Nikkomycin Z Treatment for Coccidioidomycosis

尼可霉素 Z 治疗球孢子菌病

• 批准号: 7187295
• 负责人: JOHN N GALGIANI
• 金额: $ 22.54万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7187295
• 关键词: clinical trials; infection; metabolism; model; orphan disease /drug; pharmacokinetics

DESCRIPTION (provided by applicant): Each year there are 50,000 new U.S. cases of coccidioidomycosis (Valley Fever). The majority of these illnesses occur as a result of endemic exposure in Arizona and California to residents, tourists, or military personnel during desert training. The 2001 Arizona hospital costs were over $19 million which do not include lost time from work or the large number of persons whose infections are managed without hospitalization. Coccidioides species are CDC select agents and in the past have been agents developed for bio-warfare. Current therapies for this disease are only partially effective and in themselves are unable to eradicate the fungus from sites of infection, commonly resulting in relapses when treatment is discontinued. Nikkomycin Z is a chitin synthase inhibitor with its greatest in vitro activity against Coccidioides. It is very effective as oral experimental therapy in mice with coccidioidomycosis. Notably, nikkomycin Z treatment resulted in sterilization of the murine lesions. If this effect could also be produced in patients when administered early after infection, nikkomycin Z could eliminate the progressive, debilitating, and sometimes lethal forms of disease. Previously, a pharmaceutical company had filed an IND with the FDA, and by 1997 had completed an initial phase I (single-dose) safety trial. Nikkomycin Z was sold and development was halted in 1996, solely due to financial reasons. In 2005, the University of Arizona acquired the rights, is now the sponsor of the existing IND, and now intends to continue nikkomycin Z development. We propose to first develop an overall drug development plan for nikkomycin Z as a therapy for coccidioidomycosis. Using existing GMP-grade nikkomycin Z, we propose to conduct a phase I /ll study in patients with uncomplicated, usually self-limited, coccidioidal pneumonia. The primary objective of the study is to evaluate safety, pharmacokinetics, and metabolism of nikkomycin Z administered for 2 weeks as repeated oral doses. A secondary objective is to collect exploratory observations regarding the possible therapeutic effect of nikkomycin Z. Using pharmacokinetic and pharmacodynamic analyses of data collected during this dose escalation stage, modeling and clinical trial simulations will be undertaken to select a single dose for administration to additional subjects. By carrying out the proposed work, we will resume the clinical development of nikkomycin Z as a potentially curative therapy for coccidioidomycosis so that it may become a candidate for final commercial development.

描述（由申请人提供）：美国每年有50，000例新的球孢子菌病（山谷热）病例。这些疾病大多数是由于亚利桑那州和加州的居民、游客或军事人员在沙漠训练期间暴露于地方病而发生的。2001年亚利桑那州的医院费用超过1 900万美元，这还不包括工作损失的时间，也不包括大量的感染者不住院治疗。球孢子菌属物种是CDC选择剂，并且在过去已经被开发用于生物战。目前对这种疾病的治疗仅部分有效，并且本身无法从感染部位根除真菌，通常在治疗停止时导致复发。Nikkomycin Z是一种几丁质合成酶抑制剂，在体外对球孢子菌具有最大的活性。它是非常有效的口服实验治疗小鼠球孢子菌病。值得注意的是，尼可霉素Z治疗导致鼠病变的绝育。如果这种效果也可以在感染后早期给药的患者中产生，尼可霉素Z可以消除进行性的，使人衰弱的，有时是致命的疾病形式。此前，一家制药公司已向FDA提交了IND，并于1997年完成了初步的I期（单剂量）安全性试验。Nikkomycin Z于1996年被出售，并仅因财务原因而停止开发。2005年，亚利桑那大学获得了权利，现在是现有IND的赞助商，现在打算继续尼可霉素Z的开发。我们建议首先制定尼可霉素Z作为球孢子菌病治疗药物的总体药物开发计划。使用现有的GMP级尼可霉素Z，我们建议在无并发症的、通常为自限性的球虫性肺炎患者中进行I /II期研究。本研究的主要目的是评价尼可霉素Z重复口服给药2周的安全性、药代动力学和代谢。次要目的是收集关于尼可霉素Z可能的治疗效果的探索性观察结果。将使用在该剂量递增阶段收集的数据的药代动力学和药效学分析，进行建模和临床试验模拟，以选择单次给药至其他受试者。通过开展拟议的工作，我们将恢复尼可霉素Z作为球孢子菌病潜在治疗方法的临床开发，使其成为最终商业开发的候选药物。