A Proof-of-Concept, Open-Label Study Evaluating the Safety and Tolerability of Cilofexor in Subjects With Primary Sclerosing Cholangitis (PSC) and Compensated Cirrhosis

The primary objective of this study is to assess the safety and tolerability of escalating doses of cilofexor (CILO) in participants with primary sclerosing cholangitis (PSC) and compensated cirrhosis.

开始日期2019-10-17

申办/合作机构

Gilead Sciences, Inc.

NCT03987074

/ Completed临床2期

A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)

The primary objective of this study is to evaluate the safety and tolerability of study drug(s) in participants with nonalcoholic steatohepatitis (NASH).

开始日期2019-07-29

申办/合作机构

Gilead Sciences, Inc.

[+1]

ACTRN12619000655145

/ Completed临床1期

A Phase 1 Open-Label, Parallel-Group, Two-Treatment, Single-Dose Study to Evaluate the Pharmacokinetics of GS-9674 and GS-0976 in Subjects with Normal Renal Function and Severe Renal Impairment

开始日期2019-07-24

申办/合作机构

Gilead Sciences, Inc.

100 项与 Cilofexor tromethamine 相关的临床结果

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100 项与 Cilofexor tromethamine 相关的转化医学

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100 项与 Cilofexor tromethamine 相关的专利（医药）

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项与 Cilofexor tromethamine 相关的文献（医药）

2025-01-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Cilostazol counteracts mitochondrial dysfunction in hepatic encephalopathy rat model: Insights into the role of cAMP/AMPK/SIRT1/ PINK-1/parkin hub and p-CREB /BDNF/ TrkB neuroprotective trajectory

Article

作者: Hassan, Noha F ; Gad, Enas S ; El-Ansary, Amira R ; El-Ansary, Mona R ; Aldossary, Sara A ; Abd El-Galil, Mona M ; Abd-El-Hamid, Asmaa Hassan

A devasting stage of chronic hepatic dysfunction is strictly correlated with neurological impairment, signifying hepatic encephalopathy (HE). HE is a multifactorial condition; therefore, hyperammonemia, oxidative stress, neuroinflammation, and mitochondrial dysfunction interplay in HE's progressive development. Cilostazol (Cilo) has shown promising neuroprotective and hepatoprotective effectiveness in different neuronal and hepatic disorders; however, its efficiency against HE hasn't yet been explored. This study aimed to investigate the protective role of Cilo against thioacetamide (TAA)-induced HE in rats targeting mitochondrial dysfunction via modulation of Adenosine monophosphate-activated protein kinase (AMPK)/Silent information regulator 1 (SIRT1) dependent pathways. Rats were allocated into three groups: the normal control group, the TAA group received (100 mg/kg, three times per week, for six weeks) to induce HE, and the Cilo group received (Cilo 100 mg/kg/day for six weeks, oral gavage) concurrently with TAA. Cilo counteracted HE indicated in the enhancement of cognitive impairment and the motor performance of rats (P < 0.0001), modulation AMPK/SIRT1signaling pathway causing reduction of NF-kB p65 (P < 0.0001) evoked inflammation along with histopathological alterations and glial fibrillary acidic protein (GFAP) immunoreactivity (P < 0.0001), restoration nuclear factor E2-related factor 2 (Nrf2) (P < 0.0001) antioxidant effects, reduction of Bax and elevation of Bcl2 immunoreactivity (P < 0.0001) in addition to boosting mitochondrial biogenesis by upregulation of PTEN-induced kinase-1 (PINK-1)/Parkin (P < 0.0001)and restoration of Brain-derived neurotrophic factor (BDNF) (P = 0.0002)/tropomyosin-related kinase B (TrkB) (P < 0.0001)/cAMP response element-binding (CREB) (P < 0.0001) neuroprotective axis. Collectively, Cilo activates the SIRT1 trajectory to abridge mitochondrial dysfunction invigorated in the HE rat model via restoration of mitochondrial hemostasis.

2024-12-01·JOURNAL OF CLINICAL PHARMACOLOGY

Pharmacokinetics and Safety of Cilofexor and Firsocostat in Healthy Japanese and Non‐Japanese Participants

Article

作者: Nelson, Cara ; Qin, Ann R. ; Weber, Elijah J. ; Shen, Gong ; Xiao, Deqing ; Watkins, Timothy R. ; Othman, Ahmed A. ; Younis, Islam R.

Abstract:

Cilofexor, an oral farnesoid X receptor agonist, and firsocostat, an oral, liver‐targeted inhibitor of acetyl‐coenzyme A carboxylase, are being investigated in combination with semaglutide for the treatment of metabolic dysfunction‐associated steatohepatitis (previously known as nonalcoholic steatohepatitis; NCT04971785). The pharmacokinetics and safety profiles of cilofexor (100 mg) and firsocostat (20 mg) were separately investigated in two phase 1 studies, each of which included healthy Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study) and non‐Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study). Intensive pharmacokinetic sampling was performed over 96 h following a single‐dose administration of the study drug. Safety was monitored throughout the study. In total, 39 participants completed each study. The plasma exposures of cilofexor and firsocostat (area under the concentration–time curve [AUC] calculated from time 0 to infinity [AUCinf]) in Japanese participants were 1.24‐fold and 1.98‐fold, respectively, of those in non‐Japanese participants. Both study drugs were well tolerated with no clear differences in adverse events or laboratory abnormalities between Japanese and non‐Japanese participants. The approximate 2‐fold exposure difference of firsocostat between Japanese and non‐Japanese participants at the 20 mg dose does not warrant dose reduction given the previously established safety and tolerability of once‐daily doses of firsocostat up to 200 mg.

2024-12-01·AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition

Article

作者: Luedde, Tom ; Bennett, Ashley L. ; Mayatepek, Ertan ; Dawson, Paul A. ; Ebert, Matthias ; Klindt, Caroline ; Truong, Jennifer K. ; Herebian, Diran ; Pachura, Kimberly J. ; Karpen, Saul J.

Bile acids are implicated as a common contributor to the pathogenesis and progression of cholestatic liver disease. Using a mouse model with a humanized bile acid composition, we demonstrated that mono and combination therapy using an IBAT inhibitor and FXR nonsteroidal agonist were effective at reducing hepatic bile acid accretion and reversing liver injury, without reducing hepatic bile acid hydrophobicity. The findings support the concept of a therapeutically tractable threshold for bile acid-induced liver injury.

