Development of D6PV- a novel ApoC-II peptide mimetic therapeutic

开发 D6PV——一种新型 ApoC-II 肽模拟疗法

基本信息

批准号：
10603074
负责人：
Matt Devalaraja
金额：
$ 99.75万
依托单位：
PROTEAN BIO INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-25 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10603074
关键词：
Acinar Cell Acute Address Adverse effects Agonist Alanine Antibodies Apolipoproteins Apolipoproteins C Binding Canis familiaris Chylomicrons Clinical Chemistry Clinical Treatment Clinical Trials Development Diagnosis Documentation Dose Drug Kinetics Engineering Formulation Future Goals Grant Hematology Histopathology Hospitalization Hospitals Hour Human Hypertriglyceridemia Intensive Care Intravenous Length of Stay Lipolysis Lipoproteins Maximum Tolerated Dose Methionine Methodology Methods Modality Modeling Molecular Morbidity - disease rate Mutant Strains Mice Necrosis No-Observed-Adverse-Effect Level Nonesterified Fatty Acids Nucleic Acids Organ Organ failure Pancreas Patient Admission Patients Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Phase I Clinical Trials Phase II/III Trial Placebos Plasma Positioning Attribute Proline Property Proteins Protocols documentation Rattus Regimen Regulation Report (document)Risk Rodent Safety Specific qualifier value Testing Therapeutic Therapeutic Agents Toxic effect Toxicology Triglycerides Validation Valine Very low density lipoprotein acute pancreatitis analytical method antagonist cell injury cost design first-in-human genotoxicity healthy volunteer immunogenicity in vivo in vivo Model innovation intravenous administration lead candidate lipoprotein lipase manufacture manufacturing process manufacturing scale-up mortality mouse model nonhuman primate novel novel therapeutics pain reduction peptidomimetics phase I trial phase II trial preclinical study prevent safety assessment scale up systemic toxicity

项目摘要

PROJECT SUMMARY The goal of the current study is to complete IND enabling studies to develop a therapeutic based on D6PV, a novel ApoC-II peptide mimetic, by conducting toxicology studies and manufacturing GMP drug substance and drug product for future Phase 1 trials in normal healthy volunteers. Successful completion of aims proposed here will result in the development of a novel peptide mimetic as an intravenous formulation with a rapid onset of action for the treatment of hospitalized patients with acute pancreatitis to rapidly reduce triglycerides to prevent or treat hypertriglyceridemia, and therefore will reduce the length of stay in the hospital and reduce or eliminate the morbidity and mortality. A safety assessment will be completed in IND enabling studies and a NOAEL (no adverse effect load) determined to support first-in-human dosing. This will enable Protean Bio to advance D6PV for Phase 1 clinical trials in normal healthy volunteers to evaluate the pharmacokinetics, safety and tolerability of D6PV after single and multiple ascending dosing regimens. Once completed and demonstrated to be safe in humans, D6PV is anticipated to progress to Phase 2 trials in hospitalized AP patients for proof- of-concept (i.e., efficacy) for reducing triglycerides in < 4 hours after administration as an intravenous dose. AP is one of the most common diagnosis for GI-related hospitalization with significant morbidity and at an annual cost of $2.6B. Severe Hypertriglyceridemia (SHTG) is a leading cause for AP and is known to occur in up to 38% of patients with plasma triglyceride (TG) levels of 3000-5000 mg/dL. Although there are several approved products (e.g., Vascepa®, Epanova®) and new modalities (nucleic acid drugs, antibodies) in Phase 2/3 trials for the treatment of SHTG, they have a delayed onset of action, rendering them unsuitable for rapidly lowering triglycerides in hospitalized AP patients. Therefore, there is a clear unmet need for rapidly addressing elevated TG in AP patients in an acute, hospitalized setting to reduce pain and progression of pancreatic necrosis, organ failure and mortality. Superior ex vivo results were confirmed in in vivo studies in mice models of HTG, demonstrating a ~80% reduction of plasma HTG in 3 hours post dosing and ~85% decrease in plasma ApoC-III; the latter due to displacement by D6PV and subsequent clearance. In this Direct to Phase II grant, we propose to complete engineering validation of the non-GMP manufacturing process, complete IND- enabling studies in rat and dog, and manufacture GMP drug substance and drug product.

项目概要当前研究的目标是完成 IND，使研究能够开发基于 D6PV，一种新型ApoC-II肽模拟物，通过进行毒理学研究并生产GMP药物未来在健康正常志愿者中进行的第一阶段试验的物质和药品已取得成功。完成此处提出的目标将导致开发出一种新型肽模拟物作为起效快的静脉制剂，用于治疗住院的急性发作患者胰腺炎迅速降低甘油三酯以预防或治疗高甘油三酯血症，因此将减少住院时间并降低或消除发病率和死亡率 A 安全。评估将在 IND 启用研究和 NOAEL（无不良反应负荷）中完成决心支持首次人体给药，这将使 Protean Bio 能够推进 D6PV 的阶段性工作。 1 在正常健康志愿者中进行的临床试验，评估其药代动力学、安全性和耐受性单次和多次递增给药方案后的 D6PV 一旦完成并被证明是有效的。 D6PV 对人类安全，预计将在住院 AP 患者中进行 2 期试验，以证明- 静脉注射后 4 小时内降低甘油三酯的概念（即功效） AP 是胃肠道相关住院最常见的诊断之一，具有显着的发病率。严重高甘油三酯血症 (SHTG) 的年费用为 $2.6B，是 AP 的主要原因。已知高达 38% 的血浆甘油三酯 (TG) 水平为 3000-5000 mg/dL 的患者会发生这种情况。尽管有多种已获批准的产品（例如 Vascepa®、Epanova®）和新模式（核酸药物、抗体）在治疗SHTG的2/3期试验中，它们有延迟作用开始，使它们不适合快速降低住院 AP 患者的甘油三酯。因此，对于快速解决急性AP患者中TG升高的问题，显然存在未满足的需求。医院环境可减少疼痛以及胰腺坏死、器官衰竭和死亡率的进展。 HTG 小鼠模型的体内研究证实了优异的离体结果，证明了给药后 3 小时血浆 HTG 降低约 80%，血浆 ApoC-III 降低约 85%；后者是由于 D6PV 的位移和随后的清除而导致的。在这项直接到第二阶段的拨款中，我们。建议完成非 GMP 制造工艺的工程验证，完成 IND- 能够对大鼠和狗进行研究，并生产 GMP 原料药和药品。