Slide 1: Elucidating the Gram-Positive Selective Spectrum Activity of Ibezapolstat; Secondary Analysis from the phase 2a trial
Elucidating the Gram-Positive Selective Spectrum Activity of Ibezapolstat; Secondary Analysis from the phase 2a trial Christopher K Lancaster, Jacob McPherson, M Jahangir Alam, Khurshida Begum, Md Ekramul Karim, Chenlin Hu, Eugénie Bassères, and Kevin W Garey
Slide 2: Ibezapolstat (IBZ; ACX362E)
Ibezapolstat (IBZ; ACX362E) ACX-362 dGTP • Ibezapolstat: small-molecule inhibitor of DNA pol IIIC enzyme based upon competitive inhibition of dGTP (guanosine analog) • DNA pol IIIC: essential for replication of low G+C content Gram-positive bacteria (Firmicutes) • Novel mechanism of action GPSS™ (Gr
Slide 3: IBZ Clinical update
IBZ Clinical update • Phase 1, Healthy Volunteer: Completed • IBZ 450 mg twice daily chosen for phase 2 studies • Garey et al. J Antimicrob Chemother 2020. • Microbiome evaluations predicted an anti-recurrence effects • *McPherson et al. Antimicrob Agents Chemother 2022 • Phase 2a (n=10): Completed
Slide 4: Phase 2a. Open label CDI study
Phase 2a. Open label CDI study Increased proportion of Firmicutes was observed on ibezapolstat therapy, Clostridiales most common taxa
Slide 5: Spectrum of activity: Ibezapolstat vs. vancomycin
Spectrum of activity: Ibezapolstat vs. vancomycin Expected Phylum Antibiotic activity Ibezapolstat Vancomycin (oral) Actinobacteria No Yes Bacteroidetes No Yes Firmicutes Yes Selective Yes Fusobacteria No No Proteobacteria No No
Slide 6: Study Objectives and Brief Methods
Study Objectives and Brief Methods • To better understand IBZ Firmicute Selectivity 1. Are the concentrations (quantitative) of Firmicutes decreasing with therapy? • Phase I data, qPCR of relevant taxa 2. Are there IBZ MIC differences between Firmicute species in the gut microbiome of CDI patients?
Slide 7: Q1. Relevant Firmicutes less disrupted with IBZ vs. vanco (qPCR results)
Q1. Relevant Firmicutes less disrupted with IBZ vs. vanco (qPCR results) Bacteroidetes Bacteroides Firmicutes Proteobacteria Escherichia coli [Clostridium] leptum Prevotella Blautia coccoides Bacteria 7
Slide 8: Q2. Phase 2a study: Ibezapolstat had potent C. difficile activity
Q2. Phase 2a study: Ibezapolstat had potent C. difficile activity All samples underwent a 48-hour enrichment step with taurocholate prior to plating on CCFA plates. 90% IBZ MIC 86% Sample Ribotype 80% (ug/mL) Percent of samples with C. difficile growth 70% 1 0.25 F078-126 60% 2 1 F014-020 50% 3 0.5
Slide 9: IBZ selectivity: MIC studies
IBZ selectivity: MIC studies Symbiotic Bacterial Strain Biobank. The biobank of commensal bacterial strains contains over 1,000 strains of Stool samples from the IBZ Phase 2a study. bacteria cultured from healthy donors. The strains have been sequenced and their entire genomes are available for acad
Slide 10: MIC testing results demonstrated selective activity vs. Clostridiales
MIC testing results demonstrated selective activity vs. Clostridiales Symbiotic Bacterial Strain Biobank (E Pamer) Samples from Phase 2a Clinical Trial IBZ MIC IBZ MIC (ug/mL) Phylum, Class Family Species N tested (ug/mL) Species N med min max Actinobacteria, Actinomycetia Bifidobacteriaceae Bifidob
Slide 11: Q3. Can we predict the mechanism for this selectivity?
Q3. Can we predict the mechanism for this selectivity? Phylogenetics of the PolC does not predict IBZ susceptibility
Slide 12: IBZ selectivity is likely related to unique binding sites present in select Firmicute strains
IBZ selectivity is likely related to unique binding sites present in select Firmicute strains. Will need confirmation AlphaFold2: an artificial intelligence (AI) system that can predict three-dimensional (3D) structures of proteins from amino acid sequences with atomic-level accuracy.
Slide 13: Conclusions
Conclusions • IBZ is a selective inhibitor of the PolC enzyme in clinical trials for CDI 1. Selectivity for certain Firmicutes identified by Illumina sequencing and confirmed by qPCR 2. MIC testing showed variable susceptibility amongst different Firmicutes 3. In silico prediction modeling identifie
Slide 14: Acknowledgements
Acknowledgements The Garey Lab Faculty Funding M Jahangir Alam NIAID R01AI139261 Eugenie Basseres NIAID T32AI141349 Khurshida Begum NIAID PO1AI152999 Kevin W Garey Acurx Pharmaceuticals Anne J Gonzales-Luna Merck Pharmaceuticals Chenlin Hu Paratek Pharmaceuticals Jinhee Jo Seres Health Taryn Eubank