Response to Microbiota-Based Drug RBX2660 is Associated with Reduction in Antimicrobial Resistance Genes in Patients with Recurrent Clostridiodes difficile Infections

Julia Garcia-Diaz MD, Courtney Jones, Hiren Karathia PhD, Brian Fanelli, Nur A Hasan PhD, Ken Blount PhD

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ASM Microbe 2019
June 20-24, 2019, San Francisco, CA

Antibiotic microbial resistance (AMR) is a global health challenge, and is common in recurrent Clostridioides difficile infection (rCDI) population due to high historical exposure to antibiotics.
The gut microbiota implicated as a reservoir of AMR bacteria.
Therapeutic approaches that decolonize AMR gut bacteria would be valuable.
In a previous analysis, RBX2660, an investigational standardized microbiota-restoration therapy in clinical development for preventing rCDI decreased vancomycin-resistant enterococci colonization.
Herein, we assessed the total AMR gene profile before and after treatment in fecal samples from RBX2660 treatment responders in a Phase 2 rCDI trial.

PUNCH Open Label™ (NCT02589847) – prospective, multicenter, open-label Phase 2 study assessing the efficacy and safety of RBX2660 treatment of recurrent CDI.
- PATIENT POPULATION: multi-recurrent CDI (≥ 2 recurrent episodes at enrollment)
- TREATMENT: two doses of RBX2660 administered 7 ± 2 days apart
- EFFICACY: absence of CDI recurrence at 8 weeks after last study treatment
- FAILURE: documented recurrence, including positive laboratory diagnosis for C. difficile
- CONTROL GROUP: historical chart review of patients who only received antibiotic therapy for rCDI
Analysis included 66 longitudinally matched samples from 22 treatment responsive participants, including before treatment (BL) and 7 ± 3 and 30 ± 10 days after treatment. Sample set represents 17 trial sites from US and Canada.
All samples were frozen without stabilizers after collection, extracted, and sequenced using a shallow shotgun method.
Sequencing reads were compared to a proprietary database of gene sequences annotated as related to antimicrobial resistance (CosmosID)
≥ 40% sequencing coverage of an AMR gene was considered positive identification in each sample.
AMR gene coverage for participant samples were compared to Human Microbiome Project (HMP) data for which comparable sequencing depth was simulated.

119 of 149 RBX2660-treated participants (80%) were responders at 8 weeks after treatment
57 of 110 patients (52%) in the historical control group were recurrence free 8 weeks after antibiotic treatment
Only 3 of 109 evaluable primary RBX2660 responders reported reinfection at 6 months
97% of RBX2660-treated 8-week responders who were evaluable at 6 months remained recurrence free
Follow up ongoing to 24 months

Participants were dysbiotic at study entry, with decreased Bacteroidia and Clostridia and overabundance of Gammaproteobacteria and Bacilli
Bacteroidia, Clostridia increased and Gammaproteobacteria, Bacilli decreased after treatment; durable to 6 months after treatment
Based on shallow-shotgun sequencing data

Prior to treatment (BL) rCDI participants had significantly higher abundance of antimicrobial resistance (AMR) genes than the HMP healthy population
After treatment (7 and 30 days), participants’ had decreased AMR gene abundance, not significantly different from HMP

In a Phase 2 open label trial, RBX2660 was 80% effective for preventing rCDI, with durable response to at least 6 months.
Responding participants’ microbiomes resolved toward a healthier composition after treatment.
In a 22-participant subgroup analysis, there was a significant decrease in antimicrobial resistance genes from before to after successful response to RBX2660.