Microbiome therapy for recurrent Clostridioides difficile
Authors: Judith A Gilbert
Journal: The Lancet Microbe (2022)

Clostridioides difficile is the most common hospital-acquired infection in the USA, and is classed as an urgent threat by the US Centers for Disease Control and Prevention (CDC). The CDC estimated that there were nearly 224 000 hospitalised cases and hospital-onset cases resulted in an estimated US$1 billion in medical costs in 2017. C difficile infections can result in severe diarrhoea and most frequently occur in individuals who recently received antibiotics and older (≥65 years) patients. Although hospital-acquired cases decreased in the USA between 2011 and 2017, community-acquired cases have been increasing among children and adults younger than 65 years. C difficile recurrence is the most frequent complication of infection and patients with a history of three or more recurrences have an increased risk (approximately 60%) of having another, typically within 1–3 weeks of antibiotic therapy.C difficile infection recurs because of increased disruption and decreased diversity—ie, microbial dysbiosis—of the normal gut microbiome caused by antibiotic treatment that dormant C difficile spores survive. Primary bile acids induce these spores to germinate and active C difficile vegetative cells flourish in the dysbiotic microbiome, producing diarrhoea-causing toxins. To prevent multiple recurrences, with a success rate of more than 85%, the second recurrence is treated with a course of antibiotics followed by gut microbiome restoration using faecal microbiota transplantation (FMT) from a healthy donor. However, heterogeneity of donor stool preparations and the potential for the transmission of SARS-CoV-2 or multidrug-resistant bacteria make FMT a suboptimal treatment. Thus, standardised microbiome-based therapeutics are currently under development, some of which have reached phase 3 clinical trials (whereby adults with C difficile infection receive standard-of-care antibiotics before experimental therapy or placebo, followed by 6–8 weeks of assessment for recurrence and side-effects).In January, 2022, results from a phase 3 trial funded by Seres Therapeutics were published for SER-109. SER-109 is prepared from donor stool using ethanol treatment to remove viruses, fungi, parasites, and vegetative bacteria before packaging the resulting Firmicutes spores into capsules. SER-109 is administered orally as four capsules (each ∼3 × 107 spore colony-forming units of Firmicutes spores) once per day for 3 days. In the trial, 60% of the placebo group remained recurrence-free compared with 88% of the SER-109 group. Commenting on the SER-109 phase 3 trial, Ari Grinspan (Icahn School of Medicine at Mount Sinai, New York, NY, USA), who was not involved with the study, considers the trial a major advancement and believes that an oral, microbiome-based, pharmaceutical-grade product “is exactly where the field is headed”. He added that a pill form would be easier for patients than FMT, which is typically delivered through colonoscopy in an endoscopic suite. However, “are there enough patients to show safety to the FDA [to allow providers to prescribe SER-109]?”, Grinspan added, “and will [health] insurance cover it?”In 2021, phase 3 trial results were announced for RBX2660 by Rebiotix. RBX2660 is a filtered donor stool-derived suspension, administered as a single enema. In the phase 3 study, 58·1% of the placebo group remained recurrence-free compared with 70·4% of the RBX2660 group. In the same year, a phase 3 trial for CP101 funded by Finch Therapeutics began. CP101 is a donor stool-derived complete microbiome, administered in lyophilised form as a single oral capsule (6 × 1011 cells). Previous results from the CP101 phase 2 trial were presented at the 2020 American College of Gastroenterology Annual Meeting: 61·5% of the placebo group remained recurrence-free compared with 74·5% of the CP101 group.Two experimental therapeutics composed of cultured bacteria—ie, not stool-based—are progressing to phase 3 trials. NTCD-M3 (funded by Destiny Pharma) consists of spores of the naturally occurring, non-toxin-producing C difficile strain M3, prepared for use under current Good Manufacturing Practice (cGMP) regulations and administered orally by capsule (1 × 107 spores) once per day for 1 week. The phase 2 trial results showed that 70% of the placebo group remained recurrence-free compared with 95% of the NTCD-M3 group. By contrast, VE303 (funded by Vedanta Biosciences) is a defined collection of eight individually chosen bacterial strains that are cultured in cell banks, prepared for use under cGMP regulations and administered orally by capsule once per day for 2 weeks. Phase 2 trial results were announced by Vedanta in October, 2021: 54·5% of the placebo group remained recurrence-free compared with 86·2% of the high-dose VE303 group.Sahil Khanna (Mayo Clinic, Rochester, MN, USA), whose group has been involved in studies for all of these therapeutics, commented that these treatments provide an alternative to FMT, and will eventually replace it, “there is a need for standard microbiome therapy”. He added that it is difficult to say at this stage whether one microbiome-based therapeutic is better than the other, “they’ve not been compared head-to-head, and they’ve been tested on different patient