Fecal microbiota transplants (FMTs) have played an important role in fighting disease. Because they consist of many complex bacterial strains, FMTs offer an optimal ecosystem to successfully engraft and impart therapeutic value upon the host. Technically, they’ve been in use since 700 BC (!) and in 1978, FMTs were broadly recognized as effective at treating a disease with known cause: Clostridium difficile infections. In some cases, FMTs proved more effective than antibiotics in keeping Clostridium difficile, a common cause of diarrhea, in check. In cancer immunotherapy, FMTs can help produce better prognoses for patients who previously failed to respond to immune checkpoint inhibitors.
FMT variability, development and delivery drawbacks can’t be ignored.
We’ve learned a lot from FMTs, however as a therapeutic, there are clear drawbacks. First, pathogens can exist even in healthy fecal samples, and with those pathogens passed on to patients, safety risks arise. Second, FMTs are notoriously difficult to scale commercially and highly variable. Every individual harbors a constellation of bacterial strains within their gut microbiome – a constellation that’s constantly shifting in absolute constituents and overall relative abundance – so a single bowel movement can only treat a few patients at one time, making it impossible to run a large clinical study that tests the same drug product material across an entire cohort. Because of this limitation, pharmaceutical companies have tried to pool fecal samples from multiple donors to meet clinical development demands, but it’s not possible to manufacture that same drug product again once a clinical response has been identified.
Because FMTs are uncontrolled from batch-to-batch and trial-to-trial, another drawback to this therapeutic is its development process. Complex fecal material products have been successfully developed for treating C diff, but that’s because the species important for treating C diff are abundant in nearly all healthy human fecal materials. This hasn’t been the case in developing FMTs for treatment beyond C diff. FMTs have shown promise, but they largely produce variable results, and efforts to further develop them highlight the need to be able to capture bacterial diversity from unique fecal donors, and manufacture that material for FDA-approved therapeutic trials and commercial success.
There’s also the issue of FMT delivery. Colonoscopies are the dominant format, although frozen oral capsules can also be tested clinically. The invasiveness of colonoscopic FMT delivery limits patients to a single dose, making repeat and maintenance dosing unrealistic. And while the oral frozen capsule FMT is more easily administered, it still suffers from a lack of large amounts of consistent starting material, making repeat dosing impossible. In addition to the dosing limitations, FMT products have a relatively short shelf-life, again making it difficult to run large controlled studies with the same FMT material across an entire cohort.
Next-generation LBPs can unlock the power of the gut microbiome.
To advance microbiome-based therapeutics, we need to continue to capture the bacterial complexity of FMTs, but do so with a process that’s scalable and reproducible, and able to meet the demands of clinical development and ultimately patient treatment. Moreover, to effectively fight disease, we need to be able to leverage the gut microbiome as a druggable organ, which requires overcoming two long-standing challenges:
- Understanding the microbiome: What are all the bacterial strains that are in a single gut? Where are those strains located? And what response are those strains eliciting from their host cells? Using traditional molecular techniques to decipher all of this falls short.
- Designing and developing microbiome therapies with different mechanisms of action: Relying on the presence of a single bug or two isn’t enough. We need complete, complex ecosystems because we know that microbes – just like humans! – are incredibly social and stronger together.
The good news is, the answer to both of these challenges may lie within next-generation live biotherapeutic products (LBPs). By acting in a synergistic and complementary manner to existing therapies, LBPs provide a safe method for targeting underlying disease processes, but through different pathways and with greater efficacy. As living microbes, LBPs can improve treatment outcomes for microbiome-addressable conditions, including solid organ cancer, inflammatory bowel disease, auto-immune conditions and metabolic disorders. What’s more, if devoid of pathogens, LBPs are incredibly safe and consistent from batch-to-batch, with the ability to scale-up to meet clinical development needs and eventual patient demand.
Most importantly, LBPs can help us unlock the power of the gut microbiome. The majority of high morbidity/mortality LBP-addressable indications are gut microbiome-centric, and significant value can be unlocked by learning how to formulate, dose and measure the PK/PD of human gut LBPs.
Controlling LBP dosing, measurement and host responses will be key to clinical success.
The FMT era has been productive, but now it’s time to rally together as an industry to accelerate next-generation LBP drug discovery, development and FDA approval. To do so, we must be able to control and eventually standardize the dosing of the LBP drug material in question, the measurement of that drug material (PK) and the host response (PD) – and do so with the same precision of antibody or small molecule drug development. Funding will continue to be constrained until the LBP field has a breakthrough, so we must prioritize creating value via small clinical studies that don’t require massive financial resources, but demonstrate the unique capabilities of LBP therapeutics.
Ultimately, focusing on complex gut consortia so we can learn how to formulate, dose and measure the engagement of an LBP in this organ will be key. Indications where we can run safety, dosing, PK/PD studies in the intended patient population will be critical to LBP clinical success, and indications where early clinical response is meaningful will create value faster and pave the way for funding late-stage registrational studies. Giants in our industry that pioneered this therapeutic modality have already paved a path forward for us… let’s seize the timely opportunity to deliver on the clinical promise of LBPs!
Public domain image of C. diff bacteria by the CDC
