Carl V. Crawford, MD

Before we transition out here, any thoughts on the future pipeline, phase 2 data, or phase 1 data, what’s the future here?

There are lots of potential options, more second-generation FMT [fecal microbiota transplantation] products that we can talk about, but we also have other narrow-spectrum antibiotics in the pipeline. The closest is ridinilazole, which is similar to fidaxomicin, and it’s going to target 

 and kill it very well, but also spare our commensal microbiota. The phase 2 data look great, it helped prevent recurrence among patients who received ridinilazole compared to oral vancomycin. That’s exciting to me.

There are 2 other microbiome-based therapies that have finished phase 2 clinical trials and 1 that has finished a phase 1 clinical trial. Going alphabetically, CP101 is a full-spectrum microbiome-based therapy that recently finished a phase 2 clinical trial and showed a 74.5% versus close to 60% success rates. This is going to go to a phase 3 clinical trial in the near future. There’s another one that is a room temperature stable or nonfrozen formulation of a capsule called RBX7455, and that one finished a phase 1 study with a 90% success rate, and a larger trial is being planned at this time. Then finally, moving on to what I call designer microbiome-based therapies, where the field is going to go, is VE303, which is from a donor-independent bacterial consortia. Recently in a press release, they had their phase 2 data presented, where the high-dose VE303 was statistically significant and clinically meaningfully different from the placebo in preventing recurrent 

 infection. There is lots of excitement going on in today’s world.

There’s one more. There’s a company now with a particular single strain of bacterium that thrives on a particular oligosaccharide that’s found in certain kinds of fibers where they’re hoping that this 1 strain, which would be a true probiotic, would be able to reduce the risk for recurrences of 

 We’ve really painted the entire spectrum of all the different therapeutic options. We start with full-spectrum stool, which is basically the entire biodiversity. We move toward another company that basically focuses on the different consortia, or the ecological niches, where defects in metabolism can then just be plugged right back in. Then we have these companies that are more designer that have found out that maybe we can pick this handful of species alone and give them back to our patients. And then companies that are probably more savvy have figured out that there may be some species that have multiple functions, and you may just need to give 1 species back. And of course, as we are scientists, we can figure out what we don’t need to give an organism back, we can just find the products that they produce or the proteins that are on their surface and use those. There’s a whole different spectrum of therapeutic options, which is great for our patients because at that point, we have options to choose what’s going to work best for patients in different scenarios.

So the future is bright. I would like to ask all of our participants to give us a final thought.

One of the things that we sometimes neglect is how devastating this disease is to our patients. We talked about the diarrhea itself, we talked about the hospitalization, the epidemiology, the impact on hospitals, but at the same time, there are a number of patients who have their lives turned upside down because of the first infection or the recurrences. I’ve taken care of patients who have lost their jobs, I’ve taken care of patients who can’t be with their families, who ask me if they can see their grandchildren. I’ve seen patients who have developed this post-traumatic stress disorder from having 

 infections. If we think about the thousands and thousands of recurrences that we see each year, there are thousands and thousands of people who are not the same after this infection. I’d like to stress to everyone who’s watching to read these guidelines and look to see what is the appropriate way to treat these patients the first time because that gives them the best chance of success of beating this infection so that they can go back to their normal lives afterward.

That was beautifully said, Carl. This infection creates a huge burden on individual patients, but also on our health care system. I’d also like to mention that the microbiome field and microbiome therapeutics are burgeoning right now. We are learning new things every single day, and some of these microbiome-targeted therapies are ultimately going to be studied in other diseases too, so hopefully, we can make an impact elsewhere in addition to 

 infections. And the last thing I’ll say is, eat your fiber and close the toilet lid when you flush.

I’ll add 2 things. One thing to add to Carl’s point that is paramount is educating our patients on the impact of this illness. When you see a patient for the first time, don’t just hand out an antibiotic prescription and say, “You’ll be fine.” Patient education is paramount. There are resources that are available at the CDC’s [Centers for Disease Control] website, NIH [National Institutes of Health] has resources, and also the C Diff Foundation is a tremendous resource that I suggest to my patients. The other point that I would make is that as these microbiome-based therapies become mainstay, they’re going to move from tertiary care centers, from infectious disease and GI [gastrointestinal] doctors to empower primary care providers, family practice providers, nurse practitioners, physician assistants, who are the first touchpoints that our patients sometimes have with recurrent 

 They should start thinking that they should be and will be able to prescribe these therapies to our patients.

