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Review

Quis Custodiet? Are Regulations Slowing Phage Therapy?

by
Sandra Morales
1 and
Paul Hyman
2,*
1
Phage Consulting Pty Ltd., Sydney, NSW 2100, Australia
2
Department of Biology and Toxicology, Ashland University, Ashland, OH 44805, USA
*
Author to whom correspondence should be addressed.
Drugs Drug Candidates 2025, 4(1), 1; https://doi.org/10.3390/ddc4010001
Submission received: 9 October 2024 / Revised: 23 December 2024 / Accepted: 25 December 2024 / Published: 30 December 2024
Versions Notes

Abstract

:
Rising levels of antibiotic-resistant bacteria have led to increasing interest in the use of phage therapy as an alternative treatment. While phage therapy is conceptually simple, and numerous semi-anecdotal data suggest that it could be effective if properly managed, there have been only a few randomized, double-blind clinical trials of phage therapy so far. These trials unequivocally showed that phage therapy is safe, but there is still a paucity of data on its efficacy for managing various bacterial infections. One common response to this situation is that there is a mismatch between the regulations that govern the testing of new drugs, that is, chemical agents, and biological agents like bacteriophages. Another response has been to sidestep clinical trial testing and to use phages to treat infected patients on an individual basis, sometimes called the magistral phage approach. In this paper, we argue that regulations are not the true barrier to approval of phage therapy as drugs but rather it is the lack of efficacy data. There is no one reason behind the failures of recent clinical trials. Instead, these demonstrate the complexity of implementing a therapy where both the treatment and disease are living entities interacting within another living entity, the patient. Phage banks can have an impact by monitoring these complexities during phage therapy. Importantly, phage therapy clinical trials are continuing under existing regulatory frameworks and with products manufactured under GMP (Good Manufacturing Practices).

1. Introduction

Before antibiotics became readily available, bacteriophages (phages) were used as biocontrol agents for treating bacterial infections. Early results were mixed, in part because the nature of phages as viruses, and the nature of viruses, was understood only at a rudimentary level [1,2]. As antibiotics became more available and reliable in effect, phage therapy fell into disfavor in many parts of the world, although it remained continually used in other countries such as Georgia [3,4]. The Hirszfeld Institute in Poland also has a long history of studying phage therapy, especially focusing on interactions of phages with the immune system [5,6]. With the rise of antibiotic-resistant infections [7,8,9], there has been a resurgence in interest in phage therapy. Phages as therapeutic agents are now in numerous phase 1b-2a clinical trials in the United States and Europe [10,11].
The concept behind phage therapy is quite simple. Expose patient-infecting bacteria in the body to bacteriophages, which infect and kill them. While simple in concept, phage therapy has some of the same challenges as any other drug. How to deliver sufficient phages to the infection site, especially if it is not a surface skin infection but rather a deep cavity like those in the lungs? Although long-circulating phages have been identified [12,13,14], the body’s immune system can rapidly clear phages from circulation, potentially diminishing the effectiveness of a treatment. Will the target bacteria become resistant, leading to resurgence of the patient’s bacterial infection [15]? More data collected systematically are required to understand the role that putative bacteriophage-resistant bacteria may have in the success or failure of treatments.
Another challenge is the development of the treatment itself. This challenge extends from determining the composition of the product to the production and analytical methods to be used for qualifying the safety of the final product. One question often debated is whether a phage therapy treatment should use a single phage or several phages mixed together (cocktail), with a number of perceived advantages for each approach (Table 1). Phage cocktails have become the standard in phage therapy and are often preferred because they tend to have a broader target range (i.e., they are more likely to kill more strains of the targeted bacterial species compared to a single phage) and also are believed to be less likely to fail due to pathogen mutation to phage resistance, although there are times when a single phage may be preferred, or the only option, for treatment. Just as with combination drug therapy, it is less likely that a pathogen can mutate to be completely resistant to multiple phages if there is not a common receptor or other metabolic pathway needed by all the phages.
More complex phage cocktails have been developed for infecting a broader range or spectrum of hosts [16]. Phage cocktails like Pyophage and Intestiphage, which essentially mix multiple phage cocktails to target multiple species of bacteria, are made and sold over the counter by institutions and companies like Eliava Biopreparations and BioChimPharm in the Republic of Georgia and Microgen in Russia. The Intestiphage cocktail to treat intestinal infections and prepared by the Eliava Institute contains lytic phages against seven different species and various serotypes [17]. However, complexity in the composition of the cocktail undoubtedly adds complexity to the manufacturing process, including lack of stability and analytical tools to control for it over time, which inevitably affects clinical outcomes [18]. More complexity in phage mixtures may also mean higher costs. An additional challenge arises with cocktails that are propagated as a cocktail, rather than as individual phages that are mixed together for use. Phages in propagated cocktails may interact and evolve, changing the composition of the cocktail [19,20], even if the target bacterial species remain the same. Regulations are designed for drugs that are consistent over time.
A further challenge is the division within the field among those who support either the so-called “Personalized phage cocktails” or “Fixed cocktails” [21,22]. Inadvertently, and over time, the Personalized approach has become mostly associated with academic or clinical research groups providing ad hoc treatments for patients in dire need under various regulatory frames [23]. Local phage libraries or banks targeting both common and uncommon pathogens are put together for the benefit of patients. In contrast, Fixed cocktails are associated with companies working to demonstrate the efficacy of the treatment through controlled clinical studies. Personalized phage treatments are often produced in research settings, while Fixed cocktails are associated with production processes that follow current Good Manufacturing Practices (cGMP). Both approaches face challenges. Advocates of personalized treatments acknowledge the logistical issues around delivering such treatments [22,24,25], while those wanting to run randomized controlled studies face the difficulties of developing clinical protocols that accommodate standard care of treatment and the intrinsic needs of a biological treatment, all, of course, under a hefty price tag. Neither path is easy or straightforward, yet the main objective is shared, demonstrating the efficacy of phage therapy.
Here, we present the current regulatory environment for phage therapy and review the contribution of each approach to the advancement of the field. We argue that both approaches have merits and are complementary to each other and that the real barrier to the field is the lack of conclusive clinical data to show the value of adding phage therapy treatments to the standard of care of patients. In this, we will be focusing mainly on the regulation of Fixed cocktail products, as these will likely impact more patients, being mass produced. Furthermore, we perceive there is more resistance to regulation among advocates of that approach. Finally, we examine the roles that phage banks can play in supporting both approaches.

