Intercept Pharmaceuticals, Inc.

上市8年老药—Ocaliva面临被退市的风险。 近日，FDA拒绝将Intercept公司的Ocaliva转化为完全批准，用以治疗原发性胆汁性肝硬化（PBC）。 按照近几年FDA对加速批准的收紧力度，Ocaliva不能验证临床获益转化为完全批准，最有可能的结局就是最终退出市场，终止其销售生涯。 安全隐患未解 Ocaliva是20年来首个获批治疗PBC的药物，Intercept公司开发的一种强力的特异性法尼醇X受体（FXR）激动剂，2016年5月被FDA有条件加速批准，作为原发性胆汁性肝硬化（PBC）的二线治疗。2016年12月12日在欧盟批准上市。 然而获批以来，Ocaliva始终被安全性问题（肝损伤、严重瘙痒症）困扰，不仅因此拓展新适应症NASH失败，在PBC中如今也地位难保，面临被退市的风险。 在Ocaliva获批上市的一年多时间内，FDA不良事件报告系统已经收到Ocaliva药物相关的19例死亡报告和11例严重肝损伤报告。 虽然难以评估奥贝胆酸治疗PBC的风险，但FDA在2018年初在奥贝胆酸的说明书中还是加上了黑框警告，要求该公司突出奥贝胆酸正确用量，其中强调了在中度和重度肝损害的患者中，奥贝胆酸会有肝失代偿及肝衰竭的风险。 作为一种核受体，FXR能够调节身体中多种器官的功能，激活多种基因的表达。这意味着FXR激动剂在治疗患者的同时，也会对身体其它器官产生副作用。 在正式拒绝完全批准之前，FDA在召开专家咨询委员会前发布了一份简报文件中表示了对Ocaliva在其PBC中的有效性和安全性的质疑。 在这份简报文件中，FDA对两个临床研究747-302和747-405提出了批评。FDA指出，747-302试验未能证明Ocaliva对PBC统计学上显著的益处，反而增加了患者肝脏移植或死亡的风险。而对于747-405，该项临床试验没有达到充分且控制良好的监管标准。 不意外，最终Ocaliva的完全批准得到专家组成员的反对意见。 算盘打错了 在MASH的出局让Intercept的身价大跌，停止所有NASH相关项目，并进行了三分之一的裁员。 但是PBC这个被批准适应症还是让Alfasigma公司认为有利可图。 2023年9月，Alfasigma以19美元/股（总价约8亿美元）价格成功收购Intercept，溢价约82%（相较于Intercept前一天股价）。 对此笔并购交易，几位华尔街投行分析师认为Intercept“卖得不亏”，对于投资者而言是一个巨大回报。收购消息披露后，Intercept的股价飙升近80%。 即便Ocaliva在NASH中失败，但在Alfasigma有自己的计算，虽然Ocaliva在PBC的销售额远远不及当初的预期，但是基本可以稳定在2亿美元以上，用个3-5年，Alfasigma就有望收回成本。 然而，安全性始终是个隐雷，加上已经有两款PBC药物(吉利德的Livdelzi和Ipsen的Iqirvo)获得FDA批准，Ocaliva已经不是唯一的选择，考虑到的收益/风险，FDA最终很可能让Ocaliva退出市场，Alfasigma也收不回本。 事实上，此前Ocaliva在欧洲经历了撤市风波，2024年9月3日，欧洲委员会做出了撤销Ocaliva在欧洲的附条件上市许可的决定，原因是在对该药进行重新评估后，认为其风险大过收益。不过之后欧盟普通法院毅然下令暂停执行欧洲委员会的这一决定。 FDA的拒绝完全批准的监管态度很可能也影响到欧洲委员会的决定，欧洲委员会本来也对该药产生质疑。 在欧洲受到监管质疑这对于另一家药企Advanz显然不是个好消息，在2022年，Advanz以4.05亿美元首付款收购了Intercept在欧洲、加拿大及美国以外大部分子公司和产品权益，其中就包括Ocaliva。 这些都让Ocaliva未来的命运看起来不容乐观，目前Ocaliva还面临着仿制药的市场竞争，在美国、加拿大等国家已有奥贝胆酸仿制药的上市，国内也有众多仿制药在研发或申报中，正大天晴、复旦张江均已经递交了奥贝胆酸片的上市申请，并获得CDE受理。 参考出处 再遭暴击，Intercept奥贝胆酸治疗PBC又陷肝病风险质疑 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

