Overcoming the challenges facing phage therapy
We need new ways to fight antibiotic resistant bacteria. Today, the WHO estimates that resistant microbes cause more than 700,000 deaths worldwide each year. This is equivalent to roughly 20% of the confirmed number of worldwide COVID-19 deaths in 2021 (Our World in Data). And the problem is growing.
Many scientists, doctors, and patients see hope in phage therapy. Phage are tiny viruses that infect bacteria. They have minimal impact on human cells but kill bacteria with excellent specificity. Historically, phage therapy has primarily been used in Eastern Europe. Yet, it never gained traction in the western world due to the development and relatively easy administration of small molecule antibiotics like penicillin.
With the progressive failure of antibiotics, doctors from around the world — including those at top US academic hospitals like Yale New Haven Hospital — are beginning to appreciate the vast potential of phage. In fact, there have already been many success stories featuring phage. Ella Balasa described her experience using inhaled phage to clear a cystic fibrosis-associated lung infection in the Huffington Post. In the scientific literature, others have described many successful one-off cases of phage therapy.
This raises the question: Why aren’t phage therapies mainstream?
The answer is the lack of well-designed, rigorous clinical trials. To date there have only been a few phage therapy clinical trials. Such trials are essential to demonstrate the safety and efficacy of a given treatment. However, phage therapies involve the administration of a dynamic, complex, living therapeutic. They face challenges that fall outside standard small molecule drug development. Phage researchers are overcoming these challenges with modern molecular biology, biochemistry, and bioengineering techniques.
The unique concerns facing phage therapy clinical trails
Phage therapy is unlike any other treatment currently on the market, so existing methods, tools, and regulatory structures used to assess safety and efficacy will all need to be adapted to account for this. Well designed pre-clinical research programs and clinical trials will be essential for establishing best practices for phage therapy. Below are some of the open questions in the field which need to be addressed to make these trials feasible.
Production and purity
To run a clinical trial, you need enough of your therapy to dose patients. However, many aspects of phage production are challenging. Phage are biologics, meaning they are produced by living cells. They are not nearly as easy to characterize as small molecule antibiotics. Producers must take particular care to ensure that phage manufacturing processes are well-controlled and consistent.
Researchers must also have robust methods for ensuring quality across batches of phage. While developers of small molecule antibiotics can use standardized analytical chemistry techniques to assess their products, these techniques have not been established for phage.
For example, phage are grown in bacteria. The phage grow, divide, and kill their bacterial hosts. Researchers then separate and purify the phage from the remnants of the bacteria. But if this purification step is not optimized, bacterial contaminants can be toxic to humans. To make sure no contaminants remain, researchers can add a sample of their phage preparation to human cells in the lab. If the purification was successful, the human cells will remain healthy.
This kind of analysis requires researchers to make many choices:
- They must choose what kind of bacteria to grow the phage in. They might, for example, be able to engineer a host strain that has fewer toxins overall.
- They must choose what purification technique to use. Some techniques might decrease yield but improve purity or vice versa.
- They must choose what kind of human cells to test the phage preparations on and choose a technique to measure the health of the human cells. Different cells and measurement techniques may have different levels of sensitivity.
These processes will improve as researchers conduct more pre-clinical and clinical experiments. With streamlining and standardization, researchers can apply similar processes to new phage preparations. This know-how will position phage developers to treat large numbers of patients.
Dosage, distribution, and clearance
To run a clinical trial, researchers need appropriate therapeutic doses to give patients. The dynamics of phage infection and growth can make it difficult to determine appropriate dosing. Phage replicate as they kill bacteria in the lab and in the environment, but it is unclear how much phage replicate within patients. Replication rates also vary based on the type of phage, the type of infection, and the site of infection. As a result, patients with different infections will likely need different amounts of phage.
Appropriate dosing is partially determined by how phage disperse throughout the body, AKA their distribution. Researchers don’t yet have a good understanding of phage distribution within the human body. Topics requiring further research include:
- What tissues do phage penetrate?
- Do phage accumulate at particular sites?
