Angiotensin Analogs to Treat Wound Healing

描述(申请人提供)：美国人患有糖尿病、压力和静脉淤积性溃疡相关的慢性伤口。在许多情况下，慢性伤口可能需要数年时间才能愈合，复发率很高，每年将导致54,000名患者截肢。据估计，美国有220万患者患有对传统疗法无效的慢性溃疡。在美国Biotest公司与南加州大学凯克医学院的科学家合作进行的临床前研究中，血管紧张素已被证明能有效地促进伤口愈合。在第二阶段的SBIR拨款中，美国生物测试公司开发了USB001(NorLeu3-A(1-7)在2%HEC和防腐剂中)，这是一种适合临床研究的血管紧张素多肽配方。USB001被发现是稳定的，局部使用安全，在促进糖尿病小鼠伤口愈合方面比Regranex更有效。其中大部分数据是在IND前与FDA的一次会议上审查的，当时US Biotest的临床开发计划被批准为IND备案。此外，US Biotest确定了NorLeu3-A(1-7)在伤口愈合中的治疗反应基因和两个潜在的分子作用机制。在我们的第二阶段SBIR拨款和我们的IND(FDA于2006年7月11日批准)所建立的基础上，US Biotest正在提交一份竞争性延续申请，以启动临床试验，以评估USB001的S的安全性和有效性，足以建立概念验证。在具体目标1中，我们将在正常志愿者(N=9)中进行I期安全性研究，并在我们的LC/MS/MS分析中测量NorLeu3-A(1-7)的毒代动力学和药代动力学样品。在具体目标2中，我们将制造无菌USB001，并在糖尿病合并慢性溃疡的患者中进行II期剂量反应研究(3组，每组25名研究对象)。在具体目标3中，我们将完成启动第三阶段临床研究所需的临床前安全性研究。血管紧张素类似物治疗伤口愈合糖尿病是一种疾病，在美国估计有2000万人患有糖尿病(国家糖尿病信息中心，2005年)。糖尿病的并发症包括慢性皮肤溃疡，由于持续的伤口感染，往往会导致截肢和生命损失。美国生物测试公司的先导化合物NorLeu3-A(1-7)在临床前研究中被证明比FDA批准的唯一治疗糖尿病溃疡的药物Regranex有效得多。这是我们第二阶段SBIR的竞争性延续，将使US Biotest能够进行临床疗效的第一阶段和第二阶段研究。开发一种成功的治疗糖尿病溃疡的方法将保持和提高生活质量，并降低医疗保健成本。

DESCRIPTION (provided by applicant): Americans suffer from chronic wounds associated with diabetic, pressure and venous stasis ulcers. In many cases, chronic wounds can take years to heal, have a high recurrence rate and will result in amputations for 54,000 patients annually. It is estimated that 2.2 million patients in the United States have chronic ulcers that don't respond to conventional therapies. Angiotensin peptides have been shown to effectively promote wound healing in preclinical studies undertaken at US Biotest, Inc. in collaboration with scientists at USC KECK School of Medicine. In a Phase II SBIR grant, US Biotest developed USB001 (NorLeu3-A(1-7) in 2% HEC and preservatives), an angiotensin peptide formulation appropriate for clinical study. USB001 was found to be stable, safe for topical use and more effective than Regranex in facilitating wound healing in diabetic mice. Much of this data was reviewed during a pre-IND meeting with the FDA when US Biotest's clinical development plan was approved for IND filing. In addition, US Biotest identified treatment responsive genes and two potential molecular mechanisms of action for NorLeu3-A(1-7) in wound healing. Building upon the foundation established in our Phase II SBIR grant and our IND (approved by FDA on July 11, 2006), US Biotest is submitting a competing continuation to initiate clinical trials for evaluation of USB001's safety and efficacy sufficient to establish proof of concept. In Specific Aim 1, we will conduct a Phase I safety study in normal volunteers (N=9) and measure toxicokinetic and pharmacokinetic samples in our LC/MS/MS assay for NorLeu3-A(1- 7). In Specific Aim 2, we will manufacture sterile USB001 and conduct a Phase II dose response study in diabetic patients with chronic ulcers (3 groups of 25 study subjects per group). In Specific Aim 3, we will complete preclinical safety studies required to initiate Phase III clinical studies. Angiotensin Analogs to Treat Wound Healing Diabetes is an illness that plagues an estimated 20 million individuals in the United States (National Diabetes Information Clearinghouse, 2005). Complications of diabetes include chronic skin ulcers that often lead to amputation and loss of life due to persistent wound infection. US Biotest's lead compound, NorLeu3-A(1-7), has been shown in pre-clinical studies to be significantly more effective than Regranex, the only FDA-approved drug for healing diabetic ulcers. This competing continuation of our Phase II SBIR will allow US Biotest to conduct Phase I and II studies of clinical efficacy. Development of a successful treatment for diabetic ulcers will preserve and improve quality of life as well as reduce health care costs.