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

开发 D6PV——一种新型 ApoC-II 肽模拟疗法

• 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
• 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

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 本研究的目标是完成IND研究，以开发基于以下的治疗药物： D 6PV，一种新型的ApoC-II肽模拟物，通过进行毒理学研究和生产GMP药物， 用于未来在正常健康志愿者中进行的I期试验。成功 本文提出的目标的完成将导致开发一种新的肽模拟物， 用于治疗急性呼吸道疾病住院患者的快速起效的静脉内制剂 胰腺炎，以迅速降低甘油三酯，以预防或治疗高甘油三酯血症，因此将 缩短住院时间，降低或消除发病率和死亡率。安全 将在IND使能研究和NOAEL（无不良作用负荷）中完成评估 确定支持首次人体给药。这将使Protean Bio能够推进D 6PV阶段 1项在正常健康志愿者中进行的临床试验，以评价 单次和多次递增给药方案后的D 6PV。一旦完成并证明 D 6PV在人体中是安全的，预计将在住院的AP患者中进行2期试验，以证明 概念外（即，在作为静脉内给药后< 4小时内降低甘油三酯的有效性 次给药结束AP是GI相关住院最常见的诊断之一，发病率高 每年花费26亿美元。严重高脂血症（SHTG）是AP的主要原因， 已知在高达38%的血浆甘油三酯（TG）水平为3000-5000 mg/dL的患者中发生。 虽然有几种批准的产品（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， 起效时间短，使其不适用于快速降低住院AP患者的甘油三酯。 因此，对于在急性， 住院治疗，以减少疼痛和胰腺坏死、器官衰竭和死亡率的进展。 在HTG小鼠模型的体内研究中证实了上级离体结果，证明了 给药后3小时内血浆HTG降低约80%，血浆ApoC-III降低约85%; 后者是由于D 6PV的位移和随后的清除。在这直接到第二阶段赠款，我们 建议完成非GMP生产工艺的工程验证，完成IND- 能够在大鼠和犬中进行研究，并生产GMP原料药和制剂。