Aldumastat

从BMS到默沙东与阿斯利康，全球制药巨头们近来似乎陷入了从甜蜜合作到分道扬镳的“临床研发失败”怪圈。 01、1+1未必大于2 与BMS达成36亿美元合作的Nektar公司，近来遭遇两项临床研究失败。 3月14日，BMS和Nektar共同宣布了III期临床试验PIVOT IO-001研究的首次分析结果。该项研究评估了偏向性IL-2 bempegaldesleukin联合PD-1单抗纳武利尤单抗（Opdivo）一线治疗不可切除或转移性黑色素瘤的疗效，独立数据监测委员会（DMC）的分析结果显示，双药治疗组未能显示出相较于单药组的临床获益。据悉，基于该研究未能达到无进展生存期（PFS）和客观缓解率（ORR）主要终点，且第3个主要终点总生存期（OS）在第一次中期分析中也没有统计学意义上的改善，两家公司决定揭盲并不对研究终点进行额外分析。 同时，BMS和Nektar还将终止招募并揭盲正在进行中的联合疗法用于黑色素瘤辅助治疗的PIVOT-12研究，这两项研究中的患者将被告知他们在试验中所接受的治疗方式，并和医师商议后决定后续治疗方案的调整。 自2018年官宣总额高达36亿美元的全球开发战略以来，BMS与Nektar在开发联合癌症疗法的合作不断深入，尤其是Nektar的长效IL-2免疫刺激疗法bempegaldesleukin（NKTR-214）与Opdivo的联合应用，曾被FDA授予突破性疗法认定，治疗初治无法切除或转移性黑色素瘤患者。此外，NKTR-214还获得FDA授予的孤儿药资格，用于治疗IIb至IV期黑色素瘤。 虽然两项针对治疗黑色素瘤的临床相继终止，但bempegaldesleukin与Opdivo的联合治疗仍有针对肌层浸润性膀胱癌、肾细胞癌、头颈部鳞状细胞癌等另外四项研究正在展开，其中关于肾细胞癌和尿路上皮癌的两项临床试验的初步研究结果定于今年上半年公布。 作为免疫疗法的两大“扛把子”，BMS宣布O药联合疗法遭遇临床试验失败的次日，默沙东宣布终止K药一项联合疗法的临床试验。 昨日，默沙东宣布其重磅炸弹Keytruda与阿斯利康的PARP抑制剂Lynparza的联合疗法在先前治疗过的转移性去势抵抗性前列腺癌（mCRPC）患者中并未能优于目前临床常用的抗雄激素疗法，决定终止Keytruda-Lynparza组合疗法的研发。 试验结果显示，与强生Zytiga或辉瑞Xtandi相比，Keytruda-Lynparza联合疗法未能进一步延长mCRPC患者的生命，也没能阻止肿瘤进展。值得注意的是，作为全球最畅销的PD-1与最畅销的PARP抑制剂，K药与Lynparza均是各自治疗领域内的佼佼者。但两个重磅炸弹产品的联用，却未能取得1+1＞2的效果。 甚至，更糟糕的情况是，Keytruda-Lynparza联合疗法还导致了mCRPC患者3-5级药物相关严重副作用的发生率增长。在此次III期Keylynk-010试验的中期分析结果遭遇了惨败后，默沙东决定遵循独立数据监测委员会的建议，尽早停止组合疗法的研发试验。 02、九死一生而不悔 如果梳理全球制药巨头如今的研发管线不难发现，通过收购、投资、授权合作等模式，实现对自身新药研发管线的拓宽，是大药企加速药物研发脚步过程中普遍会选择的战略。 一方面，对已上市药物而言，通过联用寻求扩大适应证范围、提高单药治疗效果的机会；另一方面，大药企也在积极寻找那些尚处于临床阶段但展示出优于现有治疗方案的临床试验数据的药物，通过项目授权引入或收购、投资公司的方式将它们纳入自身的研发体系，培养成为下一个业绩增长点。 虽然这种外部合作能够快速补充自身管线，但大药企前期动辄数亿美元甚至数十亿美元巨额资金投入换来的项目，面临着临床试验失败、市场竞争格局变化、项目研发重心调整而终止合作与研发的“竹篮打水一场空”般的不确定性。 正如50亿美元合作却几乎全部打水漂的吉利德，与Galapagos达成的为期10年合作几乎被看作近年来最失败的交易之一。 2019年07月，吉利德与Galapagos宣布签署一项为期10年的全球研发合作协议。吉利德通过支付一笔39.5亿美元的预付款和一笔11亿美元的股权投资，获得Galapagos一个创新的化合物组合，包括目前正在进行临床试验的6个分子、20多个临床前项目以及一个经验证的药物发现平台。 合作的开始往往是前途光明且充满信心的。 促成吉利德达成这项合作的原因是多重的。早在2015年，吉利德就与Galapagos曾达成总额高达20亿美元的协议，共同开发由Galapagos发现的Filgotinib。Filgotinib是一种高度选择性JAK1抑制剂，用于治疗中度至重度活动性类风湿性关节炎成人患者。彼时Filgotinib表现出的优异的临床数据让吉利德对Filgotinib信心十足，甚至在2019年花费8000万美元从Ultragenyx公司购买了优先审评券（PRV）来加速FDA的审查。 不只是Filgotinib，Galapagos还拥有两款FIC级别的化合物——GLPG1690和GLPG1972。GLPG1690临床用于特发性肺纤维化的治疗，资料显示，在IIa期临床试验中展现出优于现有治疗方案的表现；GLPG1972临床开发用于骨关节炎的治疗，在早期的临床1b试验获得了积极的初步顶线研究数据。这也就不难解释吉利德为何希望与Galapagos达成紧密合作。 但面对九死一生的新药研发，一切都是未知的。 进入2020年，吉利德与Galapagos的合作就像进入了水逆期。先是花费8000万美元购买优先审评券以加速审批的JAK抑制剂Filgotinib遭美国FDA拒绝批准，虽然目前双方还在欧洲和日本市场开展Filgotinib的销售合作，但错失美国市场，对吉利德来讲，损失是巨大的。同年10月，GLPG1972的II期ROCCELLA试验的主要结果未能达到预期，宣告其在骨关节炎领域的研究失败。 临床研究的失败对双方的打击延续到了2021年。另一个合作药物GLPG1690在特发性肺纤维化（IPF）患者中的III期ISABELA试验也遭遇终止。独立数据监测委员会认为，GLPG1690的获利-风险状况不再值得进一步开发。同时，双方也停止了关于GLPG1690的所有临床试验，包括在弥漫性皮肤系统性硬化症中的IIa期NOVESA研究的长期拓展。这也被看作可能是出现了“安全性问题”。 双方的另一款候选药物SIK2/3抑制剂GLPG3970在类风湿性关节炎/溃疡性结肠炎领域的临床试验的失败更是被列入Fiercebiotech发布的2021年十大临床失败案例榜单之中。虽然目前双方的合作还在进行中，但围绕合作药物的安全性隐患与市场竞争格局变化带来的压力来看，两家公司计划的长达10年的合作可能提前终止。 其实，因为临床数据不佳、市场格局变化、安全性隐患等问题造成的合作终止并不少见。 仅2021年，罗氏、默沙东、GSK、强生等众多MNC都因临床试验数据不佳而选择终止了与各自项目合作方的交易。 罗氏与Atea终止关于口服新冠药物AT-527的合作是过去一年间首付款金额最高的终止合作的交易，2020年10月22日，Atea与罗氏达成合作，授予罗氏在美国境外地区研究、开发和商业化AT-527的权益，同时获得3.5亿美元的预付款、未来的里程碑付款和专利使用费。一年后的2021年11月17日，Atea宣布终止与罗氏联合开发新冠口服药物AT-527的项目，合作终止的原因可能与AT-527 II期临床结果不佳相关。 GSK与默克关于结合抗PD-L1和TGF-β抑制的双功能融合蛋白Bintrafusp alfa研发的失败，也让业界感到遗憾。Bintrafusp alfa过去优异的临床数据让这一疗法被宣传为Keytruda未来强有力的竞争对手，但是Bintrafusp alfa在过去一年内遭遇四项II/III期临床研究失败，让GSK与默克不得不终止研发。这项首付款达3亿欧元、总交易金额37亿欧元的强强联合也就此作罢。Bintrafusp alfa研发项目的终止，更让众多“跟进者”重新审视起PD-L1/TGF-β双抗临床研究的价值。 有数据显示，当前全球排名前十的跨国药企中，60%~70%的产品都是通过对外合作进入管线的。有国内药企负责人曾对E药经理人表示，虽然面临巨大的研发风险，但寻找新的重磅药物与业绩增长的新动力关乎着大药企的生存与发展。授权合作作为当前最为流行的创新模式，大药厂通过“买买买”的授权交易能够快速补充管线甚至掌握一些疾病领域、新靶点研究的先机。 内容来源于网络，如有侵权，请联系删除，谢谢。