2. The Perceived Challenge—Current Regulatory Path for Bacteriophage Products

Bacteriophage products are usually described as precision therapeutics due to their targeted mechanism of action when compared to antibiotics. In the United States, the Federal Food, Drug, and Cosmetic Act, section 201(g), defines “drug” as “… articles intended for the use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals” [26]. In Europe and Australia, a medicinal product is a substance or combination of substances that is intended to treat, prevent or diagnose a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action [27,28].
It has been argued that bacteriophage products should be defined and regulated as biologicals because such a regulatory framework is perceived as more pliable and consistent with the nature of the technology [29,30]. However, the regulatory definitions of drugs/medicines exist independently of the nature or composition of the treatments, with the focus being on the mechanism of action and claims made.
As natural bacteriophages are intentionally developed to cure or prevent disease in unhealthy or diseased humans, they meet the definition of drugs or medicines under most regulatory frameworks. While genetically modified bacteriophages are an important area in the development of the field, the regulatory framework is different to that applied to natural bacteriophages, and thus, for simplicity, genetically modified phages will not be discussed in this review.
Currently, there are no registered (by Western regulatory agencies such as the FDA in the United States or EMA in the European Union) natural bacteriophage products for human treatment, and the existing regulatory framework has been repeatedly cited as the main reason behind it. This is despite active engagement, interest and support from the regulatory agencies. For example, in June 2024, the Division of Microbiology and Infectious Diseases (DMID) of the US National Institute of Allergy and Infectious Disease (NIAID) released a concept call for “Centers for Accelerating Phage (Bacteriophage) Therapy to Combat ESKAPE Pathogens” [31]. This call would solicit applications for 2026. Previously, the FDA, in collaboration with NIAID and the NIH, as well as the EMA, organized workshops on the therapeutic use of phages to facilitate product development and clinical trials.
They have acknowledged that the current drug/medicines framework may benefit from refining the specific advantages of bacteriophages and suggested that the door to discussing changes to the regulatory framework could be opened in the future. One such change that could be made in the future is the reformulation of a fixed product (i.e., the swap or inclusion of a phage component) with a like-for-like phage, following well specified preclinical characterization parameters without the need to run toxicology or clinical studies for that product again, while demonstrating that the clinical efficacy will be improved. The FDA has indicated that this would be acceptable for food safety products such as Intralytix’s ListShield. However, attaining such proposed changes is difficult in the absence of dossiers that clearly demonstrate both product safety and efficacy.
Because product regulation is focused on the assessment of the safety, quality and efficacy of a product, the current regulatory framework also inherently involves the application of process-controlled cGMP standards, which are repeatedly perceived by external stakeholders as an expensive, undue path for a product whose composition could be, at times, specific to an individual patient. What seems to be less understood is that the requirements to produce clinical trial material (CTM) or Investigational Medicinal Products (IMPs) are not as strenuous, at least in the US and Australia [33,34]. In addition, a sponsor benefits greatly from implementing cGMP as early as feasible in the development of a drug. This not only helps protect the safety of clinical trial participants but provides a foundation for a robust quality management system (QMS) and minimizes the risks as products move toward commercialization.
In Europe, Annex 13 for the Manufacture of Investigational Medicinal Products states that all IMPs must meet cGMP requirements [34]. To circumvent this limitation, a self-described pragmatic regulatory framework for tailored phage products, also known as the magistral phage approach, has been established in Belgium [29]. While this arrangement seems to have resolved, at least locally, the issue of product quality controls, the users still report a backlog in the number of patients that can be treated, especially due to logistical problems. In countries like the Republic of Georgia, where bacteriophages have been long approved, there is a regulatory process overseen by the Ministry of Health, which has not until recently required production under modern cGMP standards, but has implemented clear guidelines nonetheless to assure the safety and activity of the products, which are widely used.
It appears the existing regulatory framework, supported by the existence of phase-appropriate production guidelines, may not necessarily be the hurdle to the development of the field as argued on multiple occasions. If so, what is limiting the implementation of phage therapy?

