PARP inhibitor therapy for septic shock

PARP 抑制剂治疗感染性休克

• 批准号: 6790412
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 21.02万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2006-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790412
• 关键词: antiinflammatory agents; antioxidants; blood tests; clinical research; clinical trials; cytoprotection; disease /disorder prevention /control; drug adverse effect; drug screening /evaluation; enzyme induction /repression; enzyme inhibitors; human subject; human therapy evaluation; inflammation; necrosis; oxidative stress; oxidizing agents; patient oriented research; pentosyltransferase; pharmacokinetics; septic shock; septicemia

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.

描述（由申请人提供）： 败血性休克对多器官衰竭（MOF）的进展是通过聚（ADP-核糖）聚合酶（“ PARP”）的激活介导的，这是一种核细胞死亡酶，可催化细胞内的能量衰竭和坏死。在内毒素血症和败血症的模型中，PARP的遗传缺失或药理学抑制具有深刻的保护。 PARP激活在介导促炎性细胞因子，趋化因子和细胞粘附分子的病理过表达中也起着关键作用，该分子通过其对NF-kappab激活和AP-1表达的影响，启动细胞死亡级联反应。当休克发作后开始治疗时，PARP抑制作用是明显的保护。 Inotek正在开发一种超能力的PARP抑制剂（Ki = 15 nm），该抑制剂在E. coli诱导的LD100猪模型中降低了50％，当时在感染和血液动力学不稳定性开始后施用。在健康的人类志愿者中，INO-1001富有耐受性和安全性。在第1阶段SBIR中，我们提出了一项针对INO-1001的安全性和PK概况的主题研究的试点单中心研究。入学率将包括：1）败血性休克<24小时，2）发烧，3）低血压需要血管活性支持，4）腹腔内感染的证据和5）在24小时内没有手术。 INO-1001的给药将提供5天，这是败血症诱导的MOF的关键时期。在第2阶段SBIR中，我们将通过执行前瞻性，随机，双盲，安慰剂对照，IIB期PARP抑制期PARP激活在临床败血性休克中的作用试点研究。主要的临床终点将是：1）安全性，2）INO-1001的PK，并减少：3）外周血中的PARP激活，4）血浆炎症反应（TNF，IL-6，IL-8）和5 ）MOF的开发和持续时间，如以下方式反映：（a）代谢性酸中毒，（b）心血管不稳定性（MAP和血管孔/肌辅助者/肌肉需求）和心脏指数，（c）肝不足（PT，白蛋白，蛋白质，蛋白质），（D） ）肾功能不全（BUN/CR，CVVH，寡尿症）和（e）呼吸不足（PAO2/FIO2比，机械通气天数）。次要临床终点将是减少1）28天的所有导致死亡率，2）ICU停留时间，3）Apache II指数。基于临床前的猪休克模型和临床安全研究，我们预计INO-1001对败血性休克患者是一种安全，耐受性和有效治疗。