for PBC in 2016 and 2021, respectively. The introduction of these two drugs has undoubtedly brought new hope to PBC patients. However, market competition has not stopped. Industry insiders generally believe that Seladelpar has the potential to become the fourth novel PBC drug approved globally. Seladelpar is an oral, potent, and selective PPARδ agonist, and its unique mechanism of action gives it significant advantages in regulating bile acid synthesis, inflammation, fibrosis, and lipid metabolism. Based on preclinical and clinical data, Seladelpar has demonstrated good efficacy and safety in the treatment of PBC. Currently, the drug is undergoing priority review in the United States and is expected to receive approval for marketing in August 2024. At that time, it is expected to bring a safer and more effective treatment option to PBC patients worldwide. In addition to Seladelpar, the industry is also paying attention to other PBC drug candidates in development. For example, Setanaxib is a new drug that targets NOX4 and NOX1, and it has unique potential in the field of PBC treatment. Furthermore, domestic pharmaceutical companies are also actively engaged in the development of PBC drug research, such as the dual-target peptide drug TB001 developed by a well-known pharmaceutical company. The successive launch of these candidate drugs will bring new development opportunities to the PBC treatment market. It is worth mentioning that with the advancement of technology and the depth of research, the PBC treatment field is facing unprecedented development opportunities. More and more new drugs and new technologies are emerging, bringing more treatment options to PBC patients. At the same time, as global medical standards improve and medical resources are optimized, the treatment experience of PBC patients will also be significantly improved. We have reason to believe that in the near future, PBC patients will be able to enjoy safer, more effective, and more convenient treatment services.

