Aprocitentan

大会由扬州市人民政府主办，同写意专业策划，以“打造生物医药新质生产力”为主题，邀请众多行业领袖和先锋人物一起取势明道，就如何打造中国医药新质生产力，面向未来创新药如何立项，资本寒冬下的创新药BD与出海，GLP-1&小核酸药物以及抗体药的质量与生产四大主题展开深度研讨，为行业发展提供方向性指引。2017年初，随着强生以300亿美元的天价完成对Actelion公司的收购，作为一家成立于1997年专注于罕见病领域开发，尤其在肺动脉高压（PAH）领域的明星Biotech企业，在那一刻也完成了华丽退场，伴随着被收购，强生也顺理成章的将Actelion旗下一众管线产品收入囊中，其中也包括了后期成为PAH领域重磅炸弹的Opsumit（马昔腾坦）以及Uptravi（司来帕格）。彼时，Actelion的故事结束了，而Idorsia的故事却就此拉开了序幕。在Actelion被收购的同时，Actelion的CEO及联合创始人Jean-Paul Clozel 宣布亲自挂帅将Idorsia分拆出来，并成立一家独立运营的新公司，不仅将Actelion约六七百人的早研团队全盘带出，还手握了Daridorexant、Aprocitentan等多款FIC品种，并趁热打铁将Idorsia推向资本市场，于是在当年7月Idorsia正式登录瑞士证券交易所，几小时内股价便大涨30%。成立元年，随着Idorsia将Aprocitentan全球商业化权益以2.3亿美元（一次性付款）以及后期潜在的特权使用费的价格交给强生以及旗下Daridorexant、Aprocitentan、Clazosentan等多款品种将进入III期临床，这家只成立了一年的年轻公司看似拥有了极其光明的未来。接连在对外BD以及核心产品取得重大进展，Idorsia的股价也随之水涨船高，并在2020年达到了顶峰，达到了33.88 CHF（瑞士法郎/每股）。图1：Idorsia股价变化（参考自Idorsia官网）继承了Actelion很大一部分人才以及产品的Idorsia其实并不能算一家典型的Biotech公司，和众多初创Biotech相比，Idorsia无疑是幸运的，若按照正常的故事发展逻辑，在接下来几年中Idorsia将会在管线中持续迎来收获期并继续迎来跃迁。但令人大跌眼镜的是，在达到股价巅峰的之后短短几年时间，Idorsia在资本市场上迅速陨落，在今年一月股价仅仅剩下1.29CHF（瑞士法郎/每股），股价缩水96%，账面现金也岌岌可危。仅仅过去了四年时间，Idorsia便从顶峰跌落谷底。而翻过这四年的历史，除了时运不济，作为一家非典型Biotech公司，Idorsia却遇到了几乎每个Biotech都会面临的问题，如何推进管线，如何分配资源，如何做好产品商业化，Idorsia交出的答卷都很糟糕，几乎所有的坑都被它踩了一遍。1临床策略激进时来天地皆用力，在2021年前，Idorsia绝对可以算得上是春风得意，除了管线进展顺利，在资本市场也是一路高歌，也让其现金流状况十分充裕，但令人遗憾的是，Idorsia在临床试验上实在是气运不佳，接连遭遇厄运。2021年，Idorsia针对罕见病法布里病的在研药物Lucerastat在临床III期MODIFY试验中遭遇失败，未能达到试验的主要临床终点。Lucerastat是一种小分子葡萄糖神经酰胺合酶抑制剂，在临床III期试验中证明了Lucerastat观察到血浆Gb3持续大幅降低，具有良好的耐受性，并证实了Lucerastat的药理活性。然而患者经过六个月的治疗后，并未观察到其减轻了患者的神经性疼痛。但Idorsia骨子里透露着倔强，其对Lucerastat迅速开展了另外一项开放标签III期临床试验（Open-Label Trial），该试验将经历过107名经历过MODIFY试验的受试者继续纳入开放标签研究，并进一步评估其对成年法布里病患者肾功能和心脏功能的临床影响，这也使得临床试验额外延长了48个月，至少要等到2025年底才能结束该试验。同年11月，Idorsia另一款S1P1受体调节剂Cenerimod用于治疗系统性红斑狼疮（SLE）的临床IIb期CARE试验也未能达到主要终点。在CARE试验试验中，除了最高剂量为4mg，六个月时，受试组显示主要终点mSLEDAI-2K评分与安慰剂相比有数值改善，其他剂量均折戟沉沙。但Idorsia仍然对Cenerimod充满信心，于是便毅然决然选择继续推进这一管线的临床III期试验，OPUS临床试验于2022年底正式启动，计划纳入840名患者。临床的开发本就充满风险和不确定性，如果说Cenerimod以及Lucerastat的临床失败代表着Idorsia对未成药产品的不甘发起命运的抗争，那么Clazosentan的失败则又给了Idorsia重重一击。和Opsumit（马昔腾坦）一样，Clazosentan也是一款ETA（内皮素A受体）拮抗剂，Clazosentan的临床开发之路同样充满艰辛，其于1998年便开始开启颅内血管痉挛I期临床开发，Actelion在2010年9月公布II期临床CONSCIOUS-2未达预期后，结束已开展的III期临床CONSCIOUS-3，再加上化合物、晶型等核心专利已经到期，在综合考虑之下强生便没有拿下这一品种，反而是Idorsia一直在继续坚持。终于在2022年4月，Clzosentan（商品名为Pivlaz）在日本获批上市，用于预防动脉瘤性蛛网膜下腔出血（aSAH）固定后的脑血管痉挛、血管痉挛相关的脑梗塞和脑缺血症状。然而，令人大跌眼镜的是，今年2月5日，Idorsia宣布在美国、加拿大和欧洲进行的REACT III期临床研究失败，Clzosentan无法预防动脉瘤性蛛网膜下腔出血患者的临床恶化，故其在欧美获批时间将遥遥无期。也就是说，在短短三年时间内，Idorsia接连在临床上遭受“花式死法”，但尽管如此，Idorsia似乎陷入了牛角尖中，仍旧选择向前推进，如此激进的临床开发策略，也将直接给Idorsia的目前已不乐观的财务状况带来更大压力。2商业化困境难解Idorsia能够在上述几款品种前期临床失败的情况下仍如此激进向前，在很大程度上也是对自己已上市品种的信心，但和几乎所有的Biotech都会面临的问题一样，Idorsia似乎对商业化难题也是束手无策。除了上文中已经提到在日本获批的Clazosentan外，目前Idorsia的另外一款品种Daridorexant已经走过了近两年的商业化时间——2022年1月，Daridorexant在美国获批上市，用于治疗成人失眠症，随后在德国、意大利、西班牙、英国等国家相继获批上市。