A Randomized Phase 2A Clinical Trial Pioneering the Utility of an eNAMPT-Reducing Therapy in ARDS/VILI: the PUERTA Trial

一项随机 2A 期临床试验开创了 eNAMPT 减少疗法在 ARDS/VILI 中的应用：PUERTA 试验

• 批准号: 10581161
• 负责人: Joe G. N. Garcia
• 金额: $ 150万
• 依托单位: AQUALUNG THERAPEUTICS CORP.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581161
• 关键词: Achievement; Acute Respiratory Distress Syndrome; Address; Award; Bacterial Pneumonia; Binding; Bioreactors; COVID-19; COVID-19 pandemic; Clinical Trials; Continuous Positive Airway Pressure; Cyclic GMP; Development; Diagnosis; Dose; Double-Blind Method; Drug Kinetics; Excess Mortality; FDA approved; Family suidae; Half-Life; Hypoxemia; Incidence; Inflammation; Inflammatory; Investigation; Investigational Drugs; Ligation; Link; Lung; Mechanical Ventilators; Mechanical ventilation; Molecular; Monoclonal Antibodies; Multiple Organ Failure; NF-kappa B; New Drug Approvals; Nose; Patients; Pattern; Pharmacodynamics; Pharmacotherapy; Phase; Placebo Control; Placebos; Plasma; Pre-Clinical Model; Process; Proteins; Randomized; Rattus; Running; SARS-CoV-2 infection; Safety; Sepsis; Septic Shock; Severities; Severity of illness; Study Subject; TLR4 gene; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Trauma; Treatment Efficacy; Ventilator; Ventilator-induced lung injury; Viral Pneumonia; clinical research site; cohort; cytokine; cytokine release syndrome; druggable target; efficacy evaluation; efficacy study; extracellular; first-in-human; healthy volunteer; humanized monoclonal antibodies; lung injury; mortality; murine nodule inducing virus; nicotinamide phosphoribosyltransferase; novel; porcine model; primary endpoint; promoter; safety assessment; secondary endpoint; systemic inflammatory response; therapeutic target; ventilation

ABSTRACT The serious unmet need to address the excessive mortality observed in patients with Acute Respiratory Distress Syndrome (ARDS) has been brought sharply into focus by the current COVID-19 pandemic. In this R-44 application, Aqualung Therapeutics will address this therapeutic gap by utilizing a novel, humanized monoclonal antibody, ALT-100 mAb, which binds/neutralizes a novel ARDS target, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), to reduce ARDS/VILI severity. We have shown that eNAMPT functions as a DAMP (tissue damage-associated molecular pattern) that binds Toll-like receptor 4 (TLR4) to elicit profound NFkB- driven inflammation, processes we have shown to be involved in pathobiology of ARDS and mechanical ventilator-induced lung injury (VILI). Importantly, we demonstrated that eNAMPT is a highly druggable ARDS target with the ALT-100 mAb profoundly attenuating the cytokine storm and inflammatory lung injury in preclinical models of ARDS/VILI including a porcine model of septic shock-induced ARDS/VILI. We completed GLP IND-enabling pharmacokinetic (PK) studies (T1/2 half-life of 12-14 days) and toxicity studies (rats/pigs) which failed to identify any discernable level of toxicity even up to 50 mg/kg of ALT-100 mAb (28 day study). Importantly, we have completed CMC and a 200L cGMP Bioreactor run (expression 6 gms/L) generating sufficient mAb for completion of a first-in-human (FIH) Phase 1A safety ascending dose study clinical trial in healthy volunteers (beginning June 2022) and the Phase 2 A safety/efficacy study called PUERTA (Pioneering the Utility of eNAMPT-Reducing Therapies in ARDS/VILI) in ARDS subjects with sepsis, septic shock, trauma, bacterial or viral pneumonia, or COVID-19 infection. We anticipate FDA Investigational New Drug approval in Q2 2022 for the ALT-100 mAb as an ARDS therapeutic intervention. This R-44 award will support the PUERTA P2A trial of ALT-100 mAb in 90 severely hypoxemic subjects (2:1, ALT-100:placebo) with the diagnosis of moderate-to-severe ARDS (P/F <200) who are immediately treated with mechanical ventilation (MV), with high flow nasal O2 (HFNO) or non-invasive ventilation (NIV i.e. BIPAP/CPAP). SA #1 will assess safety, tolerability, and PK of ALT-100 mAb at 2 dose levels (1mg/kg or 4 mg/kg) compared to placebo. SA #2 will assess the capacity for ALT-100 mAb to reduce ventilator requirements (# ventilator-free days), the incidence of multi-organ failure (MOF), the need for MV in HFNO/NIV-treated ARDS subjects, and reductions in plasma cytokines i.e. pharmacodynamic effects [PD] SA #3 will assess predictive capacity of plasma eNAMPT levels and NAMPT SNPs in identifying PUERTA subjects who respond to single dose treatment with ALT-100. The R-44 PUERTA trial, overseen by our CRO, Prevail Infoworks and conducted at 5 academic clinical sites, will directly address the unmet need for novel ARDS therapies and confirm eNAMPT as a highly druggable therapeutic target for ARDS. Successful achievement of R-44 milestones will lead to further investigation of ALT-100 mAb in larger pivotal P2b/P3 studies to determine efficacy of treatment with ALT-100 mAb to reduce ARDS/VILI mortality.