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Closing out their discussion on Clostridioides difficile infection, panelists share closing thoughts on novel pipeline therapies.

Looking Toward the Future of CDI Management

Carl, how do you interpret these data? You’ve heard both of thosediscussions.

It’s clear that these agents work better than placebo, and placebo is what we’re treating patients with when we give them recurrent antibiotic courses. Both are game-changers because they offer our patients a higher chance for cure, not just treatment, but cure. And the modes of delivery are both easier than what we would typically do with an FMT [fecal microbiota transplantation], which is basically preparing someone for a procedure, whether it’s an endoscopy or a colonoscopy. I don’t perform these by using a nasoduodenal tube because there are a lot more risks associated with placing that tube and you need an x-ray. But patients must be prepared for the risk of a procedure, and these are standard risks for everyone. When we bring someone in for a colonoscopy where we believe an individual has the highest rate for engraftment of putting a microbiome-based product inside of the gastrointestinal tract, they have to accept the risks of things like infection from inserting a foreign body into a human being. There are risks of bleeding or of perforation because we’re putting a foreign body inside of a human being, as well as the risks of anesthesia that we give our patients to make them comfortable for the procedure.

There are all of these risks that we have to arrange for, and we have to bring them to a hospital or an ambulatory surgery center, and there’s an increased amount of cost that’s associated with trying to treat these patients. Being able to give someone oral pills that they can take in the office or even at home, who knows, or bringing them into the office for an hour so that they can have an infusion of something that’s rectally applied and they go home where there are no added safety risks is huge because then we have access to bring many more of these patients who are in this vicious cycle of recurrence, the chance for cure. It’s amazing, I’m excited to see these products come out. Unfortunately, there’s going to be this gap where we won’t have the ability to really treat these patients, so I’m hoping that the companies can get their acts together and we can offer our patients what looks like a golden horizon.

: We talked about my case, Lucy, who is our 65-year-old with rheumatoid arthritis on methotrexate, who has dyspepsia, is inappropriately or maybe not on a PPI [protein pump inhibitor]. On her first round of 

, we decided to treat her [in a Disneyland setting] with fidaxomicin extended course, and then maybe in reality, our optimal course here is 10 days of vancomycin followed by bezlo [bezlotoxumab]. Then if we follow the vancomycin and [bezlotoxumab] approach, on the first recurrence we would probably use fidaxomicin and maybe in the extended 10-day course that we described, and on the third round, it sounds like we have concerns. No. 1, we’d probably try and think about FMT, but we don’t know how long that’s going to last. But hopefully on the horizon are these 2 different approaches, one is our pill-based approach and the other is the enema-based approach to help with that restoration of natural flora.

I guess the one mission we would have for our treating physicians is to realize that the guidelines have changed. The strategy and structure for how we approach 

 in 2021 is very different from what we did in 2017, 2018, or maybe even 2019. Then the last one here is for our industry colleagues. There’s going to be a significant gap and a need to get these drugs to market because of this clear area where we know there’s benefit to these strategies, but we don’t really have as of yet an easily usable option.

James, I’d like to go back to Lucy because she’s here in the office with us. She says, “This is my third episode, and you’re telling me the stool bank’s not there, the FDA is going to take more than a year, maybe longer, to get this other product to market. What do we do in between?” For someone like Lucy, what I would suggest is that there is at least 1 open-label trial that I am aware of that administers the edema therapy that is available to patients to get enrolled, so try to investigate that. The information on clinical trials is very readily available, including sites of clinical trials, at the C Diff Foundation, where I refer my patients to look for sites. That’s one option. Also, there is an assured active treatment program that the manufacturer of RBX2660 runs, where you can request them to give you a therapy that you can then use either with an enema or however you would like to use that. Those are 2 options that I would think about presenting to Lucy, short of saying let’s be on vancomycin or let’s think about having another risk of recurrence.

