PARP inhibitor therapy for septic shock

描述（由申请人提供）： 脓毒性休克向多器官衰竭（MOF）的进展由聚（ADP-核糖）聚合酶（“PARP”）的活化介导，所述聚（ADP-核糖）聚合酶是一种催化细胞内能量衰竭和坏死的核细胞死亡酶。PARP的遗传缺失或药理学抑制在内毒素血症和脓毒症模型中具有深刻的保护作用。PARP活化还通过其对NF-κ B活化和AP-1表达的影响，在介导启动细胞死亡级联的促炎细胞因子、趋化因子和细胞粘附分子的病理性过表达中起关键作用。在休克发作后开始治疗时，PARP抑制具有显著的保护作用。Inotek正在开发一种超强效PARP抑制剂（Ki = 15 nM），可使LD 100猪大肠杆菌模型的死亡率降低50%。大肠杆菌诱导的腹膜炎和感染性休克，当开始感染和血流动力学不稳定发作后给药时。在健康志愿者中，INO-1001耐受性良好且安全。在1期SBIR中，我们提出了一项在8名受试者中进行的试点单中心研究，重点是INO-1001的安全性和PK特征。入组患者将包括：1）脓毒性休克持续时间< 24小时，2）发热，3）需要血管活性支持的低血压，4）腹腔内感染证据，5）24小时内未手术。INO-1001的给药将提供5天，这是脓毒症诱导的MOF的关键期。在II期SBIR中，我们将通过在符合与初步研究相同标准的200例患者中进行PARP抑制的前瞻性、随机化、双盲、安慰剂对照、IIb期研究，证明PARP激活在临床脓毒性休克中的作用。主要临床终点为：1）安全性，2）INO-1001的PK，以及3）外周血中PARP活化，4）血浆炎症反应的降低（TNF，IL-6，IL-8），和5）MOF的发展和持续时间，如通过以下反映的：（a）代谢性酸中毒，（B）心血管不稳定（MAP和血管升压药/正性肌力药需求）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（PaO 2/FiO 2比值、机械通气天数）。次要临床终点将是1）28天全因死亡率，2）ICU住院时间，3）APACHE II指数的降低。基于临床前猪休克模型和临床安全性研究，我们预期INO-1001在感染性休克患者中是一种安全、耐受性良好且有效的治疗剂。

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.