CYP1A2

2024美国癌症研究协会（AACR）年会将于当地时间4月5日至10日在美国圣地亚哥举行。作为肿瘤领域最受关注的国际学术会议之一，AACR年会聚焦肿瘤早期研究和创新进展，更新发布肿瘤领域前沿的研究成果。日前，AACR官网公布了大会标题，恒瑞医药已有卡瑞利珠单抗、阿帕替尼、SHR-4602等创新药在内的9项抗肿瘤研究成果入围 1-9 。本文特做梳理，一同浏览。 01产品：卡瑞利珠单抗+阿帕替尼 英文标题：Camrelizumab combined with apatinib and hepatic artery infusion chemotherapy (HAIC) as conversion therapy for patients with unresectable hepatocellular carcinoma(HCC): A single-arm exploratory clinical study 中文标题：卡瑞利珠单抗联合阿帕替尼和肝动脉灌注化疗(HAIC)作为不可切除肝细胞癌(HCC)患者的转化治疗：一项单臂探索性临床研究 作者：赵磊等 山东省肿瘤医院 02产品：卡瑞利珠单抗 英文标题：Camrelizumab plus chemotherapy as neoadjuvant treatment for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC): A single-center, randomized, phase II trial 中文标题：卡瑞利珠单抗联合化疗用于可切除局部晚期食管鳞状细胞癌(LA-ESCC)新辅助治疗的单中心、随机、II期试验 作者：沈琳、董晓凤等 北京大学肿瘤医院 03产品：阿帕替尼 英文标题：Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates 中文标题：200mg每日1次给药阿帕替尼对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4底物的药代动力学的影响 作者：S. Jang Elevar Therapeutics, Fort Lee, NJ 04产品：SHR-4602 英文标题：SHR-4602, next generation of HER2-targeting ADC with potent anti-tumor efficacy overcoming the resistance of HER2 ADC with Topo I inhibitor payload in xenograft models 中文标题：SHR-4602：一种具有强大的抗肿瘤疗效的新一代HER2靶向ADC药物，在异种移植模型中克服了Topo I抑制剂负载的HER2 ADC耐药性 作者：田宇楠等 江苏恒瑞医药股份有限公司 05产品：SHR1127 英文题目：Discovery of SHR1127, an orally bioavailable, highly potent and selective KRAS G12D inhibitor 中文题目：SHR1127：一种口服生物利用度高、选择性强的KRAS G12D抑制剂 作者：李心等 江苏恒瑞医药股份有限公司 06产品：HRA00184-C004 英文标题：HRA00184-C004, preclinical characterization of a novel tissue factor-targeted antibody-drug conjugate 中文标题：HRA00184-C004：一种新型组织因子靶向抗体-药物偶联物的临床前表征 作者：应晗笑等 江苏恒瑞医药股份有限公司 07产品：SDP03923-000-9106 英文标题：SDP03923-000-9106, a novel and optimized LIV-1 ADC with superior anti-tumor efficacy in breast cancer xenograft models 中文标题：SDP03923-000-9106：一种在乳腺癌异种移植模型中具有良好的抗肿瘤效果的新型优化LIV-1 ADC药物 作者：龚彦玲等 江苏恒瑞医药股份有限公司 08产品：HRA00242-C004 英文标题：HRA00242-C004, a novel anti-PSMA ADC with high DAR reveals potent in vitro and in vivo anti-tumor efficacy 中文标题：HRA00242-C004：一种在体外和体内均显示出强大的抗肿瘤作用的具有高DAR的新型抗PSMA ADC药物 作者：林广等 江苏恒瑞医药股份有限公司 09产品：HRA00130-C004 英文标题：HRA00130-C004, a novel anti-DLL3 ADC with bystander effect, high DAR and favorable safety profiles 中文标题：HRA00130-C004：一种具有旁观者效应、高DAR和良好安全性的新型抗DLL3 ADC药物 作者：姚青青等 江苏恒瑞医药股份有限公司 作为中国医药创新代表性企业，恒瑞医药多年来针对高发肿瘤领域持续开展科研攻关。公司累计研发投入近400亿元，已获批上市16款创新药，其中抗肿瘤创新药占比过半，另有80多个自主创新产品正在临床开发，270多项临床试验在国内外开展。未来，恒瑞医药将继续坚持“以患者为中心”的理念，努力研发出更多的新药好药，服务健康中国、造福全球患者。 参考文献： 1.https://www.abstractsonline.com/pp8/#!/20272/presentation/6657 2.https://www.abstractsonline.com/pp8/#!/20272/presentation/11544 3.https://www.abstractsonline.com/pp8/#!/20272/presentation/11498 4.https://www.abstractsonline.com/pp8/#!/20272/presentation/6304 5.https://www.abstractsonline.com/pp8/#!/20272/presentation/8988 6.https://www.abstractsonline.com/pp8/#!/20272/presentation/62857.https://www.abstractsonline.com/pp8/#!/20272/presentation/6839 8.https://www.abstractsonline.com/pp8/#!/20272/presentation/7655 9.https://www.abstractsonline.com/pp8/#!/20272/presentation/7656 声明： 1. 本新闻旨在分享研发前沿资讯，仅供医疗卫生专业人士基于学术目的参阅，非广告用途。 2. 恒瑞医药不推荐任何药品、适应症的使用。