It does suggest that we must think about pressuring our FDA colleagues to say, “There’s a need here guys, let’s move forward.”

Absolutely. I the FDA does realize that too because they’ve been putting out guidance for this treatment. The other thing to think about with Lucy would be the placebo-controlled trials that are going to be starting soon, and I’m hoping the FDA will move very fast on this and we should be able to have something in 2022. It feels very long for a patient.

Practical considerations for the future use of novel FMT therapy for patients with recurrent Clostridioides difficile infection. 

Practical Advice on Novel Fecal Microbiota Transplantation in CDI

Kelly, is there anything else that we should think about from the phase 3 data, as I process this enema side of things?

We have the potential to administer FMT [fecal microbiota transplantation] in other ways; enema is one of our potential routes of delivery, but one of our investigational FMT products is an oral capsule. This is SER-109. Healthy donors are used as the original source of the material, but the way that the company prepares it, they fractionate out just firmicutes bacteria and encapsulate that for oral delivery. One thing I find really cool about this product is that they use another process involving solvents to inactivate other potential pathogens, other bacteria, viruses, parasites, fungi, etc. That should be a major advantage compared to a whole microbiome transplant in that you limit the risk of potential pathogen transmission. I know we say we test for just about everything, but we’re still learning what the microbiome entails. There are many unidentified organisms that we still haven’t been able to classify in the microbiome. Although we’re testing for some of the more important organisms that we know are involved in clinical infection, we can’t test for everything. So having this, what we call narrow consortium of microbes in a capsule form, it could be a game-changer.

Now, its purpose is to change the gut microenvironment to prevent germination of our spore phase and ultimately clinical infection. It’s been studied in a phase 3 trial called ECOSPOR-III, and this was a multicenter placebo-controlled randomized controlled trial of patients with multiple recurrent 

Their primary outcome was the rate of recurrent 

 within 8 weeks following treatment between the SER-109 group and placebo, following a course of antibiotic therapy, and the phase 3 data look great. They met their primary end point in the SER-109 arm, about 88% of patients had clinical resolution without recurrence at 8 weeks compared to about 60% in the placebo group. This equates to about a 68% relative risk reduction. Then the company presented some additional results back in May, where they had followed at least some of the patients out to 24 weeks and found that there was a sustainable response out to 24 weeks. The patients who had made it that long in the SER-109 group had about a 54% relative risk reduction of recurrence at that point, too. So the phase 3 data are looking good for this oral capsule that we could potentially, at least logistically, administer easier compared to enema forms.

James, the big difference between the study design of these 2 products is the inclusion criteria and what kind of testing was allowed for patients to be part of the study. For the SER-109, they only allowed people who had a positive toxin by an EIA [enzyme immunoassay]. This included a filtered group of patients, and that allows you to pick patients who have a true infection. The difference there is that about 80% of the United States is not using just a toxin-based assay; PCR [polymerase chain reaction] is the most common assay that we use in our laboratories and everywhere else. That was the difference between this and the other study. The RBX2660 study used people who could be toxin-positive or could be PCR-positive, as long as they have a response to antibiotics. When one looks at the efficacy, and looks at the rates of recurrence after, one should definitely look at what patient population was enrolled because that does make a difference in terms of how these therapies will be administered to patients down the line.

The panel reviews phase 3 data behind SER-109, another novel FMT therapy for patients with recurrent Clostridioides difficile infection.

Results of the ECOSPOR-III Trial: SER-109 in Recurrent CDI

: Let’s talk about the current phase 3 data. What are the phase 3 data out there that we should all be aware of?

There are 2 trials that have finished phase 3 enrollment and have reported data. RBX2660 is an enema-based product derived from human stool. They take about 50 g of stool, which we all believe is probably the right dose to use. We take 50 g…in 150 cc of a…and it’s given by an enema-delivery methodology, very simple to do, no bowel preparation needed. There were phase 1 data that were positive, after 2 enemas, it was in the 87% range, then there was a phase 2 clinical trial that showed that, not 2, but 1 enema worked better than placebo. It was interesting why 2 didn’t work but 1 did, and after they had the open-label experience again, the cure rates were high in that situation. But those data were taken, and then a phase 3 large clinical trial was designed, which compared 1 dose of an active enema to 1 dose of a placebo.

