Development of Personalized Bacteriophage Therapeutic for the Treatment of Bacterial Infections
Multidrug antibiotic resistance is an emerging medical challenge that is reaching crisis proportions. Existing antimicrobials are losing their efficacy, and the drug development pipeline for traditional small molecule antimicrobials (antibiotics) is limited in new alternative candidates. One alternative to traditional antibiotics for treatment of bacterial infections is bacteriophage therapy.
Bacteriophages (phages) are viruses that specifically attack bacteria. Since their discovery a century ago, phages have been contemplated as potential therapeutic agents. However, the immature science of bacteriophage microbiology at the time, followed by the discovery and development of conventional antibiotics, diverted attention from bacteriophages. Now with the growing failure of antibiotics, bacteriophages are being reconsidered as therapeutic agents.
One key feature of bacteriophages is their host specificity. Any given bacteriophage typically will infect only a single species of bacteria, and indeed often has a restricted host range within that species, where naturally occurring genetic diversity of the host limits the bacteriophage to a subset of bacterial strains. Furthermore, it is common in a susceptible bacterial population for genetic variants to occur that gain resistance to the bacteriophage. These two points can significantly constrain the efficacy of a bacteriophage therapeutic: a single bacteriophage or defined combination of bacteriophages is unlikely to work against all clinically presented infections, and infections against which a bacteriophage therapeutic might initially be effective can ultimately overcome treatment through the emergence of a resistant subclone.
This program seeks to overcome both these failure points by using a precision medicine approach for delivering bacteriophage therapy. A submitted proposal should recognize and include means to overcome the genetic diversity of MDR bacterial clinical pathogens, and the possible emergence of phage-resistant bacterial variants during the course of precision bacteriophage treatment. At a minimum, a successful precision strategy will address both these concerns and thus help enable bacteriophage therapy to become a practical solution to the treatment of bacterial infections.
This precision medicine approach to bacteriophage therapeutics also faces a challenging product development and production pathway. Given the complexity of phages themselves and the inherent novelty of clinical, bacteriophage-based precision therapeutic approaches, US FDA requirements, including Pharmaceutical Quality/Chemistry, Manufacturing, and Controls (CMC), will entail demanding characterization and production procedures. The regulatory environment for licensure of a precision phage product is incompletely defined and as yet untested. The logistics of case-by-case design of a precision phage therapeutic and delivery to bedside in a clinically useful timeframe needs to be established. The prototyping effort sought here is intended to help resolve all these aspects of the clinical development of precision bacteriophage therapeutics for antimicrobial applications.
The goal of this research is to develop and optimize all aspects of practical precision bacteriophage therapy treatment(s) through clinical development to the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA). As understood, a “precision bacteriophage therapy treatment” refers to achieving reliable efficacy of a phage therapy by treating bacterial infections with phage therapeutics that are in some way customized to the individual cases being treated. As elaborated below, aspects of a bacterial infection that might require individual customization include the genetic diversity of circulating pathogens, and the potential for phage-resistant variant subcultures to arise in the course of treatment. Clinical questions to be addressed include determination of the ability of precision bacteriophage therapy to avoid or overcome emergence of bacterial resistance to therapeutic bacteriophages and assessment of systemic responses in human subjects following treatment with antimicrobial bacteriophage therapy. Practical questions to be addressed include assessment and improvement of the clinical feasibility of delivering a precision bacteriophage therapeutic, in terms of timely and high-quality design, production, and delivery of the characterized phage therapeutic; and development and demonstration of Current Good Manufacturing Practice (cGMP) production for clinical-grade bacteriophages suitable for use as a precision bacteriophage investigational / clinical therapeutic.
The research project award recipient was selected from the Offerors who responded to MTEC’s Request for Project Proposals (19-06-Phage).