Investigational Antibiotic CRS3123 Shows Lower Recurrence Rates Than Vancomycin in C. Diff Trial
CRS3123, an investigational antibiotic for C. difficile infection, demonstrated 97% clinical cure rates and significantly lower recurrence (4% vs 23% for vancomycin) in a Phase 2 trial. The narrow-spectrum drug better preserves gut microbiome health and secondary bile acid synthesis compared to standard vancomycin treatment. These positive results support advancing CRS3123 into Phase 3 development.
An investigational narrow-spectrum antibiotic achieved similar cure rates but substantially lower recurrence than vancomycin in a Phase 2 trial of patients with Clostridioides difficile infection. CRS3123, developed by Crestone, showed recurrence rates of just 4% for combined dosages versus 23% for vancomycin at day 40, addressing the primary unmet medical need in CDI treatment.
In this first study in patients with CDI, a serious infection that rarely resolves on its own, CRS3123 achieved clinical cure at day 12 test-of-cure in 28/29 (97%) patients receiving one of two dosages of CRS3123 versus 13/14 (93%) in those receiving vancomycin. Clinical cure was accompanied by rapid reduction in levels of C. difficile toxin, spore counts and diarrhea in all treatment groups.
The major unmet medical need in CDI is to reduce recurrence, which continues to impact 20% to 40% of CDI patients with existing therapies. It is well accepted that the key to avoiding recurrence is to preserve natural, healthy gut microbiota while selectively inhibiting C. difficile. CRS3123 was chosen for this ability. Consistent with its narrow spectrum, in this Phase 2 study rates of CDI recurrence were considerably lower in those patients who received CRS3123.
Multi-omics analysis of Phase 2 samples showed CRS3123 preserved the gut microbiome and secondary bile acid synthesis better than vancomycin. CRS3123 treatment retains bacterial diversity much better and impacts healthy gut microbiota considerably less than vancomycin treatment. CRS3123 preserves beneficial genera Bacteroides and Bifidobacterium, while vancomycin-treated patients displayed communities skewed away from Bacteroides toward Enterobacteriaceae dominance.
Metagenomics analyses showed counts of bacterial genes responsible for secondary bile acid synthesis are significantly higher at test-of-cure in CRS3123 groups compared to vancomycin. Secondary bile acids are vital for preventing CDI, inhibiting germination of C. difficile spores. Untargeted metabolomics show a less disturbed metabolome with CRS3123 than with vancomycin.
Vancomycin-resistant enterococci (VRE), which was present at baseline in some patients in each group, increased in the vancomycin group but was rapidly eliminated in both CRS3123 groups. This is consistent with preclinical data showing CRS3123 to be one of the most potent agents against enterococci (including VRE) yet described. VRE can cause serious infections, particularly in hospitalized patients or those with weakened immune systems.
Treatment-emergent adverse events were mild to moderate in severity and similar across treatment groups. Both dosages of CRS3123 were deemed safe and well tolerated, and no serious adverse events were reported with CRS3123. These data warrant advancing CRS3123 into Phase 3 development for treatment of CDI.
Based on earlier topline results of the Phase 2 CDI study, NIAID exercised its option under an existing contract with Crestone to fund these gut microbiome analyses and a series of other supporting efforts to prepare for Phase 3 development. The company has successfully completed improved chemical process for synthesizing CRS3123, including reducing the number of synthetic steps by approximately half with a favorable reduction in projected cost of goods for CRS3123.