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

尼可霉素 Z 治疗早期球孢子菌肺炎：II 期临床试验

基本信息

批准号：
7925199
负责人：
JOHN N GALGIANI
金额：
$ 299.98万
依托单位：
VALLEY FEVER SOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-08 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7925199
关键词：
Acquired Immunodeficiency Syndrome Affect African African American Animals Antifungal Agents Arizona Bacteria Bioterrorism Businesses Cell Wall Chitin Chitin Synthase Chronic Chronic Disease Clinical Clinical Management Clinical Trials Coccidioidomycosis Development Dose Drug Approval Drug Delivery Systems Drug Formulations Drug usage Early treatment Elderly Enrollment Enzyme Gene Fever Filipino Future Gene Deletion Genetic Growth Human Human Genome Immunocompromised Host Infection Investments Life Mammals Medical Methods Military Personnel Modification Morbidity - disease rate Mycoses Native Americans Organ Transplantation Orphan Orphan Disease Pathway interactions Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Phase II Clinical Trials Placebos Play Pneumonia Pregnant Women Price Process Research Risk Role Safety Solutions Source Southwestern United States Streptomyces Testing Therapeutic Time Toxic effect Training Universities Work base capsule commercialization cost efficacy trial follow-up fungus immunosuppressed inhibitor/antagonist innovation manufacturing process manufacturing scale-up medical attention nikkomycin nikkomycin X phase 1 study phase 2 study prevent process optimization public health relevance response scale up

项目摘要

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.

描述（由申请人提供）：球孢子菌病（谷热）是美国西南部流行的一种孤儿真菌感染，每年约有 50,000 人就医。它对居住在那里的美洲原住民造成了不成比例的影响，非洲裔美国人和菲律宾人更容易受到严重感染。同样面临特别风险的是免疫抑制患者，例如艾滋病患者或器官移植接受者、孕妇、老年人和在流行沙漠地区训练的军人。引起山谷热的真菌是生物恐怖主义的潜在媒介。目前可用的医疗方法仅部分有效，并且不能治愈感染。 Nikkomycin Z 是一种一流的抗真菌药物，可抑制真菌细胞壁的发育。该药物的靶标几丁质合酶在支持真菌生长方面发挥着重要作用，但哺乳动物中没有发现几丁质，人类基因组中也不存在制造几丁质的酶基因。由于这种差异，尼可霉素 Z 的抗真菌作用应该具有很强的选择性，并且如果作为医学治疗剂用于人体，可能非常安全。在实验动物感染中，尼可霉素 Z 已被证明具有治疗作用。在正在进行的多剂量人体安全 I 期试验中，尼可霉素 Z 迄今为止显示出很少或没有毒性。我们的假设是，球孢子菌感染的早期治疗将安全地根除感染，从而预防严重的并发症并避免目前需要使用常规药物进行多年甚至终生治疗的慢性发病率。我们需要继续进行临床试验，以在人体中检验这一假设。如果 Nikkomycin Z 的商业化成功，Valley Fever Solutions 业务计划预计在 NDA 批准后 5 年内年收入将达到 2.5 亿美元。为了吸引实现这一目标所需的制药投资，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“第二阶段”）。我们的新制造工艺基于我们经过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，使得之前尼可霉素 Z 的纯化效率非常低且昂贵。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产生的尼可霉素 Z，从而降低商品的总体成本。我们为第二个目标提出的临床试验将比较接受三种不同剂量/持续时间的尼可霉素 Z 或安慰剂治疗之一的受试者组的治疗反应。这应该为未来的关键试验提供基础。公共健康相关性：该项目将进一步开发一种新的、潜在的治疗药物尼可霉素 Z，用于治疗真菌感染谷热（球孢子菌病）。山谷热的治疗方法对于受感染影响较大的群体尤其有价值，例如非裔美国人、菲律宾人、美洲原住民、艾滋病患者或其他免疫抑制疾病患者、军人和老年人。我们建议开发方法以可承受的价格生产这种药物，并在人体中研究新制造的尼可霉素 Z，以确定和选择未来研究的有效剂量。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A practical and scalable manufacturing process for an anti-fungal agent, Nikkomycin Z.

DOI：
10.1021/op3003294
发表时间：
2013-02-15
期刊：
Organic process research & development
影响因子：
3.4
作者：
Stenland CJ;Lis LG;Schendel FJ;Hahn NJ;Smart MA;Miller AL;von Keitz MG;Gurvich VJ
通讯作者：
Gurvich VJ