Evaluation of a Novel Connexin-Based Peptide for the Treatment of Diabetic Wounds

新型连接蛋白肽治疗糖尿病伤口的评价

• 批准号: 9202629
• 负责人: Gautam Sudhir Ghatnekar
• 金额: $ 85.28万
• 依托单位: XEQUEL BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9202629
• 关键词: Advanced Development; Adverse event; American; Amino Acids; Amputation; Area; Award; Biological Assay; Biological Products; Biomedical Engineering; Blinded; Blood specimen; C-terminal; Caliber; Capital; Caring; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Cicatrix; Clinical; Clinical Trials; Connexin 43; Connexins; Debridement; Dermal; Detection; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic wound; Diagnosis; Dose; Evaluation; Expenditure; Extravasation; Family suidae; Fibrosis; Funding; Gangrene; Gel; Grant; Granulation Tissue; Growth Factor; Healthcare; Healthcare Systems; Hospitalization; Human; Immune; Impairment; Incidence; Industry; Infection; Inflammation; Inflammatory; Injury; Lead; Lower Extremity; Mediation; Medicine; Methods; Miniature Swine; Morbidity - disease rate; Multicenter Trials; National Institute of Diabetes and Digestive and Kidney Diseases; New Drug Approvals; Ohio; Patients; Peptides; Phase; Phase II Clinical Trials; Phenotype; Privatization; Process; Proteins; Publishing; Quality of life; Randomized; Recommendation; Recovery; Refractory; Regenerative Medicine; Research; Research Design; Risk; Rivers; Rodent; Role; Safety; Signal Transduction; Skin Substitutes; Skin wound; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Therapeutic; Thick; Time; Tissues; Topical application; Toxic effect; Toxicokinetics; Toxicology; Treatment Cost; Treatment Efficacy; United States National Institutes of Health; Wound Healing; base; chronic wound; clinical development; conventional therapy; cost; cost effective; design; healing; healthy volunteer; improved; malignant breast neoplasm; mechanical properties; meetings; mortality; novel; novel therapeutics; patient home care; preclinical study; programs; prospective; regenerative; research and development; response; standard of care; wound; wound closure

Project Summary An estimated 347 million people worldwide have diabetes, including over 29.1 million Americans. A major cause of morbidity and hospitalization in patients with diabetes is diabetic foot ulceration (DFU), which can result in infection, amputation, prolonged hospitalization, and costly treatments. Diabetes treatments cost the American healthcare system ~$245 billion annually, representing 20% of the total healthcare expenditure; and DFU treatment consumes ~50% of these costs. Chronic diabetic wounds remain stalled in the initial inflammatory phase of wound healing and remain unresponsive to conventional treatments. Current treatment approaches tend to have limited to marginal efficacy and high cost. A large unmet need exists for safe, cost- effective therapeutics that are easily applied in the home care or clinical setting and conform to practice of medicine in DFU care without reducing efficacy. FirstString Research, Inc., a clinical stage biopharmaceutical company, is advancing the development of novel bioengineered peptides based on the C-terminus of connexin proteins; a protein with important roles in the wound healing process. Our lead peptide, aCT1 (25 amino acids) based on connexin43, has demonstrated a unique capability of switching the body's healing response from excessive inflammation and scarring to a healthy regenerative stage. With the assistance of SBIR/STTR grants and significant private funding, FirstString has developed aCT1 in a topical product called Granexin® gel (Granexin); obtained IND approval; and demonstrated its mechanism of action, safety, and efficacy in a Phase 1 (N=48) and three Phase 2 clinical trials (N=276). Tissue injuries treated with Granexin show clinically and statistically significant faster healing, reduced inflammation, and improved mechanical properties without treatment related adverse events. FirstString has received Phase IIb SBIR funding to continue clinical development and evaluate the efficacy and safety of Granexin in a larger clinical trial currently underway. During the End of Phase 2 meeting, the FDA requested a 9-month repeat dose pig study as an integral part of Granexin's NDA (New Drug Approval) review process, in line with FDA's Guidance for Industry in the development and approval for chronic wound therapeutics. The Specific Aim of this CRP SB1 project is to conduct a standard 39-week repeat dose GLP dermal toxicity study of Granexin® gel in the Göttingen mini-pig followed by a 14-day recovery. Subaim 1 involves the assessment of the safety of repeat topical dosing of Granexin at low (100 μM), medium (200 μM), and high (500 μM) concentrations, with appropriate controls, on skin wounds that will be rewounded every 15 days. Subaim 2 will involve the toxicokinetic analysis of aCT1 peptide and assessment of systemic exposure. This study is similar to our previously conducted 92-day repeat dose toxicity study in pigs. Successful completion of this aim will fill in a necessary gap in obtaining NDA approval for Granexin from the FDA and support the eventual market launch of Granexin for the treatment of DFUs.

项目摘要 估计全球有3.47亿人患有糖尿病，其中包括超过2910万美国人。一个 糖尿病患者发病和住院的主要原因是糖尿病足溃疡（DFU），这是 可能导致感染，截肢，长期住院和昂贵的治疗方法。糖尿病治疗费用 美国医疗保健系统每年约2450亿美元，占医疗保健总支出的20％； DFU治疗消费约为这些费用的50％。慢性糖尿病伤口在最初停滞不前 伤口愈合的炎症阶段，对常规治疗无反应。当前治疗 方法往往仅限于边际效率和高成本。对于安全，成本 - 在家庭护理或临床环境中轻松应用的有效治疗剂，并符合实践 DFU护理中的药物，而无需降低效率。 Firststring Research，Inc。是一家临床阶段生物制药公司，正在推进发展 基于连接蛋白的C末端的新型生物工程辣椒；具有重要作用的蛋白质 伤口愈合过程。我们的铅肽Act1（25个氨基酸）基于connexin43，已证明 从过度炎症和疤痕转换为 健康的再生阶段。在SBIR/STTR赠款和大量私人资金的协助下， FirstString已在称为Granexin®凝胶（Granexin）的局部产品中开发了ACT1；获得了IND批准； 并证明了其在1阶段（n = 48）和三阶段2临床的作用机理，安全性和效率机理 试验（n = 276）。用granexin治疗的组织损伤在临床和统计上更快地愈合， 炎症减少，并改善了与治疗相关的不良事件的机械性能。 Firststring已获得IIB SBIR阶段资金，以继续临床开发并评估 在目前正在进行的较大临床试验中，granexin的功效和安全性。在第二阶段会议结束时， FDA要求进行9个月的重复剂量猪研究，作为Granexin NDA的组成部分（新药 批准）审查过程，符合FDA在慢性发展和批准方面的行业指导 伤口治疗学。这个CRP SB1项目的具体目的是进行标准的39周重复 göttingenmini-pig中Granexin®凝胶的剂量GLP真皮毒性研究，然后进行14天 恢复。 Subaim 1涉及评估在低处的granexin重复局部给药的安全性（100 μm），培养基（200μm）和高（500μm）的浓度，具有适当对照，在皮肤伤口上 每15天重新围绕一次。 Subaim 2将涉及对ACT1胡椒和评估的毒性分析 全身暴露。这项研究类似于我们先前进行的92天重复剂量毒性研究 猪。成功完成此目标将填补从中获得NDA批准Granexin的必要差距 FDA并支持Granexin最终推出DFU的市场。