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Predictive & Translatable Nephrotoxicity Models
Nephrotoxicity is a common side effect of many classes of antibacterial drugs.
Though there is plenty of literature on nephrotoxic drugs, thorough evaluations of the extent of toxicity are neither well-documented nor consistent. The “killer” combination of in vitro and in vivo assays to assess baseline nephrotoxicity and to guide optimization remains elusive.
Knowledge of the nephrotoxicity of a certain drug can be a competitive advantage for companies developing similar drugs. If a competitor learns the extent to which the competition’s drug is toxic after years in development, they can incorporate that knowledge into development of their own drug and catch up to the competition. As such, historically it has often been in drug developers’ interests not to share nephrotoxicity data.
These data would provide developers with guidance on how to test their compounds to determine which ones are likely to be nephrotoxic, so that they can more quickly discontinue the development of those compounds and integrate the information into their ongoing medicinal chemistry programs.
As CARB-X’s first PAT, CARB-X sought to take groups of known compounds – including candidates that had failed in development, in human clinical trials and in use in the market today – and to test these compounds using several dosing regimens in the multiple preclinical models to develop improved predictive models. These models could then be used by product developers to compare the toxicity of their compounds.
SRI International, supported by the US National Institute of Allergy and Infectious Diseases (NIAID), has now launched an additional effort to build on this foundational work. Rat and mouse models have been tested, and the best models and dosing regimens are under comparative assessment.
Susceptibility and Early Evaluation of Resistance Risks
To develop antibacterial products, product developers must test whether their compounds are effective against real-world bacterial isolates and assess potential resistance risks early.
Many companies do not have access to globally diverse and contemporary isolates to understand whether their product inhibits real-world isolates.
Evaluating microbiological activity of investigational molecules against real-world bacterial isolates is key to identifying pre-existing resistance risk and providing important data to benchmark against clinically used comparator compounds.
This PAT concludes with the ability of product developers to select and acquire a subset of isolates with unique resistance patterns to enable full characterization and support compound optimization and development.
These isolates are also available to diagnostics and preventatives product developers. The strain panel composition is also being shared externally so that non-CARB-X researchers can access the same IHMA strain panels for their research.
CARB-X launched this PAT in 2021 by assembling a panel of 3,000 isolates covering key priority pathogens from 67 different countries including many low-and middle-income countries (LMICs). All isolates had been collected in 2019 from a variety of clinical samples (blood, sputum, urine, etc.) CARB-X product developers who chose to participate in the PAT had representative compounds tested against these panels along with a large number of comparator drugs already on the market. Susceptibility data and population analyses were provided to CARB-X developers on their compounds along with all the clinical comparators. These data afforded them an understanding of what differentiated their compounds from clinically used comparators. They are free to publish, present, or use these data and analyses in their IND- and IND-equivalent applications. CARB-X repeated this PAT in 2024. The strains came from patients with a variety of infection types that had been isolated in 2022 or 2023.
Please see research below that utilized this PAT published by CARB-X portfolio product developers.
Antigen Conservation and Epidemiology
To develop a vaccine, product developers must select which antigenic substance elicits a protective immune response to add to their vaccine.
One challenge vaccine developers face is to ensure that their antigen is sufficiently conserved across diverse representative strains of the bacterial species they are targeting.
Genome sequencing is a powerful way to understand the level of conservation and epidemiological relatedness of different isolates. Seeking a way to help product developers obtain an early understanding of antigenic variation that may exist, CARB-X developed this PAT.
The whole genome sequence data and associated susceptibility information will be added to our curated database to improve the customized bioinformatics support that is available to CARB-X product developers. This helps developers understand the level of conservation of antigens included in the vaccine product and the level of target conservation around small-molecule targets from a geographically diverse and epidemiologically distinct set of strains.
CARB-X leveraged its partnerships to begin building databases of genomic sequence information from nearly 7,000 isolates of the key priority pathogens along with key metadata. Customized bioinformatic work packages are performed for the product developers to help them in their epidemiological understanding. CARB-X is continuing to build and expand these databases; however a significant gap exists with access to genomic data of contemporary isolates from many African countries. CARB-X has initiated a collaboration with the University of KwaZulu-Natal to collect and characterize clinical isolates of key bacterial species from countries across Africa. This work will initially focus on the collection of four key species (K. pneumoniae, E. coli, S. aureus, and A. baumannii) from different clinical indications with a strong focus on bloodstream isolates to support CARB-X programs focused on neonatal sepsis.
Animal Models of Translation
Pre-clinical animal models of infection are essential in developing antibiotic agents as well as building the required Pharmacokinetic-Pharmacodynamic (PKPD) understanding between drug exposure and pharmacological benefit. They enable proof-of-concept efficacy investigations and provide valuable information for clinical dose projections.
But extensive discrepancies exist, particularly in pneumonia models. A lack of methodological standardization with these models, the varying behavior of different bacterial strains in these models, and individual antibiotic characteristics make translating observed drug effect to clinical efficacy difficult. This makes it difficult to reproduce data and compare results across laboratories.
A standard pneumonia model would help solve these problems by making uniform: antimicrobial efficacy data interpretation, and selection of dosing regimens with a translational value.
