DHA26BZ01-DV005 — Development of Small Molecules with Antifungal Properties for Safe Use in Human Patients (Direct to Phase II)

Award Maximum: $1,400,000 Period of Performance: 24 months Phase Type: Direct to Phase II (DP2)

OBJECTIVE: This topic is intended for technology proven ready to move directly into Phase II and accepts Direct to Phase II proposals only. The proposed research will focus on identifying compounds with broad-spectrum activity against clinically relevant fungal pathogens while minimizing toxicity to humans. The primary objective is to identify a small molecule with fungicidal properties that are safe for human use, with FDA clearance.

DESCRIPTION: Fungal infections represent a growing global health challenge, particularly among immuno-compromised individuals. Invasive fungal infections caused by pathogens such as Candida species, Aspergillus species, Fusarium species, and Mucor species are associated with high morbidity and mortality rates. Fungal infections are associated with 130k hospitalizations, 13 million outpatient visits, and result in a financial burden of $19 billion on the civilian health care sector. Fungal wound infections in particular are also growing challenge for the military. Despite the availability of antifungal agents, current treatments are often limited by toxicity, drug resistance, and narrow-spectrum activity. The emergence of multidrug-resistant fungal strains, such as Candida auris, has further exacerbated the need for novel antifungal therapies. Small molecules with antifungal properties offer a promising avenue for addressing these challenges. Their ability to target specific fungal pathways, combined with the potential for oral bioavailability and low manufacturing costs, makes them ideal candidates for therapeutic development. However, significant scientific and technical hurdles remain with the discovery and optimization of small molecules that are both effective against fungal pathogens and safe for human use. Qualified proposals should identify small molecules with antifungal properties from an existing library. These small molecules should be active against all of the following fungi: Fusarium species, Aspergillus species, Candida auris, or Mucorales species. Qualified molecules will have antifungal activity at nanomolar concentrations. Further, these small molecules must have a cytotoxicity profile similar, or better than Amphotericin B.

PHASE I: This topic is intended for technology proven ready to move directly into Phase II. Therefore, the offeror must demonstrate and provide documentation to substantiate that the scientific and technical merit and feasibility described in Phase I has been met and describes the potential commercial applications. Documentation must include all relevant information including, but not limited to technical reports, test data, prototype designs/models, and performance goals/results.

Demonstrate screening of existing chemical libraries or other sources to identify a single or multiple candidate compounds with antifungal properties in vitro. The chemical candidate or candidates must demonstrate antifungal activity at nanomolar concentrations. Acceptable routes of administration are topical and systemic. Further, in vitro cell culture conditions, the chemical candidate or candidates must be as or less cytotoxic than Amphotericin B, as measured by a lactate dehydrogenase assay or similar test. Multiple candidates can be included in Phase II.

PHASE II: During this phase, the lead antifungal candidate or candidates should be optimized into a viable treatment option in vivo. The cytotoxicity must be screened against a skin organoid model and compared to Amphotericin B. The efficacy of the candidate antifungal or antifungals must be tested in these organoid models to determine if the fungal burden is reduced by at least 100-fold. Further, testing on small animals should be completed to ensure that the candidate antifungal or antifungals can reduce fungal burden in vivo. In vivo studies using a wound model are encouraged. Operational effectiveness must be demonstrated in this phase, with evaluations of the product's stability in austere conditions (temperatures ranging from -32 to 49 ℃). An optimal shelf life in these conditions is one year; a minimum acceptable shelf life is 6 months. The regulatory strategy for this product or products should be clearly defined with a detailed plan to obtain FDA clearance.

PHASE III DUAL USE APPLICATIONS: This phase is critical as it transitions the prototype from an advanced development stage to a fully viable concept ready for real-world military and civilian use. The company should develop partnerships that adhere to Quality Management System (QMS) requirements to demonstrate and commercialize the technology in civilian relevant settings, such as hospitals and clinics. The company should also investigate other funding opportunities with other government agencies, such as Congressionally Directed Medical Research Programs (CDMRP) and Biomedical Advanced Research and Development Authority (BARDA), that may be interested in supporting the development and commercialization of this technology. The goal of this phase is to secure FDA approval. This phase should include testing in large animal models and randomized clinical trials under formal institutional protocol approval. The candidate antifungals must be optimized for a shelf life of one year in austere environments. Once fully developed the antifungal should be positioned for use in both civilian and military settings. The selected offeror is responsible for making the product accessible to potential military and civilian users. Coordinate with military customers to establish a National Stock Number.