ibezapolstat (ACX-362E) / Acurx Pharma - LARVOL DELTA

A unique inhibitor conformation selectively targets the DNA polymerase PolC of Gram-positive priority pathogens. (PubMed, Nat Commun) - "The first-in-class PolC-targeting antimicrobial, ibezapolstat, is a guanine analogue in late-stage clinical development for the treatment of Clostridioides difficile infections, and related inhibitors are being developed for systemic treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). This is explained by an unusual non-planar conformation of the inhibitors that induce a binding pocket in PolC. By combining structural, biochemical, bioinformatic and genetic analyses, this work lays the foundation for the rational development of an innovative class of antimicrobials against Gram-positive priority pathogens."

Journal • Infectious Disease

New investigational agents for the treatment of clostridioides difficile infections. (PubMed, Expert Opin Investig Drugs) - "Ibezapolstat, CRS3123, and ridinilazole were identified with unique mechanisms of action and narrow spectrums of activity that result in gut microbiome preservation and reduced recurrent CDI (rCDI) rates...Some have the ability to restore the microbiome (VE303) or preserve intestinal integrity (e.g. REC-3964, LMN-201, AQ)...CDI is a significant burden to the healthcare system and the quality of life for patients who suffer from CDI and rCDI. Further development of these investigational agents to prevent this cycle are of upmost importance."

Journal • Review • Infectious Disease

Acurx Pharmaceuticals, Inc…received a positive opinion from the European Medicines Agency’s Paediatric Committee (PDCO) on its Pediatric Investigation Plan (PIP) for ibezapolstat in treating children with Clostridioides difficile infection (CDI) (Investing.com) - "The approval represents a regulatory milestone that allows Acurx to proceed with Phase 3 clinical trials in the European Union....The company plans to conduct two international Phase 3 clinical trials designed as non-inferiority studies versus vancomycin, the current standard of care."

European regulatory • New P3 trial • Infectious Disease

Clinical Validation and Mechanistic Understanding of Novel DNA pol IIIC Inhibitors to treat Gram-positive Bacterial Infections: Ibezapolstat advancing into global Phase 3 Clinical Trials for C. difficile Infection (IDWeek 2025) - No abstract available

Clinical • Gram positive • P3 data • Infectious Disease

Efficacy, safety, pharmacokinetics, and associated microbiome changes of ibezapolstat compared with vancomycin in adults with Clostridioides difficile infection: a phase 2b, randomised, double-blind, active-controlled, multicentre study. (PubMed, Lancet Microbe) - P2 | "Ibezapolstat is a Gram-positive selective spectrum antibiotic that shows potential in the treatment of initial C difficile infection and prevention of recurrence. Further clinical development is warranted."

Journal • P2b data • PK/PD data • Infectious Disease

In vitro susceptibility of clinical Clostridioides difficile isolates in Israel to metronidazole, vancomycin, fidaxomicin, ridinilazole and ibezapolstat. (PubMed, BMC Gastroenterol) - "RDZ and IBZ demonstrated potent in vitro activity against 313 C. difficile isolates belonging to different STs. These two antimicrobials may serve as effective agents for C. difficile infection."

Journal • Preclinical • Infectious Disease

Acurx Pharmaceuticals, Inc. Reports Fourth Quarter and Full Year 2024 Results and Provides Business Update (PRNewswire) - "Also in January 2025, we announced that we received positive regulatory guidance from the European Medicines Agency (EMA) for the ibezapolstat Phase 3 clinical trial program, which is aligned with FDA on matters of manufacturing, non-clinical and clinical aspects of the Phase 3 program. The EMA guidance also confirmed ibezapolstat's regulatory pathway for a Marketing Authorization Application to be filed by the Company after successful completion of the Phase 3 clinical trials. With mutually consistent feedback from both EMA and FDA, Acurx is well positioned to commence our international Phase 3 registration program."

European regulatory • Infectious Disease

Acurx Announces Publication of Nonclinical In Vivo Data Differentiating Ibezapolstat's Gut Microbiome Effects from Other Anti-CDI Antibiotics (Canada Newswire) - "'This study provides critical evidence to begin to distinguish ibezapolstat from other C. difficile directed antibiotics, especially fidaxomicin. Although both ibezapolstat and fidaxomicin were narrower spectrum than vancomycin or metronidazole, ibezapolstat's effect on the microbiome was distinctly different than fidaxomicin. How this translates into beneficial health effects or emergence of antimicrobial resistance will be an area of further study.'...Changes in alpha and beta microbiome diversities following IBZ treatment were less pronounced compared to those observed in VAN- or MET-treated groups. By the end of therapy, IBZ increased the relative abundance of Bacteroidota and Actinomycetota phyla. In microbiome-humanized mice, IBZ and FDX had smaller effects on gut microbiome diversity, a positive outcome, compared to VAN and MET."