This standardized model benefits both CARB-X product developers and the entire antibacterial drug development ecosystem by creating a standardized, validated model to measure against, creating a better baseline comparison for the effectiveness of therapeutics in preclinical development. This preclinical data will underpin a research program that is positioned to produce positive results in clinical development for lung infections.
CARB-X built upon the work of a consortium of other researchers to develop and standardize lung infection model. CARB-X and the Center for Anti-Infective Research and Development (CAIRD) at Hartford HealthCare Research published research validating the animal lung models by establishing consistent experimental methods using panels of bacterial strains. Researchers validated the model using controlled compounds whose clinical efficacy in the treatment of lung infections is understood.
The results have been published and plans to deposit the strains in globally accessible repositories are in progress. Please see the four-part publication series below:
Decolonization
Many infections, especially those in vulnerable populations, can result from multidrug-resistant (MDR) bacterial pathogens harbored in an individual’s gastrointestinal (GI) microbiome. Therefore, decolonization of the GI tract may help prevent the onset of such infections which can be difficult to treat.
Several CARB-X-funded products aim at preventing breakthrough infections in colonized patients and decreasing person-to-person transmission in healthcare settings. However, regulatory and clinical development paths for these products are not well-established, increasing the risk for investment in product development and regulatory approval.
This PAT is intended to contribute to the design of pivotal studies for the approval of new decolonization agents.
Effective decolonization of the GI tract of vulnerable patient populations can potentially reduce the incidence of infection, and the spread of infection in hospital settings. By reducing colonization, clinicians can prevent the spread of infection in hospital settings and antibiotic resistance. The findings from this PAT and its studies can inform individual patient counseling, future decolonization innovation, clinical trial design, and regulatory approval of new decolonization agents.
CARB-X, in collaboration with researchers from Massachusetts General Hospital, Tufts Medical Center, and Duke University, is undertaking a three-pronged approach to support the development of novel decolonization agents. The first prong is a systematic review to learn what is known about clinical outcomes from colonization by MDR pathogens. The second is conducting an infection control survey to understand how infection control practices vary across healthcare settings. The third is developing microbiological methods to quantify the burden of colonization by MDR pathogens in the background of the host microbiome and support endpoints from decolonization interventions.
Please see the publications below aimed at facilitating the clinical development of novel products, such as decolonization agents, where regulatory paths are not well defined.
STI Diagnostics
Diagnostic developers rely on a range of sample types throughout the product development process to evaluate and refine assay performance.
Contrived samples are often used for early assay development, which differ from clinical samples that come directly from patients. While contrived samples are valuable for early assay development, they cannot fully capture the biological variability and complexity of real patient specimens. As a result, performance challenges may not become apparent until later stages of development, when testing with clinical samples typically begins.
This PAT is intended to provide diagnostic developers with a reliable supply of well-characterized clinical samples for testing as soon as they have a working assay.
This PAT allows diagnostic developers to begin testing sooner and against a wide number of pathogen sources, before their full diagnostic device has been developed. It also provides a stronger sample to test against compared to contrived samples. By providing earlier access to clinical samples, this PAT enables diagnostic developers to assess and optimize diagnostic performance under real-world conditions, helping identify potential product performance issues sooner and increasing confidence as products advance toward clinical validation and commercialization.
CARB-X, in collaboration with the University of Alabama Birmingham, provides this PAT to diagnostic developers. The University of Alabama Birmingham collects patient samples, including vaginal, urine, anorectal, and pharyngeal. The clinical samples are collected using swabs and buffers designated by the diagnostic developers. Diagnostic developers can choose the cadence at which they receive and test against samples and whether fresh or frozen samples are used. The University of Alabama Birmingham provides reference test data generated from testing at their facility against a regulatory-approved standard assay. Diagnostic developers receive clinical data associated with each of the samples provided and have multiple samples from each patient. While most diagnostic developers have been focused on initially developing assays using urine or vaginal swabs, testing can be done against other sites known for STIs. Therefore, developers have the option to further expand their diagnostic test to accommodate other clinically relevant sites, supporting the development of more comprehensive STI diagnostics for point of care use.
Superiority Clinical Trial Design Considerations
A superiority trial is a clinical study conducted to determine if a new drug performs clinically better than the current standard of care or a placebo.
For some nontraditional antibacterial products, a superiority trial may be necessary to demonstrate how the new therapy provides an added clinical benefit when it is used in conjunction with standard-of-care antibiotics. Demonstrating the added benefit requires careful trial design because standard-of-care antibiotic treatment is already highly effective. In a superiority trial, success is typically defined by demonstrating a statistically significant clinical improvement over standard of care. However, because ethical considerations require that both groups in the trial receive effective treatment, the additional benefit of an add-on therapy may not be fully captured by traditional endpoints, such as 28-day all-cause mortality.
This PAT is intended to provide a framework for antibacterial product developers to consider when designing a superiority trial for a nontraditional therapeutic product.
This PAT provides one of the first practical frameworks for designing superiority clinical trials for novel antibacterial products, particularly nontraditional approaches such as phages, lysins, antibodies, and antivirulence therapies. This can help product developers generate meaningful evidence showing the benefit of a new therapy being used alongside standard-of-care antibiotics.
This PAT outlines key considerations for superiority trial design, including patient selection, endpoints, overall trial design, and regulatory engagement.