Microbiome diversity is a surrogate marker for microbiome health with decreased diversity observed in many diseases. Key to disease pathogenesis in recurrent Clostridioides difficile infection (CDI) is decreased microbiome diversity and impaired colonization resistance. CP101 is an investigational orally administered microbiome therapeutic designed to restore microbiome diversity and enable early intervention in the management of recurrent CDI. Microbiome diversity is a key pharmacodynamic marker in recurrent CDI; however, data on the impact of increasing diversity on efficacy is scarce.
We conducted a double-blind, randomized, placebo-controlled trial (PRISM3) enrolling adults who received standard-of-care antibiotics for recurrent CDI. Patients with first CDI recurrence at high-risk for further recurrence (≥65 years), or those with two or more recurrences were eligible. The qualifying CDI episode was diagnosed prior to study entry by guideline recommended testing (PCR-based or toxin EIA-based). Following CDI antibiotics, participants completed a minimum 2-day washout period. Eligible participants were randomized 1:1 to receive one-time oral administration of CP101 or placebo without bowel preparation. The primary efficacy endpoint was sustained clinical cure, defined as an absence of CDI recurrence through Week 8 following dosing. Diversity of the intestinal microbiome was measured at baseline, Week 1, and Week 8 using 16S rRNA gene amplicon sequencing.
Among the 198 enrolled participants analyzed, the CP101 arm demonstrated a statistically significant and clinically meaningful improvement in sustained clinical cure compared to placebo through Week 8 (74.5% [76/102] vs 61.5% [59/96], P=0.0488). Alpha diversity was low in the CP101 and placebo arms at baseline, and similar between both groups. Participants treated with CP101 achieved significantly higher alpha diversity compared to placebo, and the increase in diversity was rapid and sustained over time (p< 0.001 at Week 1, p< 0.0001 at Week 8) (Fig. 1a). Participants who received CP101 also had a significantly greater change in their microbial community composition from baseline compared to placebo at Week 1 (p< 0.001). Clinically, an increase in microbiome diversity at Week 1 was associated with sustained clinical cure through Week 8 (p< 0.001) (Fig. 1b).
These data suggest that CP101 restores microbiome diversity, leading to colonization resistance and driving sustained clinical cure in recurrent CDI.