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.

项目摘要当前研究的目的是完成基于基于的研究，以开发基于 D6PV是一种新型的APOC-II肽模拟物，通过进行毒理学研究和制造GMP药物正常健康志愿者中未来1期试验的物质和药物。成功的此处提出的目标的完成将导致新的肽模拟物作为一种静脉注射配方迅速发作，以治疗住院的急性患者胰腺炎可以快速减少甘油三酸酯以预防或治疗高甘油三酯血症，因此会降低医院的住宿时间，并降低或消除发病率和死亡率。安全评估将在IND启用研究和NOAEL中完成（没有不利影响负载）决心支持首次人类剂量。这将使Protean Bio能够推进D6PV的相位 1正常健康志愿者的临床试验，以评估药代动力学，安全性和耐受性 D6PV在单一和多次升级给药方案之后。一旦完成并证明是预计在人类中，D6PV将在住院的AP患者中进行第二阶段试验以进行证明 - 在给药后<4小时以静脉注射后，概念（即，效率）减少甘油三酸酯剂量。 AP是胃肠道相关住院最常见的诊断之一，发病率明显每年的费用为$ 2.6B。严重的高甘油三酯血症（SHTG）是AP的主要原因，IS 已知在38％的血浆甘油三酸酯（TG）水平为3000-5000 mg/dL的患者中发生。尽管有几种批准的产品（例如Vascepa®，Epanova®）和新模式（核酸药物，抗体）在第2/3阶段试验中用于治疗SHTG，它们的延迟动作发作，使它们不适合快速降低住院的AP患者的甘油三酸酯。因此，明显的未满足需要迅速解决急性AP患者TG升高的需求，住院的设置以减轻胰腺坏死，器官衰竭和死亡率的疼痛和进展。在HTG的小鼠模型中，在体内研究中证实了优质的离体结果，证明了A 剂量后3小时减少血浆HTG，血浆APOC-III降低约85％；这后者是由于D6PV的位移和随后的清除率引起的。在此直接获得第二阶段赠款中，我们提出完成非GMP制造过程的工程验证的建议，完成促进对大鼠和狗的研究，并生产GMP药物和药物产品。