摘要 严重未满足的需要解决急性呼吸窘迫患者的过高死亡率 当前的新冠肺炎大流行使急性呼吸窘迫综合征成为人们关注的焦点。在这架R-44中 应用，Aquung Treateutics将利用一种新型的人源化单抗来解决这一治疗缺口 ALT-100单抗，结合/中和新的ARDS靶标eNAMPT(细胞外烟酰胺) 磷酸核糖转移酶)，以减轻ARDS/VILI的严重程度。我们已经证明了eNAMPT起着阻尼器的作用 (组织损伤相关分子模式)结合Toll样受体4(TLR4)以诱导深刻的NFkB- 驱动炎症的过程，我们已经证明参与了ARDS的病理生物学和机械性 呼吸机相关性肺损伤(VILI)。重要的是，我们证明了eNAMPT是一种高度可下药的 ALT-100单抗靶向ARDS可显著减轻细胞因子风暴和炎性肺损伤 ARDS/VILI的临床前模型，包括感染性休克诱导的ARDS/VILI的猪模型。我们完成了 GLP Ind-Enabling药代动力学(PK)研究(T1/2半衰期为12-14天)和毒性研究(大鼠/猪) 该公司未能确定任何可识别的毒性水平，即使高达50 mg/kg的ALT-100单抗(28天研究)。 重要的是，我们已经完成了CMC和200L cGMP生物反应器的运行(表达式6 GMS/L)生成 足够的mAb用于完成首例人类(FIH)1A期安全递增剂量研究临床试验 健康志愿者(2022年6月开始)和名为普罗塔(开创性)的第二阶段安全性/有效性研究 ENAMPT减少疗法在ARDS/VILI中的应用 细菌性或病毒性肺炎，或新冠肺炎感染。我们预计FDA将在#年批准新药调查 2022年第二季度用于ALT-100单抗作为ARDS的治疗干预。这个R-44奖将支持普尔塔 90例严重低氧血症受试者(2：1，ALT-100：安慰剂)检测ALT-100单抗的临床试验 中重度ARDS(P/F&lt；200)，立即接受机械通气(MV)治疗，高度 鼻腔吸氧(HFNO)或无创呼吸机(NIV，即BiPAP/CPAP)。SA#1将评估安全性、耐受性、 ALT-100单抗在2个剂量水平(1 mg/kg和4 mg/kg)的PK与安慰剂比较。SA#2将评估 ALT-100单抗的能力，以减少呼吸机需求(#无呼吸机天数)、多器官并发症的发生率 衰竭(MOF)，接受HFNO/NIV治疗的ARDS患者是否需要MV，以及血浆细胞因子(即 药效学效应[PD]SA#3将评估血浆eNAMPT水平和NAMPT的预测能力 单剂量ALT-100治疗受试者的SNPs检测。R-44普鲁塔 由我们的CRO监督的试验，Pvive Infoworks，并在5个学术临床站点进行，将直接解决 对ARDS新疗法的需求尚未得到满足，并确认eNAMPT是一种高度可药物治疗的靶点 阿兹。R-44里程碑的成功实现将导致ALT-100单抗在更大范围内的进一步研究 关键的P2b/P3研究确定ALT-100单抗治疗降低ARDS/VILI死亡率的有效性。