A Lyophilized, Non-Frozen, Oral Microbiota-Based Drug RBX7455 is Safe, Reduces Clostridium difficile Infection Recurrence, and Restores the Microbiome

Sahil Khanna MBBS, Darrell S. Pardi MD, Dale N. Gerding MD, Ken Blount PhD, Courtney Jones, Bill Shannon PhD MBA, Elena Deych MS

Background

• Microbiota-based therapies are demonstrating efficacy in preventing recurrent Clostridium difficile infections (rCDI).
• RBX7455 is a first-of-its-kind, lyophilized, non-frozen, orally-administered microbiota-restoring drug candidate that was developed for ease-of-use for rCDI patients.
• Herein we present an interim analysis of clinical safety and efficacy of a Phase 1 investigator-sponsored trial of RBX7455 for preventing rCDI, and we present an accompanying study of microbiome restoration among trial participants.

Clinical Trial Design & Methods

• Prospective, single-center, open-label Phase I investigator-initiated trial (NCT02981316)
• Inclusion criteria: >18 years old with documentation of recurrent CDI, at least one recurrence after a primary episode and has completed at least two rounds of standard-of-care oral antibiotic therapy; diarrhea resolved, i.e., fewer than 3 watery bowel movements at the time of study enrollment for 48 hours or more; a positive stool test for the presence of C. difficile within
  30 days prior to enrollment and standard C. difficile treatment.
• Exclusion criteria: Known history of continued CDI diarrhea despite antibiotic treatment for CDI; requirement of continuous antibiotic therapy for a condition other than CDI; previous fecal transplant; previous treatment with RBX2660; history of inflammatory bowel disease(ulcerative colitis, Crohn’s disease, microscopic colitis), irritable bowel syndrome, chronic diarrhea, celiac disease; colostomy; evidence of active colitis; intended exposure to antibiotics within 6 months after study enrollment; compromised immune system (white blood cell count <1000 cells/μL); current or expected use of systemic steroids
• 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).
• Safety was assessed via a patient diary: in clinic at 1, 4, and 8 weeks and via telephone at 2, 3, between 5-7 weeks, and at 3, 6, 12 and 24 months.
• Success was defined as the absence of CDI at 8 weeks following completion of the last treatment. Treatment failure is defined as: recurrence of diarrhea <8 weeks after completion of RBX7455 treatment, a positive stool test for C. difficile, a need for retreatment for CDI, and no other cause for diarrhea.
• Stool samples were collected at baseline and at 7, 30, and 60 days and 24 weeks after treatment.

Microbiome Analysis

• 16 RBX7455 drug product samples and 84 stool samples from treatment responders were sequenced using an ultra-shallow shotgun method (CoreBiome, Minneapolis, MN).
• Multidimensional scaling analysis was performed on participant and RBX7455 operational taxonomic unit data according to a Bray-Curtis dissimilarity metric with non-metric scaling, and group mean relative taxonomic abundances at the class level were calculated by fitting to a Dirichlet-multinomial distribution

Conclusions

• In this open-label, investigator-sponsored Phase 1 study, both four and two days of RBX7455 dosing were effective at preventing rCDI.
• The RBX7455 safety profile is consistent with results from other clinical trials of microbiota-based therapies.
• Microbiota analysis suggests that RBX7455 restores a healthier microbiome composition.