Completion of IND-enabling studies required for first-in-human studies of a novel oral therapeutic agent for treating pulmonary fibrosis

完成用于治疗肺纤维化的新型口服治疗剂的首次人体研究所需的 IND 授权研究

• 批准号: 10584585
• 负责人: James Craig Hartman
• 金额: $ 70.9万
• 依托单位: MDI THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584585
• 关键词: Acute; Affinity; Alteplase; Animal Model; Cardiovascular system; Central Nervous System; Cessation of life; Chronic; Cicatrix; Clinical; Clinical Research; Collagen; Complex; Data; Disease; Disease Progression; Dose; Drug Kinetics; Enzyme Precursors; Enzymes; Epithelium; Etiology; Extracellular Matrix; Failure; Fibrinolysis; Fibronectins; Fibrosis; Gene Family; Genes; Heart Diseases; Hemostatic function; Human; Human Genetics; Hydrophobicity; Impaired wound healing; In Vitro; Inflammation; Injury; Interstitial Lung Diseases; Investigational Drugs; Investigational New Drug Application; Kidney Diseases; Lead; Lung; Lung diseases; Lung fibrogenesis; Macaca fascicularis; Medical; Modeling; Monoclonal Antibodies; Mus; Natural Products; Oral; Organ; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Physiological; Physiology; Pirfenidone; Plasma; Plasmin; Plasminogen; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Plasminogen Activator Interaction; Plasminogen Inactivators; Play; Process; Proliferating; Pulmonary Fibrosis; Resolution; Respiratory Failure; Role; Safety; Serine Proteinase Inhibitors; Serpins; Specificity; Syndrome; System; Systemic Scleroderma; Telemetry; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Toxicokinetics; Toxicology; Urokinase; Vitronectin; cofactor; commercialization; drug candidate; fibrotic lung disease; first-in-human; high throughput screening; idiopathic pulmonary fibrosis; in vivo; inhibitor; innovation; interest; member; mortality; mouse model; nintedanib; novel; novel therapeutics; pre-clinical; preclinical study; programs; pulmonary function; repaired; skin disorder; small molecule; small molecule inhibitor; success; therapeutic target; wound healing

MDI Therapeutics is an early-stage pharmaceutical company developing a new class of small molecule inhibitors of plasminogen activator inhibitor-type 1 (PAI-1) (gene: SerpinE1) for the treatment of fibroproliferative diseases. Fibrosis is defined by the excessive accumulation of components of the extracellular matrix (ECM), such as collagen and fibronectin, in and around inflamed or damaged tissue, which can lead to permanent scarring, organ malfunction and, ultimately, death. Nearly 45% of all deaths in the developed world are attributed to some type of chronic fibroproliferative disease. In patients with acute and chronic fibrotic lung disease there is a marked induction of PAI-1. PAI-1 is best understood for its role regulating fibrinolysis and wound healing by inhibiting the tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, which convert the zymogen plasminogen to the active enzyme plasmin. The role of PAI-1 as a primary regulator of wound healing, including in the lung, is consistent with its critical regulatory role in fibrosis. Wound healing is a natural repair process after injury that consists of overlapping stages, including hemostasis, inflammation, proliferation and matrix synthesis, and finally resolution. Disruption of this ordered process can result in impaired wound healing, leading to persistent inflammation and/or matrix synthesis and ultimately to a fibrotic syndrome. PAI-1, as a primary regulator of wound healing has been shown to impact all stages of wound healing, and accordingly to play a causal role in pulmonary fibrogenesis. MDI Therapeutics has developed a highly effective, orally active, small molecule inhibitor of PAI-1, MDI-2517, with demonstrated efficacy in multiple models of pulmonary fibrosis. The studies proposes here will provide critical IND-enabling data for this novel therapeutic necessary for filing an Investigational New Drug (IND) application prior to conducting first-in-human Phase 1 clinical studies of the first-in-class PAI-1 inhibitor (MDI- 2517) for the treatment of pulmonary fibrosis. Specific milestones include completion of key GLP safety pharmacology, pharmacokinetics and toxicology studies required for submission of an Investigational New Drug (IND) application for MDI-2517. The successful completion of these milestones will significantly advance this program toward commercialization by providing data necessary for the start of human Phase 1 clinical trials.

MDI Therapeutics是一家早期制药公司，开发了新的小分子抑制剂 纤溶酶原激活剂抑制剂类型1（PAI-1）（基因：Serpine1）用于治疗纤维增生性疾病。 纤维化是由细胞外基质（ECM）的分量过多积累来定义的，例如 胶原蛋白和纤连蛋白，在发炎或受损的组织中及其周围，可能导致永久性疤痕， 器官故障，最终死亡。发达国家的所有死亡中，近45％归因于某些人 慢性纤维增生性疾病的类型。在患有急性和慢性纤维化肺部疾病的患者中，有一个明显的 PAI-1的诱导。最好通过抑制纤维蛋白溶解和伤口愈合的作用来理解PAI-1 组织型（TPA）和尿激酶型（UPA）纤溶酶原激活剂，它们将酶原纤溶酶原转化为 活性酶纤溶酶。 PAI-1作为伤口愈合的主要调节剂，包括肺中的伤口愈合剂 与其在纤维化中的关键调节作用一致。伤口愈合是受伤后的自然修复过程 包括重叠阶段，包括止血，炎症，增殖和基质合成，最后 解决。这种有序过程的破坏可能导致伤口愈合受损，导致持久 炎症和/或基质合成，并最终与纤维化综合征。 PAI-1，作为伤口的主要调节剂 愈合已被证明会影响伤口愈合的所有阶段，因此在肺中起因果作用 纤维发生。 MDI Therapeutics已经开发了一种高效，口服的小分子抑制剂，PAI-1， MDI-2517，在多种模型的肺纤维化模型中证明了功效。研究提出的研究将 为提交研究新药（IND）所需的这种新颖的治疗方法提供关键的辅助数据（IND） 在进行人类第一阶段的第一阶段临床研究之前 2517）用于治疗肺纤维化。特定的里程碑包括完成密钥GLP安全性 提交研究性新药所需的药理学，药代动力学和毒理学研究 （IND）MDI-2517的申请。这些里程碑的成功完成将大大推动这一点 通过提供人类1期临床试验开始必要的数据来实现商业化的计划。