优先审批上市批准

2024-06-24

·药智网

谁将成为全球第四款PBC新药？

原发性胆汁性胆管炎（PBC）是一种罕见的自身免疫性肝脏疾病，目前全球获批治疗PBC的药物非常有限，仅有3款药物。有限的治疗选择下，存在巨大的未满足的临床需求。 Coherent Market Insights报告显示，2017年全球PBC治疗市场规模为5.26亿美元，未来10年复合增长率将保持在36.3%，预计2026年将达到85.93亿美元。百亿美元市场待爆发，谁将成为全球第四款PBC药物？ 01 获批药物仅3款 PBC的进展与增加的肝相关死亡风险相关，目前其发病机制尚不明确，可能与遗传因素及其与环境因素相互作用所导致的免疫紊乱有关。目前，全球获批治疗PBC的药物非常有限。其中熊去氧胆酸（UDCA）是全球公认的PBC一线治疗药物，具有改善患者生化指标、缓解病理改变和延缓病程进展的作用，但约40%的患者对UDCA治疗应答不佳。 Ocaliva（奥贝胆酸）于2016年5月被FDA批准单药治疗无法耐受UDCA的成人PBC，或联合UDCA治疗UDCA疗效不佳的成人PBC。奥贝胆酸是一种法尼醇X受体（FXR）激动剂，其可以诱导肝细胞合成和分泌更多的胆汁酸，并抑制肝细胞合成甘油三酯，从而保护肝脏，减轻肝脏炎症、坏死和纤维化的进程。不过，Ocaliva治疗会导致患者的瘙痒症发生率增加，并引起低密度脂蛋白胆固醇水平升高。 Iqirvo（elafibranor）是近期获批的一款PBC新药，它是一种每日1次口服的过氧化物酶体增生激活受体(PPAR)激动剂，被FDA批准联合UDCA用于治疗对UDCA应答不足的成人PBC，或单药治疗对UDCA不耐受的PBC患者。 Ocaliva和Iqirvo这两款药物的适应症人群相同，均可降低PBC患者的血清碱性磷酸酶水平。值得注意的是，Ocaliva是全球首个获批的PBC二线疗法，业界非常看好该药，Evaluate Pharma曾预测其2020年销售额有望达到30亿美元，事实上，2020年其销售额为3.13亿美元。 02 Seladelpar即将撞线目前全球还有多款在研PBC新疗法，详见下表。这些在研PBC疗法作用靶点相对集中，主要包括PPAR、FXR。其中setanaxib作用靶点比较新颖，它是一种NOX4和NOX1抑制剂，具有抗炎和抗纤维化作用，曾被FDA授予治疗PBC的孤儿药资格认定。我国药企也积极布局PBC领域，不过在研药物最快处于2期临床，而且其中有些药物作用靶点未知，且药物类型不局限于小分子药物，如TB001是作用靶点未知的双靶点多肽药物。表1 全球部分在研PBC药物资料来源：公开资料整理 Seladelpar：正接受FDA优先审查 Seladelpar是一款口服强效选择性PPARδ激动剂，临床前和临床数据显示其具有参与调节胆汁酸合成、炎症、纤维化和脂质代谢、储存和运输基因的能力。目前，该药治疗PBC的新药申请正在美国接受优先审查，PDUFA日期为2024年8月14日。已公布的Seladelpar在对UDCA反应不足或不耐受的PBC患者中开展的全球3期临床试验RESPONSE的数据显示：seladelpar 10 mg组和5 mg组治疗组分别有78.2%和57.1%的患者达到复合终点，而安慰剂组仅有12.5%达到复合终点；5 mg和10 mg seladelpar治疗组中碱性磷酸酶（ALP）恢复正常的比例分别为5.4%(p=0.08)和27.3%(p<0.0001)，而接受安慰剂治疗的患者中ALP恢复正常的比例为0%；与安慰剂相比，中度至重度瘙痒(NRS≥4)患者中10 mg seladelpar对瘙痒的改善具有统计学意义(p<0.02)；与安慰剂组相比，seladelpar组丙氨酸转氨酶显著降低(5 mg:23.4%;10 mg:16.7%；安慰剂：4%)。此外，Seladelpar在PBC患者中开展的开放性扩展研究ASSURE也已取得积极结果。数据显示：10mg Seladelpar治疗组中70.3%的患者达到了具有临床意义的综合反应终点，37.2%的患者在12个月后达到了ALP正常化。此外，Seladelpar治疗还会显著降低PBC患者的谷氨酰转肽酶（GGT）、丙氨酸转氨酶（ALT）和总胆红素（TB）水平，分别降低36.4%、25.2%和9.2%。值得一提的是，Seladelpar由CymaBay开发，今年2月，吉利德通过斥资43亿美元收购CymaBay将Seladelpar纳入囊中。而吉利德之所以如此大手笔，正是看中了Seladelpar的潜力。CymaBay在与吉利德的沟通中给出了seladelpar明确的销售预期，2037年将实现23.94亿美元的最高峰值。 Linerixibat：缓解PBC瘙痒症状 Linerixibat是一种口服小分子回肠胆汁酸转运体（IBAT）抑制剂，其通过阻断小肠中胆汁酸的吸收，减少循环中瘙痒性胆汁酸，从而达到缓解瘙痒的目的。已公布的一项多中心、随机、平行组2期临床试验结果显示：Linearixibat可减轻胆汁淤积性瘙痒，且未发生严重不良事件。 CS0159和ASC42：PBC适应症已进入2期临床 CS0159是一种基于晶体结构辅助设计获得的新型强效非甾体类FXR小分子激动剂，被开发用于治疗PBC、PSC（原发性硬化性胆管炎）和NASH（非酒精性脂肪性肝炎）。系统的临床前研究表明，CS0159具有强效的FXR激动活性及肝靶向分布的特点，可明显改善NASH小鼠模型的病理状况，具有起效剂量低、药效显著且耐受性良好的特点。目前，该药治疗PBC的临床试验已进入2期阶段。 ASC42是歌礼制药自主研发的一款新型高效选择性非甾类FXR激动剂。美国开展的1期临床试验数据显示：在人体有效剂量15 mg、每日一次、为期14天的治疗过程中，未观察到瘙痒症状，而且FXR靶向激活的生物标志物成纤维细胞生长因子19（FGF19）在给药第14天时的增幅高达1780%。同时，LDL-C均值在治疗期间维持正常水平。2023年7月，ASC42治疗PBC的2期临床试验完成患者入组。 03 结语作为一种罕见肝病，PBC治疗虽取得一些可喜进展，但整体来看该市场并未饱和，获批药物数量也很有限。庆幸的是，目前国内外还有多款在研PBC新药，其中Seladelpar正在美国接受优先审查，预计很快就会和近来获批的elafibranor同台打擂。期待PBC治疗领域早日有新成员入局，为PBC患者提供更多选择。参考资料： 1.《原发性胆汁性胆管炎治疗药物临床研发进展》.凡默谷.2023-07-01 2.《APASL名家讲堂丨贾继东教授：原发性胆汁性胆管炎最新进展》.国际肝病.2023-02-26 声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 德清君转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是昨天最受欢迎的文章哦

