The third annual Phage Futures Congress, hosted by Kisaco Research, was held online February 24-26, 2021. The event gathered a diverse international audience comprised of phage developers across biotech and pharma, such as Locus Biosciences, Adaptive Phage Therapeutics, Felix Biotechnology, TechnoPhage, PhagoMed, Vesale Pharma, Merck, Janssen, and more, as well as medical professionals exploring phage therapy at the Mayo Clinic, Westmead Institute of Medical Research, and more, and researchers studying phage interactions at all levels, from universities including Yale and the University of Pittsburgh. US government agencies such as FDA, NIH, CDC, Naval Medical Research Center, and Walter Reed Army Institute of Research were also present, as were representatives of the WHO, BARDA and CARB-X. This combination led to three days of vibrant discussions surrounding some of the key barriers to phage therapeutics progress, as well as proposed solutions, such as properly designing clinical trials, positioning phage development to maximize access to funding, and best practices for scaling up phage production.
CARB-X’s Richard Alm opens the conference with an optimistic view on the clinical phage therapy landscape
Dr. Richard Alm (CARB-X) (in-depth interview with him here!) opened the conference; he shared how he’s looking at the phage therapy field from his seat as a funder, as well as what phage developers should keep in mind as they bring phage therapeutics toward the clinic. He emphasized that though there have been numerous compassionate use examples with successful outcomes, randomized clinical trials are still key. He stressed the importance of getting clear on the target patient cohort and clinical context early on (‘where do phages fit?’). He gave an overview of several active preclinical and clinical phage studies he’s keeping an eye on, including those focused on cystic fibrosis, irritable bowel syndrome, urinary tract infections, COVID-19-associated bacterial infections, and wound infections. He emphasized that in addition to CARB-X, which has already funded two phage biotech companies (Eligo and Locus), with more to be announced soon, other funding agencies such as the US Department of Health and Human Services, BARDA and NIAID are all interested in funding phage research and phage-based applications and products. It was clear from his remarks that he is optimistic about this field, and that he sees exciting times ahead.
The US government is paying substantial attention to phage technologies — Dr. Richard Alm, CARB-X
UCSF’s Henry ‘Chip’ Chambers digs into key questions on his mind as a physician: why phage, and where’s the randomized clinical trial data?
Dr. Henry ‘Chip’ Chambers, a UC San Francisco physician, moderated the first panel, which delved into designing clinical trials to prove efficacy of phage therapy. He asked tough questions to three panelists representing pharmaceutical companies pursuing clinical phage work: Dr. Bob Blasdel (Vesale Pharma), Dr. Todd Black (Merck), and Dr. Kristin Wannerberger (Ferring Pharmaceuticals).
To start, Dr. Chambers asked, ‘why phage?’. In his experience as a clinician, he noted that there are plenty of drugs that do work for bacteria like Staph. Dr. Blasdel pointed out how drug resistance isn’t the only problem; that many infections are inaccessible by antibiotics, such as wounds and diabetic foot ulcers, which affect patients with poor circulation. For these kinds of indications, Dr. Blasdel pointed to phages being ideal even when strains are technically still sensitive to antibiotics.
Dr. Chambers then asked the panelists to describe the data they’d seen to date that shows phages are effective in the clinic. Dr. Blasdel mentioned that there have been many positive signals among case reports (he mentioned a successful case series by Dr. Randy Fish using phage to treat diabetic foot ulcers), and emphasized that controlled clinical trials are being done (mentioning a recent trial looking at phages for patients undergoing prostate resection done in Switzerland in collaboration with the Eliava Institute). Todd mentioned that because so many phage cases have involved such acute infections, the data collected to date has been limited, as compared to how many times phage therapy has been done. Dr. Chambers emphasized that as a physician, he is waiting for the results of randomized, controlled clinical trials showing phage efficacy. He expressed frustration with the ‘series of anecdotes’ he’s seen to date, which he warned could be paralyzing the field, and may put regulatory approval for phages at risk.
How to translate phage therapy from the lab to the bedside
The second panel delved into translating phage work from the lab to the clinic, and was moderated by Dr. Jessica Sacher, co-founder of Phage Directory. Panelists included Prof. Paul Turner (Yale), Prof. Martha Clokie (University of Leicester), and Dr. Bob Blasdel (Vesale Pharma).