Now, one thing to keep in mind is that these are patients with recurrent 

 infection, and they allowed people with 2 episodes in there, so people with 2 severe episodes were allowed in that trial. But again, keep in mind that when you have an active 

 infection, you don’t go to FMT [fecal microbiota transplantation] at that point. You first manage with antibiotics, kill the vegetative forms, decrease the colonic inflammation, and then the FMT reduces the rate of recurrence, and that’s how these trials were designed. For the RBX2660 trial, they also took advantage of a methodology called the Bayesian analysis because they had similar inclusion criteria for their phase 2 study, and multiply recurrent

with stringent criteria to enroll in clinical trials ends up being an orphan disease. Often you can’t find a lot of people to put in trials, so they took some patients from their phase 2 into the phase 3 when they did the final analysis; this was an a priori analysis that they had done. It was statistically significant, 70.5% cure rate from the active arm compared with 58%, and they had a posterior probability of superiority of 98.6%. It was statistically significant, clinically meaningful, but also, more importantly, no safety signals were seen.

The importance of these clinical trials is that you cut down on the heterogeneity. Meaning how I did FMT, from how Carl does it, and how you do it, and how other centers do it, everybody’s different. In order to reduce the heterogeneity, you want to have traceability of the product back to the donor in case there is any kind of an issue with an adverse event. All those things have been accounted for in many clinical trials that have a very rigorous donor program, but this is exciting. This was the first phase 3 trial that was reported positively, so I took a stab at that one. I’m going to have Kelly take a stab at the other one.

Before we jump into that, tell me a little bit more about RBX2660. What is it?

It’s derived from human stool. It’s 50 g of stool from a donor who’s been screened for every possible pathogen. They get screened by the blood bank questionnaire, they have to pass that. They must screen travel, they have to screen pathogens, they have to screen for other diseases, no PPIs [protein pump inhibitors], no antibiotics, no depression, no anxiety, no obesity, no high blood pressure, the list goes on and on and on. There was a study that was done that showed that it’s easier to get into Harvard [University] than to be a stool donor, I like to quote that. It comes from healthy, very well screened donors who donate on-site. The product is then blenderized, filtered, and placed in enema bags, and it can be kept frozen. It’s shipped frozen, and then right before administration, it gets thawed to room temperature, and you give it through an enema administration.

As an ID [infectious disease] doctor, I don’t give enemas very often. How am I going to use this?

As GI [gastroenterology] doctors, we like enemas.

Well, that was a fantastic quote. I hope we get to use that one. That’s great. You think this is relatively easy to administer?

It’s relatively easy to administer. We’ve been able to train nurses to do this easily. Just to give you an example, we have nurses in our facility and other places too where we run what we call enema preparation facilities before procedures. People are used to giving others tap water, fleet enemas, which are much more difficult to do than this. This is simple. The patient would lie down on their left side, and you do a quick rectal examination to make sure there are no obvious obstructions or anything like that. There is an enema tubing that comes out of that enema bag, you lubricate it, you insert it about a couple of inches, and you hang the enema bag up and open it, and it flows in. It takes between 5 and 15 minutes depending on how high you hang it and how much gravity is working that day.

Most patients don’t even feel what’s happening. The majority of patients do not have any kind of leakage. It’s a very small volume, it’s about 5 oz. When people think of enemas, they’re like “Oh my god, is this the 32-oz enema I’m going to get that I got when I was constipated as a kid?” That’s not the case. This is the 5-oz enema, people are able to hold it in, and if you look at the age range of people who were in these studies, the majority of them were older people. There were some people in their 80s and 90s who’ve been in these studies, and no issues. People hold this in, you lie down for some time, and then you walk out, and that’s it.

Shared insight on the phase 3 data behind RBX2660, a novel FMT therapy for patients with recurrent Clostridioides difficile infection.

Results of the PUNCH CD3 Trial: RBX2660 in Recurrent CDI

: In terms of looking at the barriers to FMT [fecal microbiota transplantation], safety is a big concern, and we should comment on that in terms of what is near and dear to my heart, ESBL [extended spectrum beta-lactamase] and colonization dynamic. Then also the logistical barriers of how we do that and in the reality of this day and age of COVID-19, and how that goes. I’m opening it up to the group.

