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By Kristy Tsang, on 27 November 2023
In this interview as part of the Early Career Researchers series, recognising the amazing translational work being done by postdocs and non-tenured researchers at UCL, Dr Umberto Villani highlights his Repurposing Therapeutic Innovation Network (TIN) Pilot Data Scheme awarded project, developing a novel approach to repurpose tebipenem for paediatric typhoid fever.
My project is entitled ‘Dose rationale for tebipenem in paediatric typhoid fever’. Tebipenem was the first orally available carbapenem to be approved and is currently under the evaluation of the FDA. This class of antimicrobial compounds possesses exceptional activity against a wide range of Gram-positive and Gram-negative bacteria, and is being considered for the treatment of otitis, urinary and pulmonary infections. My proposal is to conduct an in silico evaluation of the treatment performance, i.e., to assess the probability of microbiological cure of paediatric patients diagnosed with typhoid fever. This would represent an opportunity for the repurposing of tebipenem for a neglected paediatric disease.
Increasing antimicrobial resistance is leading to higher rates of treatment failures and consequently to hospitalization and elevated mortality rates. With typhoid fever-causing bacteria becoming more resistant to commonly used antibiotics, there is a pressing need for the development of new effective oral therapies. In November 2016, an outbreak of extremely drug-resistant typhoid fever occurred in Hyderabad, Pakistan. The bacteria responsible for this outbreak were susceptible to only one oral antibiotic, azithromycin, leaving very limited treatment options for outpatients and in community settings. As a result, patients who did not respond to azithromycin treatment, or presented additional complications, required hospitalization and treatment with injectable carbapenems. Given the evidence of good antibacterial activity in in vitro protocols, tebipenem presents a concrete alternative to address an important unmet medical need that disproportionately affects low to middle-income (LMI) countries.
The Repurposing TIN Pilot Data Fund represented the perfect opportunity to explore the feasibility of using tebipenem for a new indication, i.e., a repurposing project. The funding provided by the Pilot Data Fund is allowing me to implement an in silico evaluation of selected dosing regimens, a required step for the optimisation of a prospective Phase II study in paediatric patients affected by typhoid fever. At the same time, the fund is also supporting an initial assessment of the feasibility of developing a new paediatric low-cost formulation specifically suited for LMI countries. As an early carrier scientist, participating in this scheme also offered an invaluable opportunity to network and expand skills on planning and scoping of research. I’ve participated in several training sessions with experienced mentors, which I think have been extremely helpful for my professional growth.
The entire selection process felt agile and efficient. In this sense, the TIN staff supporting candidates in submitting their application were very helpful, especially after identifying hiccups and issues. Moreover, before the final interview with the TIN panel for the grant award, I participated at the ACCELERATE workshop on pitching skills. Convincing people that your idea is worth being funded in 3 minutes is no easy task. Participating in this learning experience made me really realize how differently I needed to approach the presentation of my project, both from a visual and oral standpoint.
This project has two major milestones. The first one is the quantitative evaluation of the probability of pharmacological success of tebipenem in a clinical setting. Should this evaluation yield promising results, an optimized clinical study protocol will also be drafted as an output of the project itself. This objective will be accomplished by performing in silico clinical trials, considering both the microbiological susceptibility of Salmonella typhi (i.e. the pathogen which causes typhoid fever) to tebipenem and the pharmacokinetics of the compound. Secondly, as the drug will be relevant for LMI countries, throughout the duration of the project several new low-cost child friendly drug formulations will be investigated, to identify suitable options. This activity will be performed thanks to the collaboration with Prof. Mine Orlu’s group at Department of Pharmaceutics, within the School of Pharmacy.
Assuming favourable results at the end of the project, I would like the information generated during the duration of the TIN project to serve as the starting evidence on which to build a proposal for additional funding, to conduct the development of a new paediatric formulation and submit a proposal for a proof-of-concept study. To this end, liaising with funding organisations like the Bill & Melinda Gates Foundation, we will explore the opportunity for advancing the clinical development. Hopefully, the TIN network will be able to provide some support and guidance in pursuing such a route.
Dr Umberto Villani obtained a MSc Bioengineering (2018) from University of Padova, Italy. Between 2018 and 2022, he worked on a PhD project aimed at biophysical modelling of magnetic resonance images, which granted him a PhD in biomedical imaging applied to Neuroscience. Eager to apply his expertise in clinical drug development, he is now a post-doctoral fellow in Translational Pharmacology, a position held within a collaboration programme between the National Research Council (Rome, Italy) and the Clinical Pharmacology & Therapeutics Group at UCL. His current research interests lie in pharmacometrics and the development of novel quantitative approaches for the assessment of the efficacy of new antimicrobial drug combinations prior to their evaluation in humans.
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