University: Temple University
Startup Officer: Steve Nappi
- Pharmaceuticals and Medical
LytPhage and its collaborators at Temple University are developing novel antibiotic products that harness modified bacterial viruses (phage). They are an attractive alternative to synthetic and fermentation derived antimicrobials because phage can infect and kill only bacterial cells (and not mammalian cells). Early clinical evaluations of phage produced mixed results, but they are receiving attention again due to the increasing need for new pathogen control strategies, and due to recent advances in microbiology and gene manipulation that allow more effective phage to be developed. This platform technology can be applied to a long list of urgent clinical problems like resistant staph, pseudomonas, C. difficile, tuberculosis, and others. LytPhage’s initial product, LYT101, is a modified lytic E. faecalis phage. LYT101 will ultimately be used as an intravenously administered agent for the treatment of systemic blood born infections in patients following a positive test for vancomycin resistant E. faecalis (VRE). Future indications could include urinary tract, deep tissue and endocardial infections.
There are numerous advantages of phage therapy over conventional antibiotic treatment: (1) They are extremely specific, sparing commensal and beneficial microorganisms and preserving the normal microbial ecology; (2) They are bacteriocidal not bacteriostatic; (3) They are self-dosing, their concentration being determined by their ability to replicate within host bacteria at the site of infection; (4) They are inherently non-toxic to human cells; (5) They are not influenced by antibiotic resistance profiles since the bacteriocidal mechanisms of phages are different from that of any antibiotic. For all these reasons, phage therapy is now poised as a practical means of combating multidrug-resistant pathogens, including VRE.
Enterococcal infections are the 5th most common hospital-associated infection in the U.S. related to surgical and catheter procedures. E. faecalis is particularly associated with systemic blood born and urinary tract infections, but has also been isolated from dental root canal infections. Resistance to first-line β-lactam antibiotics, aminoglycosides, and vancomycin has been reported among strains of E. faecalis as early as the 1980s. More recently, resistance even to third and fourth line antimicrobials such as linezolid and daptomycin have been reported. It is widely recognized that the pipeline of new antibiotics is insufficient to meet current and anticipated needs: only two new systemic antibacterial agents were approved for use in humans by the FDA from 2008 – 2012. The rising tide of antibiotic resistance, and the stagnation of new antibiotics being developed, is rapidly leading to a crisis in our ability to combat multidrug resistant “SUPER BUG” infections.
LYT101 is originally derived from phage φEf11, isolated from a lysogenic E. faecalis strain cultured from an infected root canal, and recombined with several genes from prophage φFL1C that markedly increase its reproductive rate. In LYT101, we have also deleted all genes needed for lysogeny. The resulting agent is an exclusively lytic, highly virulent agent that, freed from lysogenic repression, has a broader range of E. faecalis host strains when compared with wild type φEf11. We have demonstrated the increased virulence of the recombined phage against E. faecalis (108 pfu/ml vs. 106 pfu/ml in the wild type) and the elimination of lysogenic activity in model bacterial systems. Furthermore, we have demonstrated that LYT101 can infect 33 E. faecalis strains out of a panel of 67 tested (the wild type can infect four). However, in order for LYT101 to be clinically useful, we will have to demonstrate that its host range can be expanded further to cover most or all E. faecalis strains. Furthermore, to justify continued development, we need to validate that LYT101 confers protection in vivo.
The development timeline for such an antibiotic therapy would be very rapid compared to other types of antibiotics and LytPhage project to be in the clinic by mid-2018 with potential exit opportunities by mid 2019.
LytPhage and Temple University have concluded an agreement enabling the company to further develop and commercialize LYT101, which was originally developed at the university. While LytPhage is a new start-up, its principals have more than 45 years of experience in commercial drug development, including of antimicrobials. The company will continue to collaborate with academic inventors, through whom specialized resources at Temple University will be made available. The project has previously received, and continues to receive support and guidance on technical and commercial development from mentors at Janssen Pharmaceuticals, which continues to have an interest in the technology. LytPhage has been selected to receive financial, business advisory and network, and facility support from Phase 1 Ventures, through the University City Science Center, a private non-profit business incubator in Philadelphia whose graduates collectively generate approximately $5 billion in sales revenues annually. LytPhage’s first-in-market phage product for treating E. faecalis infection is a fresh approach that will create much-needed disruption of the antimicrobial space. Once feasibility has been demonstrated, LytPhage is well positioned to leverage its platform technology to address a variety of other important human pathogens.