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)是一种美国西南部的孤儿真菌感染，每年约有50,000人寻求医疗护理。它对居住在那里的美洲原住民的影响不成比例，非洲裔美国人和菲律宾人更有可能受到严重感染。特别危险的还有免疫抑制患者，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接受训练的军事人员。引起山谷热的真菌是生物恐怖主义的潜在代理人。目前可用的治疗方法只有部分有效，不能治愈感染。尼可霉素Z是一种抑制真菌细胞壁发育的一线抗真菌药物。该药物的靶标甲壳素合成酶在支持真菌生长方面发挥了重要作用，但哺乳动物中没有发现甲壳素，人类基因组中也不存在制造甲壳素的酶的基因。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，如果作为药物治疗用于人类，可能非常安全。在实验动物感染中，尼克霉素Z已被证明是治愈的。在正在进行的多剂量人体安全I期试验中，尼可霉素Z迄今显示出很小的毒性或没有毒性。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，并避免目前需要用传统药物进行多年甚至终身治疗的慢性发病率。我们将需要继续进行临床试验，以在人体上测试这一假说。如果尼克霉素Z的商业化成功，山谷发烧解决方案业务计划预计在NDA批准后5年内实现2.5亿美元的年收入。为了吸引所需的药品投资，我们建议通过以下方式降低合作伙伴的开发风险：1)创建成本更低的制造工艺，2)将新工艺生产的药物用于人体初步疗效试验(FDA药物批准序列中的“第二阶段”)。我们的新制造工艺是基于我们经过基因改造的一种产药细菌。这些修饰已经中断了一种非活性代谢物(尼克霉素X)的合成，这使得以前对尼克霉素Z的提纯非常低效和昂贵。通过消除尼克霉素X，在纯化过程中需要的步骤更少，产生的尼克霉素Z将得到更多的回收，从而降低商品的整体成本。我们为第二个目的提出的临床试验将比较接受三种不同剂量/持续时间的尼克霉素Z或安慰剂治疗的受试者的治疗反应。这应该为未来的关键试验提供基础。 公共卫生意义：该项目将进一步开发一种新的、具有潜在疗效的药物--尼克霉素Z，用于治疗真菌感染--谷热(球孢子菌病)。对于受感染影响不成比例的群体，如非裔美国人、菲律宾人、美洲原住民、患有艾滋病或其他免疫抑制疾病的人、军人和老年人，山谷热疗法将特别有价值。我们建议开发方法，以负担得起的价格制造这种药物，并研究新制造的尼克霉素Z在人体上的应用，以确定和选择有效剂量，用于未来的研究。

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.