Bezafibrate

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

Data from two Phase 2 studies in PBC show combination of OCA + bezafibrate achieved biochemical remission (normalization of ALP, total bilirubin, GGT, ALT and AST) in 40-44% of patients in the first 12 weeks OCA 5 or 5-10 mg + bezafibrate 400 mg cohorts in both studies showed a >60% reduction from baseline in serum ALP (primary endpoint) Treatment-emergent adverse events were generally balanced across all cohorts in both studies Data support progression to Phase 3 trials of sustained release formulation of bezafibrate with low doses of OCA Results featured in late-breaking poster presentation on Monday, November 13, during The Liver Meeting® 2023 MORRISTOWN, N.J., Nov. 13, 2023 (GLOBE NEWSWIRE) -- Intercept Pharmaceuticals, Inc., a biopharmaceutical company and wholly owned subsidiary of Alfasigma S.p.A. focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, today announced new data from two Phase 2 studies, including a topline full data analysis (Study 747-213) and an interim analysis (Study 747-214), evaluating the effects of the investigational combination of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA) and peroxisome proliferator-activated receptor (PPAR) agonist, bezafibrate, on multiple key serum biomarkers in primary biliary cholangitis (PBC) that have been shown to predict clinical outcomes. These data will be presented on Monday, November 13, 2023, at the American Association for the Study of Liver Diseases’ (AASLD) The Liver Meeting® in Boston (poster #5019-C). “The results of both Phase 2 studies reinforce our excitement for the combination of OCA-bezafibrate to build on the improved transplant-free survival seen in patients with PBC taking OCA across multiple real-world studies,” said M. Michelle Berrey, M.D., M.P.H., President of Research & Development and Chief Medical Officer of Intercept. “These data support progression to Phase 3 trials of the sustained release formulation of bezafibrate with low doses of OCA, an important step as we continue to prioritize Intercept’s investment in PBC.” Patients with PBC in Study 747-213 were randomized 1:1:1:1 to receive 12 weeks of once-daily oral therapy in addition to ongoing ursodeoxycholic acid (UDCA) treatment (if any) in one of four treatment arms: bezafibrate 200 mg immediate release (B200 IR) (n=19)bezafibrate 400 mg sustained release (B400 SR) (n=19)bezafibrate 200 mg IR + OCA 5 mg titrated to 10 mg at week 4 (OCA5-10/B200 IR) (n=19)bezafibrate 400 mg SR + OCA 5 mg titrated to 10 mg at week 4 (OCA5-10/B400 SR) (n=18) Patients with PBC in Study 747-214 were randomized 1:1:1:1 to receive 12 weeks of once-daily oral therapy in addition to ongoing UDCA treatment (if any) in one of four treatment arms: bezafibrate 100 mg IR (B100 IR) (n=11)bezafibrate 400 mg IR (B400 IR) (n=11)bezafibrate 100 mg IR + OCA 5 mg (OCA5/B100 IR) (n=9)bezafibrate 400 mg IR + OCA 5 mg (OCA5/B400 IR) (n=10) The primary endpoint of both studies is change in alkaline phosphatase (ALP) from baseline to Week 12. The study also assessed percentage change and normalization rates of several serum biomarkers of PBC-induced liver damage, such as alanine transaminase (ALT) and aspartate aminotransferase (AST), as well as markers shown to predict transplant-free survival beyond ALP, including gamma-glutamyl transferase (GGT) and total bilirubin. Safety was assessed by monitoring of adverse events (AEs) and laboratory values. Efficacy Results Study 747-213 OCA5-10/B400 SR showed a −60.6% change in ALP from baseline at week 12 (primary endpoint)At week 12, OCA5-10/B400 SR induced biochemical remission, defined as normalization of ALP, GGT, ALT, AST (all ≤ULN) and total bilirubin (≤0.6xULN), in 44.4% of patients compared to 31.6% in B400 SR, 31.6% in OCA5-10/B200 IR and 15.8% in B200 IR66.7% of patients in the OCA5-10/B400 SR arm achieved normalization of ALP (≤ULN) and 100% achieved TB ≤0.6xULN at week 12Normalization rates of GGT, ALT and AST (≤ULN) for OCA5-10/B400 SR at week 12 were 58.86%, 94.1% and 82.4% respectively Study 747-214 OCA5/B400 IR showed a −65.4% change in ALP from baseline at week 12 (primary endpoint)At week 12, OCA5/B400 IR induced biochemical remission in 40.0% of patients compared to 18.2% in B400 IR, 11.1% in OCA5/B100 IR and 9.1% in B100 IR70.0% of patients in the OCA5/B400 IR arm achieved normalization of ALP (≤ULN) and 90.0% achieved TB ≤0.6xULN at week 12Normalization rates of GGT, ALT and AST (≤ULN) for OCA/B400 IR at week 12 were 40.0%, 100%, and 90.0%, respectively Safety Results The frequency of treatment-emergent adverse events (TEAEs) reported was generally balanced across all arms in both studies. Two severe TEAEs (pruritus [OCA5-10/B400 SR] and hypertension [B200 IR]) occurred in Study 213; the severe TEAE of pruritus led to study discontinuation. One severe TEAE (pruritus, OCA5/B100 IR) occurred in Study 214; no TEAEs led to study discontinuation in Study 214. The rate of new events of pruritus or worsening of baseline pruritus was very low in the OCA5-10/B400 SR arm of Study 747-213 (2/18 patients). Preliminary data from the OCA5/B400 IR arm of Study 747-214 showed a higher rate of new events of pruritus (7/10 patients), likely due to pharmacokinetic differences between the IR formulation of bezafibrate compared to the SR formulation used in Study 747-213. “Results from these studies illustrate the OCA-bezafibrate combination’s potential to deliver biochemical responses across a range of biomarkers that predict improved clinical outcomes in PBC,” said Cynthia Levy, M.D., Hepatologist at the University of Miami Hospital and Professor of Medicine at the University of Miami. “These positive findings, including low rates of pruritus, are an important milestone for the PBC community.” The company is continuing its two ongoing Phase 2 studies (747-213 / NCT04594694, 747-214 / NCT05239468) that are exploring a range of therapeutic doses and formulations for the combination of OCA and bezafibrate. The Company expects to have the