Ursodiol

9月3日，Advanz Pharma宣布欧洲委员会（EC）已撤销奥贝胆酸在欧洲的附条件上市许可。 奥贝胆酸是是20年来唯一获得美国FDA批准用于治疗原发性胆汁性肝硬化的药物，可显著改善对熊去氧胆酸治疗应答不佳或不耐受的原发性胆汁性胆管炎（PBC）患者的生化指标，延缓疾病进展，提高生存率。 奥贝胆酸最早于2016年5月获美国FDA批准上市，于2016年12月获欧盟批准上市。2022年Advanz收购了奥贝胆酸原研药企Intercept在欧洲、加拿大及美国以外大部分子公司和产品权益。 去年10月，欧洲人用药委员会（CHMP）着手重新评估奥贝胆酸的临床风险获益比，最终在审查四期临床数据后得出结论：现有数据无法证实奥贝胆酸临床获益，建议撤市。 对CHMP的建议，Advanz认为：“该分析存在多个局限性”，即当安慰剂组中的患者更换其他疗法时，按照意向治疗（ITT）方法此类患者仍归为安慰剂组。Advanz的首席执行官则表示，“奥贝胆酸不仅是唯一一款用于PBC治疗的FXR激动剂，更是欧洲唯一获批且可用的二线治疗选择。” Advanz在新闻稿中提出抗议，认为CHMP的建议“有失公允”，未能采纳全部可用数据，特别是奥贝胆酸超过7年的临床使用现实世界证据（RWE），这代表了超过47000名患者多年的治疗经验。 虽然当时Advanz反应激烈，辩驳多次，然而，欧洲委员会依旧做了撤销决定。 两天后，事情就有了大反转，9月5日欧盟法院下令暂停执行这一法令。 Advanz 也在新一份声明中表示，该药物“仍可供欧洲各地的新老患者使用”。 本月13日，美国FDA将召开专家咨询委员会讨论由Intercept提交的补充新药申请（sNDA）207999 S-011，讨论临床获益问题。 若美国FDA也认定无法证实奥贝胆酸片临床获益性，那这个产品就真的悬了。 奥贝胆酸片暂无可替代产品，若真撤市，后续影响巨大。 其产品未在国内上市，本来对我们影响不大，但是2021年3月，奥贝胆酸片入选我国第二批鼓励仿制药品目录。目前已有多家企业进行了仿制研究及申报。 奥贝胆酸片按照化药3类申报，进度最快的正大天晴III期临床已完成，已申报上市了。 江苏恒瑞在2020年仅做BE试验申报上市，被驳回，后续正大天晴就着手进行验证性临床，且进行了两次不同目的临床，一次是奥贝胆酸片在胆管炎中的有效性和安全性。 另一次是奥贝胆酸片与熊去氧胆酸联合使用的有效性和安全性。 可以看出正大天晴对此产品势在必得，另外复旦张江也已完成III期临床，杭州民生药业对此产品的III期临床正在进行中。 去年10月，CHMP就给出了撤市建议，当时Advanz提出了强硬反驳，正大天晴也未放弃这个项目，依旧按照进度做了上市申请，并于今年2月被受理。 国内患有原发性胆汁性胆管炎的人群远小于欧美，但也在逐年增长。近年在中国三大终端六大市场胆、肝疾病治疗化药合计销售额均保持200亿元以上，2023年上半年同比增长8.34%。其中院内市场（公立医院终端+公立基层医疗终端）是主要销售渠道。 治疗原发性胆汁性胆管炎（PBC）最为人熟知的有效成分就是熊去氧胆酸了，去年全年熊去氧胆酸制剂年销售额在30亿以上，而根据公开数据可知，2022年奥贝胆酸片全球销售额已达20亿美元。 从熊去氧胆酸制剂销量来看，肝胆类药物市场潜力巨大，竞争也较少，这也许是立项之初企业的考量。 奥贝胆酸片需要进行验证性临床才能上市，正大天晴若能顺利首仿上市，就可以独占市场较长时间，产品可以谈进医保，进国谈等等，前期投入大但收益不会小，正大天晴估计也没想到迎头撞上了这么一件事。 若原研在国外真撤市，国内仿制就必定不通过么？ 也不能这么肯定，国内审批机构会参考国际反馈是肯定的，尤其是CHMP做出撤市建议是基于四期临床数据，也就是说CHMP对近8年的临床数据进行了分析，国内验证性临床最多到III期，样本数据完全不是一个量级，也不知审批机构如何考量。 但也有业内人士表示，这产品都做了验证性临床了，就是已验证过其安全性和有效性了，欧美与我国有人种差异，国内有独立自主认知，正常审核即可。 具体会有怎样的结果，还需要再等等。 投稿/内容沟通：华籍美人（Ww_150525） 近期精华文章

Analysis compares results from confirmatory trial COBALT in PBC with real-world data from a pre-specified external control group utilizing the Komodo Health U.S. claims database Findings include statistically significant and clinically meaningful reduction in death, liver transplant and hepatic decompensation in OCA-treated patients versus comparable non-OCA treated control arm MORRISTOWN, N.J., Sept. 06, 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 the first peer-reviewed publication of “COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls” in The American Journal of Gastroenterology. Importantly, the trial included a pre-specified external control (EC) analysis that found obeticholic acid (OCA) treatment significantly reduced the risk of negative clinical outcomes for people living with primary biliary cholangitis (PBC). “This analysis suggests that treatment with OCA can potentially improve clinical outcomes for patients with PBC and demonstrates the importance of pre-specified external control data in confirmatory trials,” said Dr. Kris V. Kowdley, Director of Liver Institute Northwest and Professor at the Elson S. Floyd College of Medicine, Washington State University. “External control studies are particularly beneficial in clinical trials for rare diseases such as PBC, where patient recruitment and retention are challenging and using a placebo group could be considered unethical.” COBALT is a phase 3b/4 double-blind randomized controlled trial (RCT) with supportive EC analyses designed to examine the association of OCA with clinical