A phase 2 trial published in The Lancet Infectious Diseases found that the investigational antibiotic CRS3123 achieved high clinical cure rates comparable to vancomycin while significantly reducing recurrence and preserving the gut microbiome in patients with Clostridioides difficile infection.
Crestone Inc., announced the publication of positive phase 2 clinical trial results evaluating the investigational antibiotic CRS3123 for the treatment of Clostridioides difficile infection (CDI). The study, published online in The Lancet Infectious Diseases, assessed the safety and efficacy of the therapy in adults experiencing either a primary episode or first recurrence of CDI.
In the randomized, double-blind, multicenter study, CRS3123 demonstrated clinical cure rates comparable to standard therapy. At the day-12 test-of-cure assessment, 97% of patients receiving either of 2 CRS3123 dosing regimens achieved clinical cure (28 of 29 patients), compared with 93% (13 of 14 patients) treated with vancomycin. Across all treatment groups, clinical cure was associated with rapid reductions in C difficile toxin levels, spore counts, and diarrhea.
Recurrence remains one of the most challenging aspects of CDI management, affecting approximately 20% to 40% of patients treated with currently available therapies. In this trial, CRS3123 showed a notably lower recurrence rate. By day 40, recurrence occurred in 4% of patients receiving CRS3123 across both dose groups, compared with 23% of those treated with vancomycin. Investigators attribute this improvement to the drug’s narrow antimicrobial spectrum, which selectively targets C difficile while sparing beneficial gut bacteria that help prevent reinfection.
The safety profile of CRS3123 was also encouraging. Treatment-emergent adverse events were mild to moderate in severity and occurred at similar rates across treatment groups, with no serious adverse events reported among CRS3123 recipients. Both the 200-mg and 400-mg twice-daily regimens were considered safe and well tolerated over the 10-day treatment period.
“There are a lot of people who suffer from CDI repeatedly,” Thomas Louie, MD, of the University of Calgary, the study’s first author and principal investigator, said in a statement. “It is essential that we improve patient access to clinical trials of new, more selective investigational agents like CRS3123 and to speed the development and approval of therapeutic options to avoid recurrences of CDI.”
CRS3123 achieved a 97% clinical cure rate at day 12, similar to the 93% rate observed with vancomycin.
Recurrence at day 40 was substantially lower with CRS3123 (4%) compared with vancomycin (23%).
Multi-omics analyses suggest CRS3123 preserves gut microbial diversity and bile acid metabolism, which may help prevent recurrent CDI.
Additional findings from a multi-omics analysis further highlighted CRS3123’s microbiome-sparing properties. Research conducted in the laboratory of Catherine Lozupone at the University of Colorado Anschutz showed that patients treated with CRS3123 retained greater bacterial diversity compared with those receiving vancomycin. The drug preserved beneficial bacterial genera such as Bacteroides and Bifidobacterium, while vancomycin-treated patients showed microbiome shifts toward Enterobacteriaceae dominance.
Metagenomic analysis also revealed higher levels of bacterial genes associated with secondary bile acid synthesis among CRS3123-treated patients. These bile acids are known to inhibit germination of C difficile spores, suggesting a potential mechanism for the lower recurrence rates observed in the study. Untargeted metabolomics further demonstrated that CRS3123 treatment resulted in a less disrupted gut metabolome compared with vancomycin.
The phase 2 trial enrolled 43 adults in the United States and Canada with toxin-positive CDI. Participants were randomized to receive CRS3123 at either 200 mg or 400 mg twice daily, or vancomycin 125 mg four times daily, for 10 days. The primary endpoint was clinical cure at day 12 in the intent-to-treat population, while secondary endpoints included recurrence rates, global cure, time to diarrhea resolution, and effects on the gut microbiome.
