The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection: Current Understanding and Gap Analysis
Mark H. Wilcox,1,2 Barbara H. McGovern,3, and Gail A. Hecht4,5
1 Department of Microbiology, Old Medical School, Leeds Teaching Hospitals NHS Trust, Leeds, UK, 2 University of Leeds, Leeds, UK, 3 Seres Therapeutics, Medical Affairs, Cambridge, Massachusetts, USA, 4 Department of Medicine, Division of Gastroenterology, Loyola University Chicago, Chicago, Illinois, USA, and 5 Department of Microbiology and Immunology, Loyola University Chicago, Chicago, Illinois, USA The leading risk factor for Clostridioides
Abstract: The leading risk factor for Clostridioides (Clostridium) difficile infection (CDI) is broad-spectrum antibiotics, which lead to low microbial diversity, or dysbiosis. Current therapeutic strategies for CDI are insufficient, as they do not address the key role of the microbiome in preventing C. difficile spore germination into toxin-producing vegetative bacteria, which leads to symptomatic disease. Fecal microbiota transplant (FMT) appears to reduce the risk of recurrent CDI through microbiome restoration. However, a wide range of efficacy rates have been reported, and few placebo-controlled trials have been conducted, limiting our understanding of FMT efficacy and safety. We discuss the current knowledge gaps driven by questions around the quality and consistency of clinical trial results, patient selection, diagnostic methodologies, use of suppressive antibiotic therapy, and methods for adverse event reporting. We provide specific recommendations for future trial designs of FMT to provide improved quality of the clinical evidence to better inform treatment guidelines.
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Clostridioides difficile is one of the leading causes of antibiotic-associated diarrhea.
Gut microbiota-derived secondary bile acids and commensal Clostridia that carry the bile acid-inducible (bai) operon are associated with protection from C. difficile infection (CDI), although the mechanism is not known.
In this study, we hypothesized that commensal Clostridia are important for providing colonization resistance against C. difficiledue to their ability to produce secondary bile acids, as well as potentially competing againstC. difficilefor similar nutrients.
To test this hypothesis, we examined the abilities of four commensal Clostridia carrying the bai operon (Clostridium scindens VPI 12708, C. scindens ATCC 35704, Clostridium hiranonis, and Clostridium hylemonae) to convert cholate (CA) to deoxycholate (DCA)in vitro, and we determined whether the amount of DCA produced was sufficient to inhibit the growth of a clinically relevantC. difficilestrain.
We also investigated the competitive relationships between these commensals and C. difficile using an in vitro coculture system.
We found that inhibition ofC. difficile growth by commensal Clostridia supplemented with CA was strain dependent, correlated with the production of ∼2 mM DCA, and increased the expression of bai operon genes.
We also found that C. difficilewas able to outcompete all four commensal Clostridia in an in vitro coculture system. These studies are instrumental in understanding the relationship between commensal Clostridia and C. difficile in the gut, which is vital for designing targeted bacterial therapeutics. Future studies dissecting the regulation of the bai operon in vitro and in vivo and how this affects CDI will be important.
IMPORTANCE : Commensal Clostridia carrying the bai operon, such as C. scindens, have been associated with protection against CDI; however, the mechanism for this protection is unknown. Herein, we show four commensal Clostridia that carry the bai operon and affect C. difficile growth in a strain-dependent manner, with and without the addition of cholate. Inhibition of C. difficile by commensals correlated with the efficient conversion of cholate to deoxycholate, a secondary bile acid that inhibits C. difficile germination, growth, and toxin production.
Competition studies also revealed that C. difficile was able to outcompete the commensals in an in vitro coculture system.
These studies are instrumental in understanding the relationship between commensal Clostridia andC. difficile in the gut, which is vital for designing targeted bacterial therapeutics.
Rebiotix, a Ferring Company, completes enrollment for first-ever, pivotal Phase 3 Clinical Trial of Microbiota -based RBX2660
Enrollment completion for the first Phase 3 clinical trial in microbiome industry
The largest randomized, double-blinded study, with over 300 patients enrolled aimed to demonstrate the potential benefit of RBX2660 in reducing rates of recurrent Clostridioides difficile (C. diff) infection
Rebiotix intends to use the results from the Phase 3 trial to serve as the basis for licensure application to the US Food and Drug Admin (FDA)
Saint-Prex, Switzerland – On February 4, 2020
Rebiotix, a Ferring company, announced today that it has completed enrollment of the pivotal Phase 3 clinical trial for RBX2660, an investigational therapy aimed at breaking the cycle of recurrent Clostridioides difficile (C. diff) infection, which is responsible for the deaths of thousands of people in the US alone. The Centers for Disease Control and Prevention (CDC) has classified C. diff as an urgent public health threat, with limited options for treatment.
RBX2660 was developed under Rebiotix’s investigational microbiota-based MRT™ drug platform with the goal of delivering standardized, stabilized formulations to meet unmet medical needs. Conducted in the US and Canada, this is the first Phase 3 trial of its kind to be completed using a broad consortia microbiota-based formulation.
