Escape Velocity—the Launch of Microbiome Therapies

Abstract

Food and Drug Administration approval of the first microbiome therapies represents a true expansion the treatment paradigm for Clostridioides difficile but raises new questions about the future role of fecal microbiota transplantation. The authors outline the advances in microbiome therapeutic development that have addressed fecal microbiota transplantation’s (FMT's) inherent limitations of safety and scalability. The authors also suggest that as microbiome therapeutic development continues for other indications, FMT will likely remain a necessary model of human microbiota dynamics for translational research.

FDA approval of the first microbiota therapeutics raises new questions about the future role of fecal microbiota transplantation (FMT). The authors explore these questions and suggest that FMT has unique value for research and to support patient access.

Clostridioides difficile infection (CDI) affects approximately 500 000 patients in the United States each year and is tightly linked to the intestinal microbiome [1]. The anniversary of the US Food and Drug Administration (FDA) approval of the first live biotherapeutic product (LBP) to prevent recurrent CDI is an important opportunity to reflect on shifts in the treatment paradigm for CDI. The path from development to implementation of novel treatments for CDI also provides valuable lessons in the ongoing clinical development of microbiome therapies for other indications.

After a landmark clinical trial demonstrated the superiority of donor feces installation compared to vancomycin for prevention of recurrent CDI in 2013, subsequent trials confirmed this observation [2, 3]. Based on this evidence, fecal microbiota transplantation (FMT), became a guideline-recommended treatment for prevention of recurrent CDI [4]. Although multiple randomized trials provided evidence of benefit, 2 major challenges slowed the widespread implementation of FMT in clinical practice—safety and scalability.

In the United States, access to FMT for prevention of recurrent CDI is largely reliant upon the FDA's decision to exercise enforcement discretion for this indication. In May 2013, the FDA first announced that FMT would need to be administered under an Investigational New Drug application. In response, there was an outpouring of public comment from physicians, patients, and scientists that the data for FMT were too compelling to restrict its use to this extent. In July 2013, the FDA announced a revised plan to exercise enforcement discretion for FMT used to treat patients with CDI not responsive to standard therapies who provided informed consent. At its peak before the start of the coronavirus disease 2019 (COVID-19) pandemic, the not-for-profit stool bank OpenBiome provided FMT doses to treat approximately 10 000 patients per year. Unfortunately, reports of transmission of antibiotic-resistant and pathotypic Escherichia coli through FMT raised significant safety concerns [5, 6]. These concerns were amplified by the potential risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission via FMT, which prompted the FDA to require a pause in manufacturing of FMT doses in March 2020 until reliable tests for SARS-CoV-2 were available to screen donors. Although assays to screen for these pathogens now exist, the ease of obtaining FMT from stool banks is greatly reduced, and the use of FMT in 2024 is likely a fraction of that in 2019. Taken together, these events illustrate the most important inherent but infrequent safety risks of FMT that have been identified in over 10 years of use since publication of a landmark clinical trial.

In the last year, the FDA approved the first 2 LBPs for prevention of recurrent CDI. Rebyota (Ferring Pharmaceuticals, Inc, Roseville, MN) is a liquid suspension of human intestinal microbiota delivered as an enema. Vowst (Seres Therapeutics, Inc, Cambridge, MA) is a preparation of human intestinal microbiota spores, delivered as a 3-day course of oral capsules. Both products implement standardized processes that address many FMT safety concerns and their approval could improve availability for clinical use. Shortly after approval of the first product, the FDA announced that it would no longer exercise enforcement discretion for FMT doses manufactured by centralized stool banks. Approval of these LBPs represents a major step toward mitigating safety risks of human-derived microbiota products for clinical use. However, to the extent that they are donor-derived products, they are still subject to challenges of scalability.

Also in the last year, a product called VE303 (Vedanta Biosciences, Cambridge, MA) launched a phase 3 clinical trial after a phase 2 clinical trial results showed reduced recurrence in recipients compared to placebo. VE303 is composed of 8 strains of Clostridia spp. that can durably engraft (detectable after administration) in recipients. As a defined consortium of well-characterized strains, VE303 is expected to have comparable safety to commercial pharmaceutical products while also addressing the challenge of scalability through bulk fermentation.