作为全球范围内第三款获批上市的双重食欲素受体（orexin receptor）拮抗剂，同默沙东的Suvorexant和卫材的Lemborexnat相比，临床研究显示Daridorexant的成瘾性更低，在临床上具备一定安全性优势。数据显示，目前美国约有2500万失眠患者，2022年美国失眠药物市场规模（不含中药）已经达到8.6亿美元，失眠症治疗药物也已进入以食欲素抑制剂为代表的第四代失眠药物，预计到2025年市场规模可达到10.2亿美元，2030年将达到13.4亿美元，和苯二氮䓬受体激动剂等药物相比，Daridorexant目前并没有发现依赖性、反跳性失眠以及戒断症状，可即便如此，Daridorexant也并没有将临床优势转化为市场优势。根据该Idorsia 2022年全年财报显示，Daridorexant自2022年5月在美国销售以来，当年总净销售额仅仅为650万瑞士法郎，进入到2023年以来Daridorexant的增长仍旧处于疲软状态，在目前Idorsia已经公布的前三季度数据来看，Daridorexant也仅为2020万瑞士法郎，远远低于市场预期，显然这一份答卷是不及格的。与此同时，Clazosentan的商业化在受到临床失败带来的负面影响后直接跌落谷底，在2023的第三季度销售额仅仅只有130万瑞士法郎，基本宣布了Clazosentan的商业化死刑，在目前Idorsia公布的管线中，也已经不见了Clazosentan的身影。图2：2023年前三季度Idorsia产品净销售额（单位：百万瑞士法郎）随着近期Aprocitentan获得FDA批准上市用于治疗难治性高血压，Idorsia在产品商业化上的解题思路，必须马上给出答案，尽管Aprocitentan是高血压领域30多年来首个获批的创新机制产品，但还是在获批前惨遭强生退货，只能由Idorsia重新获得其商业化权益，而这显然不是Idorsia所擅长做的，强生退货的原因很难得知，但在获批前这个时间段退货显得有些耐人寻味，Aprocitentan的商业化之路，更难以乐观。要知道仅仅是Aprocitentan的III期临床就纳入了整整730例患者，而众所周知心血管药物临床试验的费用一般是其他药物的六倍，花了如此大的代价，若是再做不好商业化，对投资者而言，更是不好交代。3沉舟侧畔千帆过全球医药资本严冬之际，连Big pharma都无法独善其身，更何况在临床以及商业化上问题不断的Idorsia，自然更难受到资本市场青睐，缺少资本输血也成为Idorsia的财务状况举步维艰的重要原因之一，2020年底其账面上还有12亿瑞士法郎，短短两年半时间内账面就只剩下3300万了。图3：Idorsia公司现金流变化趋势（2019-2023H1，参考企业年报数据）比起早年间的大手大脚，如今现金流稀缺，也让Idorsia不得不重新思考，作为一家Biotech公司，该如何合理利用资源，平衡资本市场、研发以及产品商业化之间的连接关系。“断臂求生”在近几年已经成为了圈内的高频词汇，尤其是对于Biotech而言，而现如今Idorsia也不得不选择这条路，减少研发投资，最大限度延长公司产品取得商业化成功的时间，也正是出于这一考虑，该公司提出成本削减计划，第一步便是削减近500个研发和支持职能部门职位，就目前来看，Idorsia已经完成员工精简，在最新的公司介绍中显示员工已经削减到了800人左右，裁员比例将近 40%。与此同时，Idorsia也在精简业务，并成功的将亚太地区（中国除外）的运营业务出售给日本生物制药公司Sosei Heptares，交易总价约为4亿瑞士法郎。在对外BD上其实国内对Idorsia也并不陌生，早在2022年，先声药业便以3000万美元首付款拿下了Daridorexant在大中华地区的开发及商业化的独家权利。而在今年，Idorsia宣布与Viatris（晖致）达成合作，双方就Selatogrel与Cenerimod达成授权合作，Viatris将获得两款产品的全球化权益（仅Cenerimod不包括日本、韩国和亚太地区的某些国家），Idorsia获得潜在3.5亿美元的交易总额，但同时Idorsia要在未来3年内提供高达2亿美元的资金，并将两个项目的相关人员打包给到晖致，此外双方需要共同承担研发成本。图4：Idorsia管线对外BD情况（参考自官网）自此，Idorsia管线中除了正在做III期临床的Lucerastat以及刚被退货的Aprocitentan，其他进展较快的品种以不同方式均完成了BD合作，也在一定程度上稍微缓解了Idorsia资金压力，让其可以集中资源去攻克Aprocitentan和Daridorexant的商业化难题。和绝大部分Biotech的初始艰难创业相比，Idorsia无疑是幸运的，人才、资金以及创新产品对于Idorsia全都不费吹灰之力，可胜利并不像山坡上的蒲公英一样唾手可得，就是这样一家非典型的Biotech，在迈向研发生产以及商业化的三座大山之时，也倒在了向上的最后一公里，。沉舟侧畔千帆过，无论是对于交了足够多学费正准备触底反弹的Idorsia，还是对于正处于攀爬探索阶段的Biotech们来说，情况都不会比现在更坏了。但，留给它们的时间，还多吗？参考文献：（上下滑动查看更多）1.US FDA approves Idorsia’s once-daily TRYVIO (aprocitentan) – the first and only endothelin receptor antagonist for the treatment of high blood pressure not adequately controlled in combination with other antihypertensives2.Ufer M., Kelsh D., Schoedel K.A., Dingemanse J. Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem. Sleep. 