“Rebiotix was founded to harness the power of the human microbiome to treat debilitating diseases,” said Lee Jones, Rebiotix Founder, and CEO. “Microbiota-based therapies have shown tremendous potential as an innovative, non-antibiotic therapy, starting with C. diff. The completion of enrollment of this trial is a critical next step in making microbiota-based products accessible to patients – we are excited about this important milestone and look forward to sharing results later this year.”
The Phase 3 trial builds on the company’s extensive history with the formulation, including several hundred participants previously enrolled in multiple Phase 2 clinical trials. The robust data collected over the course of the company’s multi-year clinical development program will be eventually presented to the US FDA as part of a Biological License Application (BLA).
Ferring Pharmaceuticals, also with a rich and vast history of microbiome research of its own, led the industry by becoming the first major pharmaceutical company to acquire a microbiome therapeutics company in April 2018. Headquartered in Saint-Prex, Switzerland, Ferring is expected to have the first regulatory approved microbiota-based therapeutic in the world through the potential approval of the RBX2660 in the US.
About Clostridioides difficile Infection
Clostridioides difficile (also known as C. diff) is a bacterium that causes diarrhea and colitis (inflammation of the colon). C. diff, impacts nearly a half a million people each year in the United States; of those impacted, up to one in five patients will experience a recurrent episode.1 In 2019, the U.S. Centers for Disease Control listed C. diff as an urgent threat to public health.2
RBX2660 is currently in Phase 3 clinical development for the reduction of recurrent Clostridioides difficile (C. diff) infection. RBX2660 has been granted Fast Track, Orphan, and Breakthrough Therapy Status designations from the US FDA. For more information about the RBX2660 Phase 3 study, visit http://www.clinicaltrials.gov (NCT03244644).
Rebiotix Inc., part of the Ferring Pharmaceuticals Group, is a late-stage clinical microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of challenging diseases. Rebiotix has a diverse pipeline of investigational drug products built on its pioneering microbiota-based MRT™ drug platform. The platform consists of investigational drug technologies designed to potentially rehabilitate the human microbiome by delivering a broad consortium of live microbes into a patient’s intestinal tract. For more information on Rebiotix and its pipeline of human microbiome-directed therapies for diverse disease states, visit http://www.rebiotix.com.
About Ferring Pharmaceuticals
Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group committed to helping people around the world build families and live better lives. Headquartered in Saint-Prex, Switzerland, Ferring is a leader in reproductive medicine and maternal health, and in specialty areas within gastroenterology and urology. Founded in 1950, privately-owned Ferring now employs approximately 6,500 people worldwide, has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries.
Acurx Pharmaceuticals, LLC is, a privately-held, clinical stage, biopharmaceutical company developing new antibiotics for difficult-to-treat bacterial infections, announced that its lead product candidate, ACX-362E, has successfully completed the 32-subject, double-blinded, placebo-controlled, single-ascending dose portion of this first-in-man Phase 1 clinical trial. ACX-362E is a novel, oral antibacterial agent for the treatment of Clostridioides difficile infection (CDI), an acute, serious, potentially life-threatening, intestinal infection.
ACX-362E is Acurx’s lead compound in a pipeline of molecules that target a previously unexploited mechanism of action, namely, inhibition of the bacterial enzyme DNA polymerase IIIC (pol IIIC). Pol IIIC is required for DNA replication of many Gram-positive pathogens, including not only Clostridioides but also Enterococcus, Staphylococcus, and Streptococcus. Although the trial data remain blinded, ongoing monitoring of the data show dose levels up to 600mg have been generally well tolerated. Blood levels of ACX-362E show low systemic exposure, as predicted by prior animal studies and desirable in treating CDI. Additionally, fecal concentrations of ACX-362E at higher dose levels have exceeded the concentrations known to inhibit C. difficile by several hundred-fold.
“We are very encouraged by these initial data which corroborate our nonclinical findings, showing that at well-tolerated doses ACX-362E reaches concentrations in the colon that are projected to be therapeutically relevant for patients with CDI” said Robert J. DeLuccia, Co-Founder and Managing Partner of Acurx. “This gives us confidence that the ongoing multiple-dose segment of the trial will provide data to guide selection of our Phase 2 dose and improve the probability of success and timeline efficiency of our Phase 2 clinical trial planned to start later this year.”
Dr. Kevin Garey, Professor, University of Houston College of Pharmacy and the Principal Investigator for microbiomic aspects of the Phase 1 clinical trial said: “The emerging fecal concentration data are comparable to those observed with precedent products that have advanced to demonstrate clinical success. I look forward to the multiple-dose safety data and to the results of the microbiomic analyses that our laboratory is performing which will form a template for a new paradigm in microbiome studies associated with drug discovery and development of CDI-directed antibiotics.”