3. The Major Challenge—Clinical Data

As mentioned before, changes to regulations will most likely only be considered by the various regulatory agencies after the assessment of dossiers that have clearly demonstrated both product safety and efficacy. There are a few companies developing fixed bacteriophage products, carefully characterized and methodically developed to be active against a particular pathogenic species, and initiating clinical trials (Table 2 and [10,35]). However, progress has similarly been slow, and no efficacy data has yet been generated for any indication.
Controlled clinical studies have failed due to poorly developed products or suitable clinical protocols [18,36,37]. Results from some recent high-profile trials have been well studied after completion and provide instruction on some of the challenges, beyond production and regulatory approval, that the field must consider for the successful application and the widespread use of fixed cocktails.
The first trial, designated the Phagoburn trial, was set up as a randomized phase 1/2 trial [18]. Patients had burn wounds that were infected with Pseudomonas aeruginosa. The wounds were treated with either a cocktail of 12 anti-P. aeruginosa phages or a cream containing 1% sulfadiazine silver emulsion, a standard treatment for P. aeruginosa skin infections. Both treatments were applied daily for 7 days and followed up for 14 days. Treatment effectiveness was measured by swab sampling of the infected tissue and bacterial load determined. The primary efficacy measurement was the sustained reduction in bacterial load. The trial began to recruit patients in July 2015 but was stopped during a second round of recruitment in 2017 when analysis of earlier patients showed that the sulfadiazine silver emulsion was significantly more effective than the phage cocktail. Subsequent analysis found that the phage dose administered to the patients was much lower than intended. While the individual phages were stable in storage, the titer of the 12-phage cocktail decreased 4–5 logs soon after preparation. The results were reported as sufficient to show safety but not efficacy.
The second trial attempted to show phage therapy efficacy in treating E. coli-caused diarrheal infections in children in Bangladesh [38]. This study was a prospective study with three arms—children treated with a 9-phage cocktail composed of T4-like phages developed for this trial; children treated with a commercial phage cocktail (ColiProteus) made by Microgen; and children given a placebo. About 40 children were included in each group. All the participants also received standard oral rehydration therapy at the same time. As part of the enrolment in the trial, fecal samples were tested to confirm the children were infected by a pathogenic strain of E. coli—either EPEC, ETEC or EAEC. Patients receiving phages received three doses of one of the cocktails for four days. Stool samples were collected each day during treatment and in a post-treatment follow-up. The 120 patients enrolled in the study were only half of the originally planned size. Interim analysis showed that there was no significant difference in the treatment outcome of any of the three cohorts, and the study was halted. There was also no difference in the number of adverse effects, supporting the safety of phage therapy but not efficacy. Post-study analysis of stool samples found several unexpected results. First, although phages were detected in stool, the titer was low, suggesting no phage replication in the patients. This may have been the case because, although the patients had tested as E. coli-positive, E. coli cells were only about 5% of the bacteria detected in stool. Complete microbiome analysis found that patient symptoms better correlated with Streptococcus species levels, suggesting that the disease etiology was more complex than expected and that targeting E. coli alone was not sufficient [36].