necessary data from the OCA-bezafibrate combination program to submit a request in 2023 for an End-of-Phase 2 meeting with the FDA. These data include analyses from both Phase 2 studies, in addition to Phase 1 and preclinical data. Poster Presentation“Combined Effect of Obeticholic Acid and Bezafibrate in Patients with Primary Biliary Cholangitis and Inadequate Response to Or Intolerance of Ursodeoxycholic Acid: Results from Two Phase 2 Clinical Trials” Poster #5019-CMonday, November 13, 1-2 PM ETCynthia Levy, Vaclav Hejda, Alexandre Louvet, Ziad Younes, Manuel Mendizabal, Alan Bonder, Heng Zou, Antonio Civitarese, Alejandra Villamil and Frederik Nevens A full list of sessions at The Liver Meeting® 2023 is available at https://www.aasld.org/the-liver-meeting. About the Investigational OCA-Bezafibrate Fixed-Dose CombinationIntercept, a wholly owned subsidiary of Alfasigma S.p.A., is investigating a fixed-dose combination of OCA and bezafibrate for the potential treatment of individuals with PBC. OCA, a farnesoid X receptor (FXR) agonist, is marketed by Intercept as Ocaliva in the United States for the treatment of PBC (see below for full indication and Important Safety Information). Bezafibrate, a pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, is not approved in the United States for any indication. FXR and PPAR are common and distinct pathways that each play a role in PBC. Simultaneously targeting both pathways may offer the greatest potential to impact bile acid synthesis, metabolism, and clearance that underly cholestatic liver diseases. Published studies establish a clinical proof-of-concept which suggests that the combination of OCA and bezafibrate may provide additive clinical efficacy and tolerability benefits that are unmatched in the treatment of PBC. OCA-bezafibrate combination therapy is investigational; safety and efficacy have not been established. About Primary Biliary CholangitisPrimary biliary cholangitis (PBC) is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent (approximately 1 in 10,000) in women over the age of 40. PBC causes bile acid to build up in the liver, resulting in inflammation and scarring (fibrosis), which, if left untreated, can lead to cirrhosis, a liver transplant, or death. About Ocaliva® (obeticholic acid)OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of adult patients with primary biliary cholangitis (PBC) without cirrhosis orwith compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with 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 in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. IMPORTANT SAFETY INFORMATION WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis.OCALIVA is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension.Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation; have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions while on treatment. Contraindications OCALIVA is contraindicated in patients with: decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation eventcompensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia)complete biliary obstruction Warnings and Precautions Hepatic Decompensation and Failure in PBC Patients with CirrhosisHepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated. Among post-marketing cases reporting it, median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis. Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage. Hepatotoxicity was observed in the OCALIVA clinical trials. A dose-response relationship was observed for the occurrence of hepatic adverse reactions including jaundice, worsening ascites, and primary biliary cholangitis flare with dosages of OCALIVA of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with OCALIVA in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC. Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. If severe intercurrent illness occurs, interrupt treatment with OCALIVA and monitor the patient’s liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting OCALIVA treatment. Severe PruritusSevere pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arm in a 12-month double-blind randomized controlled clinical trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Consider clinical evaluation of patients with new onset or worsening severe pruritus. Management strategies include the addition of bile acid binding resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing. Reduction in HDL-CPatients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high-density lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in OCALIVA-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to OCALIVA after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment. Adverse ReactionsThe most common adverse reactions (≥5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema. Drug Interactions Bile Acid Binding ResinsBile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.WarfarinThe International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA. Monitor INR and adjust the dose of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin.CYP1A2 Substrates with Narrow Therapeutic IndexObeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g., theophylline and tizanidine) is recommended when co-administered with OCALIVA.Inhibitors of Bile Salt Efflux PumpAvoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin. Please click here for Full Prescribing Information, including Boxed WARNING.To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. About InterceptIntercept is a biopharmaceutical company and a wholly owned subsidiary of Alfasigmna S.p.A. focused on the development and commercialization of novel therapeutics to treat rare and serious liver diseases, including primary biliary cholangitis (PBC) and severe alcohol-associated hepatitis (sAH). For more information, please visit www.interceptpharma.com or connect with the Company on LinkedIn, Threads, and X (formerly Twitter). ContactFor more information about Intercept, please contact: For media:media@interceptpharma.com