Nikkomycin Z Treatment for Coccidioidomycosis

描述（由申请人提供）：美国每年有50,000例新的球孢子菌病（谷热）病例。这些疾病大多是由于亚利桑那州和加利福尼亚州的居民、游客或在沙漠训练期间的军事人员的地方性接触而发生的。2001年亚利桑那州的医院费用超过1 900万美元，这还不包括失去的工作时间，也不包括大量没有住院治疗的感染者。球虫是疾病控制与预防中心选择的代理人，过去曾被开发用于生物战。目前针对这种疾病的治疗方法仅部分有效，而且本身无法从感染部位根除真菌，通常在停止治疗时导致复发。Nikkomycin Z是体外抗球虫活性最高的几丁质合成酶抑制剂。对球虫病小鼠口服实验治疗效果显著。值得注意的是，尼克霉素Z治疗导致小鼠病变的绝育。如果在感染后早期给药也能产生这种效果，尼克霉素Z可以消除进行性、衰弱性，有时甚至致命的疾病。此前，一家制药公司向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。1996年，Nikkomycin Z被出售，开发停止，完全是由于财政原因。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nikkomycin Z的开发。我们建议首先制定尼科霉素Z作为球虫真菌病治疗药物的总体开发计划。使用现有的gmp级nikkomycin Z，我们建议在无并发症、通常自限性球虫性肺炎患者中进行I /ll期研究。该研究的主要目的是评估尼克霉素Z作为重复口服给药2周的安全性、药代动力学和代谢。第二个目标是收集关于尼克霉素z可能的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，以选择单一剂量用于其他受试者。通过开展所提出的工作，我们将恢复nikkomycin Z作为球孢子菌病潜在治疗药物的临床开发，使其可能成为最终商业开发的候选药物。

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.