Nikkomycin Z treatment of early coccidioidal pneumonia: Phase II clinical trial

描述（由申请人提供）：球孢子菌病（谷热）是美国西南部特有的孤儿真菌感染，每年约有50,000人寻求医疗护理。它对居住在那里的印第安人的影响尤为严重，非洲裔美国人和菲律宾人更有可能受到严重感染。同样特别危险的还有免疫功能低下的病人，如艾滋病患者或器官移植接受者、孕妇、老年人和在流行的沙漠地区训练的军事人员。引起谷热的真菌是生物恐怖主义的潜在病原体。目前可用的医学治疗仅部分有效，不能治愈感染。Nikkomycin Z是一类抑制真菌细胞壁发育的抗真菌药物。这种药物的目标是几丁质合成酶，它在支持真菌生长方面发挥着重要作用，但在哺乳动物中没有发现几丁质，而制造几丁质的酶基因在人类基因组中也不存在。由于这种差异，尼克霉素Z的抗真菌作用应该是非常有选择性的，如果作为药物治疗给人服用，可能是非常安全的。在实验动物感染中，尼科霉素Z已被证明是有效的。在正在进行的多剂量人体安全性I期试验中，尼科霉素Z迄今显示出很少或没有毒性。我们的假设是，球虫感染的早期治疗可以安全地根除感染，从而防止严重的并发症，避免慢性发病率，而现在需要多年甚至终生使用常规药物治疗。我们需要继续进行临床试验，在人类身上验证这一假设。如果nikkomycin Z的商业化成功，Valley Fever Solutions的商业计划预计在NDA批准后的5年内年收入将达到2.5亿美元。为了吸引所需的制药投资，我们建议通过以下方式降低合作伙伴的开发风险：1)创造更便宜的制造工艺；2)将新工艺生产的药物用于人体初步疗效试验（FDA药物批准顺序中的“第二阶段”）。我们新的生产工艺是基于一种经过基因改造的产药细菌。这些修饰阻断了一种无活性代谢物（nikkomycin X）的合成，这使得以前提纯nikkomycin Z的效率非常低，而且价格昂贵。通过去除nikkomycin X，所需的步骤更少，并且在纯化过程中更多地回收生产的nikkomycin Z，从而降低了货物的总体成本。我们为第二个目标提出的临床试验将比较接受尼克霉素Z或安慰剂治疗三种不同剂量/持续时间之一的受试者组的治疗反应。这将为未来的关键试验提供基础。

DESCRIPTION (provided by applicant): Coccidioidomycosis (Valley Fever) is an orphan fungal infection endemic to the US southwest, for which approximately 50,000 persons seek medical attention each year. It disproportionately affects Native Americans who live there, and severe infections are much more likely in African-Americans and Filipinos. Also at particular risk are immunosuppressed patients such as those with AIDS or recipients of organ transplants, pregnant women, the elderly and military personnel who train in the endemic desert regions. The fungi that cause Valley Fever are potential agents of bioterrorism. Currently available medical treatments are only partially effective and do not cure infections. Nikkomycin Z is a first-in-class antifungal drug which inhibits fungal cell wall development. The drug's targets, chitin synthases, play important roles to support fungal growth but chitin is not found in mammals and the genes for enzymes that make chitin do not exist in the human genome. Because of this difference, effects of nikkomycin Z should be very selective for its antifungal effect and potentially very safe if administered to humans as a medical therapeutic. In experimental animal infections, nikkomycin Z has been shown to be curative. In ongoing multi-dose human safety Phase I trials nikkomycin Z has thus far showed little or no toxicity. Our hypothesis is that early treatment of coccidioidal infections will safely eradicate infection, thereby preventing serious complications and avoiding the chronic morbidity that now requires many years or even life-long treatment with conventional medications. We will need to continue clinical trials to test this hypothesis in humans. If commercialization of nikkomycin Z is successful, the Valley Fever Solutions business plan projects $250 million annual revenue within 5 years of NDA approval. In order to attract the needed pharmaceutical investment to do this, we propose to reduce the development risk for a partner by 1) creating a less expensive manufacturing process and 2) using the drug produced by the new process in an initial efficacy trial in humans ("Phase II" in the FDA drug approval sequence). Our new manufacturing process is based upon a strain of the drug-producing bacteria that we have genetically modified. The modifications have interrupted the synthesis of an inactive metabolite (nikkomycin X) that made the previous purification of nikkomycin Z very inefficient, and expensive. By eliminating nikkomycin X, fewer steps will be needed and more of the produced nikkomycin Z will be recovered in the purification process, thus reducing the overall cost of goods. The clinical trial that we propose for our second aim will compare therapeutic responses in groups of subjects receiving one of three different dose/durations of nikkomycin Z or placebo treatments. This should provide the basis for future pivotal trials. PUBLIC HEALTH RELEVANCE: This project will further the development of a new, potentially curative drug, nikkomycin Z, to treat the fungal infection, Valley Fever (coccidioidomycosis). A Valley Fever cure would be particularly valuable to groups disproportionately affected by infection such as African Americans, Filipinos, Native American peoples, persons with AIDS or other immunosuppressing conditions, the military, and the elderly. We propose to develop the methods to make this drug at an affordable price and to study the newly made nikkomycin Z in humans to identify and select effective doses for future studies.