Preclinical • Infectious Disease

The impact of ibezapolstat and other Clostridioides difficile infection-relevant antibiotics on the microbiome of humanized mice. (PubMed, Antimicrob Agents Chemother) - "Previous studies demonstrated that IBZ carries a favorable microbiome diversity profile compared to vancomycin (VAN)...Groups of germ-free (GF) mice received a fecal microbiota transplant from one of two healthy human donors and were subsequently exposed to either IBZ, VAN, fidaxomicin (FDX), metronidazole (MET), or no antibiotic (control)...In microbiome-humanized mice, IBZ and FDX had smaller effects on gut microbiome diversity than VAN and MET. Notable differences were observed between the microbiome of IBZ- and FDX-treated groups, which may allow for differentiation of these two antibiotics in future studies."

Journal • Preclinical • Infectious Disease • Transplantation

Acurx Announces Publication of Positive Results from an In-Silico Study Predicting the Microbiome-Restorative Potential of Ibezapolstat in the Treatment of CDI (PRNewswire) - "The Company today announced the results of a study and its publication in the Journal of Antimicrobial Agents and Chemotherapeutics...The purpose of this study was to utilize in silico approaches to better interpret the narrower than expected IBZ spectrum of activity observed in human trials. IBZ susceptibility to human commensal microbiota was predicted using genomic analysis and PolC phylogenetic tree construction in relation to C. difficile and commensal low G + C bacteria...The major finding of this study was that the predicted interactions between IBZ and pol IIIC is conserved across the majority of the Bacillota phylum except for Lachnospiraceae and Oscillospiraceae, and Erysipelotrichales (including Erysipelotrichaceae and Coprobacillaceae), taxa that were not killed or regrown in IBZ-treated subjects while on therapy."

Preclinical • Infectious Disease

The microbiome-restorative potential of ibezapolstat for the treatment of Clostridioides difficile infection is predicted through variant PolC-type DNA polymerase III in Lachnospiraceae and Oscillospiraceae. (PubMed, Antimicrob Agents Chemother) - "The observed IBZ sparing of Lachnospiraceae, Oscillospiraceae, and Erysipelotrichaceae/Coprobacillaceae was predicted using in silico techniques. Further studies that confirm a PolC structural basis for the IBZ narrower than expected activity are needed to confirm these in silico phylogenetic and chemical modeling data."

Journal • Infectious Disease

ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection (clinicaltrials.gov) - P2 | N=53 | Completed | Sponsor: Acurx Pharmaceuticals Inc. | N=32 ➔ 53

Enrollment change • Infectious Disease

Microbiome impact of ibezapolstat and other Clostridioides difficile infection relevant antibiotics using humanized mice. (PubMed, bioRxiv) - "Previous studies demonstrated IBZ carries a favorable microbiome diversity profile compared to vancomycin (VAN)...Groups of germ-free (GF) mice received a fecal microbiota transplant from one of two healthy human donors and were subsequently exposed to either IBZ, VAN, fidaxomicin (FDX), metronidazole (MET), or no antibiotic (control)...In microbiome-humanized mice, IBZ and FDX had smaller effects on gut microbiome diversity compared to VAN and MET. Notable differences were observed between the microbiome of IBZ- and FDX-treated groups, which may allow for differentiation of these two antibiotics in future studies."

Journal • Preclinical • Infectious Disease • Transplantation

A phase 2, randomized, double-blind study of ibezapolstat compared with vancomycin for the treatment of Clostridioides difficile infection: clinical and microbiome evaluation (IDWeek 2024) - No abstract available

Clinical • P2 data • Infectious Disease

Fighting against Clostridioides difficile infection: Current medications. (PubMed, Int J Antimicrob Agents) - "Recent guidelines recommend fidaxomicin and vancomycin as first-line drugs to treat CDI, bezlotoxumab to prevent recurrence, and fecal microbiota transplantation (FMT) for rescue treatment. Currently, researchers are investigating therapeutic antibacterial drugs (e.g., teicoplanin, ridinilazole, ibezapolstat, surotomycin, cadazolid, and LFF571), preventive medications against recurrence (e.g., Rebyota, Vowst, VP20621, VE303, RBX7455, and MET-2), primary prevention strategies (e.g., vaccine, ribaxamase, and DAV132) and other anti-CDI medications in the preclinical stage (e.g., Raja 42, Myxopyronin B, and bacteriophage). This narrative review summarizes current medications, including newly marketed drugs and products in development against CDI, to help clinicians treat CDI appropriately and to call for more research on innovation."

