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CME / ABIM MOC

Microbiome Therapeutics and Recurrent Clostridioides difficile: Where Do We Go From Here?

  • Authors: Paul Feuerstadt, MD, FACG
  • CME / ABIM MOC Released: 11/16/2022
  • Valid for credit through: 11/16/2023
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.50 ABIM MOC points

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    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for gastroenterologists, infectious disease specialists, primary care providers, and pharmacists.

The goal of this activity is for learners to be better able to describe the mechanism of action of microbiome-targeted therapies for recurrent CDI and discuss the latest data and recommendations for these treatments and how they may be applied to treat recurrent CDI.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Key data for microbiome-directed treatments for recurrent CDI
    • Role of the gut microbiome in recurrent CDI
  • Have greater competence related to
    • Management of patients with recurrent CDI


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All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Paul Feuerstadt, MD, FACG

    Assistant Clinical Professor of Medicine 
    Yale University School of Medicine 
    Attending Gastroenterologist 
    PACT Gastroenterology Center 
    New Haven, Connecticut

    Disclosures

    Paul Feuerstadt, MD, FACG, has the following relevant financial relationships:  
    Consultant or advisor for: Ferring Pharmaceuticals; Merck and Co.; Seres Therapeutics; Takeda Pharmaceuticals  
    Speaker or member of speakers bureau for: Ferring Pharmaceuticals; Seres Therapeutics; Takeda Pharmaceuticals
    Research funding from: Adare Pharmaceuticals; DaVolterra Pharmaceuticals; Ferring Pharmaceuticals; Finch Therapeutics; Seres Therapeutics

Editors

  • Roderick Smith, MS

    Senior Medical Education Director, Medscape, LLC

    Disclosures

    Roderick Smith, MS, has no relevant financial relationships.

  • Anne M. Sendaydiego, PharmD

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Anne M. Sendaydiego, PharmD, has no relevant financial relationships.

Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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  • Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 0.50 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity.

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CME / ABIM MOC

Microbiome Therapeutics and Recurrent Clostridioides difficile: Where Do We Go From Here?

Authors: Paul Feuerstadt, MD, FACGFaculty and Disclosures

CME / ABIM MOC Released: 11/16/2022

Valid for credit through: 11/16/2023

processing....

 

 

Dr. Feuerstadt (00:06):

Hello, I'm Dr. Paul Feuerstadt, and I am an Assistant Clinical Professor of Medicine at the Yale University School of Medicine and an attending gastroenterologist at the PACT Gastroenterology Center in Hamden, Connecticut. In this program, I will summarize key information that was presented at a live symposium by my colleagues, Dr. Jessica Allegretti, Dr. Krishna Rao, and myself at the 2022 American College of Gastroenterology annual meeting in Charlotte, North Carolina.

(00:34):

If you would like additional resources, please see the accompanying audio and slides from the full symposium. During this session, we will discuss the epidemiology, pathophysiology, and treatment of C. difficile infection in a very focused approach on the microbiota. C. Difficile is a major problem in the United States.

(00:54):

The Centers for Disease Control and Prevention issued a threat level of urgent for C. difficile in 2013 and then again in 2019, speaking to the gravity of the problem and the burden on our patients and the healthcare system.

(01:07):

  1. difficile is the most common healthcare-associated infection, accounting for approximately 15.5% of all healthcare associated infections, and in the United States alone, there are an estimated 365,200 patients testing positive annually. The microbiota plays an important role in our general health and a specifically important role in preventing C. difficile infection.

(01:33):

The human colonic microbiota has an estimated 100 trillion different microorganisms and between 500 and a thousand different species. Within the colonic microbiota, there are several different microorganisms including bacteria, archaea, fungi, protozoa, and viruses. There are several most common phyla that we see, including within the bacterial phyla, such as the Bacteroidetes, the Firmicutes, the Actinobacteria, the Proteobacteria, the Verrucomicrobia, the Fusobacteria.

(02:04):

Under the fungi, they're the Ascomycota and Basidiomycota and viruses, Caudiovirales. When considering the microbiota and anything within medicine, it's important to define certain terminology, and these terms include microbiota. So, what is the microbiota?

(02:21):

The microbiota is a group of microorganisms within a defined space, and that differs from the microbiome. The microbiome is the genetic compliment of all of those microorganisms. Now, dysbiosis is a really important term. Dysbiosis is any differentiation of the microbiota from what is considered to be normal for that individual.

(02:44):

Finally, and probably most importantly, the metabolum. The metabolism is the metabolic output that occurs as a result of that group of microorganisms. So, it's really important to realize that, yes, we care which microorganisms are present, but even more importantly, we care what that group of microorganisms is producing metabolically and how that interacts with the body.

(03:06):

If that interacts with the body positively, it can prevent disease. If that interacts with the body negatively, it can actually promote disease. Overall, the microbiota has many functions including aiding in digestion, forming a mechanical barrier between the intestinal mucosa and the lumen of the bowel and the so-called colonization resistance.

