Clinical stage program targeting Clostridium difficile Infection, a devastating GI-tract infection with suboptimal therapies

Clostridium difficile Infection (CDI) is a gastrointestinal condition caused by toxin-producing strains of C. difficile bacteria. CDI symptoms range from severe diarrhea to toxic megacolon, and CDI causes 29,000 deaths per year in the US alone. C. difficile forms spores that are very difficult to eliminate from the hospital environment, leading to infection of hospitalized patients. Emergence of hypervirulent and drug-resistant strains of C. difficile has resulted in an alarming increase in incidence and mortality of CDI in the past 15 years, especially among elderly patients. C. difficile is found in abundance in the environment, so exposure to this resilient, spore-forming pathogen can be presumed to be both continuous and unavoidable. Under normal circumstances, healthy gut flora keeps C. difficile growth in check. Disruption of gut flora due to exposure to broad spectrum antibiotics or chemotherapy predisposes the patient to CDI. Vancomycin and fidaxomicin are the only approved antibiotics for treatment of CDI. Paradoxically, vancomycin is also one of the broad-spectrum antibiotics that is known to induce CDI due to disruption of normal gut flora.

According to the CDC, there are an estimated 453,000 CDI infections per year in the U.S. A key unmet need in the CDI market is treatment or prevention of relapse which requires additional antibiotic treatment and often re-hospitalization. Recurrence rates range from 15-30%, and result from reinfection by spores. Recurrence rates in CDI patients treated with vancomycin exceeds 20%. Recurrence following fidaxomicin treatment is somewhat lower, with the notable exception of those infected with the recently emerging epidemic strains (BI/NAP1). Those patients suffer recurrence rates above 20% with either vancomycin or fidaxomicin treatment.

CRS3123 has successfully completed Phase 1 clinical development to determine its safety and pharmacokinetics in single and multiple ascending dose trials. CRS3123 is a small molecule protein synthesis inhibitor that acts on the novel target methionyl-tRNA synthetase (MetRS). CRS3123 has numerous potential advantages over current CDI therapies. In addition to being highly potent against all clinical isolates of C. difficile tested, CRS3123 has several desirable qualities for the treatment of CDI which include:

  • Narrow spectrum for C. difficile, which may substantially reduce the disruption of normal intestinal flora compared to current therapies;
  • Inhibition of toxin production, potentially leading to lower morbidity and mortality;
  • Inhibition of sporulation, potentially leading to lower rates of transmission and recurrence;
  • A novel mechanism of action, which means that its use will not compromise the utility of systemic antibiotics while maintaining activity against pre-existing resistance mechanisms.
CRS3123 CRS3123
CRS3123 (red) bound to MetRS (tan)  Clostridium difficile bacillus (CDC, Jennifer Hulsey)