outcomes in a high-risk population of patients with PBC, namely those with baseline biomarker levels that are associated with more advanced disease or greater risk for progression. As previously disclosed, the COBALT RCT was terminated early based on the recommendation of an independent data monitoring committee, and in agreement with regulatory authorities, given the inherent challenges of enrolling and maintaining patients in a placebo-controlled study in a rare disease when study drug is commercially available. The RCT analysis showed no statistically significant difference in the primary composite endpoint (time to first occurrence of death, liver transplant or serious liver-related events). The incidence of Treatment Emergent Adverse Events (TEAEs) in the COBALT study was consistent with the known safety profile of OCA. In anticipation of feasibility concerns, the COBALT analysis plan included a pre-specified EC group as a second comparator arm to mitigate the challenges associated with inclusion of a long-term placebo arm in the study and to evaluate the efficacy of OCA vs. a real-world comparator. COBALT + EC assessed the effect of OCA treatment on time to first occurrence of PBC disease progression (hepatic decompensation), liver transplant or death of OCA-treated subjects in COBALT RCT compared to a non-OCA-treated EC group created from the Komodo Health U.S. claims database. Key findings of the COBALT + EC analysis include: A statistically significant and clinically meaningful reduction in death, liver transplant and hepatic decompensation in OCA-treated patients vs. comparable untreated patients17 (10.1%) events occurred in patients in the COBALT OCA arm, and 35.4 (21.5%) events occurred in patients from the weighted non-OCA-treated arm (HR, 0.39; 95% CI, 0.22–0.69; P=0.0010)Patients treated with OCA had an approximately 61% lower relative risk of negative outcomes than the non-treated control patients The EC group, created from Komodo Health claims database, had to meet COBALT inclusion and exclusion criteria and were weighted using propensity score-derived standardized morbidity ratios (SMRs). The EC group was comparable to OCA-treated patients in COBALT on all measured baseline variables. Endpoints in this comparison were the same as in the primary analysis of the COBALT RCT to the extent possible; however certain variables, such as MELD (model for end-stage liver disease), were not available in the Komodo database and thus not included. “Combined clinical trial and real-world data offer important evidence of the potential long-term clinical benefit of treatment with OCA,” said Sangeeta Sawhney, Senior Vice President, Head of U.S. Research and Development, Intercept. “Findings from this study are consistent with other real-world analyses and build on the totality of evidence providing greater insight into the impact of OCA on clinical outcomes in patients living with PBC.” 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 InterceptIntercept 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 www.interceptpharma.com or connect with the Company on LinkedIn, Threads and X (formerly Twitter). 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 www.fda.gov/medwatch. ContactFor more information about Intercept, please contact: For media:media@interceptpharma.com