Journal • Review • Infectious Disease • Transplantation

ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection (clinicaltrials.gov) - P2 | N=32 | Completed | Sponsor: Acurx Pharmaceuticals Inc. | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease

Efficacy and safety of ibezapolstat compared with vancomycin for the treatment of Clostridioides difficile infection: a Phase 2, randomised, double-blind study (ECCMID 2024) - No abstract available

Clinical • P2 data • Infectious Disease

Antibacterial activity of ibezapolstat against antimicrobial resistant clinical strains of Clostridioides difficile (ECCMID 2024) - No abstract available

Clinical

Antibacterial activity of ibezapolstat against antimicrobial-resistant clinical strains of Clostridioides difficile. (PubMed, Antimicrob Agents Chemother) - "IBZ has potent in vitro activity against wild-type, susceptible strains but its effect on C. difficile strains with reduced susceptibility to metronidazole (MTZ), vancomycin (VAN), or fidaxomicin (FDX) has not been tested. This study demonstrated the potent antibacterial activity of IBZ against a large collection of C. difficile strains including multidrug-resistant strains. This study highlights the therapeutic potential of IBZ against multidrug-resistant strains of C. difficile."

Journal • Infectious Disease

ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection (clinicaltrials.gov) - P2 | N=32 | Active, not recruiting | Sponsor: Acurx Pharmaceuticals Inc. | Phase classification: P2b ➔ P2

Phase classification • Infectious Disease

ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection (clinicaltrials.gov) - P2b | N=32 | Active, not recruiting | Sponsor: Acurx Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting | N=72 ➔ 32

Enrollment change • Enrollment closed • Infectious Disease

Elucidating the Gram-Positive Selective Spectrum Activity of Ibezapolstat; Secondary Analysis from the phase 2a trial (IDWeek 2023) - No abstract available

Gram positive • P2a data • Infectious Disease

Clostridioides difficile resistance to antibiotics, including post-COVID-19 data. (PubMed, Expert Rev Clin Pharmacol) - "The mean resistance to 2 mg/l vancomycin, 2 mg/l metronidazole, 4 mg/l moxifloxacin, and 4 mg/l clindamycin was 4.7% (0 to ≥ 26% in two studies), 2.6% (0 to ≥ 40% in 3 studies), 34.9% (6.6->80%), and 61.0% (30->90%), respectively. Resistance to erythromycin (>60-88%), rifampin (>23-55.0%), imipenem (0.6 to > 78% in a clone), tigecycline (0-<5.0%), and fidaxomicin (0-2%) was also found...New approaches, including biotherapeutics (Rebyota), strains, antibiotics (ridinilazole and ibezapolstat), and monoclonal antibodies/cocktails merit further evaluation...Post-COVID-19 resistance should be separately presented. Some discrepancies between vancomycin and metronidazole results need to be clarified."

Journal • Review • Infectious Disease • Novel Coronavirus Disease

ACX-362E [Ibezapolstat] for Oral Treatment of Clostridioides Difficile Infection (clinicaltrials.gov) - P2b | N=74 | Recruiting | Sponsor: Acurx Pharmaceuticals Inc. | Trial completion date: Aug 2023 ➔ Feb 2024 | Trial primary completion date: May 2023 ➔ Oct 2023

Trial completion date • Trial primary completion date • Infectious Disease

The Phylogenetic Conservation and Alphafold2-Predicted Structural Features of the Firmicute Polc-Type Dna Polymerase III (ASM Microbe 2023) - "Ibezapolstat (IBZ) is an antibiotic in development for the treatment CDI by selective inhibition of the PolC-type DNA Polymerase III (PolC) responsible for DNA replication in low-GC genome, Gram-positive bacteria... The Firmicute phylum heavily contributes to gut microbiome structure and function, but the study of the primary replicase, PolC, remains largely unexplored. Here we explored the phylogenetic conservation of PolC structures using in silico methods."

Infectious Disease