Fungal CETR Projects

Project 1
PI: Terry Roemer, Ph.D.
Primary Organization/ Commercial entity: Prokaryotics
Development of a first-in-class antifungal agent to treat Candidiasis and Candidemia
Widespread azole resistance among Candida spp. along with a rise in clinical cases of multidrug resistant
(MDR) Candida auris and Candida glabrata that are resistant to azoles and echinocandins highlights the need for an entirely new class of antifungal therapeutics effective in overcoming MDR Candidemia and disseminated Candidiasis. This project will develop a mechanistically novel, intravenous-administered antifungal agent to treat life-threatening hospital associated Candidemia and Candidiasis infections caused by MDR Candida albicans and non-albicans yeast spp., including C. auris and C. glabrata.

Project 2
PI: David Perlin, Ph.D.
Primary Institution: HMH-CDI
Commercial Partner: Scynexis
A novel ‘fungerp’ targeting refractory Candida urinary tract infections
Urinary Tract Infections (UTIs) caused by fluconazole-resistant Candida isolates, including Candida auris and Candida glabrata, are a growing problem and pose a challenge with a lack of optimal treatments, as most current antifungals are ineffective in this disease because of their lack of ability to concentrate in urine. Our commercial partner SCYNEXIS has developed a platform of triterpenoid antifungal structures, the first-generation, IBX, was recently approved for vulvovaginal candidiasis, and the goal of this program is to develop a novel, next-generation triterpenoid compound with distinguishing features that allow it to concentrate into urine at therapeutic levels following oral administration to overcome this unmet medical need.

Project 3
PI: Arturo Casadevall, M.D., Ph.D.
Primary Institution: Johns Hopkins University
Monoclonal Antibody Therapeutics for Candida auris
Candida auris is a new fungal pathogen that is rapidly spreading in the United States. C.
auris infections are associated with high mortality and mortality and the fungus is resistant to
two of the three major classes of antifungal drugs. This application proposes to develop
immunotherapy for C. auris in the form of monoclonal antibody therapy. The development of
monoclonal antibody therapy would be a major advance against this pathogen that would
circumvent the problems of drug resistance and provide new therapeutic options for affected
patients.

Project 4
PI: David Alland , M.D.
Primary Institution: Rutgers University
Commercial Partner: Cepheid
Near patient detection of pathogenic candida species directly from blood and urine for rapid treatment response
This project will develop a highly specific, sensitive, rapid, and easy to use point of care test to rapidly detect infections from Candida including a key type of drug resistance. This research will benefit public health by increasing the speed that these infections can be detected and ensuring that the best treatments will be used. 

Pharmaceutical-style Cores

Pharmacology and Mycology Core
PIs: Vidmantas Petraitis, M.D. and Milena Kordalewska, Ph.D.

The CETR Pharmacology and Mycology (Pharm/Myco) Dual Core was established to provide comprehensive in vitro and in vivo assessments of antifungal efficacy and pharmacologic suitability of novel compounds undergoing advanced lead optimization for selection of preclinical development candidates (PDCs) and entry into IND enabling and de-risking studies. The Core provides timely assessments of key drug attributes including pharmacokinetics (PK), pharmacodynamics (PD), absorption, distribution, metabolism, and excretion (ADME), tiered toxicology, other key parameters, as well as microbiologic support to facilitate metric-based ‘go, no-go’ assessments of compounds for PDC selection and IND-enabling studies. The Pharm/Myco Core functions as an integrated component of the overall drug accelerator, which involves close interactions with all Projects and Cores.
Vidmantas.Petraitis@hmh-cdi.org
Matthew.Zimmerman@hmh-cdi.org

Medicinal Chemistry Core
PIs: James Merritt, Ph.D. and Joel Freundich, Ph.D.

The Medicinal Chemistry Core (MCC) will provide synthetic and medicinal chemistry, cheminformatics, and structure-based design resources complementary to those existing within the respective project teams. It will integrate tightly with the other Cores. The MCC resource will distinguish itself by relying on extensive pharmaceutical medicinal chemistry experience in antifungals melded with academic strengths in drug discovery and development. Critically, the MCC staff leadership has demonstrated an ability to produce drug candidates by evolving small molecules to address a wide range of problems encountered during the lead optimization process. Overall, the spectrum and depth of the MCC staff's industrial and academic background will prove critical to their ability to optimize leads within the individual projects to molecules with significant potential for positively impacting the antifungal clinical landscape to address the global health crisis.

James.Merritt@hmh-cdi.org
freundjs@njms.rutgers.edu

Animal Models Core 
PIs: Andrew Nelson, DVM and Barry Krieswirth, Ph.D.

Evaluating the efficacy of candidate compounds against drug resistant fungal pathogens in robust and reproducible animal models of infection is critical to advancing these compounds towards preclinical candidacy. To contribute to the rapid development of such medical countermeasures, the Animal Model Core will provide clinically relevant systemic, pulmonary, and urinary tract fungal infection models. Specifically, the Aims of the core are to 1) assess lead compounds against high threat fungal pathogens including Candida spp. and A. fumigatus in small animal infection models and 2) provide state of the art analytical services on host response and fungal bio-burden distribution to assess and quantify lead compound treatment efficacy. The Core leverages the AAALAC accredited, 40,000 sq ft Center for Discovery and Innovation Research Animal Facility (CDI RAF), which has dedicated space for the study of BSL2 pathogens.

Andrewm.Nelson@hmh-cdi.org
Barry.Kreiswirth@hmh-cdi.org

Administrative Core
PI: David Perlin, Ph.D.

The Administrative Core will play a crucial role in optimizing research operations and resource allocation through a lean framework that closely integrates Project Leaders and Core Directors. This centralized organization will facilitate seamless communication across multiple entities and manage all operational aspects of the Projects and Cores, ensuring efficiency and cohesion. We will provide a comprehensive support system for grant management and commercialization efforts. This includes solutions for secure data sharing and intellectual property protection, administrative systems for reporting and fiscal management, and communication protocols for collaboration and dissemination of secure and public data, as well as project reviews and updates. We will also provide support for product development, and regulatory compliance, ensuring successful initiatives. The administrative structure ensures maximal efficiency in project execution by streamlining operations and resource allocation. A robust plan led by experienced drug development experts and a world-class Scientific Advisory Board (SAB) helps guide drug candidate development and evaluate progression metrics. Pharma-style decision making with clear 'go, no-go' criteria will be used to expedite and prioritize promising candidates. External regulatory support aids in navigating requirements for pre-IND, IND-enabling and 510(k) submissions. These efforts strengthen the administrative core of the CETR-based accelerator. By leveraging the expertise of academic and industry partners and establishing a robust administrative infrastructure, we aim to combat drug-resistant fungal pathogens. This comprehensive administrative approach embodies our commitment to advancing research and translating discoveries into impactful solutions for patients.

Madhuvika Murugan, Ph.D.
Madhuvika.Murugan@hmh-cdi.org