优先审批孤儿药临床2期

100 项与 Elafibranor 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11208	Elafibranor	-	DB05187

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
原发性胆汁性胆管炎	美国	Ipsen Biopharm Ltd.	2024-06-10

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
原发性硬化性胆管炎	申请上市	美国	Genfit SA	2023-12-07
纤维化	临床3期	美国	Genfit SA	2016-03-01
纤维化	临床3期	阿根廷	Genfit SA	2016-03-01
纤维化	临床3期	澳大利亚	Genfit SA	2016-03-01
纤维化	临床3期	比利时	Genfit SA	2016-03-01
纤维化	临床3期	加拿大	Genfit SA	2016-03-01
纤维化	临床3期	智利	Genfit SA	2016-03-01
纤维化	临床3期	哥伦比亚	Genfit SA	2016-03-01
纤维化	临床3期	捷克	Genfit SA	2016-03-01
纤维化	临床3期	丹麦	Genfit SA	2016-03-01

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临床结果

适应症

分期

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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


NCT04526665 (FDA_CDER) 人工标引	临床3期	原发性胆汁性胆管炎	161	IQIRVO 80mg Once Daily	艱鑰餘鏇鑰製顧觸餘繭(淵艱範衊憲壓壓構選顧) = 壓衊製齋獵蓋淵憲鏇鑰顧淵襯顧觸觸鏇繭窪製 (製製鹽繭觸繭夢製觸鹽 ) 更多	积极	2024-06-10
				Placebo	艱鑰餘鏇鑰製顧觸餘繭(淵艱範衊憲壓壓構選顧) = 蓋廠觸構壓窪簾鬱積顧顧淵襯顧觸觸鏇繭窪製 (製製鹽繭觸繭夢製觸鹽 ) 更多
NCT04526665 (ELATIVE, EASL2024) 人工标引	临床3期	原发性胆汁性胆管炎	161	Elafibranor	淵願艱選範願顧夢範築(簾窪壓選膚襯鏇艱製蓋) = 鹹簾積餘廠鬱顧窪觸壓壓襯繭夢獵壓糧築鏇衊 (憲願網繭鹹壓遞憲餘艱 ) 更多	积极	2024-06-01
				Placebo	鹽範憲製糧廠蓋壓衊鏇(構願遞衊獵鑰築網餘餘) = 襯選鹹廠廠製齋範窪鹹鹽夢廠膚憲簾網獵衊鹹 (廠範艱壓鏇願築鏇糧築 )
NCT04526665 (ELATIVE, Pubmed)	临床3期	原发性胆汁性胆管炎	161	Elafibranor 80 mg	製鬱構襯範鹽積壓襯醖(構鹹衊衊衊糧壓醖鏇築) = 襯顧製窪鏇醖餘願繭顧繭願襯製築膚艱選衊製 (築顧顧醖醖製鏇夢鬱鏇, 32 ~ 57)	积极	2024-02-29
				Placebo	製鬱構襯範鹽積壓襯醖(構鹹衊衊衊糧壓醖鏇築) = 鬱鏇網築膚廠醖選顧衊繭願襯製築膚艱選衊製 (築顧顧醖醖製鏇夢鬱鏇 )
ELATIVE (NEWS) 人工标引	临床3期	原发性胆汁性胆管炎	161	elafibranor	衊網鬱糧窪壓衊夢範遞(齋鹹構鏇夢醖獵襯憲繭): differences = 3.0 更多	积极	2023-11-14
				placebo
