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

描述（由申请人提供）：球孢子菌病（山谷热）是美国西南部特有的孤儿真菌感染，每年约有50，000人就医。它不成比例地影响居住在那里的美洲原住民，严重感染更可能发生在非洲裔美国人和菲律宾人身上。免疫抑制患者，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也特别危险。导致山谷热的真菌是生物恐怖主义的潜在代理人。目前可用的药物治疗仅部分有效，不能治愈感染。Nikkomycin Z是一种一流的抗真菌药物，可抑制真菌细胞壁发育。这种药物的靶点是几丁质酶，它在支持真菌生长方面发挥着重要作用，但几丁质在哺乳动物中并不存在，而人类基因组中也不存在制造几丁质的酶的基因。由于这种差异，尼可霉素Z的抗真菌作用应该是非常有选择性的，并且如果作为药物治疗剂施用于人类，可能非常安全。在实验动物感染中，尼可霉素Z已被证明是治愈性的。在正在进行的多剂量人体安全性I期试验中，尼可霉素Z迄今为止表现出很少或没有毒性。我们的假设是，球虫感染的早期治疗将安全地根除感染，从而防止严重的并发症，并避免慢性病，现在需要多年甚至终身治疗的传统药物。我们将需要继续进行临床试验，以在人类身上验证这一假设。如果尼可霉素Z的商业化成功，Valley Fever Solutions的商业计划预计在NDA批准后的5年内每年收入2.5亿美元。为了吸引所需的制药投资来实现这一目标，我们建议通过以下方式降低合作伙伴的开发风险：1）创建更便宜的制造工艺; 2）在人体初步疗效试验中使用新工艺生产的药物（FDA药物批准序列中的“II期”）。我们新的生产工艺是基于一种我们已经基因改造的产药细菌菌株。这些修饰中断了无活性代谢物（尼可霉素X）的合成，这使得先前的尼可霉素Z纯化非常低效且昂贵。通过消除尼可霉素X，将需要更少的步骤，并且在纯化过程中将回收更多的生产的尼可霉素Z，从而降低商品的总成本。我们提出的第二个目标的临床试验将比较接受尼可霉素Z或安慰剂治疗的三种不同剂量/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。 公共卫生相关性：该项目将进一步开发一种新的、有潜在治疗潜力的药物尼可霉素Z，用于治疗真菌感染山谷热（球孢子菌病）。治疗山谷热对受感染影响不成比例的群体特别有价值，如非洲裔美国人，菲律宾人，美洲原住民，艾滋病患者或其他免疫抑制条件，军人和老年人。我们建议开发以负担得起的价格生产这种药物的方法，并研究新生产的尼可霉素Z在人体中的作用，以确定和选择未来研究的有效剂量。

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.