A third trial attempted to show phage therapy efficacy in treating urinary tract infections in men. The trial took place in Tbilisi, Georgia. The phage used was the Pyophage cocktail made by Eliava Biopreparations, which contain phages that infect E. coli, Enterococcus species, Staphylococcus species, Streptococcus species, Pseudomonas aeruginosa and Proteus mirabilis [37]. The study was set up as a double-blind study with three treatment groups: men receiving an intravesical (insertion into the bladder via a catheter) phage cocktail, twice daily for seven days; men receiving an intravesical buffer on the same schedule; and men receiving systemic antibiotics. In total, 113 men were recruited and underwent one of the three treatments. The phage therapy treatment was not inferior to the antibiotic treatment but also was not better than the placebo buffer treatment. As far as we can ascertain, no additional analysis has been done on these results, but the effect of the different delivery methods for the test groups is an interesting aspect of the clinical protocol that would be worth dissecting further.
Even with a lack of efficacy data from clinical trials, phage therapy is being used. Regulatory agencies have approved pathways (e.g., Expanded Access in the US, Special Access Scheme in Australia, Compassionate Use in Europe) that allow the administration of unapproved medicines to ill patients for whom registered approved medicines are no longer effective. Such pathways are less onerous on the use and production methods of the unapproved medicine. Overall, they also appear to show more positive treatment outcomes compared to the above-described trials with “Fixed cocktails”. A recent placebo-controlled, randomized clinical trial of wound infection treatments [39] supports this. In this trial, two 30-person arms (phage cocktail treated, placebo treated) were studied. The phage cocktails were customized for each patient based on the particular bacteria isolated from their wounds. Patients in both groups received conventional treatments. Overall, 93.3% of the phage-treated wounds became sterile, while only 16.7% of the placebo patients had successful treatments. Also noteworthy, there are clinical trials underway that include customized phage cocktails for treating a single type of infection. These include trials led by BiomX (formerly Adaptive Phage Therapeutics) to treat diabetic foot osteomyelitis (Clinicaltrials.gov ID# NCT05117107) and led by Shahid Beheshti University of Medical Sciences for treating chronic UTIs following kidney transplant (Clinicaltrials.gov ID# NCT05967130). Finally, using this type of “personalized” approach during phage therapy has also been reported to be superior to using “mainstream” phage preparation by several investigators in the former Soviet Union [40], further highlighting the need for both “Fixed cocktails” and “Personalized phage cocktails” approaches—and, as discussed below, the importance of phage banks for this latter in particular.
Due to the antimicrobial resistance crisis, the clinical demand for compassionate treatments has significantly increased around the world, and as a result, the number of clinicians treating patients under this pathway has increased as well. The challenge for the clinicians has been sourcing, in a timely manner, well-characterized and purified therapeutic phages that are accepted by the local ethics committees and/or regulatory agencies. Primarily, their goal is to help patients in need, but along the way some are actively trying to document evidence of the safety and effectiveness of phage therapy. The data collected under this system, and that of the magistral phage approach and others, suggest phage treatments are safe, but no evidence of efficacy has been concretely acquired because nearly every case is a unique phage–pathogen combination treating an imperfectly defined clinical condition.
Regardless of the approach taken to help patients in need, the majority agrees randomized controlled trials are required to move the field forward, as they represent the established way to demonstrate the efficacy of a treatment. That this can be done successfully is demonstrated by a different biological therapy—fecal microbiota treatment for recurrent Clostridiodes difficile infections. Two forms of this therapy were approved in 2023 following demonstration of efficacy in several clinical trials, including randomized, double-blind, placebo-controlled studies [41,42,43]. Preclinical animal studies of phage therapy have demonstrated efficacy in those systems as well [44].

