Investigative Treatment for C. Diff Aims to Restore Microbiome, Bile Acid

In an interview with Pharmacy Times, Ken Blount, PhD, chief scientific officer at Rebiotix, discusses the investigative treatment RBX2660 and its unique approach to treating Clostridioides difficile (C. diff) infection. Blount explained that the treatment works by restoring the microbiome and bile acid, which is essential to improving outcomes and reducing recurrence.

How are the microbiome and bile acid involved in C. diff infections?

Ken Blount, PhD: So, I wouldn't say C. diff affects the bile acids, [but it] gets affected by the bile acids. So, you probably are aware that one of the major ways that people contract C. diff infections—or C. difficile infections—is because they've had an antibiotic or they're exposed to spores of C. difficile. The antibiotic disrupts the microbiome, and that disrupts the bile acids. Both of those things lead to the gut being easier to colonize by C. diff. So, the healthy microbiome actually has many different mechanisms by which it can resist colonization. One of those mechanisms is that a healthy microbiome converts the primary bile acids that our liver produces into secondary bile acids. The reason that's important is because the primary bile acids produced by our liver actually stimulate C diff to germinate and to grow, whereas the secondary bile acids that are converted from primary microbiota actually repress C. difficile. So that's really the tie in. So again, when a patient gets an antibiotic, it disrupts their microbiome and that can lead to a buildup of primary bile acids that actually can stimulate C diff. So that's really the close connection between the two.

How do current treatments approach this issue? Are they effective?

Ken Blount, PhD: Well, they really don't. So, the standard of care treatment for C. difficile infections, including recurrent C. difficile infections, is an antibiotic. So, we talked about what antibiotics can do to the microbiome, and they really don't do anything to help that. Now, there have been some more recent antibiotics that are in development, but not approved, that are seeking to do less harm to the microbiome, which would then concurrently do less harm to the bile acids composition. However, unfortunately, 3 of those have failed in late-stage clinical trials in the past 10 years, so there are no new, more selective antibiotics that are really poised for an approval. And that just really underscores that patients need something else that actually addresses the problem after antibiotics, which is really what we're seeking to do, is to address that need by restoring the microbiome, and then in principle, restoring the bile acids.

What is the mechanism of action of RBX2660?

Ken Blount, PhD: Sure, you are saying that right. So, RBX2660 is a new type of investigational therapeutic called a live biotherapeutic product. That's what the FDA calls it and it is what it sounds like. It's a drug or an investigational drug made of live bacteria. And that's what we're developing. RBX2660. has been through a number of clinical trials now, 5 in particular—a very large and robust clinical trial program. And what we're trying to do is via those live biotherapeutic products, administered directly to a patient that has just recovered from an antibiotic treatment for recurrency C. difficile infection, and thereby replenish or restore that gut microbiota to a healthier state, which would then lead to restoration of bile acid composition. So, we're learning an awful lot about the mechanism of RBX 2660. We've done microbiome studies in many of the clinical trials, all 5, in fact, that we've run to date. We've also done bile acid composition studies in multiple trials. And what we found is that within days after investigational treatment with RBX2660, the microbiomes of participants in our trials were restored significantly towards a healthier composition. And we say towards because there's no gold standard for healthy but there are some very clear, known differences between what most healthy individuals look like and what a C. difficile patient looks like after they've had antibiotics. They're very, very different. Specifically, after that antibiotic treatment, participants or patients suffering from recurrent C. difficile often have lowered abundance of specific bacterial types—bacteroides and clostridia. These are two important classes of bacteria that are normally high in healthy individuals. They're very low in the participants that enter our trials. And we've seen that within days after investigational treatments, those bacteria in continuity are restored to higher levels, and then some of the other things have gone back down to where they shouldn't be at very low abundance. So, we've learned that thus far.

We've also learned from bile acid composition studies in multiple clinical trials that when participants come in to our trials just off of an antibiotic, they mostly have primary bile acids. That's not good because, as we talked about, those can actually stimulate C. diff. But within days after investigational treatment with RBX2660, we see that restoration back towards predominantly the secondary bile acids that repress C difficile. And we know from lots of work in the literature, including animal studies, that those secondary bile acids, both in vitro or in animals, can repress C. difficile. So, we're learning that there's a picture emerging in which participants have a disrupted microbiota, disrupted bile acids, and we're seeing significant changes after investigational treatment towards something that looks more similar to healthy. And really, that's what we believe will be the ultimate final picture of how this works is a restoration of microbiota and restoration of bile acids to compositions that repress C difficile.