Galapagos co-founder and chief executive officer Onno van de Stolpe has been in this position with the Belgian biotech for 22 years and is ready to step down, paving the way for new leadership. As CEO, Stolpe has presided over some highs with the launch of JAK1 inhibitor Jyseleca® (filgotinib) in Europe, as well as the devaluation of the company's share price by 70%. Stolpe is to stay in his role until a successor is found, the company announced in a statement. Because the biotech has been on potential buyers' radar as a takeover target/merger candidate, the co-founder's departure leaves the future of the business uncertain. Putting up a brave face, the CEO tweeted on his exit announcement, “Of course it would have been better if Galapagos was in a better situation. But I will leave a company with €5b in cash, guaranteed independence…” But there is no way of knowing for how long. Galapagos has left many of its investors feeling disheartened after seeing great success throughout 2019 and the beginning of 2020. In 2019, Galapagos and Gilead Sciences signed a 10-year deal worth $5.1 billion, which gave Gilead full access to Galapagos’s product pipeline. Under the terms of the agreement, Gilead gained access to a portfolio of innovative molecules, including six in clinical trials and more than 20 in preclinical development. A partnership with a multinational pharmaceutical company was termed a sure sign of Galapagos' success since most biotechs tend to get immediate benefits from such relationships. However, there has been more than one disappointment in Gilead's buy-in and it appears that the deal is crumbling. A string of disappointments has besieged the Belgian biotech. Despite its massive funding and new resources, Galapagos has yet to capitalize on the Gilead deal. In Galapagos' product pipeline, the drug filgotinib was stated to be a cornerstone development with partner Gilead for rheumatoid arthritis. With a market of $36.11 billion projected for rheumatoid arthritis drugs by 2027, the company was eager to tap into the market. However, as part of a broader investigation into the safety of the drug class, the U.S. Food and Drug Administration rejected the drug due to potential testicular toxicity concerns. This resulted in the pair missing out on a multibillion-dollar opportunity, resulting in a stock price drop of 63% compared to last year. The FDA rejection led Gilead to give back the European marketing rights to Galapagos and abandon its development plans for the drug in the US. As Gilead designated Galapagos as the sole commercialization company for the drug, Galapagos is about to launch Jyseleca in Europe and Japan for rheumatoid arthritis. Galapagos