Safety, tolerability and efficacy of a novel sustained release analog of vasoactive intestinal peptide, PB1046, in patients with pulmonary arterial hypertension

新型血管活性肠肽缓释类似物 PB1046 在肺动脉高压患者中的安全性、耐受性和有效性

• 批准号: 9753354
• 负责人: JOHN LEE
• 金额: $ 124.93万
• 依托单位: PHASEBIO PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-17 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753354
• 关键词: Acids; Adult; Adverse event; Amino Acids; Anti-inflammatory; Antibody Response; Biological; Biopolymers; Blood Pressure; Cardiopulmonary; Catheterization; Chimeric Proteins; Cleaved cell; Clinical; Clinical Research; Data; Diarrhea; Disease; Dose; Double-Blind Method; Drug Kinetics; Dyspnea; Elastin; Essential Hypertension; Exercise; Funding; Half-Life; Health; Heart; Heart Rate; Heart failure; Immunoglobulin Idiotypes; Implant; Incidence; Individual; Injections; Lung; Measures; Modernization; Monitor; Outcome; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiological; Placebos; Polymers; Process; Prognostic Marker; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Randomized; Recombinants; Recovery; Safety; Serious Adverse Event; Severities; Site; Small Business Innovation Research Grant; Special Event; Subcutaneous Injections; Surveys; Symptoms; Testing; Therapeutic; Vascular Smooth Muscle; Vascular remodeling; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Walking; analog; arterial remodeling; curative treatments; discontinuation study; exercise capacity; health related quality of life; hemodynamics; immunogenicity; improved; in vivo; indexing; interest; mortality; mouse model; novel; novel therapeutics; open label; outcome forecast; peptide analog; peptide hormone; pharmacokinetics and pharmacodynamics; phase 1 study; phase 2 study; placebo controlled study; pressure; pro-brain natriuretic peptide (1-76); pulmonary arterial hypertension; receptor; subcutaneous; targeted treatment; vascular smooth muscle cell proliferation; vasoactive intestinal peptide 2 receptor; vasoactive intestinal peptide receptor 1

Pulmonary arterial hypertension (PAH) is a rare, rapidly progressive and fatal disease that is characterized by pulmonary arterial remodeling, severe pulmonary hypertension, and progressive right heart failure. The prognosis of PAH is poor with an approximate 15% mortality within 1 year on modern therapy. Over the past two decades, a number of medications for the treatment of PAH have been shown to improve patient symptoms and exercise capacity; however, none of the current treatments are curative and long-term prognosis remains poor. There remains a high unmet need for novel PAH targets and therapies that reverse the disease process and improve long-term health outcomes. Vasoactive intestinal peptide (VIP) is a 28 amino acid peptide hormone that activates VPAC1 and VPAC2 receptors in the pulmonary vasculature and has been shown to relax pulmonary vascular smooth muscle, neutralize pulmonary vasoconstrictors, and inhibit pulmonary vascular smooth muscle cell proliferation. Additionally, VIP improves right heart systolic and diastolic function and has broad anti-inflammatory and anti-fibrotic actions. VIP has been shown to be effective in reversing pulmonary vascular remodeling and prolonging survival in a murine model of PAH. PB1046is a recombinant acid fusion protein comprising biologically active VIP at the N-terminus and a physiologically inert repeating polymeric elastin-like peptide (ELP) at the C-terminus. The fusion of VIP to the ELP moiety significantly increases in vivo exposure through sustained release from the injection site, extended circulatory half-life and protection from enzymatic degradation. PB1046 is active as a fusion protein, i.e. the VIP moiety activates the receptor without a requirement to be cleaved or released from the ELP biopolymer. PhaseBio has tested PB1046 in a single-dose Phase 1 study in which the PK and PD enhancement of VIP via the ELP fusion was clearly demonstrated in the observed week-long PB1046 exposure profile and systolic blood pressure lowering effect after a single-dose in essential hypertension patients. Importantly, PB1046 demonstrated a clean single-dose safety/tolerability profile across the expected therapeutic dose range. In this SBIR Fast-Track proposal, we are applying for funding for the Phase 1b and Phase 2 studies of PB1046 in patients with PAH. PhaseBio will investigate the multi-dose safety, PK, and PD of PB1046 in an open-label, non- placebo controlled, multi-dose Phase 1b study of PB1046 in PAH patients who have an implanted pulmonary arterial pressure monitor (cardioMEMS). In this initial study, PB1046 will be administered as once weekly subcutaneously injections x 4 weeks at a dose level previously tested and shown to be safe and well tolerated in subjects from the single-dose Phase 1 study and in an ongoing Phase 1 multiple ascending dose study in ambulatory heart failure patients. When the safety, PK, and PD profile of PB1046 are confirmed in PAH subjects, a randomized, double-blind, placebo controlled Phase 2 study of PB1046 will be initiated to investigate the potential beneficial effects of PB1046 on exercise capacity and hemodynamics in symptomatic PAH patients.

肺动脉高压（PAH）是一种罕见的，快速进行的致命疾病，其特征是 肺动脉重塑，严重的肺动脉高压和进行性右心衰竭。预后 PAH的贫困率很差，在现代疗法的1年内死亡率约为15％。在过去的二十年中， 已显示用于治疗PAH的药物数量可改善患者症状和运动 容量;但是，目前的治疗均未治愈，长期预后仍然很差。那里 对新型PAH靶标和疗法的需求仍然很高，从而扭转了疾病过程并改善了长期健康结果。 血管活性肠肽（VIP）是28个氨基酸肽激素，可激活VPAC1和VPAC2受体 在肺血管中，已被证明可以放松肺血管平滑肌，中和 肺血管收缩剂，并抑制肺血管平滑肌细胞增殖。另外，VIP 改善右心脏收缩和舒张功能，并具有广泛的抗炎和抗纤维化作用。 VIP 已被证明可以有效地逆转肺血管重塑和延长鼠的生存率 PAH的模型。 PB1046IS一种重组酸融合蛋白，该蛋白包含N末端的生物活性VIP和 在C末端的生理惰性重复聚合物弹性蛋白样肽（ELP）。 VIP与ELP的融合 通过从注射部位持续释放，部分部分会显着增加体内暴露，扩展 循环半衰期和免受酶促降解的保护。 PB1046作为融合蛋白的活性，即VIP 部分无需从ELP生物聚合物切割或释放，可以激活受体。 Cheperbio 在一项单剂量1期研究中测试了PB1046，其中PK和PD通过ELP融合增强VIP为 在观察到的为期一周的PB1046暴露概况和收缩压降低中清楚地证明了 单剂量在必要的高血压患者中产生影响。重要的是，PB1046证明了一种干净的单剂量 在预期的治疗剂量范围内的安全性/耐受性。 在此SBIR快速提案中，我们正在为PB1046的1B期和2期研究申请资金 PAH患者。 ChepyBio将在开放标签的非 - 植入肺动脉 压力监测仪（心脏膜）。在这项最初的研究中，PB1046将每周施用一次 注射x在先前测试的剂量水平下4周，并证明是安全且可容忍的受试者 单剂量1期研究以及在静态心力衰竭中进行的1阶段1多个上升剂量研究 患者。当PAH受试者确认PB1046的安全性，PK和PD分布时，随机，双盲， 安慰剂对照阶段的2阶段研究将开始研究PB1046的潜在有益作用 有症状的PAH患者的运动能力和血液动力学。