MET-2

Clostridioides difficile is one of the most important causes of healthcare-associated diarrhea. The high incidence and recurrence rates of C. difficile infection, as well as its associated morbidity and mortality, are great concerns. The most common complication of C. difficile infection is recurrence, with rates of 20-30% after a primary infection and 60% after three or more episodes. Medical management of recurrent C. difficile infection involves a choice of therapy that is different from the antibiotic used in the primary episode. Patients with recurrent C. difficile infection also benefit from fecal microbiota transplantation or standardized microbiome restoration therapies (approved or experimental) to restore eubiosis. In contrast to antibiotics, microbiome restoration therapies restore a normal gut flora and eliminate C. difficile colonization and infection. Fecal microbiota transplantation in recurrent C. difficile infection has demonstrated higher success rates than vancomycin, fidaxomicin, or placebo. Fecal microbiota transplantation has traditionally been considered safe, with the most common adverse reactions being abdominal discomfort, and diarrhea, and rare serious adverse events. Significant heterogeneity and a lack of standardization regarding the process of preparation, and administration of fecal microbiota transplantation remain a major pitfall. Standardized microbiome-based therapies provide a promising alternative. In the ECOSPOR III trial of SER-109, an oral formulation of bacterial spores, a significant reduction in the recurrence rate (12%) was observed compared with placebo (40%). In the phase III PUNCH CD3 trial, RBX2660 also demonstrated high efficacy rates of 70.6% versus 57.5%. Both these agents are now US Food and Drug Administration approved for recurrent C. difficile infection. Other standardized microbiome-based therapies currently in the pipeline are VE303, RBX7455, and MET-2. Antibiotic neutralization strategies, vaccines, passive monoclonal antibodies, and drug repurposing are other therapeutic strategies being explored to treat C. difficile infection.

Faecal microbiota transplantation (FMT) is highly effective for recurrent Clostridioides difficile infection but has inherent risks. Microbial Ecosystem Therapeutic 2 (MET-2) is an oral encapsulated formulation of 40 lyophilised bacterial species initially isolated from stool of a healthy donor, but subsequently manufactured independently of donors, eliminating potential risks introduced by changes in donor health. The aim of this study was to determine MET-2 activity, safety, and tolerability.

This phase 1, open-label, single-group feasibility study was done in Alberta, Canada. The main inclusion criteria were mild to moderate C difficile infection and at least one episode of C difficile infection recurrence (ie, two episodes of C difficile infection) within 12 months. Initial daily treatment was ten oral capsules for 2 days, then three capsules for 8 days. If C difficile infection recurred, a higher dose was offered: 20 capsules for 2 days, then three capsules for 8 days. Patients were followed for adverse events and C difficile infection recurrence up to day 130. The primary outcome was absence of C difficile infection recurrence (fewer than three unformed bowel movements in 24 h persisting for at least 2 days) at day 40 by intention-to-treat analysis. Secondary outcomes were mortality or hospitalisation due to C difficile infection, infections attributed to treatment, nausea, abdominal pain, vomiting, or diarrhoea during treatment, quality of life (C difficile Health Related Quality of Life Questionnaire) before and after treatment, and engrafted MET-2 bacteria in patient stool. Absence of C difficile infection recurrence at day 130 was an exploratory outcome. This study is registered with ClinicalTrials.gov, NCT02865616 FINDINGS: Between Sept 19, 2018, and Feb 28, 2020, we enrolled 19 adult patients with at least two episodes of mild to moderate C difficile infection (median age 65 years [IQR 56-67]; 12 women [63%], seven men [37%]). Recurrent C difficile infection was absent at day 40 in 15 (79%) of 19 patients after initial treatment, increasing to 18 (95%) 40 days after retreatment. No mortality associated with C difficile infection, infections associated with MET-2 treatment, or other serious adverse events were observed. The most common self-limited, mild to moderate symptoms reported during treatment were diarrhoea in 12 (63%) of 19 patients and abdominal cramps in 12 (63%). After MET-2 treatment, quality of life improved significantly, as did alpha diversity in stool microbial composition (p=1·93×10^-6). MET-2 associated taxa were found in greater abundance in most patients after treatment compared with baseline. 16 (84%) of 19 patients did not have recurrence of C difficile infection by day 130.

MET-2 appears to be safe, efficacious, and well tolerated among patients with recurrent C difficile infection. Results must be validated in controlled studies.

NuBiyota.