项与 Cilofexor tromethamine 相关的新闻（医药）

2025-01-30

·PRNewswire

Metabolic Dysfunction-Associated Steatohepatitis Market to Register Stunning Growth at a CAGR of 17.9% in the US by 2034 | DelveInsight

The MASH treatment landscape is evolving rapidly, driven by a diverse array of therapeutic classes, each with unique mechanisms and potential impacts. The forecast period reveals significant shifts and emerging trends that will shape future market dynamics. LAS VEGAS, Jan. 30, 2025 /PRNewswire/ -- DelveInsight's Metabolic Dysfunction-Associated Steatohepatitis Market Insights report includes a comprehensive understanding of current treatment practices, MASH emerging drugs, market share of individual therapies, and current and forecasted market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain) and the United Kingdom, and Japan]. Key Takeaways from the Metabolic Dysfunction-Associated Steatohepatitis Market Report According to DelveInsight's analysis, the market size for MASH was found to be USD 2.1 billion in the 7MM in 2023. In 2023, there were an estimated 42 million prevalent cases of MASH in the 7MM. Out of these, a total of ~15 million cases were diagnosed, and this number is projected to increase by the end of 2034 in the 7MM. Leading MASH companies such as Inventiva Pharma, Novo Nordisk A/S, Cirius Therapeutics, Akero Therapeutics, 89bio, Boehringer Ingelheim, Zealand Pharma, Galectin Therapeutics, Lipocine, Viking Therapeutics, Eli Lilly and Company, Boston Pharmaceuticals, Pfizer, HighTide Biopharma, CytoDyn, Merck & Co., Hanmi Pharmaceutical, Hepagene (Shanghai), Hepion Pharmaceuticals, Enyo Pharmaceuticals, Gilead Sciences, Poxel SA, Zydus Therapeutics, Sagimet Biosciences, Ionis Pharmaceuticals, Corcept Therapeutics, and others are developing novel MASH drugs that can be available in the MASH market in the coming years. The promising MASH therapies in the pipeline include Lanifibranor (IVA337), Semaglutide, Azemiglitazone (MSDC-0602K), Efruxifermin (EFX), BIO89-100 (Pegozafermin), Survodutide (BI 456906), GR-MD-02 (Belapectin), LPCN1144, VK2809, Tirzepatide, BOS-580, Ervogastat (PF-06865571) + Clesacostat (PF-05221304), HTD1801, Leronlimab (PRO 140), Efinopegdutide, HPG1860, Rencofilstat (CRV431), EYP001 (Vonafexor), Semaglutide/Cilofexor/Firsocostat, PXL065, Saroglitazar Magnesium, Denifanstat (TVB-2640), ION224, Miricorilant (CORT118335), and others. In March 2024, Madrigal Pharmaceuticals' groundbreaking product, REZDIFFRA (resmetirom), a once-daily, oral THR-ß agonist, received accelerated endorsement from the US FDA based on results from the Phase III MAESTRO-NASH trial. This approval marks a significant stride in the medical landscape, as REZDIFFRA becomes the inaugural and sole FDA-sanctioned therapy for adults afflicted with non-cirrhotic MASH, accompanied by moderate to advanced liver scarring (fibrosis) corresponding to stages F2–F3 fibrosis. Discover which therapies are expected to grab the major MASH market share @ Metabolic Dysfunction-Associated Steatohepatitis Market Report Metabolic Dysfunction-Associated Steatohepatitis Overview Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that stems from metabolic dysfunction, often linked to obesity, diabetes, and other conditions of metabolic syndrome. MASH is characterized by the accumulation of fat in liver cells, accompanied by inflammation and liver cell injury, which can progress to fibrosis, cirrhosis, or even liver cancer. The primary drivers of MASH include insulin resistance, obesity, type 2 diabetes, and dyslipidemia. Genetic predisposition and a sedentary lifestyle also play significant roles. Environmental factors, such as a poor diet high in sugars and fats, exacerbate the condition. MASH is often asymptomatic in its early stages. When symptoms occur, they can include fatigue, vague abdominal discomfort, or pain in the upper right quadrant. In advanced stages, signs of liver dysfunction such as jaundice, swelling of the abdomen or legs, and confusion may arise. Diagnosis involves a combination of clinical history, physical examination, and diagnostic tests. Blood tests measuring liver enzymes (ALT, AST) often indicate liver inflammation. Imaging techniques like ultrasound, MRI, or FibroScan can identify liver fat and fibrosis. In some cases, a liver biopsy is required to confirm the diagnosis and assess disease severity. Metabolic Dysfunction-Associated Steatohepatitis Epidemiology Segmentation The MASH epidemiology section provides insights into the historical and current MASH patient pool and forecasted trends for the 7MM. It helps recognize the causes of current and forecasted patient trends by exploring numerous studies and views of key opinion leaders. The MASH market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Prevalent Cases of MASH Diagnosed Prevalent Cases of MASH Gender-specific Diagnosed Prevalent Cases of MASH Severity-specific Diagnosed Prevalent Cases of MASH Metabolic Dysfunction-Associated Steatohepatitis Treatment Market The approval of REZDIFFRA (resmetirom) in March 2024 represents a pivotal achievement in medical innovation, transforming the treatment landscape for MASH disease. This groundbreaking therapy addresses the root causes of MASH, offering renewed hope to patients grappling with this challenging condition. Clinical trials have shown impressive results, with REZDIFFRA effectively reducing symptoms like inflammation and fibrosis, enhancing liver function, and improving patients' quality of life. By providing healthcare professionals with a robust treatment option, this approval addresses a critical unmet need and has the potential to significantly alleviate the complications linked to advanced liver disease. The prevalence of MASLD is strongly linked to type 2 diabetes mellitus and obesity, particularly in individuals with a higher body mass index. However, MASLD occurrence is reduced in T2DM patients receiving treatments such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, GLP-1 receptor agonists, and insulin. Vitamin E, with its antioxidant properties, is regarded as a first-line pharmacological option for managing MASH, especially when dietary and lifestyle interventions are insufficient. Antifibrotic agents can help prevent the progression of liver fibrosis and MASLD into fibrotic MASH. The role of pioglitazone, an anti-diabetic medication, in improving MASH histology in T2DM patients is well-documented, but concerns remain regarding potential side effects like weight gain, fluid retention, cancer risk, and bone fractures. Additional therapeutic targets for MASLD and MASH include G protein-coupled receptors (GPCRs), estrogen-related receptor alpha (ERRα), bone morphogenetic proteins (BMPs), and KLFs. Bariatric surgery, or weight loss surgery, is the most effective intervention for treating obesity and diabetes, as it reduces food absorption while influencing gut hormone secretion and metabolic function. To know more about MASH treatment