I’ll start because COVID-19 disrupted our program to begin with. We for the longest period have had what I call homegrown FMT or an in-house FMT program with the stool bank that we maintain with donor screening. As soon as COVID-19 hit, data were coming out that this is a viral pathogen that can be present in stool because the gut has…receptors, and the virus goes there and comes to the stool. There were data saying that you could do sewage analysis of a city and predict which city is going to get the next wave of COVID-19, or when they’re going to get it. It was a pause and we’re like, oh my God, we don’t want to be transmitting COVID-19 when we’re trying to treat 

. It’s probably a more deadly pathogen. We paused when the pandemic started and scratched our heads, put a lot of smart ID [infectious disease] people into our group, I would say that, more ID than GI [gastroenterologists] and said, what can we do to mitigate this risk of COVID-19 transmission?

We came up with a consensus of let’s screen our donors with a nasopharyngeal swab for SARS-CoV-2, this was prevaccination, and do a blood test to look for antibody responses to look for past infection, and current infection. Then once you do that on day 0, start collecting stool on multiple days, but don’t use that stool until you have an end of stool collection test at about 2 weeks. Most stool samples stay in quarantine, like people stay in quarantine, for at least 2 weeks until we have follow-up testing that is available. Again, similar testing with the nasopharyngeal swab and antibody-based test. Then moving forward, starting this year, we’ve had the vaccine available. Our donors have now gotten the vaccine. Despite the vaccine being available, we have not changed our testing and our quarantine protocol. You can imagine how an external force like this can disrupt a well-established program that we had for about 9 years. That is a big barrier for many places who either are dependent internally to have stool material or dependent externally to get it from a stool bank.

That’s the question I was going to lead to, we don’t all have the benefit of a 10-year established FMT program. For those of us who rely on external banks, what does this look like for them? Is this a real threat?

It’s interesting. The stool banks that are there have done a good job of starting to test stool for certain kinds of pathogens, antibiotic-resistant organisms, SARS-CoV-2. But at this point, as there are several companies that are going to be seeking FDA approval for their FMT products, the stool banks will start winding down because they’re not FDA-approved products. I would anticipate by the end of the year that the supplies that I would typically get will be diminished, and my ability to offer FMT as an option for patients will be confined to these clinical trials, if they’re available.

: Does everyone agree with that? That’s a big statement to say we’re looking at, you said reduced availability of outside bank FMT supplies by the end of 2021.

If you look at numbers from large stool banks in the United States, they have supplied tens of thousands of FMT products to treat tens of thousands of patients over the last 5 or 6 years of their existence. You can imagine what’s going to happen to that patient population. As Kelly mentioned earlier, epidemiological data show hundreds of thousands of people with recurrent 

 infection, tens of thousands every year with multiply recurrent 

infection. The options for those patients are going to get somewhat limited, perhaps keep them on long-term suppressive vancomycin, which we know is bad for their microbiome. I know Kelly is almost going to have a fit….

I saw that. I was getting the defibrillator out.

But that’s an option just to keep them under control. Clinical trials are an option, or think about sites that can either have their own local FMT material that’s available, or not ideal, but go back to where we first started. Every patient finds their own donor, which is very costly and health economically becomes very difficult. In today’s world, you also must screen the donor before and after just for SARS-CoV-2, forget anything else that you must screen. But we may have to go back to that, at least in the short term.

The alternative to FMT right now in today’s world is the microbiome restoration therapy clinical trials that are available. The good news is that there are now trials that have loosened their inclusion and exclusion criteria, so you can get way more people into open-label studies, which we were not able to do last year and the year before. That has helped us quite a bit.

Experts reflect on the barriers to utilizing fecal microbiota transplantation therapy in Clostridioides difficile infection. 

Addressing the Barriers to Fecal Microbiota Transplantation in CDI

Unfortunately, Lucy has a recurrence. Her recurrence is 15 days after completion of therapy. She has a recurrence of 6 loose bowel movements a day. She’s not critically ill, but she is presenting in the ED [emergency department], a little tachycardic, a little dehydrated. What’s our approach?