4. The Value of Phage Banks

At its simplest, a phage bank is a collection of bacteriophages that are actively maintained and curated. Curation means that, to some extent, the collected phages have been tested and characterized for life cycle (lytic vs. temperate) and for other growth parameters, as well as for the primary host and, to some extent, the host range. Phages will have their genomes sequenced to identify those that contain undesirable genes, such as those for lysogeny, toxicity and antibiotic resistance. Different roles for phage banks in phage therapy have been proposed [30,45]. Currently, there are no agreed upon standards as to the minimal characteristics needed to be determined. A recent series of workshops organized by Phages for Global Health and Innovate UK KTN has a goal of developing a set of recommendations for phage banks [46]. They expect to release a report in 2024.
Typically, phages are maintained so that they will be available as needed, in this context, for personalized therapy. In many ways, phage banks are specialized biological repositories, maintaining phages and the hosts needed to grow them. Table 3 lists many of the currently active phage banks around the world. They can be divided into three groups: (1) Phage banks organized specifically for phage therapy; (2) Phage banks as specialized biorepositories focusing on phages (and their corresponding hosts); and (3) Biological repositories that include phages in their collections.
Phage banks generally acquire phages in one of two ways—isolation of novel phages and receiving phages from other labs that have isolated them. Methods for isolating phages from environmental samples (sewage, patient samples, soil, etc.) have been integral to the study of phages as well as phage therapy. The most common methods—direct isolation and enrichment cultures—date back to d’Herelle’s initial isolation of phages [50,51,52,53]. More recently, high-throughput methods have been developed to simultaneously screen a sample for phages against multiple hosts [54,55]. In addition to collecting, storing and characterizing phages, phage banks can maintain phages prepared for use in phage therapy. While not yet standardized, several purification pathways have been defined for phages, including the removal of endotoxin from phage stocks prepared on Gram-negative bacterial hosts [56,57].
It is important to distinguish between different phage banks based especially on size and resources. Size can be considered in terms of production capacity as well as numbers of phage and host species maintained. Smaller banks may be limited in the batch size of phage being produced, although continuous culture systems may bypass this limit [58]. In terms of the diversity of stored phages, it is possible to have a very large phage bank that maintains stocks of phages for many different pathogens and that can distribute these to many locations around the world. These might be phage banks modeled on the general biorepositories such as ATCC and DSMZ. Most of the phage banks listed in Table 3 are smaller and more limited in resources. Rather than have a ready supply of all phages, smaller phage banks supporting a phage therapy program could choose particular pathogens to focus on and prepare phages for those pathogens while still maintaining small amounts of other phages in long-term storage. We further envisage that smaller phage banks might not be independent but rather would be part of or connected to a clinical laboratory that is based in a hospital that is using phage therapy. The hospital and clinical laboratory would be able to provide samples of strains of bacteria that are currently circulating in the population that will be treated. The phage bank can then test and prepare phages that are able to infect and lyse those specific bacteria. This is not a novel idea but rather a more focused application of what the Eliava Institute does with its over-the-counter phage cocktails, which are periodically reformulated and tested on current strains infecting the population [59].

