Ferring Pharmaceuticals and Rebiotix, a Ferring Company, today announced final results of an analysis from five prospective trials of its investigational microbiota-based live biotherapeutic, RBX2660, for the reduction of recurrent C. difficile infection (rCDI). The abstract, presented at IDWeek 2021, represents the first time these data are showcased together, and is one of only four abstracts to receive the Program Committee Choice award for outstanding scientific research.
“For years, people with recurrent C. difficile infection haven’t had an available, standardized treatment option to break the cycle of recurrence or clinically address the health of their gut microbiome composition that puts them at risk for this highly communicable disease, and they still do not,”
said Teena Chopra, MD, MPH, Professor of Medicine, Division of Infectious Disease, Wayne State University School of Medicine.
“The important data from the Ferring microbiome-based biotherapeutic trials provide a significant milestone for the C. difficile community to hopefully one day have an improved treatment option for patients suffering from this disease.”
Across the five prospective trials, which included 723 actively-treated participants, RBX2660 consistently reduced the recurrence of CDI, with up to 78.9% remaining recurrence-free for eight weeks post treatment (defined as treatment success). Among participants who did not respond to initial treatment, an optional additional treatment course was administered, resulting in overall rates of treatment success of up to 84.4%. Notably, most primary responders remained CDI-free for six months and up to two years, with a sustained clinical response success rate of up to 92.1% in the Phase 3 program.
“These data provide the totality of evidence culminating in over a decade’s worth of work that demonstrates a consistent efficacy profile for RBX2660, and importantly, a consistent safety profile across five prospective trials,”
said Lindy L. Bancke, PharmD, Head of Clinical Development at Rebiotix, who presented the research.
“They reinforce the enormous potential of microbiome-based therapeutics to transform the care of people suffering from rCDI.”
This analysis included three Phase 2 (PUNCH CD, PUNCH CD2, PUNCH CD Open Label) and two Phase 3 trials (PUNCH CD3, PUNCH CD3-OLS ad hoc analysis). All participants were ages 18 or older who had at least one recurrence after a primary episode of CDI and had completed at least one round of standard-of-care oral antibiotic therapy. According to a separate presentation on safety, RBX2660 demonstrated a consistent safety profile across all five clinical studies. The percentage of participants reporting a treatment-emergent adverse event (TEAE) in the RBX2660 group was similar to the group receiving the standard-of-care plus placebo. Most TEAEs were mild or moderate in severity, and no potentially life-threatening TEAEs were considered related to RBX2660.
A third abstract showed that, among treatment responders in the PUNCH CD3 trial, RBX2660 significantly increased gut bacteria associated with health and decreased gut bacteria associated with CDI pathology within seven days, maintaining that effect for up to six months following treatment. Specifically, RBX2660 demonstrated an increase in the relative abundance of two important classes of beneficial bacteria – Bacteroidia and Clostridia – and reduced relative abundance of classes that could be considered harmful, Gammaproteobacteria and Bacilli.
“C. difficile infection often is marked by a vicious cycle of recurrence, wherein patients’ infection may return within days after antibiotic treatment. This can significantly impact a person’s health and well-being, and burden the healthcare system,”
said Ken Blount, PhD, Chief Scientific Officer at Rebiotix and a study presenter.
“The shift of the microbiome observed in our study provides the first evidence linking Phase 3 efficacy data of RBX2660 with improved microbiota composition of the gut. This finding is important, as this is during a time when a person recovering from CDI is most vulnerable for reinfection, and these changes were durable for at least six months.”
Additional evidence from the PUNCH CD3 trial, presented in two separate abstracts, demonstrated important potential benefits that may contribute to the therapeutic efficacy seen in the clinical program. In the trial, RBX2660 appeared to remove potentially deadly antimicrobial resistant (AMR) bacteria from the gut microbiota, as researchers found that the total number of AMR genes in participants receiving RBX2660 decreased significantly after treatment and remained low for at least six months. Colonization of AMR pathogens in the gut is a known risk factor for infection and common among people with recurrent CDI. The PUNCH CD3 analysis also showed that RBX2660 treatment responders exhibited reduction in primary bile acids, known to trigger CDI spore germination, and increase secondary bile acids, known to inhibit spore germination and growth.1
About the gut microbiome and C. difficile infection
C. difficile infection (CDI) is a serious and potentially deadly disease that impacts people across the globe. The C. difficilebacterium causes debilitating symptoms such as severe diarrhea, fever, stomach tenderness or pain, loss of appetite, nausea and colitis (an inflammation of the colon).2 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.2,3,4
C. difficile infection often is the start of a vicious cycle of recurrence, causing a significant burden for patients and the healthcare system.5,6 Up to 35% of CDI cases recur after initial diagnosis7,8 and people who have had a recurrence are at significantly higher risk of further infections.9,10,11,12 After the first recurrence, it has been estimated that up to 60% of patients may develop a subsequent recurrence.13
Recurrent C. difficile infection (rCDI) is associated with disruptions to the gut microbiome, or “dysbiosis”. The gut microbiome is a highly-diverse microbial community that plays an essential role in human health. There is a growing body of evidence that shows when there is a disruption of the composition and/or diversity of the gut microbiome, there may be an associated risk for serious illnesses, including CDI. The current standard of care treatment for rCDI is antibiotics, which does not address the underlying dysbiosis or restore the gut microbiome.14 The use of antibiotics has been shown to disrupt the ecology of the gut microbiome and are a predominant risk factor for rCDI.7,8,14
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.
- Winston, Jenessa A, and Casey M Theriot. “Impact of microbial derived secondary bile acids on colonization resistance against Clostridium difficile in the gastrointestinal tract.” Anaerobe vol. 41 (2016): 44-50. doi:10.1016/j.anaerobe.2016.05.003
- 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.
- 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.
- 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.
- 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.
- 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.
Source: Ferring Pharmaceuticals