sNDA intended to satisfy post-marketing requirements to confirm a clinical benefit in patients with PBC Precedent-setting submission includes data from post-marketing studies COBALT and Study 401 as well as real-world evidence from a claims database and patient registries FDA has assigned a PDUFA target action date of October 15, 2024 MORRISTOWN, N.J., Feb. 29, 2024 (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 that the U.S. Food and Drug Administration (FDA) has accepted its supplemental New Drug Application (sNDA) for Ocaliva for the treatment of individuals with primary biliary cholangitis (PBC). The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of October 15, 2024. In this communication, the agency informed Intercept that they are planning to hold an Advisory Committee meeting to discuss the application. “The sNDA data submission asserted that, with more than seven years on the market and more than 40,000 patient-years of post-marketing experience in PBC, Ocaliva is the only second-line therapy that has multiple published analyses of registry data and real-world evidence showing significant effect on transplant-free and decompensation-free survival in people living with PBC,” said Paul Nitschmann, M.D., Senior Vice President of Regulatory Affairs at Intercept. “We are pleased that the FDA has filed the submission and look forward to continued, constructive interactions with the agency, including discussing our precedent-setting application during the forthcoming Advisory Committee meeting.” Ocaliva received accelerated approval in 2016 and is indicated for the treatment of adult patients living with primary biliary cholangitis (PBC) without cirrhosis or with 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. The precedent-setting sNDA for Ocaliva is intended to satisfy the post-marketing requirements to confirm a clinical benefit in patients with PBC. The sNDA is supported by data from the Company’s post-marketing requirement studies COBALT and Study 401 as well as real-world evidence from a U.S. claims database and international PBC patient registries. Intercept and Alfasigma remain committed to supporting people living with PBC and look forward to advancing discussions with the agency. About Primary Biliary Cholangitis Primary 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 or with 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 