guidelines, visit @ Metabolic Dysfunction-Associated Steatohepatitis Management Metabolic Dysfunction-Associated Steatohepatitis Pipeline Therapies and Key Companies Lanifibranor (IVA337): Inventiva Pharma Semaglutide: Novo Nordisk A/S Azemiglitazone (MSDC-0602K): Cirius Therapeutics Efruxifermin (EFX): Akero Therapeutics BIO89-100 (Pegozafermin): 89bio Survodutide (BI 456906): Boehringer Ingelheim/Zealand Pharma GR-MD-02 (Belapectin): Galectin Therapeutics LPCN1144: Lipocine VK2809: Viking Therapeutics Tirzepatide: Eli Lilly and Company BOS-580: Boston Pharmaceuticals Ervogastat (PF-06865571) + Clesacostat (PF-05221304): Pfizer HTD1801: HighTide Biopharma Leronlimab (PRO 140): CytoDyn Efinopegdutide: Merck & Co./Hanmi Pharmaceutical HPG1860: Hepagene (Shanghai) Rencofilstat (CRV431): Hepion Pharmaceuticals EYP001 (Vonafexor): Enyo Pharmaceuticals Semaglutide/ Cilofexor/ Firsocostat: Gilead Sciences PXL065: Poxel SA Saroglitazar Magnesium: Zydus Therapeutics Denifanstat (TVB-2640): Sagimet Biosciences ION224: Ionis Pharmaceuticals Miricorilant (CORT118335): Corcept Therapeutics Discover more about MASH drugs in development @ Metabolic Dysfunction-Associated Steatohepatitis Clinical Trials Metabolic Dysfunction-Associated Steatohepatitis Market Dynamics The MASH market dynamics are expected to change in the coming years. Growing research activities and multiple clinical trials for MASH, driven by the rapid surge in its prevalence due to rising obesity and type 2 diabetes rates, highlight an active drug development pipeline and an expanding market size. The large pool of patients and lucrative growth opportunities present attractive prospects for key players, further supported by ongoing preclinical studies aimed at advancing imaging techniques for MASH diagnosis, potentially eliminating the need for invasive biopsy-based histopathological confirmation. Furthermore, potential therapies are being investigated for the treatment of MASH, and it is safe to predict that the treatment space will significantly impact the MASH market during the forecast period. Moreover, the anticipated introduction of emerging therapies with improved efficacy and a further improvement in the diagnosis rate are expected to drive the growth of the MASH market in the 7MM. However, several factors may impede the growth of the MASH market. Lack of awareness and negligence in the early stages of MASH by physicians often lead to disease progression, culminating in irreversible damage where liver transplantation becomes the only viable option. Diagnosing advanced MASH typically requires procedures like liver biopsy, which are costly, invasive, and risky. Regulatory challenges also pose hurdles, as the FDA mandates achieving one MASH endpoint for approval, while the EMA's draft guidance requires efficacy in both endpoints, potentially delaying first-mover approvals in major European markets. Additionally, access to expensive MASH treatments may be limited in certain regions, further hindering patient adoption. Moreover, MASH treatment poses a significant economic burden and disrupts patients' overall well-being and QOL. Furthermore, MASH market growth may be offset by failures and discontinuation of emerging therapies, unaffordable pricing, market access and reimbursement issues, and a shortage of healthcare specialists. In addition, the undiagnosed, unreported cases and the unawareness about the disease may also impact MASH market growth. Scope of the Metabolic Dysfunction-Associated Steatohepatitis Market Report Therapeutic Assessment: Metabolic Dysfunction-Associated Steatohepatitis current marketed and emerging therapies Metabolic Dysfunction-Associated Steatohepatitis Market Dynamics: Key Market Forecast Assumptions of Emerging Metabolic Dysfunction-Associated Steatohepatitis Drugs and Market Outlook Competitive Intelligence Analysis: SWOT analysis and Market entry strategies Unmet Needs, KOL's views, Analyst's views, Metabolic Dysfunction-Associated Steatohepatitis Market Access and Reimbursement Download the report to understand which factors are driving MASH market trends @ Metabolic Dysfunction-Associated Steatohepatitis Market Trends Table of Contents Related Reports Non-Alcoholic Steatohepatitis Epidemiology Forecast Non-Alcoholic Steatohepatitis Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted NASH epidemiology in the 7MM, i.e., the United States, EU4 (Germany, France, Italy, Spain), the United Kingdom, and Japan. Nonalcoholic Steatohepatitis Pipeline Nonalcoholic Steatohepatitis Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key nonalcoholic steatohepatitis companies, including Madrigal Pharmaceuticals, Intercept Pharmaceuticals, Cirius Therapeutics, Novo Nordisk, Inventiva, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, 89bio, Inc., Eccogene, Novartis Pharmaceuticals, Poxel SA, AngioLab, Pfizer, Arrowhead Pharma, LG Chem, Redx Pharma, Lipocine, Inc., CytoDyn, Inc., Alnylam Pharmaceuticals, Inc., Chemomab Therapeutics, NuSirt Biopharma, HK inno. N, Aligos Therapeutics, Altimmune, Inc., Kowa Pharmaceutical, Ionis Pharmaceuticals, NorthSea Therapeutics, Rivus Pharmaceuticals, Hanmi Pharmaceutical, Hepagene Therapeutics, HighTide Biopharma, Akero Therapeutics, Merck Sharp & Dohme LLC, Cascade Pharmaceuticals, Hepion Pharmaceuticals, Chipscreen Biosciences, Boston Pharmaceuticals, Bristol-Myers Squibb, Sunshine Lake Pharma, GSK plc., Future Medicine, Gilead Sciences, ENYO Pharma, Histogen, among others. Non-Alcoholic Fatty Liver Disease Market Non-Alcoholic Fatty Liver Disease Market Insight, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key NAFLD companies, including MediciNova, Eli Lilly and Company, AstraZeneca, Inventiva Pharma, Oasis Pharmaceuticals, LLC, Madrigal Pharmaceuticals, Inc., BioMarin Pharmaceutical, GlaxoSmithKline, Zydus Therapeutics Inc., Akero Therapeutics, Inc, Pfizer, Boehringer Ingelheim, Neuraly, Inc., Merck Sharp & Dohme LLC, Rivus Pharmaceuticals, Inc., Hepion Pharmaceuticals, Inc. , among others. Non-Alcoholic Fatty Liver Disease Pipeline Non-Alcoholic Fatty Liver Disease Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key NAFLD companies, including BeiGene, Inventiva Pharma, Cirius Therapeutics, Madrigal Pharma, Novo Nordisk, Galmed Pharmaceuticals, AstraZeneca, Galectin Therapeutics, Viking Therapeutics, Dr. Falk Pharma GmbH, Sagimet Biosciences, Eli Lilly and Company, Terns Pharmaceuticals, Sinew Pharma, Novartis Pharmaceuticals, Afimmune, Poxel SA, AngioLab, Pfizer, Oramed Pharmaceuticals, Can Fite Biopharma, MediciNova, Metacrine, Inc., Lipocine, Inc., CytoDyn, Inc., Alnylam Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma, Chemomab Therapeutics, NuSirt Biopharma, HK inno.N, Kowa Pharmaceutical, Ionis Pharmaceuticals, NorthSea Therapeutics, Rivus Pharmaceuticals, Hanmi Pharmaceutical, Hepagene Therapeutics, HighTide Biopharma, Akero Therapeutics, Enanta Pharmaceuticals, Cascade Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期

