Ferring Pharmaceuticals and Rebiotix, a Ferring Company, today announced a publication detailing the development and validation of their first-of-its-kind prototype biomarker, designed to distinguish post-antibiotic disruptions to the human gut microbiota, known as dysbiosis, from healthy gut microbiota. The Microbiome Health Index for post-Antibiotic dysbiosis (MHI-A), published in Frontiers in Microbiology, was developed to better understand and manage the risks of antibiotic administration and help guide the development of live biotherapeutic products – a potential new class of drugs.1
The gut microbiome is a highly-diverse microbial community that plays an essential role in human health. Antibiotics are known to disrupt the composition and/or diversity of the gut microbiome.2,3,4 This disruption is a risk factor for serious illnesses, including C. difficile infection (CDI) and potential recurrences. While the impact of antibiotic use on dysbiosis is documented, measurements of dysbiosis are complex and often vary between studies, leaving a need for a simple biomarker identifying gut microbiota composition that can help support diagnostic decisions.1
The Ferring MHI-A algorithm was designed to differentiate post-antibiotic dysbiosis from healthy microbiota by relating the relative abundances of bacteria naturally found in the gut microbiome that are associated with health (Bacteroidia and Clostridia) versus those that could be considered harmful (Gammaproteobacteria and Bacilli).1 The study shows MHI-A has high accuracy to distinguish post-antibiotic dysbiosis from healthy microbiota. MHI-A values were consistent across multiple healthy populations and were significantly shifted by antibiotic treatments known to alter microbiota compositions and shifted less by microbiota-sparing antibiotics. The study concludes that MHI-A is a promising biomarker of post-antibiotic dysbiosis and subsequent restoration. MHI-A may also be useful for rank-ordering the microbiota-disrupting effects of antibiotics and as a pharmacodynamic measure of microbiota restoration.1
“This biomarker provides a concise metric for assessing the complex changes in the microbiome of trial participants pre- to post-treatment, expanding our understanding of microbiome restoration after antibiotic use,” said lead author Ken Blount, Chief Scientific Officer, Rebiotix, Vice President Microbiome Research, Ferring Pharmaceuticals. “This is a crucial step in unlocking the potential of microbiome-based live biotherapeutics, further demonstrating Ferring’s leadership in advanced research that addresses the urgent needs of patients with recurrent C. diff.”
About the Study
MHI-A was developed using longitudinal data from more than 200 treated patients across three controlled clinical trials of RBX2660 and RBX7455, Ferring’s two leading investigational microbiome-based live biotherapeutic products for the reduction of recurrent CDI. It was validated using published data describing the microbiome of several healthy and antibiotic-treated populations.1
Comparing the algorithm findings against baseline samples representative of post-antibiotic dysbiosis, the study authors concluded that MHI-A values were consistent across multiple healthy populations. The population microbiomes were significantly shifted by antibiotic treatments known to alter microbiota compositions, while they were shifted less by microbiota-sparing antibiotics. Study authors also observed that clinical response to RBX2660 and RBX7455 correlated with a shift of MHI-A from dysbiotic values to healthy representations.1
Based on the data sets, the study authors suggest MHI-A may rank-order specific antibiotics’ impact on the microbiota, which could be valuable for treatment decisions and the development of more microbiota-sparing antibiotics. Additionally, they concluded MHI-A might be useful for identifying patients at risk of dysbiosis-related complications.1
About C. difficile infection
C. difficile infection (CDI) is a serious and potentially deadly disease that impacts people across the globe. The C. difficile bacterium causes debilitating symptoms such as severe diarrhea, fever, stomach tenderness or pain, loss of appetite, nausea and colitis (an inflammation of the colon).5 Declared a public health threat by the U.S. Centers for Disease Control and Prevention (CDC) requiring urgent and immediate action, CDI causes an estimated half a million illnesses and tens of thousands of deaths in the U.S. alone each year.5,6,7
C. difficile infection often is the start of a vicious cycle of recurrence, causing a significant burden for patients and the healthcare system.8,9 Up to 35% of CDI cases recur after initial diagnosis2,3 and people who have had a recurrence are at significantly higher risk of further infections.10,11,12,13 After the first recurrence, it has been estimated that up to 60% of patients may develop a subsequent recurrence.14 Restoring the gut microbiome is increasingly accepted as a promising treatment option for recurrent C. difficile infection.15
RBX2660 is a potential first-in-class microbiota-based live biotherapeutic being studied to deliver a broad consortium of diverse microbes to the gut to reduce recurrent C. difficile infection. RBX2660 has been granted Fast Track, Orphan, and Breakthrough Therapy designations from the U.S. Food and Drug Administration (FDA). The pivotal Phase 3 program builds on nearly a decade of research with robust clinical and microbiome data collected over six controlled clinical trials with more than 1,000 participants.
- Blount K, Jones, C. Walsh, D et al. Development and Validation of a Novel Microbiome-Based Biomarker of Post-Antibiotic Dysbiosis and Subsequent Restoration. Frontiers in Microbiology.
- Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-834.
- Cornely OA, et al. Treatment of First Recurrence of Clostridium difficile Infection: Fidaxomicin Versus Vancomycin. Clinical Infectious Diseases. 2012;55(S2): S154–61.
- Langdon A, Crook N, Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 2016;8(1):39.
- Centers for Disease Control and Prevention. What Is C. Diff? 17 Dec. 2018. Available at: https://www.cdc.gov/cdiff/what-is.html.
- Centers for Disease Control and Prevention. Biggest Threats and Data, 14 Nov. 2019. Available at: https://www.cdc.gov/drugresistance/biggest-threats.html
- Fitzpatrick F, Barbut F. Breaking the cycle of recurrent Clostridium difficile. Clin Microbiol Infect. 2012;18(suppl 6):2-4.
- Centers for Disease Control and Prevention. 24 June 2020. Available at: https://www.cdc.gov/drugresistance/pdf/threats-report/clostridioides-difficile-508.pdf.
- Feuerstadt P, et al. J Med Econ. 2020;23(6):603-609.
- Riddle DJ, Dubberke ER. Clostridium difficile infection in the intensive care unit. Infect Dis Clin North Am. 2009;23(3):727-743.
- Nelson WW, et al. Health care resource utilization and costs of recurrent Clostridioides difficile infection in the elderly: a real-world claims. J Manag Care Spec Pharm. Published online March 11, 2021.
- Kelly, CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect. 2012; 18 (Suppl. 6): 21–27.
- Smits WK, et al. Clostridium difficile infection. Nat Rev Dis Primers. 2016;2:16020. doi: 10.1038/nrdp.2016.20.
- Leong C, Zelenitsky S. Treatment strategies for recurrent Clostridium difficile infection. Can J Hosp Pharm. 2013;66(6):361-368.
- van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.