event compensated 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 Cirrhosis Hepatic 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 Pruritus Severe 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-C Patients 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 Reactions The 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 Resins Bile 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. Warfarin The 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 Index Obeticholic 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 Pump Avoid 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 . About Intercept Intercept is a biopharmaceutical company and a wholly owned subsidiary of Alfasigma 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). Intercept owns the commercial rights to Ocaliva in the U.S. market. For more information, please visit or connect with the Company on LinkedIn, Threads, and X (formerly Twitter). Contact For more information about Intercept, please contact: For media: media@interceptpharma.com

引言肝损伤常以分区方式发生。然而，在细胞和分子水平上对这种区域性损伤的详细再生反应仍然难以捉摸。2024年2月22日，清华大学王韫芳及古槿共同通讯在Cell Stem Cell 在线发表题为“Region-specific cellular and molecular basis of liver regeneration after acute pericentral injury”的研究论文，该研究通过使用命运定位菌株Cyp2e1-DreER来阐明急性中央周围损伤后的肝脏再生，发现中央周围再生主要通过剩余的中央周围肝细胞的扩张来补偿，其次是门周肝细胞的扩张。肝脏是最具再生能力的实体器官，在维持哺乳动物生理稳态方面发挥着多种重要功能。组织学上，肝脏由重复的结构和功能单位组成，称为肝小叶。每个小叶都有一个六边形的排列，在中间有一个中央静脉，在每个六角都有一个门静脉。在功能上，有代谢梯度沿着门户-中心轴，反映了一种被称为代谢带的战略分工。根据功能梯度，肝小叶大致分为两个主要的互补区域：门静脉周围区(PP)和中心周围区(PC)，或进一步划分为三个区(1区、2区和3区)，或细化为9个分区层。由于这些功能区室的存在，肝脏病变经常表现出特定区域的模式，损伤最常发生在PP区或PC区。鉴于与PC区相关的病理，如药物性和酒精性肝损伤、脂肪性肝病、肝细胞癌、肝期疟疾等的临床意义，了解PC区特异性损伤后再生的机制至关重要。现在人们普遍认为，肝细胞补充的主要细胞机制是通过先前存在的肝细胞的复制介导的。然而，如前所述，肝小叶内的肝细胞是异质的，具有特定位置的代谢功能，确定PC损伤后新再生肝细胞的来源是一个积极研究的领域。一项早期命运定位研究显示，在肝脏稳态过程中，Axin2+ PC肝细胞是新肝细胞的重要细胞来源。然而，这一发现并未得到后续谱系追踪研究的证实。采用基于特定PP标记的谱系追踪策略，结果表明Sox9+和人含主要协助转运蛋白超家族域蛋白2A (Mfsd2a)+ PP的促进剂超家族结构域在急性PC损伤后肝细胞有轻微的扩张，并且没有从PP区延伸到受损的PC区，表明它们对修复的PC区贡献有限。模式图（Credit: Cell Stem Cell）最近的一份报告显示，通过14个小鼠命运定位菌株对不同区域进行谱系追踪显示，在慢性PC损伤后，不同的PC肝细胞被Gs、Cyp1a2、Oat或Axin2标记，几乎完全消失，PP或中间区域的剩余肝细胞再生整个肝小叶。此外，其他组的研究表明，急性PC损伤后，Axin2+或Lgr5+ PC肝细胞也几乎消失，分别由Axin2-或Lgr5-剩余肝细胞补充。值得注意的是，一项基于追踪Axin2+ PC肝细胞的研究发现，在急性PC损伤后肝脏再生过程中，增殖在所有区域的剩余肝细胞中均匀分布。然而，利用随机谱系追踪对肝细胞扩增进行克隆分析发现，增殖能力主要集中在靠近损伤区域的剩余肝细胞(损伤周围肝细胞)中，而较少分布在远离损伤区域的剩余肝细胞中。该研究开发了一个与PC区相关性肝病密切相关的遗传系统，并通过特异性标记Cyp2e1+ PC肝细胞，实现了急性PC损伤后损伤区附近残留肝细胞的细胞形态追踪。通过单细胞RNA测序、空间转录组学、免疫染色和体内功能分析，研究人员证明肝细胞中mTOR/4E-BP1轴和乳酸脱氢酶A的上调表达有助于中心周围再生，而在受损区域激活转化生长因子β (TGF-β1)信号传导介导纤维化反应并抑制肝细胞增殖。通过基于Arg-Gly-Asp (RGD)肽的策略抑制单核细胞和单核细胞源性巨噬细胞的中央周围积聚，可减弱这些细胞源性TGF-β1信号，从而改善中央周围再生。该研究为中心周围再生的细胞和分子基础提供了综合的、高分辨率的时空见解。原文链接https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00043-2责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