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

肺动脉高压(PAH)是一种罕见、进展迅速和致命的疾病，其特点是 肺动脉重塑、严重的肺动脉高压和进行性右心衰竭。其预后 PAH的死亡率很低，现代治疗1年内死亡率约为15%。在过去的二十年里，一个 一些治疗PAH的药物已被证明可以改善患者的症状和运动 然而，目前的治疗方法没有一种是治愈的，长期预后仍然很差。那里 对于逆转疾病进程和改善长期健康结果的新的多环芳烃目标和疗法的需求仍然很高，尚未得到满足。 血管活性肠肽(VIP)是一种由28个氨基酸组成的多肽激素，可激活VPAC1和VPAC2受体 在肺血管系统中，已被证明可以松弛肺血管平滑肌，中和 肺血管紧张剂，并抑制肺血管平滑肌细胞增殖。此外，VIP 改善右心收缩和舒张功能，并具有广泛的抗炎和抗纤维化作用。贵宾 已被证明在逆转小鼠肺血管重塑和延长生存期方面有效 多环芳烃模型。PB1046是一种N端含有生物活性VIP的重组酸性融合蛋白， C末端的一种生理惰性重复的聚合物弹性蛋白样肽(ELP)。VIP与ELP的融合 部分通过从注射部位持续释放而显著增加体内暴露，延长 循环半衰期和防止酶降解。PB1046是一种具有活性的融合蛋白，即VIP 部分激活受体，而不需要从ELP生物聚合物中切割或释放。PhaseBio 在一项单剂量的第一阶段研究中测试了PB1046，在该研究中，通过ELP融合增强VIP的PK和PD 在观察到的长达一周的PB1046暴露曲线和收缩压下降中清楚地显示出这一点 单次给药对高血压病患者的影响。重要的是，PB1046证明了清洁的单剂 预期治疗剂量范围内的安全性/耐受性概况。 在这项SBIR快速通道建议中，我们正申请拨款进行PB1046号工程计划的1b期和第2期研究。 帕金森病患者。PhaseBio将研究PB1046的多剂量安全性、PK和PD PB1046在植入肺动脉的PAH患者中的安慰剂对照多剂量1b期研究 压力监测器(心脏微机械系统)。在这项初步研究中，PB1046将作为每周一次皮下注射 以先前测试过的剂量水平注射4周，并被证明在来自 动态心力衰竭的单剂量1期研究和正在进行的1期多剂量递增剂量研究 病人。当PB1046在PAH受试者中的安全性、PK和PD曲线被证实时，随机、双盲、 将启动PB1046的安慰剂对照第二阶段研究，以调查PB1046的潜在益处 症状性肺动脉高压患者运动能力和血流动力学的研究

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.