Armata Pharmaceuticals Inc.’s recent $15 million award for a three-year program from the U.S. Department of Defense to partially fund a phase Ib/II study added to the already growing resurgence of notice for phage-based therapeutics, with even big pharma starting to take heed.

Marina Del Rey, Calif.-based Armata plans a randomized, double-blind, placebo-controlled, dose-escalation clinical study of AP-SA02 for the treatment of complicated Staphylococcus aureus bacteremia infections. The experiment will examine the safety and tolerability of AP-SA02 as an adjunct to best available antibiotics and help determine the right dose or doses for efficacy trials. Because of the COVID-19 pandemic, Armata doesn’t expect the trial to kick off before the middle of next year.

The three natural lytic phage that make up AP-SA01 were chosen for their ability to cover about 95% of S. aureus clinical isolates, including multidrug-resistant strains, Armata said. Human exposure obtained from two phase I studies and through use under investigator emergency IND showed that AP-SA01 was generally well-tolerated. Behind AP-SA01 for S. aureus is AP-SA02, believed to bring even better attributes. The CDC estimates that up to 1.7 million people in the U.S. develop bacteremia each year, with S. aureus the most commonly identified pathogen in both hospital- and community-acquired bloodstream infections. About 200,000 hospitalizations take place per year for people with S. aureus bacteremia. The mortality rate totals as much as 40% of all cases and 57% of patients over the age of 85.

Armata has a separate study with another candidate, AP-PA02 targeting Pseudomonas aeruginosa, on track to start enrolling later this year. The company is initially focused on cystic fibrosis (CF) patients. AP-PA01 was featured in Infection following the successful treatment of a CF patient who had developed a multidrug-resistant P. aeruginosa infection. Another success with AP-PA01 turned up in a 77-year-old patient with ventilated-associated pneumonia and empyema was described in the American Journal of Respiratory and Critical Care Medicine.

Phage therapy, which uses bacterial viruses to fight bacterial infections, has long been a known option, but weakened antibiotics brought particular focus to the field. The typical method deploys naturally occurring phages that can infect and lyse bacteria, but research has brought forth bioengineered phages and purified phage lytic proteins. “Doctors are not relying on big pharma to come up with antibiotics to treat antibiotic-resistant infection anymore,” noted Wainwright analyst Joseph Pantginis in a June note – and big pharma is turning to phage prospects.

New Brunswick, N.J.-based Johnson & Johnson (J&J), through its Janssen Pharmaceuticals Inc., is collaborating with customized phage specialist Biomx Ltd., of Ness Ziona, Israel, to apply the approach to the microbiome. J&J’s deal with another privately held firm, Research Triangle Park, N.C.-based Locus Biosciences Inc., made bigger headlines early last year, when the pair entered a deal to develop, manufacture and commercialize CRISPR/Cas3-enhanced bacteriophage products targeting two key bacterial pathogens for the potential treatment of infections of the respiratory tract and other organ systems. Locus banked $20 million in initial payments, and is eligible to receive up to a total of $798 million in potential future development and commercial milestone payments, plus royalties. Locus leverages Type I CRISPR/Cas3 system to shred the DNA of targeted bacteria cells, leaving the others alone.

An event hosted in June 2019 with key opinion leaders “revolved around how ready physicians and regulators are for phage therapies and the need to start with entering the clinic in carefully designed trials,” Pantginis recalled, pointing to the “critical importance of defining appropriate clinical endpoints (ideally with biomarkers) and accurately selected patients so that clear and definitive answers on the validity of phage therapies can be given.” Accumulating evidence “suggest[s] compelling efficacy and safety of phage treatment in defeating antibiotic-resistant infections,” in his view.

Later in 2019, researchers presented data at The Liver Meeting 2019 and published in Nature demonstrating that bacteriophages targeted to specific members of the microbiome could be useful in combating two liver diseases. At the conference, Biomx reported on targeting Klebsiella pneumoniae to fight primary sclerosing cholangitis. In the scientific journal, a team from the University of California at San Diego reported using the bacteriophage cocktail approach to destroy cytolysin-producing Enterococcus faecalis, which abolished the occurrence of alcoholic hepatitis in humanized mice.

More recently, PHAGE: Therapy, Applications, and Research published findings that suggest a phage-based approach could be useful against COVID-19. Specifically, doctors could limit the accumulation of fluid in the lungs by knocking down bacteria there. Author Marcin Wojewodzic, of the Cancer Registry of Norway in Oslo, said that “although further research is urgently needed, secondary bacterial infections in the respiratory system could potentially contribute to the high mortality rate observed among the elderly due to COVID-19,” and “the additional time needed for the human body's adaptive immune system to produce specific antibodies could be gained” by attacking bacteria. “Production of antibodies from the phage display techniques will have some costs of production but, owing to recent progress, the development should be simple.” Phages can be stored and transported easily, too. “I believe that bacteriophages have the potential to be a practical tool in mitigating the SARS-CoV-2 pandemic, especially in patients with secondary bacterial infection and high viral load,” he concluded.

In March of this year, Gaithersburg, Md.-based Adaptive Phage Therapeutics Inc., said the FDA cleared the IND for development of Phagebank, a personalized bacteriophage therapeutic for the treatment of MDR and complicated bacterial infections. The phase I/II trial represents the first study of an expanding phage library under FDA allowance for a multisite study of intravenous administration and/or bladder instillation of phage therapy, Adaptive said. In the 156-patient study, patients with neurogenic bladder and urinary tract infections will be enrolled and followed for bacterial eradication. Results from that cohort will be used to confirm or modify the phage dosing regimen before proceeding to patients with symptomatic infection at risk of recurrence.

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