(03:27):

Colonization resistance is a term used for the microbiota's ability to minimize foreign pathogenic agents from proliferating and causing disease. With this basic understanding of the microbiota in mind, let's now focus on C. difficile and its pathophysiology.

(03:44):

It's important to remember that two main things have to happen for somebody to get C. difficile. One, they need to be exposed to the bacteria and, two, they need to have a change in their microbiota, the so-called dysbiosis.

(03:57):

So, let's first focus on that bacteria itself, and I'm going to take us back to our textbook years and remind you that C. difficile is a gram-positive spore-forming anaerobic rod. There are two main phases of C. difficile infection, the spore phase and the vegetative phase.

(04:14):

The vegetative phase is the phase that each of you, if you're a clinician, thought about when you heard that we would be discussing C. difficile today, because the vegetative phase is the phase of infection that releases two main toxins, toxin A and toxin B. Those toxins act on the surface of the bowel, the epithelium of the bowel, resulting in fluid release and resulting in the clinical syndrome we most commonly associate with C. difficile infection.

(04:39):

The vegetative phase is susceptible to gastric acid and susceptible to alcohol-based hand sanitizers. So, when it comes in contact with these things, it gets wiped out. Alternatively, the spore phase is much more resistant. The spore phase is resistant to gastric acid and resistant to alcohol-based hands sanitizers. In fact, the spore phase can last on dry surfaces on the order of six to eight months and remain viable.

(05:10):

The spore phase largely explains the spread of C. Difficile, and the spore phase also explains recurrence of C. difficile because it's the spore phase that remains within our systems after a standard of care antimicrobial. If our microbiota is unable to eradicate that spore phase, we potentially could get a recurrence.

(05:29):

So, how do we actually get C. difficile? Classically, what happens is, we swallow the spore phase. It's resistant to our gastric acid, gets through our gastric acid into our small bowel where there's a rapid conversion or germination to the vegetative phase. The vegetative phase multiplies and divides and multiplies some more as it builds an army of sorts heading towards the colon.

(05:50):

In my introduction, I said I'm a gastroenterologist and, as a gastroenterologist, I think the colon is a brilliant organ because the colon has its own defense system independent of that bloodborne defense system that protects it. What is that defense system? The microbiota. What classically weakens the microbiota in patients with C. Difficile? Amoxicillin, ampicillin, clarithromycin, fluoroquinolones, cephalosporins, and piperacillin/tazobactam.

(06:17):

You weaken the colonization resistance. You deplete the diversity of the microbiota and make an environment that's more welcoming for the C. difficile and the vegetative phase to proliferate, release its toxins, and wreak havoc.

(06:30):

So now we know a little bit about the bug. Let's now talk about the dysbiosis, and probably the best test and the best study that looked into dysbiosis was a study that was conducted and published by Chang, et al in 2008. Within that analysis, they looked at 10 total patients. Three were controls. They didn't have C. Difficile. Four had initial infection and three had recurrent C. difficile.

(06:55):

When they compared no infection with initial infection, there were no statistically significant differences with regards to the diversity of the microbiota or the constituency. However, when they compared initial infection with recurrent infection, there was a statistically significant depletion of the diversity with a decrease of the Bacteroidetes and the Firmicutes.

(07:18):

So, a couple of important points with regards to this study. Firstly, we know that, in individuals who get C. difficile who are treated initially even with standard of care antimicrobials, 25 to 35% of them will recur. Of those that recur, 40 to 50% will go on to recur after that, and greater than 60% thereafter as individuals get caught in that cycle of recurrence after recurrence after recurrence. Well, this study somewhat explains that.

(07:43):

We know that when they compared no infection with initial infection, there were no statistically significant differences in the diversity. The diversity was depleted, but it wasn't devastated. However, once we got to recurrence, the diversity was devastated, there was a statistically significant decrease, and there was a depletion of the Bacteroidetes and the Firmicutes.

(08:02):

So, we know now that the Bacteroidetes and the Firmicutes play a key role in minimizing future recurrence if they're able to regrow naturally without further intervention. So, now that we know about C. difficile, the bacteria and the changes in the microbiota, what is happening with the metabolic interaction of the microbiota and these patients leaving them prone? This is essentially the metabolum that we discussed before.

(08:26):

With C. Difficile, we believe that the metabolic changes largely emanate from the bile salt milieu. So, where does the bile salt milieu start? The bile salt milieu starts within the liver. It starts with cholesterol, and in the liver there are synthesis to two primary bile salts, cholate and chenodeoxycholate. Those get released into the bowel.

(08:47):

Within the bowel, they interact with an enzyme, 7-hydroxylase. The 7-hydroxylase is released by a bacteria [inaudible 00:08:54]. That 7-hydroxylase converts cholate to deoxycholate, chenodeoxycholate to lithocholate. Those secondary bile acids, deoxycholate and lithocholate, they inhibit the vegetative phase. We want those. Those are good.

(09:11):

The primary bile acids, those enhance germination. So, those enhance the onset of infection or the onset of recurrence. So, primary bile salts are bad, secondary bile salts are good. That's a really important concept as we move forward.

