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

项目总结 当前研究的目标是完成IND使研究能够开发一种基于 一种新的载脂蛋白C-II多肽模拟物D6PV的毒理学研究和GMP药物的制备 用于未来在正常健康志愿者中进行第一阶段试验的物质和药物产品。成功 完成这里提出的目标将导致开发一种新的多肽模拟物，作为一种 起效快的静脉制剂治疗急性冠脉综合征住院患者 胰腺炎能迅速降低甘油三酯，以预防或治疗高甘油三酯血症，因此将 减少住院时间，减少或消除发病率和死亡率。一种安全 评估将在IND支持研究和NOAEL(无不良影响负载)中完成 决心支持人类第一次给药。这将使Protean Bio能够推进D6PV阶段 1例正常健康志愿者的临床试验，以评价其药代动力学、安全性和耐受性 单次和多次递增给药方案后D6PV。一旦完成并证明是 D6PV在人类中是安全的，预计将进入住院AP患者的第二阶段试验，以证明- 静脉给药后4小时内降低甘油三酯的概念(即有效性) 剂量。急性胰腺炎是胃肠道相关住院最常见的诊断之一，发病率很高 以及每年26亿美元的成本。严重高甘油三酯血症(SHTG)是AP和IS的主要原因 已知高达38%的血浆甘油三酯(TG)水平在3000-5000 mg/dL的患者会发生这种情况。 虽然有几种批准的产品(例如Vascepa®、Epanova®)和新的医疗模式 (核酸药物，抗体)在治疗SHTG的2/3期试验中，他们有一个延迟 作用开始，使其不适合在住院AP患者中快速降低甘油三酯。 因此，有一个明显的未得到满足的需求，以快速解决AP患者在急性、 住院环境，以减少疼痛和进展的胰腺坏死，器官衰竭和死亡率。 在HTG小鼠模型的体内研究中证实了优越的体外结果，证明了 服药后3小时内血浆HTG下降~80%，ApoC-III下降~85%； 后者是由于D6PV的移位和随后的间隙。在这项直接到第二阶段的拨款中，我们 建议完成非GMP制造过程的工程验证，完成IND 能够在大鼠和狗身上进行研究，并生产GMP药材和药品。

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.