The conversation centered around the experience of the panelists as research scientists first, who have each studied phages for many years (even decades), and yet who are all now moving phages into the clinic in various ways. They discussed in vivo models for phage therapy, whether the current ones are suitable for phage (the consensus was yes, e.g. epithelial cell models and insect models). However, the panel agreed that regardless of the model, we need more realism about the limitations of any model.
The conversation moved into phage data collection; what data should we be collecting, and how can we improve its standardization? Prof. Clokie stressed that we don’t know which properties are associated with which phages yet, that we don’t yet have general concepts we can use to describe them, and that we need to know how a phage changes the ecology of its surroundings, not just properties of the phages themselves. Prof. Turner echoed this, saying we only know little of the vast diversity of phages and their biology. He said the main goal is avoiding surprises in the clinic. We can’t just say a phage is a phage. Rather, we need to characterize them enough to trust them (within reason).
The panel moved on to discuss what makes a ‘good’ phage. They discussed the importance of phages that persist long enough in the body, those with good stability profiles, and those well-understood from an evolutionary biology perspective. However, it was acknowledged that perfect pharmacokinetic profiles are extremely hard to achieve and predict, since they’ll depend on the phage, its replication, the exact bacterium inside the patient, its resistance mechanisms, the antibiotic the patient is taking, and more.
In the end, even amid a good deal of discussion about not going too fast, the group agreed that we need to move forward, and holding back from moving to the clinic in favour of “perfect” modelling in the lab first isn’t the answer. But translating phage therapy into the clinic certainly needs to remain connected to a solid understanding and consideration of phage and bacterial ecology and evolution.
Marketing strategies for phage therapy: avoiding pitfalls, finding payers, pushing for change
Another major topic discussed was how to develop a robust market infrastructure for phage therapy. Dr. Peter Beyer (World Health Organization) interviewed Dr. Carrie-Lynn Furr (Bacteriophage & Drug Development Consultants LLC) and Dr. Michael Koeris (NIH) about their thoughts on the market environment for phage right now. Dr. Furr, who has gone through seven FDA approvals in her career to date, described some horror stories about blockbuster drugs that never got to patients because even though companies got them through clinical trials, they didn’t think enough about supply chain logistics prior to launch. So they had a lot ready to ship, but no clinicians ready to prescribe. This company went out of business. She emphasized that there is currently no viable route for phages to reach commercial success. She said there’s a need to create a market space for more than just MDR infections (as that’s considered a ‘rare disease’).
Regarding funding mechanisms, Dr. Furr described that there are many push mechanisms, and some pull mechanisms, so we have the ability to fund phage therapy, but we still lack sufficient pull mechanisms to ensure there’s a return on investment once phages hit the market. She explained de-linking volume from sales of antibiotics (part of the PASTEUR and DISARM acts, though these haven’t yet been enacted), to help developers understand how much they’ll be paid once their product is on the market. She mentioned that unfortunately the GAIN act does not cover phages since they are biologics. Dr. Koeris talked about how for antibiotics, the UK is starting to consider valuing antibiotics according to lives saved (and lifetime value). He emphasized that phages have similar and different challenges from antibiotics, so there’s a need to couple phage with diagnostics. He said there should be a strong drive among phage developers to focus more on the diagnostic aspect (including point of care diagnostics, or intra-hospital diagnostics), ie. to figure out what kind of bacterial infection someone has, rapidly. Having experience developing phage products in the past, Dr. Koeris shared how difficult it is to survive on government funds alone. He thinks we need a dedicated lobbying group if we want to see rapid change in market incentives for phage and other antimicrobial technologies.
There was also discussion of phage therapy as a product vs. a service. Dr. Koeris described that either could work, but it comes down to who will pay for it. Dr. Furr said there’s a need for both strategies, and that whether an infection is acute or chronic will play into which strategy is suitable. A cocktail will likely be better in an acute setting, when empiric use is needed, but one could envision personalized treatment regimens paired with diagnostics being powerful longer-term solutions that could thus make sense as a service. Dr. Beyer mentioned that diagnostics can be expensive, so it may be hard to find those willing to pay for it, rather than falling back on antibiotics.
