The overuse of broad-spectrum antibiotics has led to the development of multi-resistant bacterial strains, rendering antibiotics useless in the treatment of many infectious diseases.
As bacteriophages have re-emerged in recent times and the potential of phage or phage-derived products being used in a clinical setting is beginning to be understood, there remain several unique challenges associated with this novel therapeutic agent. These challenges range from a developing regulatory landscape and the design of clinical trials to the up-scaling of manufacturing processes are just a few of the roadblocks holding back development.
On March 23–25, hundreds of drug developers, academics, and clinical researchers united online to progress fundamental bacteriophage research into clinically-significant products by addressing the main translation challenges from the characterization of phages through to clinical development. The 3rd Bacteriophage Therapy Summit brought together a broad range of emerging phage sectors with a comprehensive list of subjects, including practicality considerations, clinical strategies, and funding concerns.
The end-to-end, specialized virtual meeting discussed preclinical and clinical development, formulation and manufacturing, regulation, and market delivery to address the clinical challenges of this niche area of phage research.
Establishing a regulatory approval path for phage products
One major focus of the meeting was to gain an understanding of the path required to reach regulatory approval of bacteriophage products in both the U.S. as well as the EU with presentations from Cara Fiore, PhD, of the FDA’s Office of Vaccines Research & Review and Jean-Paul Pirnay, PhD, at the Queen Astrid Military Hospital (QAMH) in Brussels, Belgium. They both discussed how to tackle the long and winding road from phage research to phage production and authorized phage applications in patients.
Fiore gave a general overview of FDA-regulated biological products and how phage therapy fits into this. She spoke about the regulatory considerations for use of phage therapy products in clinical trials intended to support licensure, “essentially, if you’re trying to get your phage into people and you want to move it forward in development.”
Fiore also spoke about expanded access use, or compassionate use of phage therapy products. “We do see a lot of this, and we think that we could partner with you to move phage therapy forward and into development.”
There were several questions for Fiore about whether phages would be evaluated as a probiotic treatment versus microbiome modulator.
“Depending on how you word it will determine whether or not we regulate it as a drug and biologic. So, if you’re using it to make your gut happy, then you may not come to me at all. If you’re going to market it as a treatment or cure, then it comes to the center for biologics and vaccines,” Fiore explained. “I can say from our point of view that if you’re using a probiotic to treat, prevent, or cure disease in humans, the regulations still fall under [the FDA].”
Pirnay focused on the growing interest in phage therapy as a complementary tool against antimicrobial-resistant infections and his work on building a production chain from phage isolation to phage therapy all under one roof. “We get on average one phage therapy request per working day. So, we have created a special email address to manage these requests,” he said.
Belgium is now implementing a pragmatic phage therapy framework that centers on the magistral preparation (compounding pharmacy in the U.S.) of tailor-made phage medicines. Pirnay covered case studies in which phages have been used to treat bacterial infections in well-defined cases at the QAMH as well as how his research group is dealing with the growing external requests for phage therapy. “We plan to establish a phage committee for the coordination and standardization of phage products and protocols,” he told his online audience.
One stream of questions for Pirnay was based on how often requests for phages are filled by applying the ever-growing libraries of phages or discovering new ones. Pirnay said that although the libraries are growing, the right phage doesn’t always exist.
“We also are developing more synthetic approaches where you could use AI to predict some good phages that will solve a lot of problems,” he said, adding that with synthetic production, which can be done on-site, you only need to transfer data. “That would also solve the logistical problem of sending phages all over the world.”
Applications within the wider microbiome setting
There were several presentations on recent progress from clinical-stage biotechnology companies using phage-based products. Sailaja Puttagunta, MD, CMO of BiomX, gave an update on how they are using designed phages to target and destroy bacteria in the treatment of immune-mediated and infectious diseases as well as certain cancers and conditions that affect the skin like acne.
