Â鶹´«Ã½

Study of REBYOTA (Fecal microbiota) on patients with C. diff infection

A Â鶹´«Ã½ Live Event

What: Discussion of Open Forum Infectious Diseases publication (May 4) evaluating the safety and efficacy of an FDA-approved microbiome-based treatment for the prevention of recurrent C. diff infection, following antibiotic treatment for recurrent C. diff infection, in a real-world patient population with comorbidities and risk factors.

When: May 3rd, 4:00 PM ET

Where: Live Events Zoom Room (link will be given once you register)

Who: Lead author Paul Feuerstadt, MD, F.A.C.G., A.G.A.F., Yale University School of Medicine

Transcript:

Thom Canalichio: Welcome to today's Â鶹´«Ã½ live event. Today, we have with us Dr. Paul Feuerstadt, MD, F.A.C.G., A.G.A.F. from Yale University School of Medicine, and he's here to discuss gastrointestinal infections with C. diff. 

Dr. Paul Feuerstadt: Thank you so much for having me. C. difficile is a major problem in the United States. It is the most common healthcare associated infection. It's surprising that it's the most common healthcare associated infection because the lay public thinks of MRSA or VRE as being significant threats, and they are, but C. difficile is seen more frequently. It's estimated that about a half a million people will test positive for C. difficile on an annual basis in the United States and that results in a significant burden of disease. With it, I like to think about C. difficile is it's a bacteria that infects the large bowel or the colon and there's two parts to it. There's one part that releases toxins and causes symptoms, including abdominal pain, and diarrhea. The other part is much more challenging. That's the part that transfers from person to person or remains within a person's system after receipt of a standard of care antimicrobial resulting in something called a recurrence or a repeat of the symptoms. The way that we typically treat C. difficile is with antimicrobials. Classically, Vancomycin and something called Fidaxomicin. And, and the Vancomycin or Fidaxomicin controls that phase of infection that causes symptoms, so people who are on it feel well, but after finishing the standard of care antimicrobial, the microbial consortium, the group of bacteria, or microorganisms that live within the colon are at their lowest point. What can give the other phase a knockout punch is a healthy, diverse group of microorganisms, but frequently, after we treat C. difficile, the microorganisms are depleted. We need to regrow those microorganisms and unfortunately, frequently, we aren't able to do that as well as we'd like. 

Thom Canalichio: And this is essentially because the broad spectrum antibiotics to attack the C. diff end up wiping out all the good bacteria too?

Dr. Paul Feuerstadt: Yes, it's the antibiotics that precedes C. difficile that wipe them out. And then the antibiotics that we use to treat C. difficile, also have some impact, but not as big of an impact, but once it's depleted, it's much more challenging to regrow. And if we can't regrow, then we can't give C. difficile the knockout punch, and about a third of people will get it again, and then up to 60% thereafter. So our goal is to really break that cycle.

Thom Canalichio: Thank you and tell us about the recent study, because I understand that when gaining FDA approval, trials were done, and they weren't including patients with comorbidities, those patients were excluded. And now you've done a new trial that does also include patients with comorbidities, tell us about what some of those comorbidities are and the impact that they have on outcomes and the outcome of your study to determine whether your treatment was effective in those patients also. 

Dr. Paul Feuerstadt: Sure. So when you think about that regrowth, one of the ways that we supplement the regrowth is by microbiota restoration. And a product called REBYOTA which is a broad consortium of microorganisms can be given after a standard of care antimicrobial to prevent recurrence and it's given to adults 18 and over for prevention of recurrence after that standard of care antimicrobial. The pivotal trials showed efficacy at eight weeks where patients had a better sustained response when they received REBYOTA versus the placebo arm. But as you alluded to, within the phase III trials, it's a clean study. We're looking at patients with disease and then we remove the confounders. Well, in the real world, patients that I see, they have things like irritable bowel syndrome, Crohn's disease, ulcerative colitis, microscopic colitis, other things that can cause chronic diarrhea. So the real world evidence also goes a long way to validate a product. While the pivotal phase II and phase III trials were going on, this product REBYOTA was available to patients who either chose not to participate in the trial or weren't eligible. Their ineligibility was usually a result of confounding factors like what I listed. So this is a retrospective analysis that looked back at five centers, 94 total patients that received this product, and what their assessments look like. Of the 94 patients, 64 had a complete dataset and in eight weeks, 82.8% remained responsive, and of those that remained responsive, 88.7% kept that response at six months. So we see a very consistent efficacy profile and also safety profile. The safety profile within this real world analysis of patients that weren't eligible for the clinical trial was consistent with the phase II and phase III studies.

Thom Canalichio: How is this different than taking the types of probiotics that you can get at a health food store? 

Dr. Paul Feuerstadt: So probiotics are usually a single strain or maybe up to 10, or 15 strains of fungi and other elements. Probiotics are supplements, what that means is that they have not gone through rigid phase II, phase III clinical trials and do not have safety and efficacy profiles associated with them. So they do have spaces because they do have some trials but this product is a much broader consortium of microorganisms adds to the diversity of our microbiota, the health of our gut, our immune system, among many other things. Most importantly, the data shows that it reduces rates of recurrence of C. difficile. 