2022;45:zsab224. doi: 10.1093/sleep/zsab224.3.Idorsia initiates OPUS a Phase 3 program to investigate cenerimod for the treatment of patients with systemic lupus erythematosus4.Idorsia to advance cenerimod into Phase 3 development for treatment of patients with systemic lupus erythematosus5.Improving Cardiovascular Drug and Device Development and Evidence Through Patient-Centered Research and Clinical Trials，Circulation: Cardiovascular Quality and Outcomes. 2020;13:e0066066.药时代：从强生出走的Biotech做不好商业化，Biotech夹缝求生实录。更多优质内容，欢迎关注↓↓↓

An Akebia Therapeutics drug for a type of anemia has won FDA approval, a regulatory decision that comes nearly two years after the agency rejected the drug due to safety concerns. Safety remains a concern about the small molecule, vadadustat. The drug’s label carries a black box warning about an increased risk of death from a variety of cardiovascular complications. But the Akebia product, which will be branded as Vafseo, now introduces a new treatment option for the estimated 500,000 adults in the U.S who suffer from anemia due to chronic kidney disease (CKD). To use this drug, patients must have been receiving dialysis for at least three months. Anemia develops when there aren’t enough healthy red blood cells to carry oxygen to tissues in the body. It’s common in chronic kidney disease patients because their kidneys do not produce enough erythropoietin, a hormone that helps regulate red blood cell production. This anemia can be treated with erythropoietin-stimulating agents, engineered versions of the hormone administered as chronic injections. Akebia’s Vafseo offers more convenient oral dosing. This drug belongs to a class of drugs called hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors. By mimicking the effects of high altitude on the body, these drugs get the body to produce erythropoietin. When the FDA rejected this drug in 2022, it flagged cardiovascular risks and asked Akebia to run another clinical trial. Instead, the company resubmitted an application with additional post-marketing safety data from Japan, where the drug has been used since its approval there in 2020. Vafseo will compete against GSK’s Jesduvroq, which last year became the first FDA-approved oral medication for anemia caused by CKD. Jesduvroq is limited to patients who have been on dialysis for at least four months. Similar to Akebia’s drug, Jesduvroq’s label carries a black box warning for cardiovascular risks. Akebia said it will commercialize Vafseo in the U.S. with its established commercial team, which has renal experience and a relationship with CSL Vifor, the kidney disease-focused company that is the product of CSL Limited’s 2021 acquisition of Vifor Pharma. Here’s a recap of other recent regulatory news: —Winrevair, the pulmonary arterial hypertension (PAH) drug that was the