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

项目摘要 据估计，全世界有3.47亿人患有糖尿病，其中包括超过2910万美国人。一 糖尿病患者发病和住院的主要原因是糖尿病足溃疡（DFU）， 可能导致感染、截肢、住院时间延长和治疗费用昂贵。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处理消耗了这些成本的约50%。慢性糖尿病伤口在最初的 伤口愈合的炎症阶段，并保持对常规治疗无反应。当前治疗 这些方法往往局限于边际功效和高成本。存在大量未满足的需求，安全，成本- 容易在家庭护理或临床环境中应用并符合以下实践的有效疗法： 药物在DFU护理中不会降低疗效。 FirstString Research，Inc.，一家临床阶段的生物制药公司，正在推进开发 基于连接蛋白C-末端的新型生物工程肽;连接蛋白是一种在 伤口愈合的过程我们的先导肽，aCT 1（25个氨基酸）的基础上连接蛋白43，已经证明， 一种独特的能力，将身体的愈合反应从过度炎症和疤痕转变为 健康的再生阶段。在SBIR/STTR赠款和大量私人资金的帮助下， FirstString开发了一种名为Granexin®凝胶（Granexin）的局部产品中的aCT 1;获得IND批准; 并在1期（N=48）和3个2期临床试验中证明了其作用机制、安全性和疗效。 试验（N=276）。用Granexin治疗的组织损伤显示出临床上和统计学上显著的更快愈合， 减少炎症和改善机械性能而没有治疗相关的不良事件。 FirstString已获得IIb期SBIR资金，以继续进行临床开发并评估 目前正在进行的一项更大规模的临床试验中评估Granexin的疗效和安全性。在第二阶段结束会议期间， FDA要求进行一项为期9个月的重复给药猪研究，作为Granexin新药申请的一个组成部分 批准）审查过程，符合FDA在开发和批准慢性 创伤治疗学。本CRP SB 1项目的具体目标是进行标准的39周重复 Granexin®凝胶在哥廷根小型猪中的剂量GLP皮肤毒性研究，随后进行14天 复苏Subaim 1涉及以低（100 μM）、中等浓度（200 μM）和高浓度（500 μM），以及适当的对照品， 每15天就会被再次伤害。Subaim 2将涉及aCT 1肽的毒代动力学分析和评估 全身暴露。本研究与我们之前在美国进行的92天重复给药毒性研究相似， 猪这一目标的成功完成将填补Granexin在获得NDA批准方面的必要空白， 并支持Granexin用于治疗DFU的最终上市。

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.