populations. Some patients may benefit from one or the other”. Clostridioides difficile is the most common hospital-acquired infection in the USA, and is classed as an urgent threat by the US Centers for Disease Control and Prevention (CDC). The CDC estimated that there were nearly 224 000 hospitalised cases and hospital-onset cases resulted in an estimated US$1 billion in medical costs in 2017. C difficile infections can result in severe diarrhoea and most frequently occur in individuals who recently received antibiotics and older (≥65 years) patients. Although hospital-acquired cases decreased in the USA between 2011 and 2017, community-acquired cases have been increasing among children and adults younger than 65 years. C difficile recurrence is the most frequent complication of infection and patients with a history of three or more recurrences have an increased risk (approximately 60%) of having another, typically within 1–3 weeks of antibiotic therapy. C difficile infection recurs because of increased disruption and decreased diversity—ie, microbial dysbiosis—of the normal gut microbiome caused by antibiotic treatment that dormant C difficile spores survive. Primary bile acids induce these spores to germinate and active C difficile vegetative cells flourish in the dysbiotic microbiome, producing diarrhoea-causing toxins. To prevent multiple recurrences, with a success rate of more than 85%, the second recurrence is treated with a course of antibiotics followed by gut microbiome restoration using faecal microbiota transplantation (FMT) from a healthy donor. However, heterogeneity of donor stool preparations and the potential for the transmission of SARS-CoV-2 or multidrug-resistant bacteria make FMT a suboptimal treatment. Thus, standardised microbiome-based therapeutics are currently under development, some of which have reached phase 3 clinical trials (whereby adults with C difficile infection receive standard-of-care antibiotics before experimental therapy or placebo, followed by 6–8 weeks of assessment for recurrence and side-effects). In January, 2022, results from a phase 3 trial funded by Seres Therapeutics were published for SER-109. SER-109 is prepared from donor stool using ethanol treatment to remove viruses, fungi, parasites, and vegetative bacteria before packaging the resulting Firmicutes spores into capsules. SER-109 is administered orally as four capsules (each ∼3 × 107 spore colony-forming units of Firmicutes spores) once per day for 3 days. In the trial, 60% of the placebo group remained recurrence-free compared with 88% of the SER-109 group. Commenting on the SER-109 phase 3 trial, Ari Grinspan (Icahn School of Medicine at Mount Sinai, New York, NY, USA), who was not involved with the study, considers the trial a major advancement and believes that an oral, microbiome-based, pharmaceutical-grade product “is exactly where the field is headed”. He added that a pill form would be easier for patients than FMT, which is typically delivered through colonoscopy in an endoscopic suite. However, “are there enough patients to show safety to the FDA [to allow providers to prescribe SER-109]?”, Grinspan added, “and will [health] insurance cover it?” In 2021, phase 3 trial results were announced for RBX2660 by Rebiotix. RBX2660 is a filtered donor stool-derived suspension, administered as a single enema. In the phase 3 study, 58·1% of the placebo group remained recurrence-free compared with 70·4% of the RBX2660 group. In the same year, a phase 3 trial for CP101 funded by Finch Therapeutics began. CP101 is a donor stool-derived complete microbiome, administered in lyophilised form as a single oral capsule (6 × 1011 cells). Previous results from the CP101 phase 2 trial were presented at the 2020 American College of Gastroenterology Annual Meeting: 61·5% of the placebo group remained recurrence-free compared with 74·5% of the CP101 group. Two experimental therapeutics composed of cultured bacteria—ie, not stool-based—are progressing to phase 3 trials. NTCD-M3 (funded by Destiny Pharma) consists of spores of the naturally occurring, non-toxin-producing C difficile strain M3, prepared for use under current Good Manufacturing Practice (cGMP) regulations and administered orally by capsule (1 × 107 spores) once per day for 1 week. The phase 2 trial results showed that 70% of the placebo group remained recurrence-free compared with 95% of the NTCD-M3 group. By contrast, VE303 (funded by Vedanta Biosciences) is a defined collection of eight individually chosen bacterial strains that are cultured in cell banks, prepared for use under cGMP regulations and administered orally by capsule once per day for 2 weeks. Phase 2 trial results were announced by Vedanta in October, 2021: 54·5% of the placebo group remained recurrence-free compared with 86·2% of the high-dose VE303 group. Sahil Khanna (Mayo Clinic, Rochester, MN, USA), whose group has been involved in studies for all of these therapeutics, commented that these treatments provide an alternative to FMT, and will eventually replace it, “there is a need for standard microbiome therapy”. He added that it is difficult to say at this stage whether one microbiome-based therapeutic is better than the other, “they’ve not been compared head-to-head, and they’ve been tested on different patient populations. Some patients may benefit from one or the other”.