centerpiece of an $11.3 billion Merck acquisition, won FDA approval. The PAH drugs already available treat symptoms. Winrevair is the first drug that addresses an underlying cause of this disorder affecting heart and lung function. —In other PAH news, the FDA approved Johnson & Johnson’s Opsynvi. This drug combines two older PAH drugs, macitentan and taladifil. Macitentan blocks the endothelin receptor while taladifil is a phosphodiesterase 5 inhibitor. Addressing both pathways requires patients to take multiple pills. Opsynvi is the first drug that combines both mechanisms in a single once-daily pill. —AstraZeneca’s drug Ultomiris added neuromyelitis optica spectrum disorder (NMOSD) as a new indication for the blockbuster drug. NMOSD is an autoimmune disease affecting the central nervous system, including the spine and optic nerves. Ultomiris blocks C5, a protein of the complement system, a part of the immune system. The drug has approvals for treating several other rare, complement system disorders. —Metabolic dysfunction-associated steatohepatitis (MASH), a fatty liver disease that affects as many as 7 million Americans, now has its first approved drug. The FDA gave the green light to Rezdiffra, a Madrigal Pharmaceuticals’ medication that posted clinical trial results showing it can reverse the liver scarring that is characteristic of the disorder. Madrigal’s once-daily pill carries an annual wholesale price of $47,400. —An Italfarmaco drug for Duchenne muscular dystrophy won FDA approval for treating all patients who have the inherited muscle-wasting disorder, regardless of the genetic variant driving their disease. Corticosteroids are a standard first-line therapy for Duchenne. The Italfarmaco drug, Duvyzat, is the first nonsteroidal therapy approved for the disease. —Orchard Therapeutics gene therapy Lenmeldy is now the first FDA-approved treatment for metachromatic leukodystrophy (MLD), a rare enzyme deficiency. Lenmeldy is made by modifying a patient’s hematopoietic stem cells to carry a functional gene that codes for the deficient enzyme. Orchard is now part of Japanese drugmaker Kyowa Kirin following a $387 million acquisition announced last year. —Regeneron Pharmaceuticals’ drug odronextamab was turned down by the FDA for two indications: follicular lymphoma and diffuse large B-cell lymphoma. According to Regeneron, the agency did not flag any safety, efficacy, or manufacturing issues for the bispecific antibody. The FDA told Regeneron it cannot resubmit applications until confirmatory studies are underway and completion timelines are agreed upon. Regeneron said it will share updates on enrollment and regulatory timelines later this year. The drug is still under regulatory