How Does Ridinilazole Affect the Gut Microbiome?

Dr. Richard Vickers, chief scientific officer of R&D at Summit Therapeutics, explains how ridinilazole affected the gut microbiome in participants of a phase 2 study.

Interview Transcript (modified slightly for readability):

“In our phase 2 proof-of-concept study, we showed great clinical efficacy, but what we also did in that study was a very detailed examination of the microbiome of all 100 patients enrolled in the study during the course of therapy and in that post-dosing follow-up period. The data were extremely encouraging.

If you look after 10 days of treatment with ridinilazole, you can see loss of Clostridium difficile from the gut microbiome which is very important, and really little to no effect on any other organisms that are making up the gut microbiota. Any activity was isolated to just 1 or 2 closely-related Clostridia species. But if you look at the vancomycin-treated patients, then you actually see microbiome-wide damage; you see loss in the Gram-positive spore-forming anaerobes as you might expect given the profile of vancomycin. We also started to see significant reductions, almost below the limit of detection in the Bacteroides fragilis group—these are Gram-negatives—but the concentration of vancomycin in the gut is so high that we start to knock out some of those organisms. The same in the Actinobacteria, which contains many important members of the gut microbiota that we all know about, things like Bifidobacteria, and we saw reductions in these organisms. But I think one of the things that was most interesting was not only do we see these reductions because vancomycin has antibacterial activity against these bacteria but suddenly, the gut became dominated by the Gram-negatives. And so, we see overgrowth of the Proteobacteria, the Enterobacteriaceae; a huge microbiome-wide shift when we treat for 10 days with vancomycin.

When you look at this, it’s no wonder that patients are primed for recurrent disease; that niche that C. difficile can exploit, that environment that made it so conducive to overgrowth of C. diff still exists, and this is what patients treated with drugs like vancomycin go on to have a return of the infection. Yet, when you look at ridinilazole, you don’t see that. There was even some evidence of recovery of the gut microbiome during the 30 days post end of therapy, minimizing risks of recurrent disease. One of the nice things as well, when we look to this data from the phase 2, was we had this hypothesis right at the early stages of discovery, when we were at the bench—that we have a very targeted spectrum, we preserved the microbiome, we’re a gut-restricted drug, and that should minimize recurrences. To see this strong translational story play out, to demonstrate that in phase 2 in C. diff patients was really pleasing.”