2024-10-28

·药智网

2024年集体爆发的MASH市场，竞争格局几何？

继今年3月，全球首款MASH新药——Resmetirom获FDA批准用于治疗伴有肝纤维化的成人MASH患者，填补了MASH药物的空白状态后，近段时间以来，国内MASH领域的“新药曝光度”有目共睹的在增加。 10月15日，微芯生物宣布，其研发的西格列他钠治疗非酒精性脂肪性肝炎（NASH）/代谢相关性脂肪性肝炎（MASH）的2期临床研究（CGZ203试验）摘要入选美国肝病研究学会年会（AASLD 2024），11月17日以口头报告形式公布。 10月18日，中国国家药监局药品审评中心（CDE）官网公示，康弘药业1类THR-β新药KH629片获得临床试验默示许可，拟开发用于治疗成人非酒精性脂肪性肝炎。为何沉寂40余年的MASH新药研究，短时间内俨然成为“流量”的代名词，成为众多药企争相入局的潜力市场，其背后又是怎样的底层逻辑使然？患病率高涨 MASH是临床需求愈发迫切其实，与大多数肝脏慢性病不同，近年来非酒精性脂肪性肝病（NAFLD）的患病率不降反增，现阶段已取代乙肝成为我国最常见的慢性肝病。资料显示，中国成年人中NAFLD患病率高达29.2%，10年内整体增长10%，中国MASH患病率约为2.4%～6.1%，我国NAFLD/MASH患者疾病负担极其沉重。据弗若斯特沙利文报告预计， 2030 年全球 MASH 患病人数将达到 4.9 亿人，全球MASH药物市场将达到 322 亿美元。作为NAFLD中最严重的发展阶段，原理上MASH是一种与代谢紊乱相关的肝脏疾病，其特征是肝脏中脂肪的异常积累，伴随着炎症和肝细胞损伤，早年间被称为非酒精性脂肪性肝炎（NASH）。 40余年的相关研究下，人们对MASH的发病机制仍尚未完全明确，目前认为其乃是一种代谢应激性肝损伤，与多种因素相关，复杂的级联反应下的肝细胞损伤机制有以下几种，主要包括胰岛素抵抗、氧化应激、炎症反应和脂质代谢异常等多个环节。在临床表现方面，MASH通常情况下起病隐匿且缓慢，且通常无症状，多于常规检查过程中无意发现，并且由于MASH通常情况下难以自发缓解，在早期无干预的情况下进展为肝纤维化的风险很高，大约有15%的患者会发展为肝硬化、肝衰竭和肝细胞癌。临床药物缺乏 MASH传统治疗局限性大在Resmetirom获FDA批准上市之前，全球尚无治疗 NAFLD/NASH 的靶向性药物，而由于MASH与肥胖、2 型糖尿病、高血压、血脂紊乱等疾病的密切相关性，目前普遍认为控制这些疾病可有效改善 NAFLD/NASH的代谢状态，从而延缓疾病进展。因此，NAFLD以及MASH的治疗基础仍是生活方式的干预和饮食方案的优化，生活习惯的改善，尤其饮食的控制及锻炼减重等可减少肝脏脂肪沉积，有利于改善 MASH 的生化指标和肝组织学病变，相关研究显示，体重减轻 3% 即可改善 NAFLD患者脂肪肝病情程度，减重 7% 可改善肝脏炎症等组织学指标，减重 10% 可逆转肝纤维化水平。而在药物治疗方面，临床上主要针对抗胰岛素抵抗、抗氧化应激、降血脂、促进脂质代谢及保护肝细胞膜等对MASH进行治疗，如二甲双胍、维生素 E、熊去氧胆酸、FXR激动剂奥贝胆酸、肝损伤治疗药物等保肝药物的使用。但同时，上述药物治疗方式的局限性也很大，一者药物的治疗剂量、有效性及安全性均尚不明确，有待进一步研究；二者，如奥贝胆酸等FXR激动剂的不良反应也极大限制了其在MASH领域的应用。故现阶段的MASH临床治疗上，迫切需要一种副作用低、能逆转肝纤维化、患者顺应性佳的创新疗法。四大方向推动MASH机制逐渐清晰就目前而言，通过对MASH的发病机制研究，目前已有多款靶点给予了MASH有效干预，是目前乃至未来MASH治疗的主要方向。从类型上来看主要分为代谢、消化、抗炎、抗纤维化四种方向：代谢类：改善胰岛素敏感性、抑制脂肪生成各种酶、促进线粒体摄取脂肪酸等。消化类：调控肝肠轴的循环、改善胆汁酸的循环与信号传导、改善肠道菌群的平衡等。抗炎类：抑制炎症细胞聚集、阻断炎性信号传导、降低氧化作用和内质网应激反应、防止肝细胞凋亡等。抗纤维化：针对肝脏中的星形细胞、减轻肝脏中胶原蛋白的沉积、增强纤维分解等。而在这四种类型药物之下，又可以细分出不同的靶点选择，各靶点方向之下又存在不同的技术优势与产品差异。数据来源：公开数据整理（点击查看大图）据不完全统计，全球现有MASH在研疗法已突破350款。其中代谢类与消化类的数量最多，而前者主要机制集中于肝内，在逆转纤维化方面具有优势，而后者则是从肝外机制着手，在降低肝脏脂肪积累与纤维化进展方面优势明显，两者机制各有优劣，未来大概率会是协同合作的关系。临床阶段方面，虽绝大多数创新疗法均集中在临床前阶段，但跨入临床阶段的产品依旧不少，其中以临床II期管线数量最多，共计108款；而进入临床III期产品则也有18款之多。表1.MASH临床III期管线药品名称靶点适应症最高阶段原研单位利莫纳班 rimonabant CB1 临床Ⅲ期赛诺菲依碳酸瑞格列净 remogliflozin etabonate SLC5A2 临床Ⅲ期 BHV Pharma Inc;格兰马克制药有限公司沙格列扎镁 aroglitazar magnesium INS 临床Ⅲ期 Zydus Lifesciences Ltd 司美格鲁肽 semaglutide GLP-1R 临床Ⅲ期丹麦诺和诺德公司腺苷蛋氨酸 ademetionine Transferase 临床Ⅲ期雅培制药芦比前列酮 lubiprostone CFTR;ClC-2;PGE1 临床Ⅲ期 Sucampo Pharma LLC 佩玛贝特 pemafibrate PPAR-alpha 临床Ⅲ期 Kowa Co Ltd 塞拉德帕 seladelpar PPAR-delta 临床Ⅲ期 CymaBay Therapeutics Inc;强生创新制药 aramchol SCD1 临床Ⅲ期 Galmed Pharmaceuticals Ltd survodutide GLP-1R;GCGR 临床Ⅲ期 Zealand Pharma A/S;勃林格殷格翰 FXR314 NR1H4 临床Ⅲ期 Organovo Holdings inc 拉尼兰诺 lanifibranor PPAR-alpha;PPAR-delta;PPAR-gamma 临床Ⅲ期 Inventiva 可妥度肽 cotadutide GLP-1;GCGR 临床Ⅲ期阿斯利康瑟隆舍替selonsertib MAP3K5 临床Ⅲ期美国吉利德科学公司塞尼韦洛 cenicriviroc CCR2;CCR5 临床Ⅲ期 Tobira Therapeutics Inc;武田药品工业株式会社 ENB-106 / 临床Ⅲ期上海轶诺药业有限公司依鲁西夫明 efruxifermin FGF21 临床Ⅲ期安进公司 norucholic acid / 临床Ⅲ期德国霍克大药厂数据来源：药智数据三大靶点引领MASH新药加速落地就MASH在研药物靶点分布上而言，glp-1、FXR、THR-β、FGF19/21与PPAR是现阶段MASH最主要的在研药物类型。数据来源：药智数据从数量上来看，FXR激动剂、GLP1在研发热度上远超其他靶点，其在研数量也最多，目前均有超过30款相关疗法布局；其次是THR-β、FGF19/21与PPAR，分别有19、18与13款新药布局；其余靶点数量则相对较少，其临床阶段也相对靠后。从趋势上来看，FXR激动剂虽然是MASH领域的老牌靶点之一，但由于靶点特殊作用机制，其在副作用上的局限性太大，直接影响了其在临床上的应用潜力。至少就现在而言，反而是glp-1与THR-β两种机制的MASH新药更受关注，未来也更容易占据头牌。数据来源：药智数据 GLP-1 由于原理上GLP-1类似物能够有效改善糖脂代谢异常，因此GLP-1受体激动剂在糖尿病与减重适应症外，也被视为潜在的MASH治疗药物。