Thom Canalichio: And this is something that's taken regularly or how is it administrated and for how long after recovering from the C difficile?

Dr. Paul Feuerstadt: So what happens is patients receive the standard of care and a microbial and then there's what we call a washout period of one to three days where patients move their bowels and they pass the antibiotic that's in their system. And then this is given as a single dose, it's rectally instilled, takes about 15 minutes to do in the office. And that's it. That's all that's required with it. It doesn't require a bowel prep, or anything along those lines, no colonoscopy, nothing like that. 

Thom Canalichio: Could it be best described as an enema? 

Dr. Paul Feuerstadt: It is an enema formulation, although most people associate an enema with passage of elements, this is something where we're actually passing into the rectum. So it's kind of the opposite. 

Thom Canalichio: What were the adverse events that should be reported as part of this? 

Dr. Paul Feuerstadt: So the adverse events most commonly seen in the phase three trial, as well as the real world evidence analysis include abdominal pain, diarrhea, distension, nausea, and flatulence. These were mostly mild to moderate nature, there were no really significant severe associated side effects. With this real world analysis. Really importantly, only 17.2% of the adverse events were associated or thought to be associated with the product, and only 4.7% through the administration. So again, the safety profile is really excellent for this and the majority of these adverse events were short lived, lasting less than two weeks. This was published in the Open Forum Infectious Diseases and we're incredibly excited about it, because it's a true validation of the phase three trial that PUNCH CD3 trial, which was a large trial. But what this does is it validates it in patients that we see in the office, and those patients that we see in the office, are patients that have other things, the FDA wants to isolate disease with intervention. And of course, that's what the phase II, phase III trials do. This really looks at a complicated patient population, and shows that within that complicated patient population, this is both safe and effective. 

Thom Canalichio: You have a presentation coming up at the DDW; can you tell us a little bit about that, and what you're getting into with those subjects. 

Dr. Paul Feuerstadt: The presentation at Digestive Disease Week covers a subgroup of this. So historically, when people receive what's called a fecal microbiota transplant, originally, we used to do colonoscopically or through a colonoscope. Through this real world analysis, 10 of the patients involved actually received REBYOTA via colonoscopy and what we're presenting at Digestive Disease Week in a couple of days is that the efficacy in that cohort was 80% or eight out of 10 patients responded. Now, this is obviously a small patient group. It's an off label indication usage for the product but what it shows is that even using some of the antiquated techniques, this still can be safe and effective. A prospective data is needed in larger cohorts to further validate.

Thom Canalichio: And what was the role of Ferring pharmaceuticals that you've worked with on this? 

Dr. Paul Feuerstadt: So Ferring pharmaceutical sponsored the clinical trial. Obviously, they sponsored the phase III study, but they also sponsored this retrospective real world analysis as well. 

Thom Canalichio: Doctor Feuerstadt, what's the AAT program that allows patients to participate in this study? 

Dr. Paul Feuerstadt: So the AAT program is the program that actually enabled patients the ability to participate in this study because the AAT program was a program where this product REBYOTA was offered under enforcement discretion through the FDA, in plain English when the patients chose either not to participate in the trial or weren't eligible, the enforcement discretion, the FDA said you can use this product because it has an investigational new drug application and Ferring provided the product free of charge to all of those patients. And this is a retrospective look back at those patient’s experience, that's what the study essentially is. It's a retrospective look back at patients that received the product under enforcement discretion through what's called the Assured Active Treatment program.

Thom Canalichio: Were there patients in this cohort that did get reinfection, but your treatment demonstrated that the reinfection was less severe?

Dr. Paul Feuerstadt: So there was a portion of patients that recurred after this. That was a small portion of the population and the severity of the infection has shown throughout the course of data not within this study specifically, because that's not something that we looked at but there's over 1000 patients that have participated in clinical trials with REBYOTA. And the overall clinical experience has been that even if patients recur after they received this product, you're right, their symptomatology decreases and there's really interesting data looking at health related quality of life associated with this product. And we've published on this as well, fascinatingly enough, even patients that recur who received this product, their health related quality of life improved, whereas the patients that received placebo, it stayed the same. So there is something there that we're teasing out, we've presented that in abstract form in the past in the fall of 2022. 

Thom Canalichio: Is REBYOTA the only available microbiome-based treatment of this type?

Dr. Paul Feuerstadt: So REBYOTA  was the first FDA approved, live biotherapeutic product, there is now a second live biotherapeutic product that has been approved. 

Thom Canalichio: And how does that compare with that that's called Vowst and how does that compare to this? 

Dr. Paul Feuerstadt: So Vowst is a different product, Vowst takes a completely different approach. REBYOTA is a broad consortium of micro organisms, a wide array of micro organisms, Vowst on the other hand, says look, we believe the deficiency associated with C. difficile is Bacteroidetes, so we're just going to give firmicutes, so they just give one bacterial phyla in an encapsulated form. It's administered as four capsules daily for three days after standard of care anti-microbial. So REBYOTA  is a single dose that's administered in the office, Vowst is a 3- day dosing of four capsules, and it takes a different approach. It's a narrow consortium of micro organisms.

