Oral PCSK9/LDLR antagonist direction to the clinic

口服 PCSK9/LDLR 拮抗剂临床指导

基本信息

批准号：
9906738
负责人：
Nabil A Elshourbagy
金额：
$ 94.39万
依托单位：
SHIFA BIOMEDICAL CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906738
关键词：
Acids Advanced Development American Heart Association Animal Model Animals Atherosclerosis Binding Bioavailable Biological Assay Biological Availability Blood Blood Pressure Canis familiaris Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cessation of life Chitosan Cholesterol Cholesterol Homeostasis Chromatography Chromosome abnormality Clinic Clinical Conscious Cost of Illness Coupled Cytochrome P450 Data Degradation Pathway Development Documentation Dose Drug Kinetics Dyslipidemias Ensure Enzyme Precursors Epidemic Exhibits Failure Formulation Goals Half-Life Heart Diseases Heart Rate High Fat Diet Hour Human In Vitro Individual Inflammatory Injectable Investigational Drugs Investigational New Drug Application LDL Cholesterol Lipoproteins Label Lead Liquid substance Liver Liver Microsomes Low Density Lipoprotein Receptor Low-Density Lipoproteins Microbiology Micronucleus Tests Microsomes Molecular Chaperones Monkeys Monoclonal Antibodies Mus Mutagenesis Myocardial Infarction Neuraxis Oral Oral Administration Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Plasma Polymorph Population Preparation Process Protein Precursors Rattus Recombinants Risk Factors Rodent Safety Serine Protease Severities Small Business Innovation Research Grant Solid Subtilisin Like Proprotein Convertases Testing Toxicogenetics Toxicology United States Validation Value of Life Woman Work aggressive therapy atherosclerosis risk base carcinogenicity clinical candidate cost developmental toxicology drug development drug market efficacy study first-in-human human study hypercholesterolemia improved in vivo liquid formulation meetings men method development nanoformulation nanomolar nanoparticle novel pharmacokinetics and pharmacodynamics pre-clinical reproductive respiratory scale up small molecule therapeutic target uptake virtual screening

项目摘要

Project Summary/Abstract Heart disease has been the leading cause of death in the United States and the world for more than a century, ever since the early 1900s. About 610,000 people die of heart disease in the United States every year–that's 1 in every 4 deaths. The epidemic burden is enormous; in 2016, cardiovascular disease (CVD) cost $555 billion in the US alone, and by 2035, the cost will skyrocket to $1.1 trillion. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, more than 7M patients have high LDL-cholesterol and not responsive to statin, and an additional 4M statin intolerance and 1.3M are familial hypercholesteremic (FH). These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel orally bioavailable drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing. Secreted PCSK9 binds to the LDL-receptor (LDLR) and chaperones it to the degradation pathway. To achieve our goal, we identified a nanomolar orally active small molecule PCSK9/LDLR antagonist (P-21) that showed outstanding potency in mice fed high-fat diet. The LDL- cholesterol lowering effect of P-21 is as potent as the marketed monoclonal antibodies. As part of this Phase-II SBIR proposal, our goal is to advance the development of our lead compound (P-21) to Phase-I clinical trial. Our studies will focus on ensuring that P-21 adheres to the set of established criteria as a pre-clinical candidate and on undertaking the work required to obtain the safety and toxicology studies in two mammalian species required for a GLP-IND enabling study application submission.

项目摘要/摘要心脏病一直是美国和世界的主要原因，一个多世纪以来自1900年代初以来。每年美国约有61万人死于心脏病 - 这是1人每4人死亡。流行病伯宁是巨大的。 2016年，心血管疾病（CVD）的费用为5550亿美元仅在美国，到2035年，成本将飙升至1.1万亿美元。高胆固醇水平是众所周知的风险心脏病的因素。尽管可以使用多种销售药物降低血液胆固醇，但哪种汀类药物是领先的药物，超过700万名患者的LDL-胆固醇高，对他汀类药物，另外400万他汀类药物和130万是家庭高胆固醇（FH）。这些和其他患者将受益于高胆固醇血症的积极治疗。长期目标这项工作是为了开发新型的口服生物利用药物来降低胆固醇。我们的治疗目标是蛋白酶蛋白转化酶枯草蛋白样Kexin型9（PCSK9）。 PCSK9控制着降解肝脏中的LDL受体（LDLR），从而导致胆固醇稳态。 PCSK9合成为经历加工的前体蛋白。分泌的PCSK9与LDL受体（LDLR）结合，并且伴侣到降解途径。为了实现我们的目标，我们确定了一个纳摩尔的口服活性小分子PCSK9/LDLR拮抗剂（P-21），在喂养高脂饮食的小鼠中表现出出色的效力。 LDL- P-21的胆固醇降低作用与销售的单克隆抗体一样潜在。作为该阶段的一部分 SBIR提案，我们的目标是将我们的铅化合物（P-21）的开发发展为I期临床试验。我们的研究将着重于确保P-21遵守已建立的标准作为临床前的标准候选人并从事两种哺乳动物的安全和毒理学研究所需的工作 GLP启用研究申请提交所需的物种。