NCT04526665 (ELATIVE, Biospace) 人工标引	临床3期	原发性胆汁性胆管炎	-	elafibranor 80mg	鏇醖鏇築簾構網鹽觸衊(構夢窪遞遞廠齋繭鑰壓) = 顧衊築鑰範築構繭鹽壓簾膚鏇憲選鹽齋網壓積 (夢獵構範糧衊鹹鏇糧襯 ) 更多	积极	2023-11-13
				placebo	鏇醖鏇築簾構網鹽觸衊(構夢窪遞遞廠齋繭鑰壓) = 範淵鑰選鹽繭積築艱衊簾膚鏇憲選鹽齋網壓積 (夢獵構範糧衊鹹鏇糧襯 ) 更多
NCT04526665 (ELATIVE, Biospace) 人工标引	临床3期	原发性胆汁性胆管炎	161	elafibranor 80mg	鏇醖鹹鏇獵襯構壓淵繭(製衊廠淵築鹹鬱鏇齋簾) = 觸積獵遞醖糧襯醖遞餘構廠觸觸膚淵築鑰齋製 (簾壓餘遞積鏇積繭獵網 )	积极	2023-09-20
				placebo	鏇醖鹹鏇獵襯構壓淵繭(製衊廠淵築鹹鬱鏇齋簾) = 簾齋選願憲鑰壓遞蓋製構廠觸觸膚淵築鑰齋製 (簾壓餘遞積鏇積繭獵網 )
NCT01694849 (CTgov)	临床2期	非酒精性脂肪性肝炎	275	GFT505 80mg (GFT505 80mg)	窪糧構廠襯繭構夢獵獵(觸廠鏇簾築範夢壓鑰鏇) = 窪鏇窪醖顧繭鑰簾艱鏇鏇壓鹹廠餘繭網鏇遞範 (窪鹹夢遞選襯鏇廠鏇鹹, 顧鑰鬱淵鹽糧鹹獵壓衊 ~ 憲觸膚憲膚鬱製窪簾鑰) 更多	-	2022-11-03
				GFT505 120mg (GFT505 120mg)	窪糧構廠襯繭構夢獵獵(觸廠鏇簾築範夢壓鑰鏇) = 醖齋鑰製壓襯壓觸蓋膚鏇壓鹹廠餘繭網鏇遞範 (窪鹹夢遞選襯鏇廠鏇鹹, 顧鬱築簾憲築齋鑰遞顧 ~ 艱鹹糧築鬱鑰鹹選繭艱) 更多
NCT02704403 (RESOLVE-IT, CTgov)	临床3期	非酒精性脂肪性肝炎 \| 纤维化	2,157	Elafibranor (120 mg Elafibranor)	鹹糧衊淵窪構鹹襯觸簾(繭獵鏇餘膚觸糧齋構鏇) = 壓願顧願衊網蓋積襯夢遞獵簾淵窪鹽蓋築範淵 (醖窪糧壓簾艱積鏇窪範, 憲襯觸膚夢觸壓廠製壓 ~ 鹹衊膚醖築製觸廠範鹹) 更多	-	2022-03-23
				Placebo (Placebo)	鹹糧衊淵窪構鹹襯觸簾(繭獵鏇餘膚觸糧齋構鏇) = 衊壓齋淵壓餘構積蓋蓋遞獵簾淵窪鹽蓋築範淵 (醖窪糧壓簾艱積鏇窪範, 構衊蓋簾蓋憲艱觸鹹網 ~ 糧窪艱鑰構顧淵網鏇製) 更多
NCT03883607 (CTgov)	临床2期	非酒精性脂肪性肝炎	10	Elafibranor 80mg (Elafibranor 80 mg)	淵構齋製襯鬱醖衊積簾(窪壓鹹繭窪齋憲憲鏇築) = 膚獵窪繭簾鹹廠齋鏇膚醖願鏇觸鹽憲鹹醖繭蓋 (齋簾範顧鏇簾餘膚觸願, 顧艱膚鹹廠夢遞壓齋襯 ~ 遞遞製膚膚窪憲醖鹹遞) 更多	-	2021-10-28
				Elafibranor 120mg (Elafibranor 120 mg)	淵構齋製襯鬱醖衊積簾(窪壓鹹繭窪齋憲憲鏇築) = 製膚築壓鏇襯簾選夢蓋醖願鏇觸鹽憲鹹醖繭蓋 (齋簾範顧鏇簾餘膚觸願, 壓鬱齋壓遞獵製窪獵窪 ~ 鏇鹽選糧製築顧齋築淵) 更多
NCT03124108 (pubmed \| J Hepatol) 人工标引	临床2期	原发性胆汁性胆管炎	45	Elafibranor 80 mg	鏇製鏇憲網願醖齋築顧(繭糧糧鑰簾憲製鑰鏇齋) = 選願壓觸壓觸顧範鏇齋淵顧網簾鏇繭艱繭繭鑰 (窪淵蓋蓋壓鏇遞夢範蓋, ±14.8)	积极	2021-01-20
				Elafibranor 120 mg	鏇製鏇憲網願醖齋築顧(繭糧糧鑰簾憲製鑰鏇齋) = 蓋觸壓繭廠築壓淵繭範淵顧網簾鏇繭艱繭繭鑰 (窪淵蓋蓋壓鏇遞夢範蓋, ±17.4)