The U.S. Food and Drug Administration (FDA) made an important decision on Tuesday, denying full approval of Intercept Pharmaceuticals' liver disease drug. The decision raises questions about the drug's future market prospects. Still, Intercept Pharmaceuticals said that despite the FDA's denial of full approval, their drug Ocaliva will continue to receive accelerated approval in the United States. Under the accelerated approval pathway, the FDA requires additional trials to verify a drug's benefits. If data from these trials do not prove a drug's effectiveness, regulators can require companies to withdraw the drug from the market. Ocaliva received accelerated FDA approval in 2016 to treat patients with primary cholangitis. Primary cholangitis is a rare disease that causes inflammation of the small bile ducts in the liver and eventually destroys them. Because of the rarity of the disease, recruiting patients for confirmatory trials has become very difficult. According to the American Liver Foundation, fewer than 200,000 cases of primary cholangitis are recorded in the United States each year. Intercept Pharmaceuticals said it will continue to submit safety data on the drug to health regulators. The FDA's decision is in line with recommendations made by an independent panel of experts in September. The panel said the available data did not definitively prove the drug's effectiveness or dispel doubts about its safety. "I think the future of this drug is now very much up to the applicants and potential patients who will participate in the new trial," Julia Wattacheril, an assistant professor at Columbia University's Wagelow Snake School of Surgery, said before the FDA decision. She also added that it is unclear whether there is the will to devote more resources to gathering further data on the drug. Ocaliva and ursodecylcholic acid were among the first treatments. Since then, several other drugs, including Gileads Livdeizi, have been made available to patients. In June, the European drug regulator revoked Ocaliva's conditional authorization, saying its efficacy had not been proven.

The FDA decision comes in the wake of a negative AdCom opinion in September. Image credit: Shutterstock/ Dilok Klaisataporn. On the heels of an unfavourable advisory committee (AdCom) meeting, the US Food and Drug Administration (FDA) has decided not to approve Intercept Pharmaceutical’s Ocaliva (obeticholic acid) for primary biliary cholangitis (PBC). The agency issuing a complete response letter means the US pharma company’s bid to turn Ocaliva’s accelerated approval into full approval has come up short. The drug will continue to be available for patients with the liver disease in the US under the accelerated approval granted in 2016, as per a 12 November press release. The FDA said it was “unable to approve the supplemental new drug application (sNDA) in its current form”, which tallies with the opinion formed at the Gastrointestinal Drugs AdCom (GIDAC) meeting held in September 2024. During the discussion, 13 panel members did not believe Intercept’s data adequately proved Ocaliva’s clinical benefit, whilst just one panellist voted in favour of the drug. In a second separate vote, 10 experts said the drug’s benefits did not outweigh its risks. One panellist voted that the therapy’s benefits did outweigh its risks while three panellists abstained. In its letter to Intercept, the FDA also said it was continuing to consider data from a post-marketing study called 747-302 (NCT02308111), in addition to other safety information. Ocaliva comes with a boxed warning of heightened risk of liver decompensation or failure if patients are dosed incorrectly. Intercept’s US president Vivek Devaraj said: “We believe in the totality of evidence supporting Ocaliva and intend to work closely with the FDA on next steps.” Ocaliva has suffered a rocky regulatory road in both the US and Europe. The FDA rejected Ocaliva’s use in nonalcoholic steatohepatitis (NASH) in June last year, a blow which forced Intercept to cut its workforce by a third. The company was then kept waiting on an FDA decision in PBC this year after the agency asked for more time to consider full approval, delaying the Prescription Drug User Fee Act (PDUFA) date that was originally set for 15 October. In the same month as the negative AdCom meeting, the European Commission (EC) withdrew Ocaliva’s conditional marketing authorisation as a second-line treatment for patients with PBC. The EC made its decision following the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use, which reassessed the benefit-risk profile of the drug. In a surprise decision just days later, the President of the General Court of the European Union overruled the decision, allowing Ocaliva to remain on the market. PBC, which disproportionally affects women, is a type of liver disease characterised by inflamed bile ducts which are progressively destroyed due to the build-up of bile. Ocaliva targets the farnesoid X receptor (FXR) to reduce bile acid production and promote its removal. Ocaliva’s scrutiny comes at a time of a new arrival in the PBC space. The FDA granted accelerated approval to Gilead’s Livdelzi (seladelpar) in August this year, a drug Gilead acquired from CymaBay Therapeutics in a $4.3bn dea l. Livdelzi is forecast to generate $558m in 2030, according to GlobalData’s Pharma Intelligence Centre. GlobalData is the parent company of Pharmaceutical Technology . Intercept has been operating as a subsidiary of Italy-based Alfasigma following a $794m acquisition in September 2023. Before coming under the Alfasigma umbrella, Ocaliva earned $285.7m in 2022.