E0096 - Evaluation of Engraftment and Diversity Following Open-Label Administration of CP101, an Investigational Oral Microbiome Therapeutic for the Prevention of Recurrent C. difficile Infection, in the PRISM-EXT Trial

Introduction: Disruption of the microbiome is key to the pathogenesis of recurrent Clostridioides difficile infection (CDI). CP101 is an investigational orally administered microbiome therapeutic designed to restore microbiome diversity and potentially enable early intervention in the management of recurrent CDI. The safety and efficacy profile of CP101 for the prevention of recurrent CDI has been evaluated in a Phase 2 placebo-controlled trial (PRISM3) and an open-label trial (PRISM-EXT). However, pharmacology data for investigational microbiome therapies, including engraftment of microbes and changes in microbial diversity remains limited.

Methods: PRISM-EXT enrolled participants with ≥1 CDI recurrences at 51 sites. The qualifying CDI episode was diagnosed by guideline-recommended testing (PCR or toxin EIA) and clinical symptoms. Following standard-of-care (SOC) antibiotics, participants received a one-time oral administration of CP101 without bowel preparation. The primary efficacy endpoint was the proportion of participants without CDI recurrence through Week 8. Exploratory microbiome endpoints were measured at baseline following SOC antibiotics, Week 8 and 24 using 16S rRNA gene amplicon sequencing. Engraftment of CP101-associated taxa was determined by identification of CP101-associated operational taxonomic units (OTUs) in participants’ post-treatment samples which were absent at baseline, as well as by global similarity between participants’ microbiome and CP101. Alpha diversity was measured using ecological richness, i.e., the number of unique OTUs per sample.

Results: Among the 132 PRISM-EXT participants, the proportion without CDI recurrence following administration of SOC antibiotics and CP101 was 80.3% through Week 8 and 78.8% through Week 24. No treatment-related serious adverse events were reported. Microbiome analysis showed that diversity significantly increased from baseline through Week 8 (p< 0.0001) and Week 24 (p< 0.0001, Fig 1A). Participant microbiomes became more similar to CP101 after treatment compared to baseline. Higher engraftment of CP101-associated taxa and improvement in diversity were both associated with prevention of CDI recurrence at Week 8 (Fig 1B).

Discussion: The majority of PRISM-EXT participants treated with CP101 had no CDI recurrence through Week 8 and 24. Microbiome analysis suggests that treatment with CP101 led to engraftment and an increase in gut microbiome diversity, both important factors that were associated with the prevention of recurrence.