马萨诸塞州，剑桥——2020年9月17日，由维亚生物投资孵化的生物医药公司Dogma Therapeutics（以下简称“Dogma”）与阿斯利康就收购其口服PCSK9项目全球权益达成协议。阿斯利康将支付Dogma首付款，并在全球监管和商业里程碑达成后，向Dogma支付里程碑款项。
Dogma科学家团队持续致力于研发出一种方便的、可供口服的PCSK9药物。通过维亚生物全球领先的基于结构的药物发现平台， Dogma团队成功将化合物与PCSK9蛋白的亲和力优化到皮摩尔级别。临床前试验已验证，采用口服给药的多个Dogma小分子抑制剂被证明能够在几周后显著降低LDL-C水平。维亚生物科技公司首席科学家叶志雄博士表示：“维亚生物自2017年起投资孵化Dogma Therapeutics，我们就PCSK9项目与Dogma团队展开了紧密合作，这对维亚团队来说也是一次非常有益的经验。口服小分子PCSK9抑制剂的成功研发将极大程度地满足心血管疾病患者的临床需求。”
在PCSK9靶点经过人类基因组学的快速验证之后，已有两个PCSK9抗体药物（Repatha以及Praluent）被FDA批准上市。近年来，大规模试验显示PCSK9抗体药能使心脏疾病的概率降低15-20%，被认为是他汀类药物之后最可靠的降脂药物靶标。但PCSK9抗体的售价较高，且必须以注射的形式给药。此外，由于抗体药物在PCSK9的结合界面较大，使得针对该界面的非抗体类抑制剂的研发面临诸多挑战。迄今为止，仅有几例通过间接方法抑制PSCK9的小分子化合物的新闻被公开报道。
（Dogma首席执行官Brian Hubbard博士）
Dogma首席执行官Brian Hubbard博士指出：“Dogma团队已经累积了有力的实验数据，以证明口服PCSK9抑制剂项目在降低胆固醇方面的药效，及其良好的潜在安全性。本次与阿斯利康达成的收购协议，将加速推动项目的开发进度，更快地为需要降低低密度胆固醇水平的患者带来新治疗方案。在这里我想要感谢Dogma的科学合作伙伴们——Charles River 实验室、维亚生物、安济药业及其他CRO伙伴，是他们对项目的付出和世界顶尖的业务能力成就了Dogma。”
针对本次收购，阿斯利康生物制药研发部执行副总裁Mene Pangalos表示：“低密度胆固醇水平的上升是心血管疾病的关键风险因素，每年造成全球约260万人的死亡。PCSK9已被验证可有效降低低密度脂蛋白胆固醇水平，然而以小分子抑制PCSK9靶点仍非常困难，本次与Dogma成功达成的收购协议，为阿斯利康开发生物可利用性的首创小分子口服PCSK9抑制剂提供了机遇，将有望降低高血脂患者冠状动脉疾病的发生几率及疾病的严重程度。”
CAMBRIDGE, MASSACHUSETTS – Dogma Therapeutics (“Dogma”), a Viva Biotech Portfolio Company, has reached an agreement for the acquisition of its oral PCSK9 program by AstraZeneca. Dogma will receive upfront as well as downstream payments linked to global regulatory and commercial milestones.
The pursuit of a convenient, oral PCSK9-based therapy has been the singular focus of Dogma scientists for nearly a decade. Through Viva Biotech’s world-leading structure-based drug discovery platform, the Dogma team improved the Dogma inhibitors’ binding to PCSK9, ultimately achieving picomolar affinity. In preclinical models of hypercholesterolemia, multiple Dogma small molecule inhibitors were proved to significantly lower the LDL-C level when dosed orally. “Viva Biotech has begun to incubate and invest in Dogma Therapeutics since 2017. It was an exceptionally rewarding experience for our team to have a close partnership with Dogma during the exciting discovery phase,” said Dr. Zhixiong Ye, the Chief Scientific Officer at Viva Biotech. “An orally-bioavailable small molecule PCSK9 inhibitor will greatly impact the unmet medical needs of cardiovascular patients.”
Historically, several antibody-based inhibitors emerged following the rapid accreditation of the PCSK9 target through human genetics. However, despite large outcome trials showing a 15-20% reduction in cardiac events, the cost-effectiveness and wide use of antibody-based PCSK9 injectables have been questioned. Alternate approaches to PCSK9 inhibition have been stymied by the expansive binding surface targeted by the antibodies, and to date, only indirect approaches to PCSK9 inhibition by small molecules have been reported.
“We have built a robust data package that highlights the cholesterol-lowering and safety potential of our oral PCSK9 program,” noted Dogma CEO Brian Hubbard, Ph.D. “This agreement with AstraZeneca meets our strategic goal to accelerate access to patients unable to meet target LDL-C. I would like to especially thank our scientific partners – Charles River Laboratories, Viva Biotech, Anji Pharma, and our CRO partners - for their commitment to this project and their world-class problem solving.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca said: “Raised LDL cholesterol is a key risk factor for cardiovascular disease and is estimated to cause 2.6 million deaths worldwide every year. Whilst PCSK9 is a well validated target for lowering LDL cholesterol it has been a hugely challenging target to inhibit with small molecules. This agreement with Dogma Therapeutics offers us the opportunity to develop the first small molecule, orally bioavailable PCSK9 inhibitor, for patients at risk of cardiovascular disease.”
About Dogma Therapeutics
Dogma Therapeutics has discovered bona fide small molecule inhibitors of PCSK9 function that are orally bioavailable across multiple preclinical species. Guided by dozens of high-resolution x-ray structures of our molecules bound to PCSK9, we have utilized structure-based design to achieve picomolar affinity.
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