Novel C. Difficile Treatment Reduces Recurrence in Key Subgroups

In an interview with Pharmacy Times, Paul Feuerstadt, MD, FACG, AGAF, discussed research into the novel C. difficile treatment RBX2660 and what investigators have found about its efficacy in key subgroup analyses.

Q: Can you discuss why there is a need for new treatments to reduce the recurrence of C. difficile infection?

Paul Feuerstadt, MD, FACG, AGAD: You know, that's an excellent question. C. difficile is such a major problem in the United States, it's estimated that 500,000 people test positive for C. difficile on an annual basis. And as a result of that, there's significant morbidity, mortality, and health care resource utilization. Now, one of the biggest challenges with C. difficile infection is recurrence. It's estimated that up to 35% of all people with an initial infection of C. difficile that are treated with a standard of care antimicrobial will recur. And of those that recur twice, 65% or more will go on to get caught in that cycle of recurrence after recurrence after recurrence. So really, the question is, why do so many patients recur? And the answer comes from really understanding a little bit of the basic science behind C. difficile.

There's 2 phases. There's a vegetative phase that kind of causes the symptoms, and then there's a spore phase that causes recurrence and spread. Well, it turns out that the antimicrobials that we use most commonly—vancomycin and fidaxomicin—they do a really nice job treating the vegetative phase, but it's up to our microbiota to eradicate that spore phase. And after we treat with antimicrobials, without any supplementation, the microbiota has to regrow on its own. And when it does that, it most commonly is able to eradicate C. difficile spores. Unfortunately, though, as I alluded to before, not all the time, and a lot of patients get caught in this cycle of recurrence with a huge burden of disease. So, what we've learned over the last couple of decades is that by supplementing the microbiota through a procedure called fecal microbiota transplantation, we've been able to replace those deficiencies and reduce future recurrences. So, with that thought in mind, a product called RBX2660 has gone through quite a few clinical trials, including 3 phase 2 trials, and 2 phase 3 trials, where it has been given following a standard of care and for microbial with very consistent safety and efficacy.

Q: What is RBX2660?

Paul Feuerstadt, MD, FACG, AGAD: RBX2660 is what we call a broad consortium, meaning it has a wide array of microorganisms, including both spore and non-spore forming bacteria. It is administered as a single rectal installation, usually within a couple of days following a standard of care antimicrobial.

Q: Prior to this subgroup analysis, what did efficacy data show about RBX2660?

Paul Feuerstadt, MD, FACG, AGAD: Like I said before, there's quite a few clinical trials considering 2660. It's one of the strong suits with this product. There were 3 phase 2 trials and 2 phase 3 trials, all of them showing consistent safety and efficacy. Now, as relates to the subgroup analysis, this was a pooled analysis combining the phase 2B study—the PUNCH CD 2 study—and the phase 3 clinical trial within the phase 2 study. This was a prospective, double blinded, randomized, placebo-controlled trial where patients with 2 or more occurrences of C. difficile were randomized to all receive standard of care antimicrobial and then either 2 doses of placebo a week apart, a dose of RbX2660 followed a week later by placebo, or 2 doses of RbX2660. They were then followed for 8 weeks for recurrence and 2 years for safety.

As a result of that clinical trial, it was found a single dose of RBX2660 was optimal. So, this proceeded to the phase 3 trial—the PUNCH CD3 study. In this trial, patients that had 1 or more recurrence of C. difficile were all given a standard of care antimicrobial and then randomized to either receive a placebo or a single dose of RBX2660, followed for 8 weeks for recurrence, and 24 weeks or 6 months for safety. Given the same product being used in the 2 trials, similarities of diagnostics, similarities of follow up, these 2 studies were pooled together to consider a number of different subgroups.

We hypothesized with our study that there would be no differences based on the subgroups, specifically, age, gender, number of previous episodes, duration of antimicrobial used, site of geography of administration, race, and ethnicity. When we pooled the 2 studies together, overall, there were 221 individuals who received RBX2660—180, from the PUNCH CD3 trial and 41 from the PUNCH CD2 trial. In addition, there were 131 individuals who received only placebo—that included 87 from the PUNCH CD2 study and 44 from the PUNCH CD3. When we looked at these 2 groups together, we found there were no differences with regard to their demographics overall. Within the RBX2660 cohort, there was a trend for slightly older age. But like I said, no statistically significant differences, fitting with major other C. difficile trials. About 60% of the patients included in this were women, and over 90% were Caucasian.

So, what did we do to actually compare the subgroups? What we did was something called a Breslow-Day analysis for larger numbers, and Zelen exact tests for smaller numbers. Plainly stated, we looked at odds ratio for treatment success at 8 weeks. And what we found was that there were no statistically significant differences based on age, gender, number of previous episodes, race, ethnicity, duration of antimicrobial prior to the intervention, and the site of geography of administration. What this really speaks to is that this product can be broadly used with consistent safety and efficacy, there isn't one group that's better than the next to use it in, and so on.

Also, within this pooled analysis, we looked at the efficacy at 8 weeks. The efficacy for RBX266 8 weeks pooling the 2 studies together was 68.3% versus 55.0% in the placebo arm, through a chi square analysis that showed a statistically significant difference. That is, again, consistent with all the other trials showing consistent efficacy of the product, but also a very consistent safety [profile].

Q: What subgroups were analyzed in your research and what is their significance?

Paul Feuerstadt, MD, FACG, AGAD: Now, that's a really important question. Really, the subgroups speak to a lot of the risk factors for future recurrence. So, the question is, is there a sweet spot for a product or can it be used broadly and have similar efficacy? And what this study shows is that this can be used broadly and have similar efficacy across a really broad range of patients.

Q: How could these findings impact the trajectory of C. difficile treatments?

Paul Feuerstadt, MD, FACG, AGAD: So, treatments like this—the so-called microbiota-based live biotherapeutic products, of which RBX2660 is one—really are hopefully going to be advancing our ability to treat recurrent C. difficile in the future. It's our hope that we're able to triage patients who are at greatest risk for recurrence and identify them and try to shut down that recurrence by giving a standard of care antimicrobial that's appropriate. But then supplementing that, remember treating the vegetative phase with that standard of care into microbial, but using a product like RBX2660 to reduce future recurrence, fulfilling the deficiency in the microbiota that's there as opposed to allowing it to naturally regrow. By fulfilling that deficiency, we really reduce rates of recurrence.

Q: Is there anything you would like to add?

Paul Feuerstadt, MD, FACG, AGAD: Wonderful. I think the subgroup analysis further validates the multiple clinical trials that have really assessed RBX2660. You know, it's one thing to kind of look at broad groups of patients and look at demographics, and look at table ones from manuscripts and abstracts, but it's another to actually do a comparison of the odds ratio for treatment success at 8 weeks. And this really spoke to the fact that this can be broadly applied and doesn't need one specific group to allow it to be more successful than another group.