Presentation: Anaerobe Conference 2024, Garey, Phase 2 Microbiome Data

Microbiome evaluation from the phase 2b,

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

Ibezapolstat Phase 2 Investigator Group

July 2024 Anaerobe

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 (Gram Positive Selective Spectrum)

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1. Xu et al. Bioorg Med Chem. 2019 Aug 1;27(15):3209-3217

IBZ Clinical Trial Update

Healthy

Adult

Volunteers

(n=22)

Ibezapolstat 450 mg BID x 10 days

Ibezapolstat 300 mg BID x 10 days

Vancomycin 125 mg QID x 10 days

Placebo x 10 days

Stool collected daily x 13 days

Analysis:

• Adverse effects
• Pharmacokinetics in plasma and stool
• Shotgun metagenomics (Illumina NextSeq 500)

Phase 1 Results

Safe and effective for GI infections

IBZ Phase 2a

CDI patients with

mild/moderate disease diagnosed via toxin EIA (n=10)

	Day 12: Initial	Day 38:
IBZ Therapy	clinical cure	Sustained
		clinical cure

10/10 patients achieved clinical cure and sustained clinical cure

Ibezapolstat

450 mg BID x 10 Stool collected during therapy and at follow up days

IBZ shown to have favorable effects on the microbiome

IBZ Phase 1 Healthy volunteer study in comparison with VAN

IBZ Phase 2a. Single arm, no-comparator study

of CDI patients (n=10)

IBZ:

More narrow spectrum

Increased proportion of Actinobacteriota

McPherson et al AAC 2022

IBZ:

Increased proportion of Actinobacteriota Increased proportion of Clostridiales

Garey et al CID 2022

IBZ Phase 2b Microbiome Objectives

• Evaluate IBZ vs vancomycin (VAN) in patients with CDI for fecal microbiome effects:
• • Microbiologic eradication
  • Metagenomic proportional change
  • Quantitative changes in relative taxa

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Phase 2b Study design

Patients with mild/moderate CDI diagnosed using an EIA free toxin kit

Ibezapolstat 450 mg BID X 10 days

Vancomycin 125 mg QID X 10 days

Patients followed daily for 12 days + follow-up

Outcomes Measured

Initial clinical cure (day 12 evaluation) Sustained clinical cure (day 38) Extended clinical cure (3 months)

Time to resolution of diarrhea (TTRD) (days 0-12) Safety (day 38)

Microbiologic eradication (days 0-12)

anaerobic culture on CCFA

Microbiome changes (days 0-12)

qPCR and 16S rRNA

ClinicalTrials.gov ID NCT04247542

Consort Diagram

Patients enrolled (n=32)

IBZ			VAN
(n=18)			(n=14)

Completed			Completed
study (n=16*)				study (n=14)

Modified intent to treat population

*One patient given IBZ withdrew consent prior to first dose; one patient given IBZ had a history of underlying irritable bowel disease and was excluded from analysis.

Demographics and Baseline Information

	IBZ (n=16)	VAN (n=14)	P value
Age, years	64±13	62±10	0.57
>75 y/o	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 UBMs at baseline	6 (3-15)	6 (4-13)
Median (minimum, maximum)
Baseline C. difficile ribotype strains
F014-020	0	3
F027	1	2
F106	3	1
F002	1	1
F116	0	1
Other	6	3