Thom Canalichio: My understanding if left untreated, or in very severe cases, it can result in needing to have portions of the bowel resected, for example, what? So understanding the importance of preventing a recurrence, what what can you tell us to understand a little bit more about that. 

Dr. Paul Feuerstadt: So C difficile is a really fascinating infection because we do have a little bit of a crystal ball with it. We look back at a commercially insured database a couple of years ago, so aged 18 to 64 individuals and we looked at the number of episodes of C difficile that they had. And then we looked at their diagnoses with sepsis and collectively within 12 months, overall, with a single episode of C. difficile 16.5% of that young population was diagnosed with sepsis, and 4.6% had their colon removed within 12 months. But once you get to that third recurrence and beyond 43.3% had sepsis, and 10.5%. colectomy. So this really speaks to, Yes, I alluded to it earlier, health related quality of life, essential, we take care of patients, not diseases. But when we do that shutting down the cycle of C difficile is really important. Another study looked at at mortality associated with this overall mortality 2.7% in a Medicare population. But the more frequent patients get recurrences, the more likely C difficile is to cause or be a cause of the death going from about 16.4% cause of death in with a single episode to 39% with three or more episodes. So shutting down this cycle can play a really important role in keeping people healthy and unfortunately, alive. 

Thom Canalichio: Some very serious consequences if left untreated or not treated appropriately. Thanks for clarifying some of that and as sobering as all that is, to segue into why do you feel that this study was important to conduct and where do we go from here? 

Dr. Paul Feuerstadt: So this study was incredibly important to conduct because it really shows that we're able to shut down that cycle of recurrence in the appropriate patients. The patients that have recurrent C. difficile, what this does is it supplements what one of our weaknesses was before, the weakness before was that our hands were tied, we only had anti microbials and we were relying on the gut microbiota to regrow itself. With REBYOTA, we can supplement that decreased recurrence and this study shows in a real world population patients not eligible for clinical trials, they responded really well and it was safe. 

Thom Canalichio: Is it fair to say that a healthy flourishing microbiome, these good bacteria, that these essentially out compete and sort of muscle out or elbow out whatever remaining C Diff might be lingering after treatment? Is that Is that a fair way to assess it? 

Dr. Paul Feuerstadt: 100%, you hit the nail right on the head. What you're doing is out competing, this is Darwinism at its finest. You're supplementing a deficiency, and then the stronger, healthier micro organisms are able to beat out the challenging C difficile. 

Thom Canalichio: Fascinating to understand more about the microbiome and I feel like, while it's a popular topic, people don't fully get it. What else would you say about the microbiome in general that you would want audiences of the public and media to understand about its importance? 

Dr. Paul Feuerstadt: So the microbiome and the microbiota are we're just scratching the surface here. First of all, the microbiota is the micro organisms, the microbiome is the genetic complement. But what we're really concerned about is the deficiencies in certain diseases. So C. difficile is a lock and key effect. We know that deficiency, we supplement it and patients get better. What we're doing now is we're defining the deficiencies in the alterations and a whole host of other diseases, pulmonary diseases, liver based diseases, anybody with autoimmune diseases, and as we define these deficiencies, then we can try to supplement or replace those deficiencies, and hopefully help either alleviate disease, probably aid symptomatology, or cure disease. So with C difficile, it will be kind of a one time application. But with recurrent disease, or with persistent chronic diseases, like I was alluding to, it might require frequent supplementation or supplementation on a weekly basis, we're not really sure we're really defining the surface. But we've opened the door, and science, hopefully, we'll keep that door open. This will not cure every disease but I think that there will be a whole host of diseases that we will make a lot of progress in by understanding the microbiota and understanding how we can best manipulate it and make it healthier. 

Thom Canalichio: Where do you go from here? Is there something next for REBYOTA or for other similar kinds of applications and what's on the horizon for you? 

Dr. Paul Feuerstadt: So what's on the horizon is a moveable feast, as I alluded to earlier, there's so many different disease states that we could potentially study this within. But right now we're focusing on the seat up world and what this really does is it opens the key to access. Previously, patients who needed supplementation of their microbiota could only go to isolated centers, there were only maybe 15 or 20 of them, or 30 of them throughout the country. Now, with an FDA approved product, patients will get better access, they'll be much less likely to be fearful, the providers to be fearful to use the product because it has that FDA stamp of approval for safety and efficacy. And trials like what we're talking about today, validated further for those providers to use this, shutdown the cycle and decrease the burden of this infection on our society.

Thom Canalichio: Dr Feuerstadt, any final thoughts before we sign off? 

Dr. Paul Feuerstadt: I want to thank you so much for having me. We are at such an exciting point, we've been running towards the horizon for years and the horizon has arrived and patients are going to benefit.

Thom Canalichio: Okay, thank you, Doctor Feuerstadt. Thank you everyone for attending. Have a great rest of your day.