review in Europe. —The FDA awarded full approval to AbbVie ovarian cancer drug Elahere. The antibody drug conjugate developed by ImmunoGen won accelerated approval in 2022. AbbVie acquired ImmunoGen last year in a $10.1 billion deal. —Invivyd antibody drug Pemgarda was granted emergency use authorization for prevention of Covid-19 in adults and adolescents with moderate-to-severe compromised immune systems. Other Covid-19 antibody drugs have had their authorizations revoked as they proved ineffective against new variants. Pemgarda comes from an Invivyd platform technology designed to address rapid viral evolution. —Idorsia Pharmaceuticals’ aprocitentan, brand name Tryviao, received FDA approval for treating hypertension when used in combination with other antihypertension drugs. The once-daily pill is designed to block the endothelin receptor. It’s the first approved high blood pressure drug with this mechanism of action. —Takeda Pharmaceutical drug Iclusig is now FDA approved for treating Philadelphia chromosome-positive acute lymphoblastic leukemia when used in combination with chemotherapy. The once-daily pill works by blocking enzymes associated with cancer growth. The accelerated approval adds to the list of indications for the drug, which is used to treat three types of leukemia. —The European Commission granted marketing authorization to Prevnar 20 for preventing pneumococcal disease in infants and children. The conjugate vaccine, which is designed to protect against the 20 circulating strains responsible for most pneumococcal infections, won European approval for adults in 2022. Prevnar 20 was first approved by the FDA for adults in 2021 and for children last year. —BeiGene cancer immunotherapy Tevimbra received a long-awaited FDA approval for treating adults with advanced esophageal squamous cell carcinoma. The FDA decision expected in 2022 was delayed by Covid-19. Though the drug received European Commission approval last year, BeiGene lost Novartis as a partner on the cancer therapy along the way. BeiGene said it expects Tevimbra, part of the class of drugs known as checkpoint inhibitors, will become available in the U.S. in the second half of this year. —Mirum Pharmaceuticals drug Livmarli landed FDA approval for treating pruritus, or severe itching, caused by the rare liver disease progressive familial intrahepatic cholestasis (PFIC). The approval cover patients age 5 and older. The company has also submitted an application seeking approval of a higher concentration formulation for treating younger PFIC patients. Livmarli was first approved by the FDA in 2021 as a treatment for pruritus caused by Alagille syndrome. Public domain image by Flickr user SciTechTrend