What have efficacy data shown for RBX2660?

Right, so I mentioned we've run 5 clinical trials, 2 of those have been large, placebo-controlled, randomized, double blinded trials, and 3 of those have been open label. So, I'll start with the double blinded trials, because those are really the gold standard for efficacy. We had a phase 2, we had a phase 3, and most recently, last year, we reported a positive outcome for phase 3. Specifically, RBX2660 was shown to be superior to placebo and that matched with our earlier data. And that's really what it comes down to is demonstration of efficacy compared to placebo. We've also seen high response rates defined as an absence of C. difficile recurrence 8 weeks after treatment in those open label trials. So, it's really a consistent picture across the trials program of reducing recurrent C. difficile infections in each of the clinical trials. We've run today, with just that emphasis that what you really want to see the phase 3 clinical trial showing superiority to placebo, which is what we reported last year.

Can you review clinical trial findings with regard to microbiome and bile acid restoration?

Yes, so specifically, as I had mentioned a bit earlier, when participants come into our trials, we actually have what's called an LCMS, or mass spectrometry assay, to quantify over 30 independent specific bile acids in the fecal composition. What we found was that most of the ones that were present before RBX2660 treatment were primary bile acids, and those are the ones that are just produced by our liver before a healthy microbiome converts them. Again, that's not good because those can actually stimulate C. difficile to grow and to recur. That's what the participants looked like prior to RBX2660 treatment. Within days after RBX2660, that had shifted. Most of the bile acids present were the secondary bile acids, which can repress C difficile growth and germination and therefore lead to the resistance to colonization. So, we saw that within days, and we also saw that that change was quite significantly greater in participants that responded to treatment compared to those who did not. We also saw that the placebo-treated patients, whereas some of them clinically did not recur, they had less bioacid restoration or the changes that I just described, when compared to patients who responded after RBX2660 treatment. So, there was a nice correlation between this within days restoration towards secondary bile acid predominant as well as correlation with clinical response, as well as specific correlation with RBX2660 treatment compared to placebo treatment.

How does this aspect of C. diff treatment impact outcomes for patients?

Yeah, so, that's a great question. Normally, you measure a primary endpoint in recurrent C. difficile infections as being 8 weeks after treatment. So, that's where doctors would consider it to be a recurrence of it happened within 8 weeks. And that's the data that I just told you that we showed superiority of RBX2660 compared to placebo. Now, it doesn't stop there. We have long-term follow up in all of our clinical trials. Some trials went out to 24 months and in those cases, we asked the question, during that time did those trial participants remain free of CDI recurrence.

In the phase 3 that I told you about with RBX2660 compared to placebo, we had a 6-month post-treatment monitoring period. And during the six months, the absence of CDI recurrence was sustained to the end of that 6-month period, through a vast majority of the participants. For the bile acid data, we haven't looked at out to 6 months, but the microbiome data we have. And we saw that those changes I described to you were also sustained out to 6 months. So, in general, this does appear to have a sustained response both clinically in microbiome, although I will just remind you, that was not the primary efficacy output.

Is there anything you would like to add?

Sure, a couple of things. Some of this data has been published. Our largest open label trial was published earlier this year and that's the one where we saw the freedom from recurrence at the 8-week point as well as sustained through 24 months, as well as microbiome changes sustained through 24 months. So that's kind of a good showcase of the long-term data we just talked about. And in addition, you know, one of the other posters that we presented was really a breakdown of that phase 3 trial of the different types of patients that could potentially benefit. And what we were seeking to answer in that that analysis was, is the efficacy maintained a lot across the different patient groups, because typically, when you see a C difficile study, you'll see a breakdown of higher risk groups like higher age, higher number of recurrences, other comorbidities. What we saw in that poster, which again, was presented just last week, was that the efficacy was consistent across all of those participants subgroups. So that was very exciting. And I think we'll see that in our future trials that it is broadly applicable across the treatment groups. So very exciting data. It was a very exciting for us.