5. Can Phage Banks Prepare Phages Following cGMP?

For those who have not worked in a GMP environment, the task can seem daunting; however, it is straightforward in principle [60]. The challenge is in completing a highly detailed process in a highly controlled environment. In essence, designing a GMP process can be reduced to a few broad steps, although each step can be highly detailed. The first is to understand how the regulatory requirements of drug manufacturing, as determined by the FDA or other country regulations, apply to phage preparations. Then the phage preparation steps need to be determined and key quality control (QC) steps identified. A documentation mechanism to test the quality and record the results of each QC test must be designed. Certified equipment for all stages of preparation is needed and maintenance documentation added to the documentation system. Finally, quality assurance (QA) systems must be implemented; employees must be trained and their training documented. Of these steps, the major challenges are likely understanding and applying the appropriate regulations and a precise, consistently implemented documentation system. The other steps (using proper equipment, the actual isolation procedures, training personnel and so on) are not very different from any other phage production operation.
The challenge to producing phages under 21 CFR 210/211-compliant cGMP regulations then is the significant resources needed for the implementation of QC and QA systems rather than the actual procedures. Phages produced using cGMP can be used for interim personalized phage therapy treatments as well as clinical trials with individual phages or cocktails.
In summary, phage banks can play several important roles supporting phage therapy. First, they can isolate and maintain phage stocks. Second, they can formulate, test and prepare phage cocktails for the general public and for individualized phage therapy treatments. Third, in conjunction with a clinical lab, they can surveil the local strains of pathogens and identify potential therapeutic phage cocktails as needed. Such potential therapeutics phages can be produced and maintained following cGMP if the resources are available. However, the costs of doing so for every phage isolated would be simply prohibitive. A goal for such facilities could be to develop well-characterized, broad-spectrum phage cocktails for specific clinical indications and their specific target bacteria. These phages can be used to produce personalized treatments, and/or products can be licensed to interested partners for testing and characterization, potentially securing a return in their investment to support further their activities.

6. We Are Better Together

Personalized treatments and phage banks add valuable data to the existing vast body of literature, but the underlying concerns about the safety of personalized preparations should not be dismissed under the premise of it being a long, expensive exercise. Better attempts to understand cGMP appropriate processes could be made. Seemingly, those developing fixed cocktails need to do a better job of presenting the rationale for product development to truly mitigate long-term efficacy concerns, as well as of learning from personalized treatments to design suitable clinical protocols that avoid the repeat of past errors.
Manufacturing bacteriophages following cGMP guidelines is not an impossible task any longer. In fact, there are companies that now offer their manufacturing services (Table 4). These GMP-licensed facilities are in addition to those established within the various companies for their own internal projects.

7. Conclusions

As antibiotic-resistant bacteria continue to increase in frequency, phage therapy remains an important option. Numerous studies and clinical trials have shown that phage therapy is safe. Demonstrating efficacy in clinical trials has been more elusive. In part, this shows that, while phage therapy is simple in principle, implementation is complex.
We argue here that one perceived challenge in the implementation of phage therapy, regulatory requirements, is not a true drawback. Regulatory agencies in multiple countries have shown a willingness to work with companies and other groups developing phage therapy to outline pathways to approval. Producing phage following cGMP protocols, as needed to meet many regulatory requirements, is not an insurmountable challenge either, given the increasing number of commercial phage production companies. At this time, this potential challenge is one that can be solved by money, not the development of new technologies. We do not suggest that raising funds is a trivial undertaking, but in this way, phage therapy is not different from the development and testing of any other new drug.
The real problem for approval of phage therapy at this time is the lack of clinical data to demonstrate efficacy to meet regulatory requirements. Clinical trials of phage therapy have been done, and they show that phage therapy is safe. But, for various reasons, they have not shown a clear result of greater efficacy than other treatments. These reasons include issues of quality control (Phagoburn study) and disease etiology (Bangladesh study), as explained above. In part, this highlights the need for good quality control in trials, but it also is a reminder that applying a single treatment to a larger group of patients is not simply a scaled-up treatment of a single patient for whom better matching of phage and pathogen can be done. Nevertheless, clinical trials of phage therapy are ongoing (Table 2), and infrastructure supporting phage therapy continues to be developed (Table 3 and Table 4). We see these as signs that phage therapy is moving along a path to becoming an accepted and reliable treatment for bacterial diseases.

Author Contributions

Both authors contributed to all aspects of the preparation of this work including drafting, editing, and revising. All authors have read and agreed to the published version of the manuscript.

Funding

The preparation of this manuscript was not supported by external funding.

Acknowledgments

We would like to thank Alexander “Sandro” Sulakvelidze for his review and comments on a draft of this manuscript. We would also like to thank the reviewers, whose suggestions and comments helped us in finalizing this article.

