PARP inhibitor therapy for septic shock

描述(由申请人提供)： 感染性休克发展为多器官衰竭(MOF)是由多聚腺苷二磷酸核糖聚合酶(PARP)的激活所介导的，PARP是一种催化细胞内能量衰竭和坏死的核细胞死亡酶。在内毒素血症和败血症模型中，PARP的基因缺失或药物抑制具有深远的保护作用。PARP的激活也通过影响NF-kappaB的激活和AP-1的表达，在介导促炎细胞因子、趋化因子和细胞黏附分子的病理性过度表达中发挥关键作用，这些分子启动了细胞死亡级联反应。当休克发作后开始治疗时，抑制PARP具有显著的保护作用。INOTK正在开发一种超强的PARP抑制剂(Ki=15 NM)，在感染和血流动力学不稳定开始后使用，可以将LD100猪大肠杆菌诱导的腹膜炎和感染性休克模型的死亡率降低50%。在健康人体志愿者中，INO-1001耐受性良好且安全。在第一阶段的SBIR中，我们建议在8个受试者中进行一项试验性的单中心研究，重点是INO-1001的安全性和PK概况。登记的患者将包括：1)感染性休克和持续24小时，2)发烧，3)需要血管活性支持的低血压，4)有腹部感染的证据，5)24小时内没有手术。INO-1001的使用将持续5天，这是败血症引起的多器官功能衰竭的关键时期。在2期SBIR中，我们将通过对200名符合初步研究相同标准的患者进行前瞻性、随机、双盲、安慰剂对照的IIb期PARP抑制研究，来证明PARP激活在临床感染性休克中的作用。主要的临床终点将是：1)安全性，2)INO-1001的PK，以及减少：3)外周血中PARP的激活，4)血浆炎症反应(TNF，IL-6，IL-8)，以及5)MOF的发展和持续时间，反映为：(A)代谢性酸中毒，(B)心血管不稳定(MAP和血管加压/肌力抑制需求)和心脏指数，(C)肝功能不全(PT，白蛋白，总蛋白)，(D)肾功能不全(BUN/Cr，CVVH，少尿)，和(E)呼吸功能不全(PaO2/FIO2比率，机械通风天数)。次级临床终点将减少1)28天全因死亡率，2)在ICU停留的时间，3)APACHE II指数。基于临床前猪休克模型和临床安全性研究，我们期望INO-1001是一种安全、耐受性良好和有效的感染性休克患者的治疗方法。

DESCRIPTION (provided by applicant): Progression of septic shock to multiple organ failure (MOF) is mediated by the activation of poly(ADP-ribose) polymerase ("PARP"), a nuclear cell death enzyme that catalyzes intracellular energetic failure and necrosis. Genetic deletion or pharmacologic inhibition of PARP is profoundly protective in models of endotoxinemia and sepsis. PARP activation also plays a key role in mediating the pathologic overexpression of pro-inflammatory cytokines, chemokines, and cell adhesion molecules that initiate the cell death cascade, via its effects on NF-kappaB activation and AP-1 expression. PARP inhibition is dramatically protective when therapy is begun after the onset of shock. Inotek is developing an ultrapotent PARP inhibitor (Ki = 15 nM) that reduces mortality by 50% in an LD100 porcine model of E. coli-induced peritonitis and septic shock, when administered AFTER the initiation of infection and onset of hemodynamic instability. In healthy human volunteers, INO-1001 is well-tolerated and safe. In a Phase 1 SBIR, we propose a pilot single-center study in 8 subjects focused on the safety and PK profile of INO-1001. Enrollment will include patients with: 1) septic shock < 24 h duration, 2) fever, 3) hypotension requiring vasoactive support, 4) evidence of intra-abdominal infection, and 5) no surgery within 24 h. Administration of INO-1001 will be provided for 5 days, the critical period of sepsis-induced MOF. In a Phase 2 SBIR, we will demonstrate the role of PARP activation in clinical septic shock by carrying out a prospective, randomized, double-blind, placebo-controlled, Phase IIb study of PARP inhibition in 200 patients meeting the same criteria as in the pilot study. The primary clinical endpoints will be: 1) safety, 2) PK of INO-1001, and reductions in: 3) PARP activation in peripheral blood, 4) plasma inflammatory response (TNF, IL-6, IL-8), and 5) development and duration of MOF, as reflected by: (a) metabolic acidosis, (b) cardiovascular instability (MAP and vasoporessor/inotrope requirement) and cardiac index, (c) hepatic insufficiency (PT, albumin, total protein), (d) renal insufficiency (BUN/Cr, CVVH, oliguria), and (e) respiratory insufficiency (PaO2/FiO2 ratio, days of mechanical ventilation). Secondary clinical endpoints will be reductions in 1) 28-day all cause mortality, 2) duration of ICU stay, 3) APACHE II index. Based on pre-clinical porcine shock models and clinical safety studies, we expect INO-1001 to be a safe, well-tolerated and effective therapeutic in patients with septic shock.