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）：美国每年新增 50,000 例球孢子菌病（谷热）病例。这些疾病大多数是由于亚利桑那州和加利福尼亚州的居民、游客或军事人员在沙漠训练期间接触流行病所致。 2001 年亚利桑那州的医院费用超过 1,900 万美元，其中不包括误工时间或大量感染无需住院治疗的患者。球孢子菌属是 CDC 选择的药剂，过去曾被开发用于生物战。目前对该疾病的治疗仅部分有效，并且其本身无法根除感染部位的真菌，通常会在停止治疗时导致复发。 Nikkomycin Z 是一种几丁质合酶抑制剂，对球孢子菌具有最大的体外活性。作为球孢子菌病小鼠的口服实验疗法，它非常有效。值得注意的是，尼可霉素 Z 治疗导致小鼠病变部位的绝育。如果感染后早期服用尼可霉素 Z 也能在患者身上产生这种效果，那么尼可霉素 Z 就可以消除进行性、使人衰弱、有时甚至致命的疾病。此前，一家制药公司已向 FDA 提交了 IND 申请，并于 1997 年完成了初始 I 期（单剂量）安全性试验。仅由于财务原因，Nikkomycin Z 于 1996 年被出售并停止开发。 2005年，亚利桑那大学获得了该权利，现在是现有IND的申办者，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治疗球孢子菌病的总体药物开发计划。使用现有的 GMP 级尼可霉素 Z，我们建议对无并发症、通常为自限性球孢子菌肺炎患者进行 I/II 期研究。该研究的主要目的是评估尼可霉素 Z 重复口服给药 2 周的安全性、药代动力学和代谢。次要目标是收集有关尼可霉素 Z 可能治疗效果的探索性观察结果。通过对剂量递增阶段收集的数据进行药代动力学和药效学分析，将进行建模和临床试验模拟，以选择向其他受试者给药的单剂量。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药物的临床开发，使其成为最终商业开发的候选药物。