Phage therapy isn’t ever going to be the cure-all envisioned by overly-enthusiastic science writers. But it doesn’t have to be. Curing some patients of some indications is a noble and worthy goal in and of itself. And maybe when we learn to use phage therapy in limited applications, we can start thinking about tackling sepsis and solving the antibiotic resistance crisis.
What are some of those indications? My thesis is that phage therapy is most likely to succeed where antibiotic therapy is ineffective, especially because of biofilm involvement; where delivery of phage is easy and clearance rates are low; and where just one or two bacterial species need to be targeted. Bacterial vaginosis is one indication which meets those criteria; lung infections–specifically, chronic infections by Pseudomonas aeruginosa in cystic fibrosis patients–is another.
From Gene Therapy
CF disrupts some of the innate immunity mechanisms that block bacterial colonization and infection. Nearly all CF patients eventually develop chronic lung infections. 80% of those infections are due to P. aeruginosa (the remainder are mostly S. aureus).
From Pseudomonas cepacia colonization in patients with cystic fibrosis: risk factors and clinical outcome
Antibiotic therapy for these infections may be successful initially, but inevitably fails. Even if not resistant to start with, Pseudomonas develops resistance during the course of treatment both by accumulation of resistance mutations and formation of biofilms. Biofilms physically shield bacteria from antibiotic (and immune cell) attack; they also harbor subpopulations of dormant cells that are intrinsically resistant to antibiotics.
None of this is news. Pseudomonas infections in CF patients have been a prime target for phage therapy development for years if not decades. A number of preclinical studies have been published, showing that natural and engineered phages have strong activity against Pseudomonas in ex vivo biofilm models. Many mice have been saved by phage therapy from otherwise lethal lung infections (see, for instance, here and here). These studies are stronger than most in that the phage were effective even when given hours or days after the start of infection, a more-realistic clinical scenario than studies which administer phage before bacterial infections can be established. But mice don’t suffer chronic Pseudomonas infections, so the relevance of these results to human infections is questionable.
However, a recent paper reports efficacy in a newly-developed mouse model of chronic infection, and shows an impressive degree of bacterial eradication:
Lung bacterial levels 2 days after phage administration. Treatments 1, 2 and 3 correspond to phage administration at 1, 2, and 6 days after bacterial infection. From Phage therapy is highly effective against chronic lung infections with Pseudomonas aeruginosa.
AmpliPhi Bio has a phage therapy treatment for Pseudomonas in their pre-clinical pipeline. No clinical trials appear underway, but they have reported successful treatment in a case study of a lung transplant recipient suffering from a MDR Pseudomonas infection.
Significant hurdles remain. Although lung infections are more accessible to PT than systemic infections, delivery of phage (or any therapeutic) throughout the lung is not trivial. Clearance may also be an issue. Clearance of phage from lung is not likely to be nearly as rapid as it is from blood (half-life = minutes), but there are plenty of macrophages roaming the lung whose job it is to gobble up viruses; they make no distinction between bacteriophage and flu viruses. I can find only one paper that reports phage clearance from mouse lung, and it suggests a half-life on the order of 3-4 hours. That paper was published in 2011. I hope we don’t have to wait another decade before more phage lung PK data are published.
PT has a real shot to succeed as a treatment for CF-associated infections, albeit likely in combination with antibiotics. Phage break down biofilms and increase the exposure of bugs to antibiotics. Some phage also target the very proteins that Pseudomonas uses to pump antibiotics out and thereby render themselves resistant. This targeting puts the bugs in a bind: mutations that reduce sensitivity to phage increase sensitivity to antibiotics, and vice-versa. This is a virtuous cycle that is all too rare in treating infectious diseases, and we should exploit it.
Using phage as an adjunct therapy will also ease acceptance in the clinic. It’s a much easier ask for doctors to add PT to antibiotic therapy rather than to abandon antibiotics in favor of phage, or wait until antibiotic therapy is completely useless.
There is a substantial market here, about 30K CF patients in the US. Antibiotic therapy is insufficient. These are conditions that create an opportunity for alternative therapies. Unlike other indications, PT can justify premium prices for this one–a treatment that keeps patients out of hospitals and ICUs would save a lot of money. The prospect of being able to charge tens of thousands of dollars for a course of therapy, rather than hundreds, would do much to help bring PT to the clinic.
The investment world doesn’t see it that way, however. AmpliPhi Bio has a market cap of $8M. Given that they had cash on hand of $18M in Jan 2019, this implies that Wall Street values their pipeline and technology at minus $10M. By contrast, Alnylam, an RNAi company focused on diseases that affect a few hundred people, is valued at $9B. That makes no sense to me, but then I am just a lowly scientist, not nearly as smart as an investment banker.
I’ll go out on a limb anyway, and predict that treatment of Pseudomonas infections in CF patients will be the first significant approval and application for phage therapy. There are not many indications for which the strengths of phage therapy, the weaknesses of antibiotic therapy, and a significant market opportunity align so well. Let’s hope that AmpliPhi (or someone) can make this happen.