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）： 感染性休克进展为多器官衰竭(MOF)是由聚(ADP-核糖)聚合酶(“PARP”)的激活介导的，PARP是一种催化细胞内能量衰竭和坏死的核细胞死亡酶。 PARP 的基因缺失或药物抑制在内毒素血症和脓毒症模型中具有深远的保护作用。 PARP 激活还通过影响 NF-κB 激活和 AP-1 表达，在介导促炎细胞因子、趋化因子和细胞粘附分子的病理性过度表达（启动细胞死亡级联）中发挥关键作用。当休克发作后开始治疗时，PARP 抑制具有显着的保护作用。 Inotek 正在开发一种超强 PARP 抑制剂 (Ki = 15 nM)，在感染和血流动力学不稳定的 LD100 猪模型中，在大肠杆菌诱导的腹膜炎和感染性休克后施用，可将死亡率降低 50%。在健康的人类志愿者中，INO-1001 具有良好的耐受性且安全。在 1 期 SBIR 中，我们提议在 8 个受试者中开展一项试点单中心研究，重点关注 INO-1001 的安全性和 PK 特性。入组患者将包括以下患者：1) 感染性休克持续时间 < 24 小时，2) 发烧，3) 需要血管活性支持的低血压，4) 有腹腔内感染的证据，5) 24 小时内未进行手术。 INO-1001 的给药时间为 5 天，这是脓毒症诱发 MOF 的关键期。在 2 期 SBIR 中，我们将通过对 200 名符合与标准相同的患者进行 PARP 抑制的前瞻性、随机、双盲、安慰剂对照 IIb 期研究来证明 PARP 激活在临床败血性休克中的作用。试点研究。主要临床终点为：1) 安全性，2) INO-1001 的 PK，以及以下方面的降低：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 和血管加压剂/正性肌力药物需求）和心脏指数，(c) 肝功能功能不全（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，我们预计 INO-1001 将成为感染性休克患者安全、耐受性良好且有效的治疗方法。