Conflicts of Interest

Author Sandra Morales is the managing director of Phage Consulting Pty Ltd. The remaining author, Paul Hyman, declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Table 1. Perceived advantages/disadvantages of phage cocktail vs. single-phage therapeutics.
Table 1. Perceived advantages/disadvantages of phage cocktail vs. single-phage therapeutics.
Phage Cocktail Single Phage
Phages may recombine during repeated cocktail growth cycles, creating hybrid phages, which may improve cocktail efficacyEvolution limited to mutation, potentially keeping phage more consistent over time
Broader host range, less need for susceptibility testing *Narrow, but specific, range of activity to target strain
Less development of phage resistance by bacteriaHigher risk of development of phage resistance by bacteria
Harder to monitor PK/PD and characterize host immune responsesEasier to monitor PK/PD and characterize host immune responses
More complicated production process and analytical testingLess complicated production process and analytical testing
* Like broad-spectrum antibiotics, well-designed cocktails may be used without identification of the pathogen. If the infection persists, pathogen identification can be done and a customized phage cocktail prepared. PK: Pharmacokinetics: host response to the phage(s). PD: Pharmacodynamics: effect of the phage(s) on the body.
Table 2. A sample of fixed bacteriophage mixtures in active clinical trials beyond phase I. Trial information obtained from clinicaltrials.gov, last updated 4 October 2024.
Table 2. A sample of fixed bacteriophage mixtures in active clinical trials beyond phase I. Trial information obtained from clinicaltrials.gov, last updated 4 October 2024.
Company/Agency
(Clinicaltrials.gov ID)		Product NameProduct Target(s) and Clinical Trial Information
Armata Pharmaceuticals
(NCT05616221, NCT04596319,
NCT05184764)		AP-SA02, AP-PA02, AP-PA03AP-PA02 completed a phase 1b/2a trial in CF patients with chronic P. aeruginosa pulmonary infections and a phase 2, multi-center, double-blind, randomized, placebo-controlled study to evaluate the safety, phage kinetics, and efficacy of inhaled AP-PA02 administered in subjects with non-cystic fibrosis bronchiectasis and chronic pulmonary Pseudomonas aeruginosa infection
Currently enrolling a Phase 1b/2a, randomized, double-blind, placebo-controlled, multiple-ascending, dose escalation study of the Safety, Tolerability, and Efficacy of Intravenous AP-SA02 as an adjunct to best available antibiotic therapy compared to best available antibiotic therapy alone for the treatment of adults with bacteremia due to S. aureus
Locus Biosciences
(NCT05488340)		LBP-EC01, LBP-PA01, LBP-SA01, LBP-KP01LBP-EC01 targets E. coli in UTIs. Currently enrolling its ELIMINATE trial, registration-enabling Phase 2/3 trial
BiomX
(NCT05010577)		BX004, BX005BX004 completed part 2 of a Phase 1b/2a trial in CF patients with chronic P. aeruginosa pulmonary infections
Intralytix
(EcoActive—NCT03808103,
VRELysin—NCT05715619,
Shigactive—NCT05182749)		EcoActive
VRELysin
Shigactive		Currently enrolling a phase 1/2a trial to assess safety and efficacy of EcoActive on AIEC in patients with Inactive CD
Currently enrolling a phase 1/2a trial to assess safety and efficacy of VRELysin in healthy and VRE-colonized subjects
Currently enrolling a phase 1/2a trial to assess safety and efficacy of Shigactive in healthy adults with experimental Shigella challenge
MB Pharma
(NCT06319235)		DuofagRecruiting patients for Phase I/IIa clinical trial to demonstrate the safety and efficacy of DUOFAG® in bacterial infection treatment in patients with surgical wounds
NIAID
(NCT05453578)		WRAIR-PAM-CF1WRAIR-PAM-CF1 is enrolling a phase 1b/2 trial to assess safety of a single IV dose in clinically stable CF subjects with P. aeruginosa in sputum.
Pherecydes Pharma (now Phaxiam)
(S. areus—NCT05369104)		PneumoPhage
Anti-S. aureus		PneumoPhage targets ventilation-associated Pneumonia and cystic fibrosis pneumonia caused by P. aeruginosa. Yet to enter clinical trials.
