In 2020, CARB-X launched several Portfolio Acceleration Tools (PATs) to develop a higher-level understanding of common issues facing developers, create efficiencies across multiple funded product developers, and create potential funding calls around focused areas of innovation and development. Outcomes from the PATs are also intended to benefit the larger AMR community and accelerate the development of products for patients. Below are some examples.
Predictive and 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 is neither well-documented nor consistent, and 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.
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 scompounds using several dosing regimens in multiple preclinical models in an attempt to develop improved predictive models. These models could then be used by 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. 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 their development and integrate the information into their ongoing medicinal chemistry programs.
Susceptibility and Early Evaluation of Resistance Risks
During the process of antibacterial drug development, the molecule being developed is tested and evaluated against panels of bacterial strains. Bacteria evolve over time under selective pressure and develop ways to defend themselves against antibacterial drugs. New variants can emerge frequently which contributes to the growing threat of bacterial resistance. (Resistance is also growing due to the over-prescription of antibiotics; learn more about stewardship here.)
It is important to evaluate the level of activity of a compound against contemporary and diverse isolates to understand the potential breadth of coverage against a target species. If it is an early-stage program, it is important to set a baseline for hits so that there are guides for an optimization campaign.
To help developers evaluate their compounds against real-world contemporary isolates, and to understand the prevalence of resistance, CARB-X set out to evaluate a panel of recent, geographically-diverse strains. A panel of 3,000 isolates covering all the key WHO priority pathogens was assembled 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.).
Representative compounds from CARB-X developers who chose to participate were then 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 were free to publish, present, or use these data and analyses in their IND- and IND-equivalent applications. Furthermore, CARB-X also provided developers the opportunity to select and obtain isolates from the collection to facilitate follow-up studies if, for example, a particular strain showed reduced susceptibility to their compounds.
These isolates are also available to product developers in the portfolio who are advancing preventatives and diagnostics. Exemplary of the use case, CARB-X created blinded “challenge panels” for diagnostic developers to test the robustness of both species identification and antibiotic susceptibility early. This was done so that, if necessary, an optimization campaign would have clear areas of focus.
This PAT launched in 2021, and CARB-X plans to conduct similar studies when warranted by a critical mass of new compounds.
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 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, there are several geographic areas where access to genomic sequences from contemporary isolates is more limited. Working together with the Danish Technical University and SEQAFRICA (supported by The Fleming Fund) CARB-X is collecting and sequencing K. pneumoniae and S. aureus isolates across Africa.
In vivo Models of Translation
By creating standardized and reproducible animal models, better translation to human dose estimates and prediction of clinical success are possible. Ideally, methodologies can be published and any product developer could follow these methods in different laboratories around the world to demonstrate their “proof-of-concept”. Having readily-available strains of bacteria would also allow developers to use the same standard strains, further harmonizing these models.
There are several examples of animal efficacy models where CARB-X has an interest. CARB-X is exploring ways to develop standardized animal models that are reproducible with readily-available strains of bacteria. These could also show strong correlation of the performance of these models with clinical outcomes. Importantly, this includes an assessment of drugs that both succeeded and failed clinically to demonstrate sufficient efficacy. CARB-X chose to focus initially on models of respiratory infection since the majority of the CARB-X therapeutic portfolio aspires to treat hospital-acquired or ventilator-associated pneumonias. Additionally, Neisseria gonorrhoeae requires transmission from one human host to another to survive. This is a challenge to reproduce in animals because not every strain creates a strong infection in animals that can be used to test the efficacy of new drugs. Furthermore, drugs targeting Gram-negative bacteria often use Urinary Tract Infections (UTIs) as the entry indication. (Likewise, Gram-positive drugs often use Acute Bacterial Skin and Skin Structure Infections.) This is because populations with UTIs (and ABSSSIs) do not have a high mortality rate and because it is easier to recruit patients for these studies. While the ABSSSI animal models of infection have been robust predictors of success in human clinical studies, the UTI models have failed to predict successful outcomes in clinical trials. Finally, when testing drugs in infected animals and humans, developers use a pharmacokinetic/pharmacodynamic (PK/PD) study to determine the bacterial burden in the infected tissue in response to the administration of a drug dose over time. For a variety of indications, including UTIs, CARB-X is working with other AMR accelerators to develop the best model (e.g. thigh or lung, ascending track or direct inoculation of the kidney) and the best marker to indicate that it will yield success in the clinic.
An adjuvant is a substance that is paired with an antigen in a vaccine to provoke a stronger immune system response. Today, not many are approved for human use because they are not inert substances and need to be tested for safety before use. CARB-X is working with NIAID to gain access to novel adjuvants for CARB-X vaccine developers to use in their animal models. Issues of patenting a vaccine that uses adjuvants developed from public funds is a barrier that CARB-X is working to overcome.