How to raise funds for phage therapy
Dr. Richard Alm (CARB-X) led a panel on securing financial support for phage development from the public, private & philanthropic sectors. Panelists were Greg Merril (Adaptive Phage Therapeutics) and Dr. Joseph Campbell (NIAID). Greg shared his experiences raising funds for private ventures (he is now working on his fourth life sciences start-up, and has raised over $100M). His main advice was to keep trying even when things are difficult (which he said is essentially all the time). He has found that the key is to understand the risk profile of who you’re talking to; some investors are comfortable with scientific risk if market risk has been addressed.
I think we’re seeing some of the halo effect from COVID; investors have renewed interest in infectious disease and anti-infectives. — Greg Merril, Adaptive Phage Therapeutics
Dr. Campbell, a NIAID program officer, provided interesting facts about how NIAID sees phage, and suggested some approaches for accessing NIAID funds and resources. He said phages should be treated and tested like antibiotics, and that recent funding has been given to companies and projects focusing on animal studies. He also pointed out that NIAID has preclinical services, where they pay contractors to test potential therapeutics for developers. The preclinical service is available to international groups too.
We’re always interested in funding grants for phage, and in general, the best thing to do is identify the program officer in charge of the pathogen your phages are attacking. Reach out to me and I can help you find the right one. — Dr. Joseph Campbell, NIAID
The panel also discussed the route to raising funds through engaging more with the public, and how the phage field should be thinking about the power of patient advocacy groups.
Cancer survivors form advocate groups, whereas people who recover from AMR are less prone to form a group. We really need people to bang the drum. — Dr. Joseph Campbell, NIAID
Why does phage therapy not always succeed?
Dr. Shawna McCallin (Balgrist University Hospital) moderated a panel on the success and failure of phage therapy as compassionate use to date. The panelists were Dr. Benjamin Chan (Yale University), Dr. Gina Suh (Mayo Clinic), Prof. Graham Hatfull (University of Pittsburgh), and Prof. Jonathan Iredell (Westmead Institute for Medical Research). Dr. Suh shared her experiences with treating four prosthetic joint infection patients with phage therapy at Mayo Clinic, where they have seen different degrees of success. She said while there have been good outcomes and positive feedback, not all cases have been home runs.
Prof. Iredell discussed how with compassionate use, the success rate is all about case selection, and heavily depends on partnership between the scientific community and clinical partners. He emphasized that collecting basic data during case studies is important for adding to the body of data that will impact future success of phage therapy, as there is no universal guide to how to do these things. Each case is unique, and dosages, length of administration, and phage susceptibility are all different for different people. For phage susceptibility, he said it would be nice to see the interaction of phages with antibiotics (is there synergy or antagonism?).
We need high quality surveillance programs to have a nice set of phages that work locally, for example phages that work in Tokyo might not work well in Sydney or New York. — Prof. Jonathan Iredell, Westmead Institute for Medical Research
Prof. Hatfull mentioned that one of the key aspects to study is phage resistance, and highlighted the importance of animal studies. He said in the case of many pathogens, we are just scraping the surface of what there is to uncover, and we would benefit to know more about cross-resistance, as well as the impact of phage resistance on antibiotics and virulence. He said much remains to be understood about how phage treatment works in the absence of antibiotics, as it is very difficult to measure while phages are still at a very experimental level. Everyone agreed that we can focus on co-use of antibiotics and phages, as this can reduce overuse of antibiotics while likely increasing the success rate of the treatment.
We should embrace that antibiotics can be used in combination, and we can greatly reduce the amount of antibiotics used. I disagree with the idea that “this is garbage if we also have to use antibiotics”. — Dr. Gina Suh, Mayo Clinic
In the end, the panel agreed that it is very important to share negative experiences with phage therapy, as this helps to understand what we need to focus on in the future.
US regulatory pathways for phage therapeutics
There was an in-depth discussion on US regulatory pathways for phage therapeutics. Dr. Cara Fiore (FDA), who has been involved in much of the phage therapy regulation at the FDA to date for human cases, described the FDA’s regulatory requirements for the approval of phage therapeutics for humans. She emphasized that phage therapy products are investigational biological drugs, and clinical evaluation must thus be conducted under the IND pathway. She highly recommends phage developers have pre-IND meetings with the FDA. Regarding phage preparations, she said phages should be grown in animal-free media, have minimal endotoxin content and not contain exotoxins. She highly recommends phage genome sequencing and characterization. Lastly, she emphasized that expanded access IND is available for phage therapy, but is not a substitute for controlled clinical trials intended to support product licensure. The eIND pathway is not a product development pathway.
