Phase I Amount
$2,999,834
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.
Public Health Relevance Statement: Nikkomycin Z Treatment of Early Coccidioidal Pneumonia: Phase II Clinical Trial Project Narrative 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.
Project Terms: Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Active Follow-up; advanced age; Affect; African; African American; Afro American; Afroamerican; Aged 65 and Over; AIDS; Animals; anti-fungal; Antifungal Agents; Antifungal Drug; antifungals; Arizona; Armed Forces Personnel; Bacteria; base; Biological Terrorism; Bioterrorism; black American; Black or African American; Black Populations; Businesses; CAPS; capsule (pharmacologic); Capsules; Cell Wall; Chitin; Chitin Synthase; Chitin-UDP Acetylglucosaminyltransferase; Chronic; Chronic Disease; chronic disease/disorder; chronic disorder; Chronic Illness; Clinical; clinical investigation; Clinical Management; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Phase II; Clinical Trials, Unspecified; Clinical, Transplantation, Organ; Coccidioidomycosis; commercialization; cost; Development; Dose; Drug Approval; Drug Delivery; Drug Delivery Systems; Drug Formulations; Drug Targeting; Drug Targetings; Drug usage; drug use; drug/agent; Drugs; Early treatment; Early-Stage Clinical Trials; efficacy trial; Elderly; Elderly, over 65; elders; enroll; Enrollment; Enzyme Gene; febrile; febris; Fever; Filipino; follow-up; Food and Drug Administration Drug Approval; Formulation; Formulations, Drug; fungal infection; Fungicides, Therapeutic; fungus; Fungus Diseases; fungus infection; Future; Gene Deletion; gene deletion mutation; Generalized Growth; Genetic; geriatric; Grafting Procedure; Growth; Human; Human Genome; Human, General; Hyperthermia; Immunocompromised; Immunocompromised Host; Immunocompromised Patient; Immunologic Deficiency Syndrome, Acquired; immunosuppressed; Immunosuppressed Host; immunosuppressed patient; Infection; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; Investments; late life; later life; Life; Mammalia; Mammals; Mammals, General; Man (Taxonomy); Man, Modern; manufacturing process; manufacturing scale-up; Medical; medical attention; Medication; Methods; Military; Military Personnel; Modification; Morbidity; Morbidity - disease rate; Mycoses; Native Americans; neopolyoxin C; nikkomycin; nikkomycin X; nikkomycin Z; older adult; older person; ontogeny; organ allograft; organ graft; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; organ xenograft; Orphan; Orphan Disease; pathway; Pathway interactions; PBO; Persons; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; phase 1 study; phase 1 trial; Phase 2 Clinical Trials; phase 2 study; phase 2 trial; Phase I Clinical Trials; Phase I Study; phase I trial; Phase II Clinical Trials; phase II trial; Placebos; Play; Pneumonia; Pneumonitis; Pregnant Women; prevent; preventing; Price; pricing; Process; process optimization; protocol, phase I; protocol, phase II; public health relevance; Pulmonary Inflammation; Pyrexia; Research; response; Risk; Role; Safety; scale up; senior citizen; sham therapy; Sham Treatment; social role; Solutions; Source; Southwest U.S.; Southwest US; Southwestern United States; Streptomyces; study, phase II; Testing; Therapeutic; Time; Tissue Growth; Toxic effect; Toxicities; Training; trans-N-Acetylglucosaminosylase; Transplantation Surgery; UDP-N-acetyl-D-glucosamine[{..}]chitin 4-beta-N-acetylglucosaminyltransferase; Universities; Work