表2.GLP-1应用于MASH的创新疗法药品名称靶点原研单位适应症最高阶段司美格鲁肽 semaglutide GLP-1R 丹麦诺和诺德公司临床Ⅲ期 survodutide GLP-1R;GCGR Zealand Pharma A/S;勃林格殷格翰临床Ⅲ期可妥度肽 cotadutide GLP-1;GCGR 阿斯利康临床Ⅲ期替尔泊肽 tirzepatide GIPR;GLP-1R 礼来制药临床Ⅱ期 RAY-1225 GLP-1;GIP 广东众生睿创生物科技有限公司临床Ⅱ期 HEC-88473 FGF21;GLP-1R 东莞市东阳光生物药研发有限公司临床Ⅱ期派维度肽 pemvidutide GLP-1R;GCGR Altor BioScience Corp合作：Altimmune Inc 临床Ⅱ期尤曲格鲁肽 utreglutide GLP-1R 印度太阳药业有限公司临床Ⅱ期巴度肽 bamadutide GLP-1R;GCGR 赛诺菲临床Ⅱ期依福培肽 efocipegtrutide GIPR;GLP-1R;GCGR 韩美药品株式会社临床Ⅱ期数据来源：药智数据截止目前，随着人们对 GLP-1 的焦点由减肥向在抗 MASH转变之下，已有超30种GLP-1药物正在研究其治疗MASH的潜力，临床上推进较快的产品不少，较出名的产品有诺和诺德的司美格鲁肽、勃林格殷格翰的survodutide、阿斯利康的cotadutide、礼来制药的tirzepatide。其中，Semaglutide与替尔泊肽作为GLP-1两大重磅产品，在关于MASH的治疗研究中均显示出减少肝脏脂肪积累、降低炎症水平的潜力，极大地振奋了行业对GLP-1作用于MASH的信心。但与此同时，GLP-1在治疗MASH上的局限性也逐渐体现，即虽然在减少肝脏脂肪积累和纤维化方面的效果显著，但对逆转肝脏纤维化上却缺乏足够、全面、多维度的有效证据。这就导致GLP-1疗法单药治疗既无法完全满足现有的临床需求，也很难与其他疗法拉开差距。对此，有关人士表示，GLP-1未来要想在MASH领域站稳脚跟，要么就逆转纤维化做出更多差异化成果，要么依靠肝外机制改善代谢紊乱的特点，与众多肝内机制的MASH疗法形成联动与互补，以协同策略解决MASH的临床需求。 Fxr（NR1H4）作为曾经治疗MASH最重要的靶点，也是MASH早期阶段最主要的在研药物形式，FXR作为一种肠肝调节因子，不仅参与胆汁酸信号传导，调控胆汁酸合成和转运，还可以调节葡萄糖稳态、脂质和胆固醇代谢等其他生理功能以及抑制炎症，在MASH治疗上，目前已显示出一定的治疗效果。截止目前，除已经宣布终止MASH适应症开发的奥贝胆酸外，领域内仍有超过30款Fxr激动剂涉及MASH适应症，其中Organovo的FXR314已进入了临床III期，是现阶段推进最快的Fxr激动剂；之后，还有10余款管线进入了临床II期，较受期待的有吉利德的cilofexor、诺华制药的nidufexor、东阳光药业HEC96719等。表3.MASH中Fxr激动剂创新疗法药品名称靶点原研单位适应症最高阶段奥贝胆酸 obeticholic acid NR1H4 Intercept Pharmaceuticals Inc 注册申请 FXR314 NR1H4 Organovo Holdings inc 临床Ⅲ期昔洛法克索 cilofexor NR1H4 Phenex Pharmaceuticals AG;美国吉利德科学公司临床Ⅱ期尼度法克索 nidufexor NR1H4 诺华制药临床Ⅱ期 HEC96719 NR1H4 广东东阳光药业股份有限公司临床Ⅱ期卓匹非索 tropifexor NR1H4 诺华制药临床Ⅱ期 CS-0159 NR1H4 Van Andel Institute;中国科学院上海药物研究所;凯思凯迪（上海）医药科技有限公司临床Ⅱ期 EDP-305 NR1H4 Enanta Pharmaceuticals Inc 临床Ⅱ期 TERN-101 NR1H4 上海拓臻生物科技有限公司;礼来制药临床Ⅱ期 MET-642 NR1H4 Metacrine Inc 临床Ⅱ期 MET-409 NR1H4 Metacrine Inc 临床Ⅱ期 HPG1860 NR1H4 雅创医药技术（上海）有限公司临床Ⅱ期 EYP-001 NR1H4 Poxel SA 临床Ⅱ期数据来源：药智数据而与此同时，虽然近年来Fxr激动剂领域用于MASH治疗的研究开发正在进入快速发展期，但临床获益有限，副作用严重等局限性也制约了其在临床上应用，最显著的例子就是奥贝胆酸，其2015年获FDA突破性疗法资格认定，是全球第一个进入临床3期的MASH候选产品，但最终仍因获益不确定性、副作用较大而折戟，经历多次被FDA否决后，最终无奈宣布终止其用于MASH领域的开发。因此，对于Fxr激动剂整体而言，在保证创新疗法的有效性，研究机构未来更大的精力或将集中于创新疗法的不良反应的减少与安全性的提高上。 THR-β THR-β是一种核激素受体，其主要在肝脏中高表达，能够调节脂代谢，降低低密度脂蛋白胆固醇（LDL-C）、甘油三酯和致动脉粥样硬化性脂蛋白，因此成为理论上MASH最具潜力的治疗靶点。此外，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。这也是为何THR-β激动剂会具备调控多种肝脏代谢通路来治疗MASH的潜力的原因。其在MASH上的主要作用有以下5点：调控脂肪合成调控脂肪酸氧化作用调控胆固醇代谢调控线粒体功能通过抑制TGF-β信号通路发挥抗炎和抗纤维化作用 2024年3月，Resmetirom成为首款获FDA批准上市的治疗代谢功能障碍相关脂肪性肝炎（MASH）的新药，也是THR-β激动剂领域首款撞线的产品。表4.MASH中THR-β激动剂创新疗法药品名称靶点原研单位适应症最高阶段瑞司美替罗 resmetirom THRB Madrigal Pharmaceuticals Inc;罗氏制药批准上市 VK-2809 THRB Ligand Pharmaceuticals Inc;Viking Therapeutics Inc 临床Ⅱ期 ASC41 THRB 歌礼制药有限公司;甘莱制药有限公司临床Ⅱ期 TERN-501 THRB 上海拓臻生物科技有限公司临床Ⅱ期 HSK-31679 THRB 海思科医药集团股份有限公司临床Ⅱ期 ALG-055009 THRB Aligos Therapeutics Inc 临床Ⅰ期 ASC-43-F THRB;NR1H4 歌礼制药有限公司;甘莱制药有限公司临床Ⅰ期 RJ-4287 THRB 南京奥利墨斯医药科技有限公司临床Ⅰ期 Kylo-0603 THRB 厦门甘宝利生物医药有限公司临床Ⅰ期 CS-060304 THRB 凯思凯迪（上海）医药科技有限公司临床Ⅰ期 CS-060380 THRB 凯思凯迪（上海）医药科技有限公司临床Ⅰ期数据来源：药智数据 Resmetirom的成功获批一方面为MASH患者的治疗提供了新手段，同时另一方面也证明了THR-β激动剂路线的可行性。也正是因此，THR-β激动剂成为全球MASH新药研发的主要集中方向，多款THR-β激动剂紧随其后，均表现出不俗的潜力，目前临床阶段进展较快的主要有四款，分别是Ligand的VK-2809、歌礼制药的ASC41、拓臻生物的TERN-501以及海思科的HSK-31679，均已进入了临床II期。而更值得注意的是，THR-β激动剂也是目前国内MASH在研新药最集中的方向，处于领先地位（临床进度靠前）的创新疗法数量远高于其他几种类型。未来，不出意外的话，国内在该领域的突破大概率也将集中此，或许还有望领先于海外药企，成为MNC争夺的关键。小结纵观MASH领域40余年的发展历史，从致病机制的不断完善，到临床上的对症治疗出现，再到今年首款新药获批上市，MASH的新药研发充满坎坷。但随着MASH新药研发的四大机制方向、10余款创新靶点的逐步落地，领域内似乎正在逐渐形成一个系统化、宏观化的研发格局，过程中不断有更多如GLP-1、THR-β等全新的疗法加入，至少目前看来俨然一副百废待兴，可大展拳脚的状态。而对于国内药企而言，虽然某种程度上做不到如海外一般全赛道布局，但在个别如THR-β激动剂等潜力领域的优势却反而更大，或许这种强调聚焦的国内赛道模式，未来或许真能让中国企业站上国际舞台，成为MASH领域的龙头之一。来源 | 博药（药智网获取授权转载）撰稿 | 头孢责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