I would first talk to my ED guys and say, we have 3 different guidelines, pull any one of them. You won’t go wrong this time around because the guidelines are updated. In my practice, I would think about starting on something different than the first time if Lucy got fidaxomicin.

Let’s assume Lucy who got vancomycin up front.

If Lucy got vancomycin up front, I would think about using fidaxomicin, either standard course or extended course, whatever we are able to get. The number of pills is the same though. We must keep that in mind, the standard course is 20 pills, extended course is 20 pills. It’s just about how you instruct your patients to take it, so they don’t forget.

That’s the key, it’s the instructions because we don’t know how sometimes patients take their medicines, whether someone else is giving it to them, or they’re taking it on their own, so it all depends on what the compliance will be.

I agree. If they got oral vancomycin up front, I would probably do fidaxomicin in the extended-pulsed regimen.

Where in this world do we think about fecal transplant?

Not quite yet for clinical fecal microbiota transplantation [FMT] because most of the guidelines, what the studies have done, and what the FDA says, it’s for multiply recurrent 

 infection. But for 2 episodes, we do have microbial restoration therapies that patients may be eligible to be in clinical trials for. For 2 episodes, they start thinking about clinical trials, placebo controlled or open-label, but fecal transplant, not quite yet.

You must wait for that second recurrence, that’s a third episode that they’ve received before we can start considering that. It’s an option. It’s not FDA approved, but it is something for us to consider because it’s still considered investigational.

Jimmy, the trouble that I get from patients is why do you want to wait for that third episode, which I don’t have a good answer for myself despite doing this for so long. Why can’t you do it when I have that 40% chance of it coming back? Why do you have to go against that until you get a 60% chance of it coming back? That’s something that we need to keep discussing as a scientific community. The newer trials that are happening for microbial restoration that are including people early, that will help solve that problem too.

That’s what I was going to say. It’s just because we don’t have the data. What’s interesting, the current recommendations, waiting until that third episode, most of those patients were treated with oral vancomycin or even metronidazole before the FMT. Now that we have therapies that are more effective in preventing recurrence up front, I tend to think we may end up moving FMT up front. If you fail or have a recurrence on fidaxomicin or extended-pulsed fidaxomicin, I tend to think, again, we need the data to support this, but we may end up moving FMT earlier.

I agree. I think one of the things that you had mentioned earlier was how the microbiome is very similar to a fingerprint. Every time one considers doing an FMT, you’re basically giving a unique product to an individual. From an FDA perspective, they’re concerned about giving something that’s uniquely different to individuals over time because there is some unknown with what we’re doing. That’s why they consider it investigational, and it’s for the safety of the patient because there are some things that we never knew were associated with the microbiome. Earlier, Dr Khanna had mentioned that there are some dysbiotic changes that can affect extraintestinal parts of the human body. There are relationships with dysbiosis and obesity, and cardiometabolic effects, muscular disorders, neurologic disorders, autism, Parkinson disease, multiple sclerosis. There’s so much unknown about FMTs that we do have to use caution. Instead of using it up front, we see a patient who has multiple recurrences and we say, “Well, at this point, the risks of your recurrences are so high that we can now accept the benefits over the risk of FMT.” As we do more and more studies that move from case controls and retrospective reviews, and we start doing randomized placebo-controlled trials, we’ll start to see that FMT can be used in the correct populations at the correct times in order to get the kinds of outcomes we really desire.

We also need long-term safety data, and there are already efforts around that. A lot of the clinical trials are now extending their safety from 1 year to 2 years. Also the American Gastroenterological Association, or the AGA, has set up an NIH [National Institute of Health]-funded 10-year registry where they plan to enroll about 4000 patients and follow them for 10 years, so that we don’t have a hepatitis C-like story from blood transfusion back in the day come up. There are already safety signals that have come up. There is infectious transmission of ESBL [extended-spectrum beta-lactamases], 

], that we’ve all seen, 2 unfortunate cases related to FMT. We have to always pause. We must make sure that we are doing everything that we can to make this particular experimental therapy very safe for our patients.

The panel considers optimal therapy for recurrent CDI, particularly the role of fecal microbiota transplantation. 

Carl V. Crawford, MD

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