Fast on the heels of understanding what makes a healthy microbiome were the many investigations of what causes an unhealthy microbiome -- and what could be done to fix it. This is the second in a series of three microbiome posts. In my last post, we had a friendly introduction to the microbiome; in this post, we’ll talk about how the microbiome is being harnessed in therapeutics and healthcare. Stay tuned for the next article on the microbiome in consumer products!
Remember how we said in the last post that the microbiome is so critical to healthy human functioning that it’s often referred to as another organ? Just like an individual may have bad lungs, or experience kidney failure, so too can the microbiome become diseased. This can happen if the microbiome is weakened in some way--such as through antibiotics--and in its weakened state, it is unable to protect against an invading pathogen. This is what happens in C. difficile infection, a bacterial disease that infects the colon. In this case, treating the microbiome itself is a promising avenue for therapeutic benefit.
But of course, it’s more complicated than that. There are a growing number of cases in which the microbiome, while not apparently dysbiotic itself, appears to be influencing or to be influenced by another diseased state in the body. For example, patients with certain kinds of cancer appear to respond differently to immunotherapy in relation to the makeup of their microbiome. So while the microbiome itself may not be strictly “sick,” its composition is impacting the sickness of other parts of the body; and changing that composition can potentially improve a patient’s response to treatment for these seemingly unrelated conditions.
Dozens of start-ups and research labs have arisen to further investigate the potential of microbiome therapeutics, but they’re mostly focusing in a few key areas. As you might expect from predominance of the gut microbiome, one of the therapeutic areas of most immediate interest has been gut diseases. But a host of other conditions within autoimmune diseases, cancer, and neurology are also under investigation.
At their core, microbiome therapeutics attempt to rebalance a dysbiotic microbial environment. The first microbiome therapeutic was documented in fourth-century China, and the method is still being used today. This method is called Fecal Microbiota Transplant, or FMT. The concept of FMT refers to transplanting faecal matter from a healthy donor to a patient experiencing gut dysbiosis in order to improve their microbial composition and cure them of disease. The transferred microbiota colonize the intestine and shift gut composition, ideally rebalancing the host environment and eliminating intestinal pathogens.
Although an apparently simple solution, cure rates of certain gut diseases after FMTs are surprisingly high. C. difficile Infection (CDI) has received by far the greatest experimentation with FMT, and systematic reviews from early 2010s suggest cure rates as high as 90% for patients of recurrent or refractory CDI, compared to only a 20-30% cure rate from antimicrobials. CDI is the only disease for which FMT is officially classified as a treatment; however, a series of pilot studies have begun to examine other gut diseases, such as Crohn’s and irritable bowel syndrome.
FMT came under significant criticism, however, after a patient died as a result of the transfer of a sample containing drug-resistant E. coli. Transplants are screened in order to catch pathogenic material, but the screens aren’t fool proof. Screening methods have improved, however, and biotechs such as Finch Therapeutics are still pursuing the potential of FMT--albeit in a more appetizing pill form.
Some companies have attempted to refine FMTs to reduce the risks associated with full microbial environment transmission by transferring defined bacterial consortia or filtrates. Defined consortia are compositions of bacteria manufactured from purified donors, reducing the risk of donor contamination and specifying the bacterial colonies to a patient’s specific disease. Sterile faecal filtrates, in comparison, remove the actual living bacteria from a sample and transfer only filtrates—including bacterial debris, proteins, antimicrobial compounds, metabolic products, and oligonucleotides—to stimulate readjustment of the gut microbiome.
It’s important to note that in these examples, microbiome environments are the problem and the solution; healthy bacterial therapeutics are used to treat dysbiotic bacterial communities. But not all companies are using bacteria to fight bacteria: Axial Biotherapeutics, for example, is using traditional small-molecule methods to address dysbiotic microbiomes. The concept of readjusting an unhealthy microbial community, however, remains the same.
It’s also important to note that all of these examples relate to a dysbiotic gut microbiome; but as I mentioned in my previous article, the microbiome is also concentrated in the mouth, on the skin, and in the vagina. And though gut microbiome therapeutics are the most advanced, research on other areas of the microbiome is rapidly accelerating.
While apparently a diverse group, a lot of the gut conditions under investigation for microbiome therapeutics are autoimmune diseases. This includes Crohn’s disease, for which 4D Pharma, Assembly Biosciences, Enterome, and Finch Therapeutics all have candidates in development; as well as Ulcerative Colitis, which all the same companies (except Finch) are also investigating. The greatest number of drug candidates addressing infectious diseases are for the previously mentioned C. difficile infection (Finch, Seres, Rebiotix) but Vedanta Biosciences (in addition to C. diff) is also addressing broader multi-drug resistant organisms.
Microbiome therapeutics in cancer aim to improve the efficacy of existing cancer drugs, specifically checkpoint inhibitors, which are a newer class of oncology therapeutics that help the immune system attack cancer cells. These “combination studies,” such as those being undertaken by 4D Pharma in collaboration with Keytruda for solid tumors, aim to improve the efficacy of an existing drug by improving the “immune-stimulatory host-response profile.” Vedanta Biosciences is undertaking a similar study with BMS’s cancer drug, OPDIVO. The role of the microbiome in chemotherapy response is also being investigated.
Neurology is the earliest stage of microbiome therapeutics development, and for that reason, efforts in ongoing drug development are not always transparent. Evelo Biosciences has a non-disclosed target in “Neuro-inflammation”; Finch Therapeutics is developing a product for children with Autism Spectrum Disorders experiencing significant GI symptoms; and 4D Pharma is investigating “neurodegeneration.” Kallyope, which closed a $112 million Series C in March 2020, is entirely focused on the gut-brain axis but is opaque on any specific diseases. Their website states “defects in the gut-brain axis have been linked to diseases including obesity, diabetes, NASH, functional gastrointestinal disorders, inflammatory disorders, depression, autism, and Parkinson's disease,” demonstrating the breadth of neurological applications for future microbiome therapeutics.
There are a variety of other indications being pursued, if not perhaps at the same frequency as those previously mentioned. These include drugs for metabolic conditions, such as Pendulum’s Type-2 Diabetes product. Vedanta Bio is investigating childhood food allergies, and 4D Pharma looking at respiratory diseases. For a non-gut example, Rebiotix is working on multi-drug resistant UTIs, and Kaleido and Finch are also both investigating liver conditions.
The microbiome has a systemic and critical influence on the healthy functioning of our bodies, so it follows that the breadth of therapeutic indications for microbiome therapeutics would be equally broad. As research continues, I am sure we will continue to see novel applications of microbiome therapeutics, as well as therapeutic-enhancing probiotics (such as those already in development for immuno-oncology).
This field is still in its early stages, and upcoming approvals and Phase III clinical readouts due in 2021 could soon define the future of the field. But optimism is well-deserved; all eyes will be on the future of these drugs.
Next, we’ll take a look at the role of the microbiome in consumer products and wellness. This is a much less strictly regulated industry, but the role of the microbiome in future development could be equally huge.
Cover Photo: “Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome,” The Microbe Discovery Project, 03-Jul- 2016.
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September 14, 2020