With the anticipated declining use of FMT, FDA approval of 2 LBPs, and progression of a third LBP to a phase 3 clinical trial, this is an important point to take stock of the needs of patients in the present and the future. Progress made by the field has been fraught with risk and loss. In November 2022, the FDA announced its decision to end its policy of enforcement discretion for FMT distributed from stool banks to other facilities for recurrent CDI (docket number FDA-2013-D-0811). This guidance specifically notes FDA will extend its enforcement discretion policy for FMT products not sourced from a stool bank, such as an “establishment that collects or prepares FMT products solely under the direction of licensed health care providers for the purpose of treating their patients (eg, a hospital laboratory) is not considered to be a stool bank.” This decision makes sense considering the new, safe, and effective LBP treatment options for adults with recurrent CDI. However, the resources required for individual facilities to maintain a rigorous stool donor program are likely to be available at just a handful of academic medical centers. Thus, the availability of LBPs and challenges of treating institutions maintaining their own FMT product manufacturing may also paradoxically reduce overall access to effective recurrent CDI treatment relative to the FMT era. Moving forward, we suggest 2 dynamics should be closely monitored by clinicians, regulatory agencies, and federal grant-making agencies.

First, can we expect access to LBPs with higher efficacy for prevention of recurrent CDI compared to antibiotics to increase or decrease after FDA approval? Although it is rare for patients to pay the full sticker price of biologic therapies, Rebyota and Vowst are expected to cost 3 and 8 times the cost of an FMT dose from OpenBiome, respectively. No studies have directly compared the safety and efficacy of FMT to Vowst or Rebyota, and it is not clear how society treatment guidelines will address them. Preferential use of LBPs over FMT, if not supported by evidence from rigorous clinical trials, may impede progress in the development and implementation of the most effective microbiota therapeutics. Groups for which LBPs have not been approved (eg, pediatric patients) and patients who fail initial treatment with LBPs may have worse outcomes if FMT is no longer available. We should actively seek to avoid the worst-case scenario of a decelerated paradigm shift through declining access to FMT and replacement by LBPs that may have access challenges due to cost or other factors (Figure 1).

Figure 1.

Maturation of live biotherapeutic product (LBP) clinical development beyond fecal microbiota transplantation (FMT) expands treatment options for patients. Systems biology and microbiome analyses allow for refinement of products beyond FMT that can overcome FMT challenges of safety and scale but may not render FMT obsolete in research settings. As the number of LBPs expand, policy makers should closely monitor the extent to which patients can access therapies with demonstrated safety and efficacy (created with BioRender.com).

Second, human microbial communities did not evolve solely to restrict germination of C. difficile spores and it is short-sighted to presume that microbial therapeutics that reduce recurrent CDI risk will be optimal for all indications. Although LBPs offer more consistent composition and less risk of contamination, they may have a narrower therapeutic potential beyond prevention of recurrent CDI. Many groups now have large strain banks; however, funders and regulators should carefully consider the efficiency of “top-down” well-designed FMT studies compared to the cost and complexity of iteratively studying new “bottom-up” consortia with similar efficacy for patients [7]. FMT has demonstrated efficacy for several other conditions without effective treatments like multidrug-resistant organism colonization [8].

The history of FMT demonstrates the need for robust donor screening and manufacturing protocols, to ensure a safety profile that is comparable to LBPs. With appropriate screening and manufacturing, FMT remains a valuable tool to advance effective treatment of CDI and other multidrug-resistant organism infections. To leverage the translational strengths of FMT studies, teams need skills in regulatory science, good manufacturing practice, clinical microbiology, advanced culture-independent analytic approaches (such as metagenomic and metabolomic assays), and the design and conduct of clinical trials. If a study team assembles this skillset, they still face unpredictable recruitment and enrollment. Platform studies or collaborative trial networks that rigorously investigate diverse dosing approaches and outcome measures for a given indication could accelerate and de-risk clinical translation to spur development of effective microbiome-based therapeutics. A central challenge in accelerating progress in the field is allocation of risk. Commercial LBP manufacturers are under intense pressures to get to clinic and establish market share for the broadest indications with the most patients. Thus, they are exposed to precisely the same market dynamics that have slowed antibiotic development. On the other hand, academic investigators may have more flexibility to pursue other indications in more challenging populations and clinical settings but fewer resources to maintain local FMT manufacturing programs, much less weather the risks of extended regulatory review or screening stool donors, which can take months to years. If commercial manufacturers were incentivized to provide FMT or LBP products for clinical trials, this would be expected to accelerate translation and clinical development where possible.

We suggest that approval of the first LBPs is the beginning, not the end, of the journey in microbiota therapeutic development. Much more research is needed to understand the mechanisms by which FMT exerts effects in humans—including microbe-microbe interactions and microbially mediated influence on host immune effectors. In reflecting on the year after FDA approval and commercial marketing of the first microbiome therapy, we conclude that to realize the full potential of LBPs, including new indications beyond CDI, FMT will remain an invaluable home base for microbiome therapy development even after launch of the first LBPs.

Notes

Acknowledgment. Figure created with BioRender.com.

Financial support. M. H. W. is supported by the Centers for Disease Control and Prevention (grant number U54CK000601); and the National Institute of Allergy and Infectious Diseases (grant number K23AI144036).