ASH会议临床2期申请上市临床结果上市批准

2024-10-22

·BioSpace

Gilead to Present Latest Research Across Key Liver Disease Indication at the American Association for the Study of Liver Disease (AASLD) Meeting 2024

- Key Insights from Viral Hepatitis, PBC, and MASH/Fibrosis Studies Highlight Gilead’s Ongoing Commitment to Advancing Life-Changing Liver Disease Research - FOSTER CITY, Calif.--(BUSINESS WIRE)--Gilead Sciences, Inc. (Nasdaq: GILD) today announced new research to be presented at The Liver Meeting ® 2024, hosted by the American Association for the Study of Liver Diseases (AASLD) from November 15-19 in San Diego, Calif. More than 40 abstracts will be presented with key data, including 11 abstracts reporting new data on primary biliary cholangitis (PBC). The data will include findings from the RESPONSE trial that demonstrate the efficacy and safety pro Livdelzi ® (seladelpar) in people living with PBC and compensated cirrhosis. Additionally, data will be presented on the effects of Livdelzi on pruritus (chronic itching), a symptom that has significant impact on the quality of life of people living with PBC, along with interim long-term efficacy and safety results from the ongoing ASSURE study. Beyond PBC, Gilead will be presenting an interim analysis of the Phase 3 MYR301 study, which is evaluating people living with hepatitis Delta virus (HDV) who received bulevirtide monotherapy (2 mg for 144 weeks; 10 mg for 144 weeks; or 10 mg for 96 weeks) for chronic HDV and have been off treatment for 48 weeks. The study is evaluating whether or not patients treated with bulevirtide monotherapy for 2-3 years maintained virological and biochemical responses one year after stopping treatment. An additional 144-week analysis of patient-reported outcomes for individuals treated with bulevirtide 2 mg will also be presented, adding to the wealth of long-term data for the treatment for chronic HDV. “We’re excited to share our latest research at The Liver Meeting, as we push the boundaries of what’s possible in liver disease treatment. The breadth of this research reflects Gilead’s unwavering dedication to advancing life-changing science and shaping healthier futures for people living with liver disease,” said Anu Osinusi, Vice President of Clinical Development for Hepatitis, Respiratory and Emerging Viruses, Gilead Sciences. “The depth and range of our data, spanning both viral and inflammatory liver diseases, underscores our commitment to making a meaningful impact at every stage of a person’s journey in liver disease. Our goals go far beyond treatment alone—our work spans awareness, education, screening, diagnosis, and long-term care, all intending to address unmet needs and enhance treatment outcomes.” Gilead will also present hepatitis C virus (HCV) data which will include safety and tolerability outcomes for Epclusa ® (velpatasvir/sofosbuvir) in pregnant individuals with chronic HCV (the STORC study). As a special population that is often excluded from clinical research, these results may help clinicians better support pregnant people living with HCV, which in turn may reduce the risk of transmission to infants. Furthermore, real-world findings from the SVR10K study on HCV will be showcased, demonstrating the effects of direct-acting antivirals against all HCV genotypes across diverse regions. Late-breaking data from a Phase 2a open-label study assessing the safety and efficacy of novel combination therapies for chronic hepatitis B virus (HBV) will also be presented by Gilead. Key Abstracts at AASLD 2024: ID Abstract Title PBC 164 Efficacy and Safety of Seladelpar in Patients with PBC and Compensated Cirrhosis in the Phase 3 Placebo-controlled RESPONSE Trial 167 Attenuation, Near Resolution, and Prevention of Pruritis in Patients with PBC Treated with Seladelpar: A Secondary Analysis of Patterns of Pruritis Change in the RESPONSE Trial 4339 Alkaline Phosphatase Changes with Seladelpar Across Subgroups of Primary Biliary Cholangitis Patients in the RESPONSE Trial 4342 Seladelpar and Reductions in Lipids in Patients with Primary Biliary Cholangitis with and without Statin use in the Phase 3 Placebo-controlled RESPONSE Study 4341 Long-term Safety of Seladelpar 10 mg with up to 5 Years of Treatment in Patients with Primary Biliary Cholangitis Primary sclerosing cholangitis (PSC) 151 Associations Between Biomarkers and Magnetic Resonance Imaging-derived ANALI Score in Patients with Primary Sclerosing Cholangitis: Analysis from the Phase 3 PRIMIS Study HDV 1147 Efficacy and Safety of BLV Monotherapy for Chronic Hepatitis Delta: Post Treatment Results through 48 Weeks after the End of Treatment from an Interim Analysis of a Randomized Phase 3 Study MYR301 1193 Patient-reported Outcomes among Patients with Chronic Hepatitis Delta Treated with Bulevirtide 2 mg: A Long-term Analysis of the Phase 3 MYR301 Trial at 144 Weeks 139 Long-term Bulevirtide Monotherapy in Patients with HDV-related Compensated Cirrhosis: Effectiveness, Safety and Clinical Outcomes from the Retrospective Multicenter European Study (SAVE-D) HCV 222 Safety, Tolerability, and Outcomes of Velpatasvir/Sofosbuvir in Treatment of Chronic Hepatitis C Virus during Pregnancy (STORC) 1455 The SVR10K Study: A Real-world Data with Pangenotypic Direct-acting Antivirals across Multiple Diverse Regions 1476 Hepatitis C Treatment Uptake Differs by Gender among a Commercially Insured Population in the United States HBV 1380 Results from a Phase 2a, Open-label Study to Evaluate the Safety and Efficacy of Novel Combination Therapies Containing VIR-2218, Selgantolimod, and Nivolumab for the Treatment of Chronic Hepatitis B 1252 Effectiveness and Safety of Tenofovir Alafenamide in Chronic Hepatitis B Patients with Suboptimal Response to Antiviral Therapy 1337 Characterization of Changes in Noninvasive Fibrosis Markers over 8 Years of Tenofovir-based Treatment in Chronic Hepatitis B Patients Enrolled in Two Phase 3 Trials Nonalcoholic steatohepatitis (NASH)/Fibrosis 1520 Prospective Validation of the Mediterranean Diet Adherence Screener (MEDAS) for Point-of-care Assessment of Diet Quality in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease For more information, including a complete list of abstract titles being presented at the meeting, please visit the AASLD website . In July 2023, the European Commission (EC) granted full Marketing Authorization (MA) for bulevirtide 2 mg for the treatment of adults with chronic HDV and compensated liver disease. Bulevirtide’s conditional MA license in Great Britain was converted to a full MA in August 2023 and a full MA was granted in Switzerland and Australia in 2024. In regions where it is not approved, including the U.S., bulevirtide 2 mg is an investigational product. In these regions, health authorities have not established the safety and efficacy of bulevirtide. Bulevirtide 10 mg is an investigational product and has not been approved anywhere. Cilofexor and selgantolimod are investigational compounds and are not approved by the FDA or any other regulatory authority; their safety and efficacy have not been established. Please see below for the U.S. Indications and Important Safety Information, including BOXED WARNINGS, for Epclusa and Livdelzi. U.S. Important Safety Information And Indication for EPCLUSA BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with EPCLUSA. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated. Contraindications If EPCLUSA is used in combination with ribavirin (RBV), all contraindications, warnings and precautions, in particular pregnancy avoidance, and adverse reactions to RBV also apply. Refer to RBV prescribing information. Warnings and Precautions Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with EPCLUSA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia. Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers and/or Moderate to Strong Inducers of CYP2B6, CYP2C8 or CYP3A4 : Rifampin, St. John’s wort and carbamazepine are not recommended for use with EPCLUSA as they may significantly decrease sofosbuvir and/or velpatasvir plasma concentrations. Adverse Reactions The most common adverse reactions (≥10%, all grades) with EPCLUSA in adults and pediatric patients 6 years of age and older were headache and fatigue; and when used with RBV in adults with decompensated cirrhosis were fatigue, anemia, nausea, headache, insomnia and diarrhea. The most common adverse reactions (≥10%, grade 1 or 2) in pediatric patients less than 6 years of age were vomiting and spitting up the drug. Drug Interactions Coadministration of EPCLUSA is not recommended with topotecan due to increased concentrations of topotecan. Coadministration of EPCLUSA is not recommended with proton-pump inhibitors, phenobarbital, phenytoin, rifabutin, rifapentine, efavirenz, and tipranavir/ritonavir due to decreased concentrations of sofosbuvir and/or velpatasvir. Consult the full Prescribing Information for EPCLUSA for more information on potentially significant drug interactions, including clinical comments. Indication EPCLUSA is indicated for the treatment of adult and pediatric patients 3 years of age and older with chronic hepatitis C virus genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis and in combination with ribavirin for those with decompensated cirrhosis. U.S. Important Safety Information for LIVDELZI Warnings and Precautions Fractures: Fractures occurred in 4% of LIVDELZI-treated patients compared to no placebo-treated patients. Consider the risk of fracture in the care of patients treated with LIVDELZI and monitor bone health according to current standards of care. Liver Test Abnormalities: LIVDELZI has been associated with dose-related increases in serum transaminase (AST and ALT) levels > 3 x ULN in patients receiving 50 mg and 200 mg once daily (5x and 20x higher than the recommended dosage of 10 mg once daily). Perform baseline clinical and laboratory testing when starting LIVDELZI and monitor thereafter according to routine patient management. Interrupt treatment if the liver tests (ALT, AST, total bilirubin, and/or ALP) worsen, or if the patient develops signs and symptoms of clinical hepatitis (eg, jaundice, right upper quadrant pain, eosinophilia). Consider permanent discontinuation if liver tests worsen after restarting LIVDELZI. Biliary Obstruction: Avoid use of LIVDELZI in patients with complete biliary obstruction. If biliary obstruction is suspected, interrupt LIVDELZI and treat as clinically indicated. Adverse Reactions The most common adverse reactions (≥5%) with LIVDELZI were headache (8%), abdominal pain (7%), nausea (6%), abdominal distension (6%), and dizziness (5%). Drug Interactions OAT3 Inhibitors and Strong CYP2C9 Inhibitors: Avoid coadministration with LIVDELZI due to increased LIVDELZI exposure. Rifampin: Monitor biochemical response (e.g., ALP and bilirubin) when patients initiate rifampin during LIVDELZI treatment. Coadministration may result in delayed or suboptimal biochemical response of LIVDELZI. Dual Moderate CYP2C9 and Moderate-to-Strong CYP3A4 Inhibitors and BCRP Inhibitors (eg, cyclosporine): Monitor closely for adverse effects. Concomitant administration with LIVDELZI may increase LIVDELZI exposure. CYP2C9 Poor Metabolizers Using Moderate-to-Strong CYP3A4 Inhibitors: Monitor more frequently for adverse reactions as concomitant use of a moderate-to-strong CYP3A4 inhibitor in patients who are CYP2C9 poor metabolizers may increase LIVDELZI exposure and risk of LIVDELZI adverse reactions. Bile Acid Sequestrants: Administer LIVDELZI at least 4 hours before or 4 hours after taking a bile acid sequestrant, or at as great an interval as possible. Pregnancy and Lactation Pregnancy: There are insufficient data from human pregnancies exposed to LIVDELZI to allow an assessment of a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Gilead Sciences, Inc., at 1-800-445-3235. Lactation: There are no data on the presence of LIVDELZI in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LIVDELZI and any potential adverse effects on the breastfed infant from LIVDELZI. Indication LIVDELZI is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. This indication is approved under accelerated approval based on a reduction of ALP. Improvement in survival or prevention of liver decompensation events have not been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Limitations of Use: Use of Livdelzi is not recommended in patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, hepatic encephalopathy). About HDV HDV is considered the most aggressive or severe form of viral hepatitis, associated with more rapid progression towards liver-related death and liver cancer in people with HBV. On average, HDV progresses to cirrhosis within 5 years and to liver cancer within 10 years. Nearly 5% of people who have a chronic infection with HBV are estimated to have HDV, equating to 12-15 million people worldwide. The prevalence of HDV infection is largely underestimated due to lack of universal testing of HBV-positive individuals for HDV. About PBC PBC is a rare, chronic inflammatory liver disease primarily affecting women (1 in 1,000 women over the age of 40 or about 130,000 total people in the U.S.). PBC is characterized by impaired bile flow (known as cholestasis) and the accumulation of toxic bile acids in the liver, leading to inflammation and destruction of the bile ducts within the liver and causing increased levels of alkaline phosphatase (ALP), alanine transaminase (ALT) and gamma-glutamyl transferase (GGT), enzymes found primarily in the liver, as well as total bilirubin. The most common symptoms of PBC are pruritus and fatigue, which can be debilitating for some people. Progression of PBC is associated with an increased risk of liver-related mortality. About Gilead Sciences in Liver Disease For decades, Gilead has pioneered the way forward to improve the lives of people living with liver disease around the world. We have helped to transform hepatitis C from a chronic condition into one that can be cured for millions of people. For people living with hepatitis B or D, our focus on advancing our medicines drives hope that today’s research will turn into tomorrow’s cures. Beyond viral hepatitis, we’re working to deliver advanced treatments for people living with PBC. But our commitment doesn’t stop there. Through our ground-breaking science and collaborative partnerships, we strive to create healthier futures for everyone living with liver disease. We are committed to a future without liver disease. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California. Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials or studies, including those involving Epclusa, Hepcludex (bulevirtide), Livdelzi (seladelpar), cilofexor and selgantolimod (such as the ASSURE, RESPONSE, MYR301, STORC and SVR10K studies); uncertainties relating to regulatory applications and related filing and approval timelines, including the risk that the FDA and other regulatory authorities may not approve bulevirtide for the treatment of HDV, and the risk that any such approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; the possibility that Gilead may make a strategic decision to discontinue development of investigational programs for indications that are currently under evaluation and, as a result, these programs may never be successfully commercialized for the indications currently under evaluation; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. Epclusa, Hepcludex, Livdelzi, Gilead and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies. For more information about Gilead, please visit the company’s website at , follow Gilead on Twitter (@Gilead Sciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000. Contacts Meaghan Smith, Media public_affairs@gilead.com Jacquie Ross, Investors investor_relations@gilead.com

