PMID- 35134880 OWN - NLM STAT- MEDLINE DCOM- 20221004 LR - 20221219 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 75 IP - 7 DP - 2022 Sep 30 TI - Efficacy, Safety, Pharmacokinetics, and Microbiome Changes of Ibezapolstat in Adults with Clostridioides difficile Infection: A Phase 2a Multicenter Clinical Trial. PG - 1164-1170 LID - 10.1093/cid/ciac096 [doi] AB - BACKGROUND: This study was the first human validation of the gram-positive bacterial DNA polymerase IIIC target in patients with Clostridioides difficile infection. The primary objectives were to assess clinical cure rates and adverse events (AEs). Secondary objectives were to evaluate plasma/fecal pharmacokinetics, microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) with ibezapolstat. METHODS: This single-arm, open-label, phase 2a study enrolled adults with C. difficile infection at 4 US centers. Patients received ibezapolstat 450 mg orally every 12 hours for 10 days and followed for an additional 28 days to assess study objectives. RESULTS: Ten patients with a mean (standard deviation [SD]) age of 49 [15] years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233 to 578 ng/mL while mean (SD) fecal levels were 416 (494) microg/g stool by treatment day 3 and >1000 microg/g stool by days 8-10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy, which was maintained after completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (mean change [SD], -10.0% [4.8%]; P = .04) with a concomitantly increased proportion of Firmicutes phylum (+14.7% [5.4%]; P = .009). Compared with baseline, total primary bile acids decreased by a mean (SD) of 40.1 (9.6) ng/mg stool during therapy (P < .001) and 40.5 (14.1) ng/mg stool after completion of therapy (P = .007). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). CONCLUSIONS: In this phase 2a study, 10 of 10 patients achieved SCC, demonstrated favorable pharmacokinetics, minimal AEs, and beneficial microbiome and bile acids results. These results support continued clinical development. CI - (c) The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. FAU - Garey, Kevin W AU - Garey KW AUID- ORCID: 0000-0003-2063-7503 AD - University of Houston College of Pharmacy, Houston, Texas, USA. AD - The University of Texas Health Science Center at Houston School of Public Health, Houston, Texas, USA. FAU - McPherson, Jacob AU - McPherson J AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Dinh, An Q AU - Dinh AQ AD - The University of Texas Health Science Center at Houston School of Public Health, Houston, Texas, USA. FAU - Hu, Chenlin AU - Hu C AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Jo, Jinhee AU - Jo J AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Wang, Weiqun AU - Wang W AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Lancaster, Chris K AU - Lancaster CK AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Gonzales-Luna, Anne J AU - Gonzales-Luna AJ AUID- ORCID: 0000-0003-1906-359X AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Loveall, Caroline AU - Loveall C AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Begum, Khurshida AU - Begum K AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Jahangir Alam, M AU - Jahangir Alam M AD - University of Houston College of Pharmacy, Houston, Texas, USA. FAU - Silverman, Michael H AU - Silverman MH AD - Acurx Pharmaceuticals, Inc, Staten Island, New York, USA. FAU - Hanson, Blake M AU - Hanson BM AUID- ORCID: 0000-0003-2949-7818 AD - The University of Texas Health Science Center at Houston School of Public Health, Houston, Texas, USA. LA - eng SI - ClinicalTrials.gov/NCT04247542 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - 0 (Anti-Bacterial Agents) RN - 0 (Bile Acids and Salts) RN - EC 2.7.7.7 (DNA-Directed DNA Polymerase) SB - IM MH - Adult MH - *Anti-Bacterial Agents/adverse effects/pharmacokinetics MH - Bile Acids and Salts MH - *Clostridioides difficile MH - *Clostridium Infections/drug therapy/microbiology MH - DNA-Directed DNA Polymerase MH - Humans MH - Middle Aged PMC - PMC9525077 OTO - NOTNLM OT - Clostridioides difficile OT - DNA polymerase IIIC OT - Enterocolitis OT - Female OT - Male OT - humans COIS- Potential conflicts of interest. K. W. G. received research grant support from Acurx Pharmaceuticals, Paratek, and Summit Pharmaceuticals. M. H. S. is a shareholder and paid consultant for Acurx Pharmaceuticals and received consulting fees from Summit, Paratek, Tetraphase, and Seres. M. H. S. is a shareholder of and paid consultant to Acurx Pharmaceuticals, Inc. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. EDAT- 2022/02/09 06:00 MHDA- 2022/10/05 06:00 PMCR- 2022/02/04 CRDT- 2022/02/08 20:22 PHST- 2021/11/16 00:00 [received] PHST- 2022/02/09 06:00 [pubmed] PHST- 2022/10/05 06:00 [medline] PHST- 2022/02/08 20:22 [entrez] PHST- 2022/02/04 00:00 [pmc-release] AID - 6522822 [pii] AID - ciac096 [pii] AID - 10.1093/cid/ciac096 [doi] PST - ppublish SO - Clin Infect Dis. 2022 Sep 30;75(7):1164-1170. doi: 10.1093/cid/ciac096.