Slide 1: Microbiome Results from the phase 2 study of ibezapolstat vs vancomycin for CDI
Microbiome Results from the phase 2, randomized, double- blind study of ibezapolstat compared with vancomycin for the treatment of Clostridioides difficile infection. Kevin W. Garey, M Jahangir Alam, Khurshida Begum, Jacob McPherson, Taryn A. Eubank, Jinhee Jo, Michael H. Silverman for the Ibezapols
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 (Bacillota / Firmicutes) • Novel mechanism of acti
Slide 3: IBZ has been shown to have favorable effects on the microbiome
IBZ has been shown to have favorable effects on the microbiome IBZ Phase 2a. Single arm, no-comparator study IBZ Phase 1 Healthy volunteer study in comparison with VAN of CDI patients (n=10) IBZ: More narrow spectrum IBZ: Increased proportion of Actinobacteriota Increased proportion of Actinobacteri
Slide 4: Phase 2b Study design
Phase 2b Study design Patients followed daily for 12 days + follow-up Patients with mild/moderate CDI Outcome Measures diagnosed using an EIA free toxin kit Initial clinical cure (day 12 evaluation) Ibezapolstat 450 mg BID X 10 days Sustained clinical cure (day 38) Extended clinical cure (3 months)
Slide 5: IBZ PH2b Microbiome Objectives
IBZ PH2b Microbiome Objectives • Evaluate IBZ vs. vancomycin (VAN) in patients with CDI • Fecal microbiome effects • Pharmacokinetics • Microbiologic eradication • Metagenomic proportional change (16s rRNA) • Quantitative changes in relative taxa (qPCR)
Slide 6: RESULTS: Demographics and Baseline Information
RESULTS: Demographics and Baseline Information IBZ (n=16) VAN (n=14) P value N 16 14 Age, years 64±13 62±10 0.57 >75 yo 5 (31.2%) 2 (14.3%) Female 13 (81%) 11 (79%) 0.85 White 16 (100%) 13 (93%) 0.27 Hispanic or Latino 11 (69%) 11 (79%) 0.54 Charlson Comorbidity index 2.6±1.5 2.2±1.5 0.47 Number of
Slide 7: Efficacy analysis and time to resolution of diarrhea
Figure 2a. Efficacy analysis Figure 2b. Time to resolution of diarrhea Cumulative incidence of UBM resolution 94% 86% SCR: sustained clinical response; UBM: unformed bowel movement
Slide 8: IBZ Plasma and Fecal Concentrations
IBZ Plasma and Fecal Concentrations a. Plasma concentrations b. Fecal concentrations
Slide 9: Microbiologic Eradication
Microbiologic Eradication 80% 73% 71% 70% IBZ VAN 60% 50% 40% IBZ: RT 106 VAN: RT Other VAN RT 027 VAN RT 106 VAN RT Other 30% 20% 10% 7% 8% 7% 7% 7% 0% 0% 0% 0% 0% 0% Baseline (15,14) Day 3 (15,13) Day 5 (16,14) Day 8 (11,14) Day 10 (15, 14) Day 12 (16, 13) IBZ: One patient with positive C. diffici
Slide 10: Microbiome. Favorable microbiome results were observed with IBZ
Microbiome. Favorable microbiome results were observed with IBZ Phylum Class IBZ VAN IBZ VAN
Slide 11: IBZ qPCR microbiome analysis
IBZ qPCR microbiome analysis ** ** ** ** **p<0.01
Slide 12: Focus on CDI Recurrence. Alpha and Beta Diversity
Focus on CDI Recurrence. Alpha and Beta Diversity IBZ: n=16; VAN (no recurrence): n=12; VAN (recurrence: n=2)
Slide 13: CDI recurrence associated with marked microbiome disruption
CDI recurrence associated with marked microbiome disruption
Slide 14: CDI recurrence associated with marked microbiome disruption
CDI recurrence associated with marked microbiome disruption
Slide 15: Conclusions
Conclusions • IBZ had a clinically comparable cure rates and safety profile to VAN • No CDI recurrence vs. 2 VAN-treated patients • IBZ had favorable PK and microbiome results to VAN • Higher colonic / low systemic concentrations • Fewer cases of persistently positive C. difficile • Increased propor
Slide 16: Acknowledgements
Acknowledgements UH Center for Infectious Diseases and Microbiome Research Faculty GareyLab Funding Kevin W Garey NIAID R01AI139261 Chenlin Hu NIAID T32AI141349 Taryn A. Eubank NIAID PO1AI152999 M Jahangir Alam Merck Pharmaceuticals Eugenie Basseres Paratek Pharmaceuticals Khurshida Begum Seres Heal