- How quickly are phage cleared from different parts of the body?
- How does the mode of administration impact distribution and clearance?
- How does the immune system respond to different types of phage?
Pre-clinical research will help answer some of these questions. Others will be answered in the clinical trials. When researchers will have the opportunity to track how dosage and delivery impact the efficacy of the phage therapy, they will gain a much better understanding of how to use phage therapy successfully.
Definitions of success
While phage therapy has potential for treating many types of infections, antibiotics are still powerful. Typically, for the FDA to approve a drug, trialists need to show that it outperforms the standard-of-care therapy. This means that phage would need to beat antibiotics in a head-to-head comparison. However it can be difficult to find enough patients with antibiotic resistant infections to run a successful clinical trial. Therefore, not all phage therapy clinical trials will involve treating resistant infections. Instead, phage therapies might be compared to antibiotic treatments for non-resistant bacteria. Phage therapy may also supplement antibiotic treatment instead of replacing it. Thus, success might be defined as treating an infection as effectively as an antibiotic or boosting antibiotic effectiveness. Phage may not have to perform better than antibiotics to still provide value to doctors and patients.
Officials at the FDA know that phage therapies need different metrics of success. They appear willing to be flexible in the development of phage therapy clinical trials. Researchers need to work with the FDA to establish reasonable endpoints for phage therapy clinical trials. Such endpoints will demonstrate efficacy while acknowledging that outperforming antibiotics might not be an appropriate measure of success.
Differences in phage
Phage are highly diverse and can have a wide range of characteristics. For example, many phage only kill very specific bacteria, sometimes down to the subspecies (strain) level of bacteria. This can be a benefit if it prevents phage from killing the “good” bacteria inside us. Yet, it also means that one phage cannot treat all strains of bacteria that may be causing an infection. In addition, bacteria can evolve resistance to phage over a course of treatment. Indeed, a phase II clinical trial appears to have failed because the bacteria were resistant to the phage.
Many organizations attempt to get around the issue of phage specificity and resistance through an approach called phage cocktails. These are mixtures of different phage that may infect multiple strains of a bacterium or even multiple species of bacteria. Cocktails may effectively treat infections caused by different strains of bacteria in different patients. They may also work if bacteria evolve resistance to one or more of the phage in the cocktail. Theoretically, the other phage will compensate. Nonetheless, it is possible for bacteria to evolve resistance to all the phage used in a cocktail.
To avoid this issue, clinicians can instead use what’s called serial monophage therapy. To do so, they monitor resistance as treatment with a single, specific phage progresses. If the bacteria become resistant, the clinicians can quickly isolate a new phage to which the bacteria are susceptible and continue treatment with this phage. This prevents the development of pan-phage resistance and makes phage therapy more viable over the long term.
At Felix, we’re going one step further and designing phage that drive bacteria to become sensitive to antibiotics if they become resistant to phage. Thus, we’re using our understanding of phage and resistance evolution to make better treatments.
The flexibility to create phage cocktails and to engineer or evolve new kinds of phage is useful, but it does create issues for the clinical trial process. Usually clinical trials involve testing one, well-defined drug or biologic. Phage researchers must establish metrics to show that new phage formulations can be swapped with one another. They may be able to work with the FDA to establish these metrics through clinical trials.
Clinical trials and the phage research revolution
The scientific community has a robust and growing interest in phage. The chart below shows that the number of phage publications has roughly quadrupled since the year 2000 (PubMed).
This increase is likely fueled by case studies featuring phage therapy successes. Looking back at these case-studies, researchers have identified gaps in our understanding of phage therapy, some of which are mentioned above. New research is beginning to fill those gaps and setting the stage to resolve the remaining challenges with pre-clinical research and clinical trials.
At Felix, we’re excited to be at the forefront of phage research and clinical trials. We are building a team of experts to fill in the knowledge gaps that have hindered the clinical development of phage. By doing so, we hope to provide new solutions to the hundreds of thousands (and soon to be millions) of people facing the dire consequences of antibiotic resistance. If you’d like to join us, check out our open positions!
