Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study

Abstract

Clostridium difficile causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase and has potent activity against C. difficile and aerobic Gram-positive bacteria but little activity against Gram-negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects each received CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC-MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active-treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. The absorbed drug was glucuronidated at reactive amino groups on the molecule, which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for C. difficile infections. (This study has been registered at ClinicalTrials.gov under identifier NCT01551004.)

Roles of aminoacyl-tRNA synthetases in immune regulation and immune diseases

“…Specifically, compounds 3h and 9b had the best antibacterial activity against Staphylococcus aureus, while compounds 8, 10, and 9b had the best antibacterial activity against Escherichia coli. CRS3123 inhibited protein synthesis in Clostridium difficile by targeting MetRS, thereby preventing the bacterial toxin production and sporulation 51 . Noteworthily, in the phase 1 clinical trial of CRS3123, the healthy subjects did not experience serious adverse events and were well tolerated at all doses tested.…”

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

“…CRS3123 (REP3123) is a novel narrow-spectrum antibiotic produced by Crestone Inc. that acts by inhibiting bacterial methionyl-tRNA synthetase, with high activity against Gram-positive bacteria and C. difficile but low activity against Gramnegative bacteria. 72,73 CRS3123 was reported to reduce spore formation and toxin formation in a hamster model. 74 One phase I trial found CRS3123 to be well tolerated at multiple doses (100, 200, 400, 800, and 1200 mg) and the indicated safety of the drug supported further research into its efficacy.…”

“…CRS3123 (REP3123) is a novel narrow‐spectrum antibiotic produced by Crestone Inc. that acts by inhibiting bacterial methionyl‐tRNA synthetase, with high activity against Gram‐positive bacteria and C. difficile but low activity against Gram‐negative bacteria . CRS3123 was reported to reduce spore formation and toxin formation in a hamster model .…”

“…CRS3123 was reported to reduce spore formation and toxin formation in a hamster model . One phase I trial found CRS3123 to be well tolerated at multiple doses (100, 200, 400, 800, and 1200 mg) and the indicated safety of the drug supported further research into its efficacy . Further research is necessary to test the efficacy of CRS3123 for the treatment of CDI.…”

Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota

“…As a protein synthesis inhibitor, CRS3123 inhibits C. difficile toxin production and sporulation, and it is superior to vancomycin in protecting hamsters against recurrence in an in vivo model of CDI (29,30). In addition, CRS3123 has exhibited low systemic absorption following oral dosing in preclinical testing, as well as in a first-in-human single-ascending-dose (SAD) study at doses ranging from 100 mg to 1,200 mg, in which the drug was also safe and well tolerated (32). Here we report the results of a randomized, double-blind, placebo-controlled, multiple-ascending-dose (MAD) phase 1 clinical trial in healthy subjects who received 200 mg, 400 mg, or 600 mg twice-daily (BID) oral doses of CRS3123 or placebo for 10 days, the intended dose frequency and duration of therapy in CDI patients.…”