Investigational drug therapies currently in early-stage clinical development for the treatment of clostridioides (clostridium) difficile infection

ABSTRACT

Introduction: Clostridioides (Clostridium) difficile Infection (CDI) is an urgent global threat causing ~500,000 infections annually in the United States of America (USA) and is associated with a 36% 30-day attributable mortality rate. Despite the availability of three therapeutic agents, CDI recurrence occurs in 20–40% of patients, with a 30–40% second recurrence rate in these patients. Consequently, there is a need for novel agents for treating CDI.

Areas covered: We searched MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for agents in early stages of clinical development. These drugs include ACX-362E, DS-2969b, LFF 571, RBX2660, ribaxamase, ridinilazole that have advanced to at least phase 2 and several other drugs in phase 1 development.

Expert opinion: The challenge for these new agents is three-fold: (1) to have a novel approach such as a different target/mechanism of action; (2) be ‘significantly’ better than existing agents in regard to ‘sustained clinical response’; or (3) be priced at a reasonable cost when it comes to market or perhaps all three. Their utility can only be proven by clinical trials.

Trial registration: ClinicalTrials.gov identifier: NCT0241900.

Trial registration: ClinicalTrials.gov identifier: NCT02473640.

Trial registration: ClinicalTrials.gov identifier: NCT01232595.

Trial registration: ClinicalTrials.gov identifier: NCT02784002.

Trial registration: ClinicalTrials.gov identifier: NCT03595566.

Trial registration: ClinicalTrials.gov identifier: NCT02419001.

Trial registration: ClinicalTrials.gov identifier: NCT02473640.

Trial registration: ClinicalTrials.gov identifier: NCT01925417.

Trial registration: ClinicalTrials.gov identifier: NCT02299570.

Trial registration: ClinicalTrials.gov identifier: NCT02106338.

Trial registration: ClinicalTrials.gov identifier: NCT01551004.

Trial registration: ClinicalTrials.gov identifier: NCT01987895.

Trial registration: ClinicalTrials.gov identifier: NCT01597505.

Trial registration: ClinicalTrials.gov identifier: NCT01232595.

Trial registration: ClinicalTrials.gov identifier: NCT02419001.

Trial registration: ClinicalTrials.gov identifier: NCT02473640.

Trial registration: ClinicalTrials.gov identifier: NCT02981316.

Trial registration: ClinicalTrials.gov identifier: NCT01983683.

KEYWORDS:

• ACX-362F
• DS-2969b
• LFF571
• ribaxamase
• ridinilazole
• RBX 2660
• CRS3123
• MCB3681/MCB3837

Article highlights

• Clostridioides (Clostridium) difficile infection (CDI) represents the most common cause of nosocomial diarrhea worldwide. However, currently approved agents for CDI therapy (metronidazole, vancomycin, and fidaxomicin) still carry a high rate of recurrence (20–40%).

• New agents with novel mechanisms of action, narrow spectrums of activity, different targets or approaches must show superiority in relapse rates to achieve market penetration. ACX-362E, a small molecule using a new target DNA polymerase IIIC inhibition, is about to start Phase 1 trials. Early studies have suggested inhibition of DNA replication by ACX-362E in a mechanism that is unique to anti-C. difficile drugs. Ribaxamase (SYN-004), an orally ingested coated enteric enzyme formulation, prevents microbiome disruption by degrading selected beta-lactam agents.

• RBX2260 is a commercially prepared, standardized fecal microbiota suspension packaged as a single administered enema bag.

• Cadazolid and surotomycin were costly mistakes, failing to achieve final approval due to phase 3 clinical trials not meeting the primary endpoints. Future clinical trials conducted in the pipeline agents must have consistent inclusion and testing definitions used in Phase 2 and Phase 3 trials as well as set considered primary and secondary endpoints.

This box summarizes key points contained in the article.

Declaration of interest

EJC Goldstein has served on Advisory boards for Merck & Co, Bayer Pharmaceuticals, BioK+, Sanofi-Adventis, Summit Corp. plc, Cutis Pharmaceuticals, Kindred Healthcare Corp., Novartis, Sankyo-Daichi, Paratek Pharma, and Shionogi Inc. EJC Goldstein has also been on the Speakers’ bureau for Bayer Inc., Merck & Co, Medicines Co., Allergan Inc and has received research grants from Bayer Inc., Cutis Pharmaceuticals, Entasis Therpaeutics, Merck & Co., Micromyx LLC, Parateck Pharmaceuticals, Spero Therpaeutics, Tetraphase Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.