is set to face an uphill battle in the commercialization of drugs and medicines, however, since it can be a very challenging process for small biotech companies. The failures continued to pile up. Another molecule canned was AdamTS-5 inhibitor GLPG1972, which missed the mark in a phase 2 trial in osteoarthritis last year. Again in early February, Galapagos and Gilead decided to halt the ISABELA Phase 3 clinical studies with the investigational autotaxin inhibitor ziritaxestat in patients with idiopathic pulmonary fibrosis. The original formulation of ziritaxestat was developed by Galapagos to inhibit autotaxin, an enzyme thought to be responsible for IPF progression. Ziritaxestat's ex-European rights were licensed to Gilead, which was sharing Phase III trial costs. Ziritaxestat was developed for the treatment of idiopathic pulmonary fibrosis and was set to penetrate a market that could generate up to $1 billion in sales annually. The dream, however, came undone this February. In May, Galapagos decided to refocus its clinical pipeline and make some cost adjustments expected to save the company €150 million. The Belgian biotech, however, just kept suffering disappointment after disappointment. Lead asset, GLPG3970 turned out to be another failed candidate in the 'Toledo' project, which aims to treat a broad range of autoimmune conditions with a range of SIK drugs. Following the failure of two out of three clinical trials of GLPG3970, Galapagos had no choice but to return to the drawing board last month with its SIK inhibitor program. After a Phase I trial with GLPG3312, Galapagos abandoned another Salt-inducible Kinase (SIK) 1/2/3 inhibitor. Though the company still has another idiopathic pulmonary fibrosis drug in its pipeline, these developments allow other companies to break into the market before Galapagos. Though Gilead and Galapagos intend to continue to broaden their pipelines to boost business, their blockbuster relationship has so far done nothing but disappoint. The exit of the CEO marks yet another downturn. "My time at the helm of Galapagos will come to an end. We have built a great company that bridges novel target discovery all the way to new medicines in the clinic and to the patient. Despite recent setbacks, we continue to progress a deep pipeline of novel target-based compounds, while the commercial roll-out of our first approved product is underway," Stolpe said in a statement. Dr. Raj Parekh, chairman of the Galapagos supervisory board added in the statement that Stolpe has built one of the most important biotechnology companies in Europe, guiding it from a new start-up to a public company that recently launched its first approved medicine. Incidentally, two weeks ago, Galapagos' chief scientific officer Piet Wigerinck announced that he would end his nine-year term at the company later this year. The question now doing the rounds is: Will the new CEO help Galapagos optimize its position in the European and Japanese market, or will a European heavyweight decide to purchase Galapagos to maximize its exposure and sales of filgotinib in Europe? Only time will tell.