Investigational Treatment Agents for Recurrent Clostridioides difficile Infection (rCDI)

Figures & data

Table 1 Therapeutics in Development for Clostridioides difficile Infection

Treatment in Development	Mechanism of Action	Minimum Inhibitory Concentrations Against C. difficile	Status in Development	Notable Findings
Ibezapolstat (formely ACX-362E)	Inhibits DNA^a polymerase IIIC, which stops bacterial DNA replication^Citation12	MIC50: 2 mg/L^Citation20	-Completed Phase 1 trial -Granted QIDP^b status by the US FDA^Citation22 -Phase 2 (NCT04247542) began on January 30, 2020^Citation22	-Ibezapolstat showed reduced rCDI^c cases vs oral vancomycin in Syrian hamster model^Citation18 -In a phase 1, dose ranging study, Ibezapolstat showed similar safety and adverse reactions vs placebo^Citation21
Alanyl-L-glutamine A water-soluble dipeptide molecule	Inhibits the apoptosis of T84 cells by preventing caspase 8 activation and reduced TxA^d-induced intestinal secretion and disruption^Citation24	N/A	Recruiting for Phase 1 (NCT02053350)	-With adenosine 2A receptor agonist, has been shown to reverse TxA induced epithelial injury, inflammation, secretion and apoptosis in animals^Citation25
Bezlotoxumab	Human monoclonal antibody that inhibits binding of toxin B to the luminal gastrointestinal tract	N/A	Phase 3 Ongoing clinical trials (ClinicalTrials.gov Identifiers: NCT03880539; NCT04075422; NCT03182907; NCT03756454; NCT03829475; NCT04415918).	-Phase 3 MODIFY I and MODIFY II demonstrated reduction in rCDI in BI and non-BI strain population (bezlotoxumab 23.1%, placebo 43.9%)^Citation28 -In a follow up with 295 patients who completed MODIFY I and II studies, 3 patients experienced rCDI at some point in the subsequent 9 months^Citation29
CRS3123 (REP 3123)	A fully synthetic small molecule inhibits bacterial protein synthesis -Acts on bacterial MetRS^e of Gram-positive bacteria -Stops toxin production and spore formulation^Citation33	MIC90 o 1 μg/mL (range of 0.5–1 μg/mL)^Citation33,Citation34	Phase 1 completed. Awarded NIAID^f contract to proceed to phase 2 in September 2019	-Phase 1, double blind placebo controlled, dose ranging study showed that CRS3123 was safe and well tolerated^Citation36,Citation37
DNV3837 (MCB3681/MCB3687)	A water-soluble hybrid combination prodrug consisting of an oxazolidinone–quinolone combination that converts to the active form DNV3681 that has activity in vitro against Gram-positive bacteria including C. difficile.^Citation38	MIC90 of 0.064 μg/mL (range, 0.032 μg/mL-0.064 μg/mL)^Citation40 MIC90 of 0.25 µg/mL (range, 0.008–0.5 μg/mL)^Citation41	Phase 1 completed. Two-part exploratory, open-label Phase 2 clinical trial (ClinicalTrials.gov Identifier: NCT03988855) ongoing	Phase 1 trial with 12 healthy male subjects showed that it was well tolerated with minimal systemic absorption^Citation38,Citation42
DS-2969B	A GyrB^g inhibitor^Citation43,Citation44 -Binds to the ATP^h-binding site of DNA gyrase, which inhibits the supercoiling.	MIC50 of 0.06 μg/mL and a MIC90 of 0.125 μg/mL (range: 0.03–0.125 μg/mL)^Citation45 MIC50 of 0.06 μg/mL and a MIC90 0.125 μg/mL (range: 0.03–0.125 μg/mL)^Citation45	As of June 2020, Daiichi Sankyo has not reported on further development plans for DS-2969b.^Citation48	Two phase I studies show that DS-2969b was safe and well tolerated^Citation46,Citation47
LFF571	A semisynthetic thiopeptide -Interferes with bacterial protein synthesis by inhibition of EF-Tu^i	MIC90-0.25, μg/mL	Development has halted after Phase 1 and 2 studies completed.	When LFF571 was compared to oral vancomycin in a hPase 2 trial, LFF571 was noninferior^Citation54
MGB-BP-3	A synthetic polyamide related to Distamycin A, which selectively binds to the minor grove of microbial DNA.^Citation56		Received QIDP status from the FDA; is eligible to participate in the DISARM^k program	-MGB-BP-3 was well tolerated in Phase 1 and Phase 2a trials^Citation56   -The 250 mg dose showed an initial cure and sustained cure of 100% at 4- weeks post-therapy.
Ramoplamin	A glycolipodepsipeptide non-absorbable antibiotic -Inhibits the bacterial cell wall by blocking the N-acetylglucosaminyltransferase-catalysed conversion of lipid intermediate II.^Citation58^–^Citation61	0.25 to 0.50 μg/mL.^Citation63,Citation64 MIC 90 of 0.25 μg/mL^Citation63	Phase 2 study completed. No new data published.	A open label Phase 2, randomized, parallel group, multicenter, trial revealed that ramoplamin was noninferior to vancomycin.
Ramizol	A MscL ligand^j -Targets bacterial cell wall lysis by decreasing the tension across the cell membrane and slowing bacterial growth.	≤0.12–8 μg/mL	Preclinical stage with no additional trials published	Was shown to have sufficient therapeutic levels with poor systemic absorption in hamsters and rats^Citation69,Citation71
Ridinilazole	A non-absorbable antibacterial that arrests cell division, inhibits sporulation and toxin production	0.015–0.5μg/mL, with a MIC90 of 0.25μg/mL.^Citation75^–^Citation78	Phase 3 trials, denoted Ri-CoDIFy 1 and 2, are ongoing (ClinicalTrials.gov Identifiers: NCT03595553; NCT03595566), with estimated completion of	Phase 2 trial found that ridinilazole (200 mg every 12 hours) was non-inferior to vancomycin (125 mg every 6 hours) in the primary endpoint of sustained clinical response (defined as clinical cure and the absence of downstream recurrence)^Citation80

Notes: ^aDNA, deoxyribonucleic acid; ^bQIDP, Qualified Infectious Disease Pathogen; ^crCDI, recurrent Clostridioides difficile infection; ^dTxA, Clostridioides difficile toxin A; ^eMetRS, methionyl-tRNA synthetase; ^fNIAID, National Institute of Allergy and Infectious Diseases; ^gGyrB, DNA gyrase subunit B; ^hATP, Adenosine triphosphate; ⁱEF-Tu, elongation factor thermo unstable; ^jMscL, mechanosensitive ion channel of large conductance; ^kDISARM, Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms.

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