Anti-S. aureus phage (PP1493 and/or PP1815) currently enrolling a pilot study in patients with hip or knee PJI due to S. aureus treated with DAIR
Technophage
(TP-102—NCT04803708, NCT05948592)		TP-102, TP-122, TP-164TP-102 is enrolling a phase 2b trial to assess safety, tolerability, clinical enhancements and influence on wound healing process in patients with diabetic foot ulcers infected with P. aeruginosa, S. aureus and A. baumannii
Yale UniversityYPT-01A single-site, randomized, double-blind, placebo-controlled study of bacteriophage therapy YPT-01 for Pseudomonas aeruginosa infections in adults with cystic fibrosis
Abbreviations: AIEC—Adherent Invasive Escherichia coli; CD—Crohn’s disease; CF—Cystic fibrosis; DAIR—Debridement, antibiotics and implant retention; NIAID—US National Institute of Allergy and Infectious Diseases; PJI—Prosthetic joint infection; VRE—Vancomycin-Resistant Enterococci (VRE).
Table 3. Phage banks. All web sites accessed 23 December 2024.
Table 3. Phage banks. All web sites accessed 23 December 2024.
NameLocationApproximate Phage
Collection Size		Involved in Phage Therapy Currently?Reference or Web Site
Phage banks organized to support phage therapy
George Eliava Institute of Bacteriophages, Microbiology and VirologyTbilisi, Georgia>1000 phagesYeshttp://eliava-institute.org/?lang=en
Hirszfeld Institute of Immunology and Experimental TherapyWroclaw, Poland>850Yeshttps://hirszfeld.pl/en/
and [5]
Queen Astrid Military HospitalBrussels, BelgiumUnknownYes[47]
BiomX (acquired Adaptive Phage Therapeutics in 2024)Gaithersburg, MD, USA>1000Yeshttps://www.biomx.com/ and [48]
Israeli Phage BankJerusalem, Israel>300 phagesYes[49]
FagenbankDelft, The Netherlands~120 phagesYeshttps://www.fagenbank.nl/english/
Tailored Antibacterials and Innovative Laboratories for Phage Research (TAILΦR)Houston, TX, USAUnknownYeshttps://www.bcm.edu/research/research-centers/tailor
Australian Phage Biobanking NetworkMulti-site consortium in Australia342 Yeshttps://www.phageaustralia.org/
Kenya Medical Research Institute (KEMRI)Nairobi, Kenya245Unknownhttps://www.kemri.go.ke/
International Livestock Research Institute—KenyaNairobi, Kenya60Unknownhttps://www.ilri.org/
Phage banks organized as phage repositories
Felix d’Herelle Reference Center for Bacterial VirusesQuebec, Quebec, Canada>400Nohttps://www.phage.ulaval.ca/en/home/
Bacteriophage Bank of KoreaSeongnam, Gyung-Gi Do, Korea>1900Nohttp://www.phagebank.or.kr/intro/eng_intro.jsp
Biological repositories that include bacteriophages
American Type Culture Collection (ATCC)Gaithersburg, MD, USA>340Nohttps://www.atcc.org/
Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbHBraunschweig, Germany>600Nohttps://www.dsmz.de/
National Collection of Type Cultures (NCTC)Salisbury, UK>100Nohttps://www.culturecollections.org.uk/
Table 4. Companies manufacturing phages via GMP processes. All web sites accessed 23 December 2024.
Table 4. Companies manufacturing phages via GMP processes. All web sites accessed 23 December 2024.
CompanyLocationYear FoundedYear License for GMP Production
MB Pharma * (https://www.mbph.cz/?lang=en) and FAGOFARMA * (https://www.fagofarma.cz/?lang=en)Prague, Czech Republic1998 (MBP), 2013 (F)Approved to produce under GMP in 2015 at MB Pharma facility, 2023 at FAGOFARMA facility
Clean Cells (https://clean-cells.com/)Montaigu—Vendée
France		2000Approved to produce under GMP in 2023
Creative Biolabs (https://phagenbio.creative-biolabs.com/)Shirley, NY, USA2005Produces phage using GMP protocols
Phagelab (https://phage-lab.com/) Santiago, Chile2010Phage production with cGMP quality procedures
JAFRAL (https://jafral.com/) Ljubljana, Slovenia2011Develops production protocols and produces phage using cGMP protocols
Vector B2B (https://vectorb2b.com/) Lisbon, Portugal2019Association of academic and industrial groups, including ones able to manufacture phages with GMP protocols
* Self-described as “sister companies”.
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