The take home message for phage developers is when they start out they should have a simple and streamlined process for their clinical trials to collect the most basic data as a foundation for their future clinical trials. — Dr. Cara Fiore, FDA
Dr. Carrie-Lynn Furr (Bacteriophage & Drug Development Consultants LLC) described the yet-to-be-passed PASTEUR act (Pioneering Antimicrobial Subscriptions to End Upsurging Resistance) and its potential implications for phage therapy, which were quite positive. The act would de-link sales volume from the value of an antimicrobial, and provide a guaranteed return on investment once a developer gets an antimicrobial to market. She highlighted that the act includes biologic-based antimicrobials, and thus would apply to phages. Unfortunately, PASTEUR has not been enacted into law yet. Phage developers should make a point of learning about this act so they can receive the correct designation for reimbursement for their phage product development if it does become law.
Strategies for large-scale phage production
The topic of large-scale phage manufacturing was discussed in multiple sessions. Dr. Frenk Smrekar of JAFRAL, a CMO + CRO in Slovenia dedicated to phage, first gave an overview of how they go from phage isolation all the way to clinical and commercial stages. After this, Dr. Michael Koeris moderated a panel discussion with Dr. Smrekar and Dr. Nick Conley of Locus Biosciences. They discussed how Locus set up their in-house phage manufacturing facility completely from scratch, and the panel compared this strategy with outsourcing to a company like JAFRAL. Ultimately it came down to access to funds and desired level of control over the process, but both strategies clearly have their strengths.
A second panel discussion on this topic went deeper into the mechanics of scaling up phage production, and the associated challenges. This was moderated by Dr. Adam Ostrowski (Cellexus), and gathered Teresa Duarte (Vector B2B), Dr. Manuel Garrido (TechnoPhage), Dr. Jonathan Kotula (Felix Biotechnology), and Dr. Rodrigo Garcia González (Instituto de Biología, Pontificia Universidad Católica de Valparaíso). The group discussed how the cost-effectiveness and scalability of phage production can be especially challenging for academic production units. Liquid lysate production can be scaled to larger amounts, but the foaming can cause clogging, so the use of antifoaming agents can be helpful. The panel also discussed the production of lysogenic phages. Dr. Kotula specified that their aim at Felix Biotechnology is to produce only lytic phages, and thus they aim to monitor production strains for lysogeny, and try to remove such capacity among phages and strains. The experts also discussed the different ways regulatory agencies in the US and Europe look at clinical trial product quality, and how GMP standards differ at different phases of trials.
Interactive roundtables on phage-based applications
A large focus of the conference was on interactive round-table discussions; these sessions were led by phage experts on topics such as phage-based applications for wound, urinary tract, lung and prosthetic joint infections, phage-based vaccine development for COVID-19, and more. The discussions were particularly fruitful, as the audience had the chance to prepare by watching pre-recorded video sessions from each roundtable leader prior to the conference.
For example, a discussion run by Dr. Minmin Yen, CEO of PhagePro, gathered points of view on how to provide phages to the developing world, as well as the key elements and challenges to fund research to support junior researchers.
I think there’s a lot of room for creativity in the Global South, & for strategic partnerships — there’s a lot of inspiration and motivation to start phage therapy in a lot of areas of the world that currently don’t have it. — Dr. Minmin Yen, PhagePro
Dr. Gina Suh, a physician at the Mayo Clinic, led a discussion on her experience treating patients with prosthetic joint infections. Ella Balasa (Virginia Commonwealth University), a patient advocate who previously received phage therapy as a patient herself, shared her experience in another room. Dr. David Pride (IPATH, UCSD) led a discussion on the human virome, how important it is to think about the effects of phages on entire bacterial communities, and how complex it is to actually test this.