临床2期临床结果上市批准临床3期

100 项与 Cilofexor tromethamine 相关的药物交易

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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	临床3期	美国	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	日本	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	澳大利亚	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	奥地利	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	比利时	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	加拿大	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	丹麦	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	芬兰	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	法国	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	德国	Gilead Sciences, Inc.	2019-03-27

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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


NCT04060147 (Phase 1B Study, Pubmed)	临床1期	原发性硬化性胆管炎 alanine transaminase \| alkaline phosphatase \| gamma-glutamyl transferase ... 更多	11	Cilofexor 30 mg	鏇選構遞鬱製糧壓糧憲(製鹹鬱願範襯積淵積遞) = fatigue (2/11 [18.2%]) 鹹醖醖簾積餘淵製襯襯 (淵願淵積網膚醖鏇醖艱 ) 更多	积极	2024-07-01
				Cilofexor 60 mg
NCT03890120 (PRIMIS, CTgov)	临床3期	原发性硬化性胆管炎	419	Cilofexor (Cilofexor 100 mg (Blinded Phase))	鏇鑰鑰壓鏇選壓網範餘(夢選糧蓋網廠蓋選艱繭) = 鏇鹽淵襯淵簾齋夢簾壓醖蓋憲艱糧鬱膚觸蓋遞 (築憲遞艱範積網鑰夢簾, 廠鹹壓鑰廠艱衊範鹹簾 ~ 製鏇鬱鹽襯鑰憲膚憲遞) 更多	-	2023-11-29
				Placebo (Placebo (Blinded Phase))	鏇鑰鑰壓鏇選壓網範餘(夢選糧蓋網廠蓋選艱繭) = 齋壓衊簾齋糧糧淵蓋願醖蓋憲艱糧鬱膚觸蓋遞 (築憲遞艱範積網鑰夢簾, 壓顧網衊糧艱積醖淵繭 ~ 淵鑰膚夢襯衊餘繭積築) 更多
NCT04060147 (Phase 1B Study, CTgov)	临床1期	纤维化 \| 原发性硬化性胆管炎 \| 代偿期肝硬化	11	Cilofexor	艱構壓廠網憲築遞簾夢(選齋觸鬱簾憲餘衊壓積) = 鏇願鑰齋獵鏇糧淵膚鬱窪鏇壓餘鑰獵顧衊簾鏇 (製遞鑰顧壓鹹窪選簾觸, 願醖網窪遞廠憲襯艱衊 ~ 選築齋繭顧鏇製遞觸夢) 更多	-	2023-07-27
NCT03890120 (PRIMIS, EASL2022)	临床3期	原发性硬化性胆管炎	11	Cilofexor 30 mg	餘憲膚積遞範廠鑰鑰憲(壓鹽衊觸簾願繭遞廠窪) = 夢網簾築選壓觸鏇製襯願廠積簾簾壓餘壓觸積 (構窪願壓構鹽網淵糧餘 ) 更多	积极	2022-06-23
NCT03987074 (Pubmed \| J Hepatol) 人工标引	临床2期	非酒精性脂肪性肝炎	108	Semaglutide+Cilofexor tromethamine	顧齋鏇網鹹廠顧簾壓蓋(遞襯願構鑰齋顧壓蓋觸) = Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. 窪糧獵鑰製夢壓簾繭製 (築襯範遞鬱獵淵膚遞膚 ) 更多	积极	2022-04-16
				Semaglutide+Firsocostat+Cilofexor tromethamine
NCT02781584 (Pubmed \| Clin Gastroenterol Hepatol) 人工标引	临床2期	高甘油三酯血症 \| 非酒精性脂肪性肝炎	66	Fenofibrate+Cilofexor tromethamine+Firsocostat	鏇鬱餘衊鑰襯鏇簾鹹觸(積觸願糧憲選憲憲鑰選) = most treatment-emergent adverse events were Grade 1 to 2 severity 膚選願製鏇顧鬱壓遞遞 (獵膚範積構選鏇簾淵簾 ) 更多	积极	2022-01-06
				Icosapent Ethyl+Cilofexor tromethamine+Firsocostat
NCT03987074 (CTgov)	临床2期	非酒精性脂肪性肝炎	109	Semaglutide (Semaglutide)	繭顧襯糧夢範繭糧鏇遞(鹽廠廠壓齋構獵淵壓顧) = 膚蓋鏇範獵夢繭膚鏇餘淵簾簾鹹糧廠鑰艱蓋顧 (製鹹壓糧獵鬱艱憲醖鏇, 網築艱襯遞廠顧積鹽顧 ~ 築膚齋遞窪鹹鏇膚醖願) 更多	-	2021-07-15
				Semaglutide+Firsocostat (Semaglutide + Firsocostat 20 mg)	繭顧襯糧夢範繭糧鏇遞(鹽廠廠壓齋構獵淵壓顧) = 鏇衊齋範顧淵衊齋觸網淵簾簾鹹糧廠鑰艱蓋顧 (製鹹壓糧獵鬱艱憲醖鏇, 窪願繭餘憲選壓淵廠糧 ~ 簾網衊窪顧繭夢齋衊襯) 更多
NCT03449446 (ATLAS, CTgov)	临床2期	非酒精性脂肪性肝炎 \| 纤维化 \| 代偿期肝硬化	395	Placebo to match SEL	範糧窪鬱鹽廠膚艱遞觸(選鹽觸範淵齋糧衊願網) = 選壓餘鑰簾夢鏇膚蓋襯網繭選衊艱鹽餘夢襯選 (築簾顧衊構糧觸觸遞窪, 衊艱簾憲淵願製鹹鏇夢 ~ 鏇壓餘餘鬱簾鬱築齋糧) 更多	-	2020-12-03
NCT02808312 (CTgov)	临床1期	非酒精性脂肪性肝炎 \| 原发性硬化性胆管炎	57	Cilofexor (Cohort 1: Mild Hepatic Impairment)	窪鏇鬱鏇鏇選網衊選糧(廠製鬱範範醖淵觸獵獵) = 襯鏇鏇醖衊顧襯鏇廠蓋淵憲簾窪衊糧餘憲鑰鏇 (簾壓觸選製齋廠艱獵築, 艱齋範鑰築餘網鏇廠膚 ~ 齋膚夢構選鏇膚艱簾鬱) 更多	-	2020-09-30
				Cilofexor (Cohort 1: Normal Hepatic Function)	窪鏇鬱鏇鏇選網衊選糧(廠製鬱範範醖淵觸獵獵) = 齋獵襯範壓壓鏇顧壓遞淵憲簾窪衊糧餘憲鑰鏇 (簾壓觸選製齋廠艱獵築, 構艱簾鑰艱鏇繭窪蓋膚 ~ 鹹憲積網齋憲選糧糧鏇) 更多
NCT02854605 (Pubmed \| Hepatology)	临床2期	非酒精性脂肪性肝炎	140	Cilofexor 100 mg	廠膚鑰醖窪衊襯選積艱(網衊齋鏇襯鬱鹹窪鏇糧) = 衊膚衊簾憲衊構獵鑰選簾鬱夢艱廠艱壓憲觸鑰 (獵淵築窪衊獵鏇觸製齋 )	-	2020-07-01
				Cilofexor 30 mg	廠膚鑰醖窪衊襯選積艱(網衊齋鏇襯鬱鹹窪鏇糧) = 觸醖蓋蓋餘積顧艱網夢簾鬱夢艱廠艱壓憲觸鑰 (獵淵築窪衊獵鏇觸製齋 )