A Prototype Biomarker for Microbiome Rehabilitation in Patients with Clostridium difficile Infections: Application to a Clinical Trial of a Lyophilized, Non-Frozen, Oral, Microbiota-Based Drug RBX7455

Ken Blount PhD, Courtney Jones BS, Sahil Khanna MBBS, Elena Deych MS, Bill Shannon PhD MBA

Background

• Recurrent Clostridium difficile infections (rCDI) are strongly associated with dysbiosis—disruption of a healthy intestinal microbiome
• We have developed two forms of Microbiota Restoration Therapy™: RBX7455 is a first-of-its-kind room temperature stable, orally administered MRT; and RBX2660, a ready to use liquid suspension MRT
• In a recent investigator-sponsored Phase 1 trial, RBX7455 was effective at preventing rCDI and restored a healthier microbiome among responding participants
• Since quantitative markers have not been definitively confirmed a prototype MICROBIOME HEALTH INDEX™ (MHI™) to enable unidimensional quantitation of microbiome health and restoration
• Here we report MHI data from an interim analysis of the Phase 1 trial of RBX7455 in the context of two previous clinical trials of RBX2660 for preventing rCDI

Phase I Clinical Trial of RBX7455

• Prospective, single-center, open-label Phase I investigator-initiated trial (NCT02981316) that enrolled single- and multi-recurrent CDI patients
• After successful resolution of enrolling CDI episode, antibiotics were discontinued 24-48 hours prior to first RBX7455 dose
• Participants received 8 RBX7455 capsules per day for four days (Cohort 1) or two days (Cohort 2)
• Success was defined as freedom from CDI recurrence 8 weeks after treatment
• 9 of 10 participants responded in cohort 1
• 8 of 10 participants responded in cohort 2

RBX2660 Trials

• PUNCH CD2™ (NCT02299570): a randomized, double-blinded, placebo-controlled trial of RBX2660 for preventing rCDI and PUNCH Open Label™ (NCT02589847) an open-label controlled trial of RBX2660 for preventing rCDI
• PUNCH CD2: 64% of multi-recurrent CDI participants treated with at least RBX2660 dose were recurrence free 8 weeks after treatment, compared to 45% of placebo-treated participants (p=.047)
• PUNCH Open Label: 79% of multi-recurrent CDI participants treated with at least one RBX2660 dose were recurrence free 8 weeks after treatment, compared to 47% in historical control arm

Microbiome Analysis

• 8 RBX7455 drug product samples and 84 participant stool samples were sequenced using a shotgun sequencing method
• Relative taxonomic abundances at the class level were calculated from OTU data for each time, treatment, outcome group, and the mean and upper/lower confidence limits defined by fitting to a Dirichlet-multinomial distribution using maximum likelihood estimation.

MICROBIOME HEALTH INDEX™ (MHI™) Analysis

MHI as a potential diagnostic (view poster for graphs; PDF 229 KB)

Successful response to microbiota-based therapies RBX7455 and RBX2660 is associated with increased MHI.

• RBX7455 and RBX2660 product MHI values are similar
• Baseline participant MHI values are similar among the trials
• Responder MHI values (30 days) are similar among the trials

Conclusions

• Among rCDI trial participants, MHI increased sharply after RBX7455 and RBX2660 treatment, with a majority of responders above a defined diagnostic threshold
• Pre- and post-treatment MHI data are consistent among three clinical trials of both RBX2660 and RBX7455, regardless of sequencing methods
• Future efforts will focus on prospective evaluation of MHI as a clinical trial endpoint to confirm the robustness of the metric