Is there a long-lost fix for superbugs hiding in plain sight?

For many years, politicians, patients and drugmakers alike have warned about the risk posed by growing antimicrobial resistance (AMR), a problem exacerbated by the liberal use of antibiotics in farming, and in general medical practice.

The World Health Organization’s (WHO) “Global action plan on antimicrobial resistance,” published in 2015, calls for “harmonized and immediate action on a global scale,” to avoid “a post-antibiotic era in which common infections could once again kill.”

But an increased focus on longer-term therapies and reduced attractiveness of antibiotics have diminished the level of investment in this area. After all, how can the costs of R&D be met if a product is designed to be used only sparingly?

Political action

Government efforts, such as a novel subscription model for payment currently on trial in the UK, could provide some answers.

This would see pharmaceutical companies being paid upfront for access to certain antibiotics, rather than by the volume of drugs used.

Part of the government’s “2040 AMR vision” and “Five-year national action plan,” published in January 2019, this approach would enable drugmakers to invest safe in the knowledge that their products will be paid for, even if they are kept in reserve as a later-line defence against AMR.

And if carrots don’t work, the government has suggested the use of sticks, too.

The UK’s Review on Antimicrobial Resistance proposed, among other things, that pharma companies should pay a levy of 0.25% of annual sales should they fail to devote enough resources to developing antibiotics.

This money could then be used to support firms which do make the required investments to develop alternative therapies.

There are ideas on the regulatory front too. The Infectious Diseases Society of America, an advocacy group which represents more than 10,000 medical professionals, has called for the introduction of a  new accelerated approval pathway, which it calls LPAD (Limited Population Antibacterial Drug), specifically to promote the development of novel antibiotics.

Phage therapy

Despite these initiatives, physicians are still lacking the tools needed to fight superbug-resistant infections, and the antibiotic pipeline remains thin.

With efforts to promote new antibiotics seemingly stalled, some are asking whether an alternative, innovative form of treatment could represent a viable option.

Phage therapy involves the introduction of bacteriophages to a patient, with the aim of killing the infectious bacteria. Advocates argues that this approach is much more specific, allowing physicians to target a particular form of bacterial infection, while leaving other gut flora intact.

Discovered in the UK more than 100 years ago, phages are not a new form of therapeutic modality, but an approach that has fallen out of fashion in the West.

In the USA, phage therapy was pursued in tandem with antibiotics in the 1940s, with Eli Lilly (NYSE: LLY) selling Staphylo-jel, and other products, for treatment of streptococcus and colon bacilli infections.

But the success of antibiotics soon led to a loss of interest in this area. The specificity of the therapy, while now considered an advantage, could also be a weakness. Instead of finding particular phages for particular bacteria, physicians could simply use a single antibiotic to treat multiple types of infection.

But in Russia and other countries of the former Soviet Union, research in the area remained strong throughout the Cold War, and phage therapy is still a standard of care today, particularly in pediatric, burn and surgical settings.

If it works there, why can’t it be used globally?

Market forces

A powerful problem for phage therapy developers is that, despite the growing threat of AMR, antibiotics still work most of the time, and the market for therapies that treat superbugs is small.

Despite the small patient population, rare infections are not classed as rare diseases, and so phage therapies would not benefit from the advantages of Orphan Drug legislation.

With a small market and a low price, the potential for redeeming R&D investments in phage therapy remains low.

Perhaps just as concerning is that, despite positive signals from Russia and Georgia where therapies are widely used, the clinical data needed to support registration is not robust, largely due to an absence of placebo-controlled trials.

In a  recent paper, researchers from The University of Western Australia concluded that while “numerous studies highlight the in vitro and in vivo potential of therapeutic phages, and while a number of clinical trials have taken place over the last decade, further data is needed to present a robust regulatory case for clinical use.”

The regulatory framework required to accommodate phage therapies is not sufficiently developed. The authors note: “While the field is rapidly progressing toward therapeutics, fuelled by the evident need for antibiotic alternatives, regulatory processes must be refined and approached from a novel phage-based perspective.”

Adaptive Phage Therapeutics

One example of a firm seeking to overcome these hurdles and develop the next generation of phage therapies is privately-held US biotech Adaptive Phage Therapeutics (APT).

One of the challenges faced by phage therapy developers is a consequence of the therapy’s great strength, in the context of antimicrobial resistance. Unlike antibiotics, phage therapies are highly specific, targeting a particular infection and leaving the body’s microbiome intact.

While this enables minimal collateral damage, it means that developers must find a particular phage for a particular infection.

APT, which recently inked an important collaboration with the Paul Turner Lab at Yale University, believes the answer lies in robotic automation and personalization.

Companies such as BioNTech (Nasdaq: BNTX) and others are racing ahead with the concept of highly individualized therapeutic interventions, and the advent low-cost, more flexible and efficient biotechnologies has raised the prospect of tailoring a phage therapy for a particular infection.

Under the terms of its deal with Yale, APT will use a US Good Manufacturing Practice (GMP)-certified facility to rapidly deliver phage therapies for use in a clinical trial program at the university.

APT uses a robotic filling system, separate phage amplification and purification labs, and automated diagnostic systems, to enable rapid matching of a patient’s bacteria to the world’s largest collection of therapeutic phages, dubbed PhageBank.

Chief executive Greg Merril said: “APT is thrilled to partner with the Paul Turner Lab to support their pioneering phage therapy initiatives, which have the promise to help combat the growing antibiotic resistance crisis.”

“This collaboration with Yale, and their planned clinical trials, will allow us to bring phage therapy to a broader range of clinical indications and an additional group of patients who may benefit from new therapies,” he added.

A call for action

Each year in Europe, between 5% and 12% of hospital patients acquire an infection during their stay, and some 25,000 people die due to bacteria that have become resistant to the standard lines of antimicrobial defence.

In its list of key action points for policy makers, the WHO calls for sustainable investment enabling increased investment in “new medicines, diagnostic tools, vaccines and other interventions.”

Turn the clock back half a century or more, and a call for more investment in antibiotics would have seemed redundant, with all the major drugmakers working on new products.

But the reality of superbugs makes the call all the more pressing, and if new antibiotics aren’t forthcoming, alternatives such as phage therapy could be well placed to fill the gap.