Bacterial communities tend to remain somewhat stable, especially in the short term. If you’ve got phages that are predators of all of those bacteria, what are they doing? — Dr. David Pride, IPATH, UCSD
A discussion led by Dr. Biswajit Biswas (US Naval Medical Research Center) and Subhendu Basu (Adaptive Phage Therapeutics) covered the advantages of phage-based COVID vaccines. In another room, Dr. Steven Theriault (Cytophage) led a discussion on using synthetic phages to target poultry pathogens in a Canadian context, which led to a discussion of how different countries regulate phage use (for example, Canadian regulators seem surprisingly permissive to genetically-modified phages in an agricultural context). Dr. Sailaja Puttagunta (BiomX) led a discussion into their work on phage therapy for acute and chronic infections, such as IBD, while Dr. Lorenzo Corsini of PhagoMed led a discussion on their work toward phage lysins for bacterial vaginosis.
Establishing an international database for phage therapy
In a pre-conference webinar connected to the conference, Dr. Shawna McCallin (Balgrist University Hospital), Sarah Djebara (Queen Astrid Military Hospital), and Aliza Fink (Cystic Fibrosis Foundation), introduced their plans to implement an international phage therapy database. They described the clear need for a unifying database, as many phage therapy cases are reported around the world, but it’s been very difficult to compare across cases and learn from what is happening due to a lack of data collection standards. Reporting of treatments and patient follow-ups are inconsistent among different groups. And as the number of patient cases and publications has been increasing rapidly since the beginning of 2000s, the group stressed that the time is now to establish a unified data collection framework.
Ultimately the mission of the International Phage Therapy Database (IPTDB) will be to standardize reporting by delineating minimal reporting criteria, to increase transparency and reduce positive bias. Through this developing initiative, they aim to bring patients and their treatment teams (pharmacist, researchers, clinicians, nurses, etc) onto one platform, and to use this to help legitimize phage therapy and ensure best practices are followed, and make sure safety is maximized for patients.
Concluding remarks
The conference concluded with a large panel of phage therapy experts discussing their overall thoughts on the field and its prospects going forward. There was a lot of optimism, with many people calling for a focus on sound fundamentals and phage biology, and a more concerted effort toward data collection when phages are used in the clinic.
I think it’s going to be a really active and interesting field over the next 2-3 years, but it’s going to be built upon a foundation of biology — Prof. Graham Hatfull, University of Pittsburgh
The complexity of phage therapy was highlighted as a major point to keep in mind.
It’s going to behave differently. It’s not just a small molecule bacterial interaction — it’s two living things interacting with each other. — Dr. Richard Alm, CARB-X
The point was also raised that there’s no ‘ribbon’ (or public advocacy group) for antimicrobial resistance, but that there’s a need to talk to the public about this growing problem. However, there was optimism when it came to the effect of the COVID-19 pandemic on public understanding of infectious disease.
We’ve seen such an amazing understanding from the public in light of COVID, which is going to do the phage field a lot of good. — Dr. Danish Malik, Loughborough University
All in all, the conference covered many key aspects of current translational phage research, use of phage in the clinic to date, manufacturing and scale-up, regulatory specifics, and funding opportunities, clearly delivering on its promise to bring together public, private and academic sectors in a fruitful way. The many opportunities for in-depth interactive roundtable discussions, as well as plenty of time for one-on-one meetings, meant that even though the meeting was virtual, there was ample chance for participants to share ideas and really go deep on the barriers and opportunities in this exciting field. We look forward to taking part in this event when it returns again!
Young researchers spotlight
Last but not least, the conference also included a poster competition for early-career scientists, called the Young Researchers Spotlight. In a post-conference session, the four finalists each gave a 5-min talk on their poster, and answered questions. The session was moderated by Dr. Jessica Sacher and Dr. Bob Blasdel. You can watch the recording here!
Congratulations to:
- Carmen Gu Liu (Baylor College of Medicine) “Lighting Viral Dark Matter: Revealing Earth’s Cryptic Genosphere Through Environmental Sampling”
- Matti Ylanne (University of Helsinki) “Phage therapy treatment of chronic sinusitis caused by Pseudomonas aeruginosa”,
- Meaghan Castledine (University of Exeter) “Parallel phage resistance – virulence trade-offs during clinical phage therapy and in vitro”
- Stephanie Lynch (La Trobe University) “Phage therapy for Staphylococcus pseudintermedius infections in canines.”
Want more?
Thanks to Atif Khan for contributing summaries for the What’s New section this week! And thanks to Atif Khan, Curtis Hoffmann, Stephanie Lynch and Jan Zheng for their help with social media and note-taking during the conference — this helped us a ton when writing this report!
