Repurposing Misoprostol to Prevent Recurrence of Clostridium Difficile Infection

PROJECT SUMMARY:Clostridium difficile infection (CDI) is a leading nosocomial infection and the primary identifiable cause ofantibiotic-associated diarrhea. It can lead to multiple CDI recurrences, sepsis, toxic megacolon, and death.Recurrent CDI (rCDI) complicates 20-30% of primary episodes of disease is associated with an increased riskof death (nearly 45,000 deaths per year) and a poor quality of life. While probiotics, new biologic therapies, andfecal transplantation have met with some success in breaking the cycle of rCDI, there remains a need for simple,safe, and cost-effective solutions to this problem. We have assembled three independent, converging lines ofevidence that suggest the already FDA-approved drug misoprostol (a prostaglandin analog) as a candidate forpreventing rCDI. First, there is an emerging epidemiologic association between the clinical use of inhibitors ofprostaglandin (PG) synthesis and an increased risk for CDI. Second, we performed a Phenome-WideAssociation Study (PheWAS) based on ICD-9 billing code and genotype data in a disease-agnostic cohort of~40,000 patients. We used PheWAS to identify potential novel genotype-phenotype associations related to theSNPs in the genes for the targets of misoprostol (PGE2 receptors). This innovative analysis predicted a potentialnew indication for misoprostol to treat (or prevent) C. difficile colitis. Third, we obtained preclinical data from amouse model of antibiotic-associated CDI that show misoprostol has beneficial effects against CDI.In order to take they key next step in translating these findings into the clinic, we are planning a phase II proofof concept study: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO ASSESS THEEFFICACY AND SAFETY OF MISOPROSTOL IN THE PREVENTION OF FIRST RECURRENCE OFCLOSTRIDIUM DIFFICILE INFECTION IN ADULTS AGED 50 AND OVER. We propose three aims: (1)Evaluate the safety and efficacy of misoprostol for prevention of rCDI, by determining if misoprostol can modifythe rate and severity of rCDI in adults ?50 years of age during the first 8 weeks after standard oral vancomycintherapy is completed; (2) Determine the effect of misoprostol on the gut microbiome and metabolome, diarrheaoccurrence/severity, and the development of anti-C. difficile toxin antibodies, in order to inform the design offuture studies, and (3) Continue the clinical development of misoprostol to optimize its potential to impact clinicalpractice and rapidly affect human health. The successful completion of these studies could have rapid clinicalimpact in the prevention of rCDI infection. Additionally, the scope of this work goes well beyond initial clinicalproof of concept and also includes elements of real-world translation including production of an optimizedformulation of the drug, a Pre-IND meeting with the FDA to discuss bridging studies needed for 505(b)(2)approval, and conduction of preliminary bridging studies based on input from the FDA.1