The Boulder, Colorado-based company, Crestone, recently announced results of a phase 2 clinical trial for their investigational antibiotic, CRS3123, which showed a clinical cure at day 12 in 97% of study participants. Among the 43 patients in the primary intent-to-treat (ITT) analysis population, clinical cure rates were comparable in all 3 treatment groups, including 28/29 (97%) in patients receiving 1 of 2 dosages of CRS3123 versus 13/14 (93%) in those receiving vancomycin. There were no clinical failures at the day 12 time point; the results in 2 patients were indeterminate.
“It is now abundantly clear that curbing C difficile while preserving healthy intestinal flora is what we want in a CDI therapeutic,” Mark Wilcox, MD, professor at Leeds Teaching Hospitals and University of Leeds and lead on CDI for UK Health Security Agency, said in a statement. “The outcome of this phase 2 study further reinforces that goal.” The university is performing the epidemiology analysis and toxin testing for this study.
The trial is a randomized, double-blind, comparator-controlled, multicenter study evaluating the safety and efficacy of 2 dosages of CRS3123 (200 mg and 400 mg) administered twice-daily compared with vancomycin 125 mg administered 4 times daily in 43 adults diagnosed with a primary episode or first recurrence of CDI. The duration of treatment for all study treatment arms was 10 days. Patients with clinically documented, toxin-positive CDI were enrolled at sites in the U.S. and Canada. The primary endpoint was defined as the rate of clinical cure at day 12 in the ITT population. Secondary and exploratory endpoints included rates of recurrence and global cure, time to resolution of diarrhea and the effect of CRS3123 on commensal bacteria in the gut.
What You Need to Know
Crestone’s CRS3123 demonstrated a 97% clinical cure rate by day 12 in patients with C difficile infections (CDI), comparable to vancomycin, a commonly used antibiotic.
CRS3123 targets a specific bacterial enzyme (methionyl-tRNA synthetase) that is not present in human cells or other gut microbiota, making it effective in treating C difficile while preserving healthy gut bacteria.
Based on the positive results of the Phase 2 trial, the National Institute of Allergy and Infectious Diseases (NIAID) is providing $4.5 million in funding to support further microbiome studies and manufacturing process optimizations.
What the Phase 1 Data Showed
In a previous reporting from Contagion, a phase 1 study inlcude 5 cohorts of 8 subjects, who each received CRS3123 or placebo in a 3:1 ratio; with 100mg, 200mg, 400mg, 800mg and 1,200mg.The investigators reported no serious adverse events or immediate allergic reactions. They concluded that the study drug was well tolerated over that range of doses, and that the safety profile supports progressing to clinical study of its effectiveness for C difficile infections.2
The Molecule
CRS3123 is a small molecule that selectively inhibits one form of the bacterial methionyl-tRNA synthetase, which is the mechanistic basis of its narrow spectrum. This target is not present in human cells, nor in other important bacterial species that are part of the normal microbiota of the gut. As a protein synthesis inhibitor, CRS3123 blocks not only C difficile growth, but also toxin production and spore formation. In phase 1 trials in healthy subjects and in this phase 2 trial in CDI patients, CRS3123 achieved high intestinal concentrations, low systemic exposure and was generally safe and well tolerated. The FDA has granted QIDP and Fast Track designations to CRS3123 for the treatment of CDI.
What’s Next
Crestone is a clinical stage biopharmaceutical company focused on inventing and developing novel mechanism of action, small molecule antimicrobial drugs. The company also announced that based upon the results of the study, the National Institute of Allergy and Infectious Diseases (NIAID) has exercised its option under an existing agreement with Crestone to provide $4.5 million in new funding for microbiome analyses, manufacturing process optimization and other phase 2 supporting studies.