Presenting BiomX’s phages in order of their likelihood for time-to-clinic, Puttagunta first focused on BX001, a topical gel comprised of a cocktail of naturally-occurring phage targeting Cutibacterium acnes, bacteria implicated in the pathophysiology of acne vulgaris.
The second phage of focus was BX002, BiomX’s orally administered phage therapy candidate targeting Klebsiella pneumoniae bacteria in the gut, which have been linked to the pathogenesis of both inflammatory bowel disease and primary sclerosing cholangitis.
Puttagunta emphasized the applicability of phages, even for their acne treatment.
“The safety of phage is widely accepted because it’s been around for over 100 years. Specifically, our product for subjects with acne is a topical product that doesn’t get absorbed and only acts superficially on the skin,” she said. “There is precedent for phage being used in cosmetics already being marketed in different regions of the world. So, we believe that this is safe enough to be cosmetic. Phages have been labeled by multiple regulatory agencies as being agents generally recognized as safe, with its extensive history of safety, so that makes this path feasible.”
Using phages for gene therapy of the microbiome
Xavier Duportet, PhD, co-founder and CEO of Eligo Bioscience, discussed the company’s “unique approach to engineering the microbiome at the gene level to address a number of unmet medical needs.” Duportet gave an update on how the company’s proprietary modality called Eligobiotics® allows modulation of the microbiome’s composition and function to address human disease.
Eligobiotics use phage-derived particles to deliver an RNA-guided CRISPR-Cas nuclease into bacterial populations of the microbiome.
Duportet focused on EB005, Eligo Bioscience’s discovery program in acne. Eligo Bioscience is leveraging recent insights in acne showing that otherwise beneficial skin bacteria, when expressing pro-inflammatory molecules, trigger the immune system and drive inflammation. The program aims to develop Eligobiotics for topical application to precisely and selectively remove these pro-inflammatory bacterial strains from the microbiome while sparing the rest of the skin microbiome.
Duportet also delved into how phage-centric approaches can be cost-effective. “We found out that you can get something at a relatively good price. Our production is mostly fermentation-based. It’s not phage production per se. We’re producing the particles and packaging DNA into it, so there are multiple ways to increase the titers through genetic engineering to get down to very good pricing in terms of production,” he explained.
Mina Pastagia, MD, VP of clinical development at Armata Pharmaceuticals, presented how synthetic biology tools enable Armata to precisely engineer natural phages in ways that further improve their pharmacological properties and antimicrobial activity. Their goal is to create synthetic phages that can be deployed in the clinic in the fight against multidrug-resistant bacterial infections.
Pastagia reviewed various pharmaceuticals clinical candidates, including AP-PA02 for cystic fibrosis lung Infection and AP-SA02 for bacteremia.
“We are evaluating phage therapy for chronic and acute infection,” said Pastagia. “For chronic infections, we evaluate phage cocktails delivered locally to the sites of infection in clinical indications, such as cystic fibrosis, non-cystic fibrosis, bronchiectasis, and prosthetic joint infections. This will hopefully result in lasting therapeutic benefits through dosing that is less burdensome than chronic suppressive antibiotics for acute infections, such as bacteremia and pneumonia.”
But this goal is still in its infancy, at least in the context of clinical trials.
“As most of you are aware,” noted Pastagia, “there are few randomized placebo-controlled clinical trials assessing phage therapy. Armata’s goal is to test phage cocktails through the rigor of randomized placebo control studies in clinical indications that may benefit the unique characteristics of phage.
“We seek to evaluate natural phage cocktails with broad host range together, safety, kinetic, and proof of concept data. These learnings will then be applied to advance engineered phage that has the potential for improved host range, coverage, potency half-life, and tissue distribution.”
The 3rd Bacteriophage Therapy Summit was able to bring together a broad range of emerging phage sectors to identify common challenges and goals with the potential to drive the entire phage industry forward. With lots of good science, practicality considerations, and clinical strategies along with funding concerns, this meeting provided a great opportunity to discuss the current state of phage therapy and the pathway to regulatory approval.