Emerging Treatment Options for Recurrent C. Difficile Infection - Episode 3
Dr Feuerstadt discusses data with 4 emerging microbiota-based live biotherapeutics for treatment of rCDI: RBX2660, SER-109, CP101, and VE303.
Paul Feuerstadt, MD: What we’re driving toward is something called, microbiota-based live biotherapeutic products. This is the FDA moniker for forms of fecal transplant. We are at a really exciting point right now because there are 4 products going through the FDA process. Two have finished phase 3 trials, including RBX2660 and SER-109, and 2 have completed phase 2 studies, all with positive results. Now, there are certain similarities among all of the studies I’m going to talk about. One, all of the studies involve patients with recurrent Clostridioides difficile [C diff]. Two, all of the studies required that patients receive a standard course of antimicrobials prior to the transplant; you have to control that vegetative phase before you try to eradicate the spore phase. Three, all of these studies had an 8-week assessment for recurrence. Let’s talk briefly about these products.
The first product I’d like to talk about is something called, RBX2660. This is a broad consortium microbiota-based live biotherapeutic. That means there’s a wide array of microorganisms including both spore and nonspore forming bacteria within the formulation. RBX2660 is rectally administered. In order to understand the phase 3 trial, we have to understand the phase 2 trial. The phase 2 trial that assessed RBX2660 included patients with 2 or more recurrences of C diff infection. They all received standard of care antimicrobial, and then they were randomized to 1 of 3 groups. One group was given 2 doses of placebo approximately a week apart. The next group was given a dose of RBX2660 followed a week later by placebo, and the third group was given 2 doses of RBX2660 rectally administered 1 week apart. They were followed for 8 weeks for recurrence and 24 months or 2 years for safety. As a result of this trial, a single dose of RBX2660 proceeded to the phase 3 trial. The phase 3 trial included patients with 1 or more recurrence of C diff. All received standard of care antimicrobial, and then they were randomized to receive a placebo, or a single dose of RBX2660. They were followed for 8 weeks for recurrence, and 24 weeks or 6 months for safety.
This trial was important because it performed a Bayesian analysis. The reason I introduced the phase 2 study design was the similarity between the phase 2 and phase 3, with similar diagnostics, same intervention, and similar follow-up for recurrence. As a result, a Bayesian analysis allows you to leverage 2 studies’ data together to produce a larger study if the intervention of placebo and the intervention of interest, in this case RBX2660, show similar efficacy across both trials, and that of course was achieved here. Within the phase 3 trial, the quoted efficacy for RBX2660 was 70.4% compared to 58.1% in the placebo arm. The posterior probability of superiority was 0.986, showing a statistically significant difference between RBX2660 and placebo, favoring the RBX2660. So this product is most likely going to be reviewed by the FDA soon and has very exciting results.
Another exciting product is SER-109. This is a capsule formulation that says, look, we have a deficiency of the Bacteroidetes and Firmicutes, causing dysbiosis. Why don’t we supplement the Firmicutes spores in a capsule formulation? This is administered as 4 capsules daily for 3 days, following a standard of care antimicrobial. The phase 3 trial data from this product was published in the New England Journal of Medicine earlier this year. Within this trial, patients with 2 or more occurrences of C diff were randomized to all receive standard of care antimicrobial, and then either placebo or SER-109 at 4 capsules daily for 3 days, following that standard of care antimicrobial. They were then followed for 8 weeks for occurrence and 24 weeks for safety. The overall efficacy for SER-109 within this analysis was 88% versus 60% in the placebo arm, showing statistical significance. This product also will likely be considered by the FDA over the coming months to a year.
There are 2 products that have completed phase 2 trials. One is a product called CP101. This is a capsule formulation that is a broad consortium, or a wide array of microorganisms. This is administered as 10 capsules on a single day following standard of care antimicrobial. The phase 2 study design for this product included patients who had 1 or more occurrences of C diff; all received standard of care antimicrobials. Then they were randomized to either the 10 capsules of CP101 or a placebo, followed for 8 weeks for recurrence, and 24 weeks for safety. The efficacy within the CP101 arm was 74.5% versus 61.5% in the placebo arm. This also achieved statistical significance, and this is proceeding into a phase 3 trial, which is ongoing.
The final product is a bit of a different product. This includes 7 bacterial strains, a so-called defined consortium. These bacterial strains originated from the human digestive tract, but now are synthetically reproduced. At a major international conference in San Diego, California, in May 2022, the phase 2 trial data were presented, and this was a dose-ranging study for patients with 1 or more recurrence of C diff. All received standard of care antimicrobial, and then were randomized to either a placebo for 14 days, a low dose of this product called VE303 for 14 days, or a high dose of VE303 for 14 days. Overall, the lower dose did not achieve statistical significance, but the higher dose had an efficacy at 8 weeks of 86.2% compared with 54.5% in the placebo arm. So this too will likely proceed to a phase 3 trial.
The treatment of C diff now is emerging and it’s evolving. Previously, we just had standard of care antimicrobials, and those work relatively well, but we see high rates of recurrence after completion of therapy because that spore phase is regerminating to the vegetative phase. With the foundational clinical trials considering fecal microbiota transplantation and the rudimentary technology and techniques, we saw nice efficacies. But the predictability of safety and efficacy due to the heterogeneity of these products led us to scratch our heads a bit and not apply this more broadly. As we go into this next phase of microbiota-based live biotherapeutics, we have several exciting products, including RBX2660, SER-109, and a little further down the pipe, CP101 and VE303. The future in the world of fecal microbiota transplantation and now the more sophisticated microbiota replacement therapy is incredibly bright, and I’m so excited that you joined us today for this learning session.
Transcript Edited for Clarity