About the Phase 1 Clinical Trial This Phase 1 trial, conducted in the U.S., is a double-blinded, placebo-controlled study to determine safety, tolerability, pharmacokinetics and fecal concentrations of ACX-362E in healthy volunteers. It is being conducted in two parts; first, single ascending doses are administered to four cohorts of 8 subjects each, and second, multiple ascending doses are given that simulate the anticipated clinical treatment regimen. Safety information is analyzed through assessment of adverse events and other standard safety measures, while concentrations of ACX-362E are determined in both the blood and the feces, the latter being the critical site of drug delivery for treating CDI. In addition, Acurx has partnered with the laboratory of Dr. Kevin Garey at the University of Houston to perform state-of-the-art microbiomic testing of gastrointestinal flora in trial subjects.
About ACX-362E, FDA QIDP and Fast Track Designation FDA Fast Track Designation is a process designed to facilitate the development and expedite the regulatory pathway of new drugs to treat serious or life-threatening conditions and that fill a high unmet medical need. ACX-362E is a novel, first-in-class, orally-administered antibacterial. It is the first of a novel class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections. Acurx acquired ACX-362E from GLSynthesis, Inc. in February 2018.
ACX-362E is a Qualified Infectious Disease Product (QIDP) for the treatment of patients with Clostridium difficile infection (CDI). Under QIDP designation, ACX-362E will now be eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (the GAIN Act). These incentives include Priority Review and eligibility for Fast Track status. Further, if ultimately approved by the FDA, ACX-362E is eligible for an additional five-year extension of Hatch-Waxman marketing exclusivity. ACX-362E is being developed as a targeted, narrow spectrum oral antibiotic for the treatment of patients with CDI. Acurx anticipates completing the Phase 1 clinical trial in the second quarter of 2019 and is planning to advance ACX-362E into a Phase 2 clinical trial in the fourth quarter of 2019. The CDC (Centers for Disease Control & Prevention) has designated Clostridium difficile bacteria as an urgent threat highlighting the need for new antibiotics to treat CDI.
Mice experiments and small studies of people with depression have suggested the involvement of the gut microbiome in both behavior and depression, respectively. However, human research addressing how gut microorganisms might contribute to depression—in large samples and considering confounding factors that can affect the microbiota—is lacking.
Ten genus abundances were correlated with quality of life scores, including both mental and physical scores. Among these bacterial genera, Faecalibacterium, Coprococcus, Dialister, Butyrivibrio, Gemmiger, Fusicatenibacter and Prevotella were consistently associated with higher quality of life scores, whereas Parabacteroides, Streptococcus and Flavonifractor showed negative associations. After controlling for a wealth of confounding factors, the authors validated some of these associations in the LLD cohort.
The researchers found that Dialister and Coprococcus genera were reduced in people with depression, after taking into account antidepressant drugs as confounders. Furthermore, the authors described an association between enterotype distribution in relation to quality of life scores and diagnosis of depression in the Flemish cohort. For instance, a higher prevalence of Bacteroides enterotype 2 was linked to lower quality of life and depression.
Finally, the authors dug through metagenomic data to create a catalogue describing the gut microbiota’s ability to synthetize or degrade molecules that can cross-talk with the human nervous system. With this aim, Raes and colleagues assessed the distribution of 56 compounds that play an important role in proper nervous system function, which gut microbes either synthesize or metabolize, in human gut-associated microbial genomes (n=532).
Certain neuroactive compounds might explain the beneficial relationship between gut microbes and quality of life. The researchers found, for example, that GABA and tryptophan metabolism pathways were expressed in human gut-associated microorganisms.
Furthermore, some positive correlations were also observed between quality of life and the potential ability of the gut microbiome to produce 3,4-dihydroxyphenyalcetic acid -a breakdown product of the neurotransmitter dopamine-, isovaleric acid and histamine. Of these, the association between 3,4-dihydroxyphenylacetic acid and quality of life was also replicated in the LLD cohort. As neurotransmitters and neuroactive compounds can also have an impact on bacterial growth, further research is needed to disentangle the contribution of microbe-derived neuroactive molecules to a person’s behavior.
This is the first approach to build a database for studying the gut microbiome’s neuroactive potential and it will help future research to interpret microbiome-gut-mental axis research in a clearer way, supporting the translation of such complex research from the bench to the clinic.
Although these new findings do not prove cause and effect due to the observational design of the study, this research contributes to mounting evidence about mechanisms by which the “microbiome-gut-brain axis” is involved in the development of depression. Further options to experimentally prove the association between the gut microbiota and depression might include rodent models and large studies with enough follow-up periods that explore the role of probiotics, prebiotics, a healthy diet and fecal microbiota transplantation for recovering microbiota, considering the confounding effects of microbiome covariates.
On the whole, this new study strengthens the link between gut bacteria and depression. This is a first step towards understanding how the gut microbiome and its metabolites might affect mood in humans
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