(09:29):

So, as we start to contextualize this basic science information, it is important to realize that antimicrobials such as vancomycin and fidaxomicin control the vegetative phase of infection, but the spore phase remains and is associated with the spread of infection and recurrence, as I just alluded to.

(09:46):

This is a really important point because antimicrobials largely control that vegetative phase, which is why when patients are on antimicrobials, as a clinician would attest to, they usually will have complete control of their symptoms. But after that antimicrobial's removed, it is up to the microbiota to eradicate that spore phase. A deficient microbiota or a microbiota that has a hard time replenishing itself leaves patients prone to recurrence.

(10:11):

So, before we focus on the microbiota, an intervention to heal a damaged microbiota, it is important that we discuss the recommendations for antimicrobial and non-microbiota-based treatments.

(10:23):

So what are the American College of Gastroenterology guidelines published in 2021 recommend for the treatment of C. difficile infection, and what they recommend is for a initial infection, we triage patients based on severity. If patients have a white cell count less than 15,000 and a creatinine less than 1.5 milligrams per deciliter, they have non-severe infection.

(10:45):

With non-severe infection, the ACG guidelines recommend that we use either vancomycin 125 milligrams four times daily for 10 days, fidaxomicin 200 milligrams twice daily for 10 days or metronidazole 500 milligrams three times daily for 10 days, metronidazole all largely being reserved for a patient cohort that is at very low risk for occurrence.

(11:08):

Once we get to that severe form of C. difficile where the white cell count's greater than 15,000 or the creatinine is greater than 1.5 milligrams per deciliter, we pull off that metronidazole, only 10 day treatments of vancomycin or fidaxomicin.

(11:22):

Now for the recurrent cohort, they made some recommendations with regards to what the patients failed the first time. If patients failed vancomycin, metronidazole, or fidaxomicin initially, it was recommended that we consider a taper/pulse course of vancomycin. If patients failed vancomycin or metronidazole initially, it was recommended that we consider a 10-day treatment course with fidaxomicin.

(11:45):

Now, before we move on to the microbiota-based therapies, let's briefly discuss a product called bezlotoxumab. So, what is bezlotoxumab? Bezlotoxumab is a fully humanized monoclonal antibody designed to bind toxin B in a very specific manner. It is given as a onetime infusion in addition to a standard of care antimicrobial.

(12:07):

So, what's the data for bezlotoxumab? Bezlotoxumab ran through two prospective multi-centered randomized controlled trials where patients with C. difficile infection all received the standard of care in a microbial and then were randomized to either receive an infusion of placebo, an infusion of bezlotoxumab, an infusion of bezlotoxumab and a product called actoxumab or an infusion of actoxumab alone.

(12:31):

The short is that actoxumab was not productive. It didn't help patients, so it didn't come to market. So, when we look at the results of these MODIFY I and MODIFY II trials, we really largely need to look at the 90-day recurrence rates in the placebo arm versus bezlotoxumab. Recurrence rates in modify one and the placebo arm were 28% versus 17% in the bezlotoxumab arm.

(12:53):

In the MODIFY II, 26% placebo, 16% bezlotoxumab. The number needed to treat to reduce one recurrence with bezlotoxumab was 10. However, in an Apriori set analysis looking at risk factors for recurrence in the age over 65 cohort, the number needed to treat was six. So, really a profound difference in something that we should think about in our patients with recurrent C. difficile infection to break that cycle. So the ACG guidelines recommend that we use this in patients at high risk for recurrence.

(13:25):

So what defines that? I think there's another study that looked at that, a subgroup analysis of the Apriori set risk factors for occurrence from the MODIFY I, MODIFY II trials. Those include age over 65, any history of C. difficile over the previous six months, any form of immune compromise, the hypervirulent strain, as well as severe infection. If patients had three or more of those risk factors, the recurrence rates in the placebo group was 46.1% versus 21.2% in the bezlotoxumab arm.

(13:55):

If they had two risk factors, 41.1% recurrence rate in the placebo arm, 26.9% in the bezlotoxumab arm. Even one single risk factor, 31.3% in the placebo arm, 17.1% in the bezlotoxumab arm. So, if patients have at least one risk factor, and I would argue that one risk factor be age over 65, this should be strongly considered. So, those are the recommendations for antimicrobials and for bezlotoxumab.

(14:23):

But even with the best treatments that we have available with regards to antimicrobials, about 25 to 35% of patients with initial infection will recur, 40 to 50% of those with a single recurrence will recur, and up to 60% thereafter will get caught in this vicious cycle of recurrence after recurrence after recurrence. This is where microbiota-based therapeutics can come into play.

(14:49):

We identify deficiencies in the microbiota that were seen in the Chang, et al study from 2008, specifically the bacteroidetes and Firmicutes. If we replace those deficiencies and not simply allow the microbiota to naturally repair itself as we do with only antimicrobial therapy, we can likely decrease rates of future recurrence. That is the theory behind fecal microbiota transplant, and that is what we see in clinical practice.

(15:14):

So, let's consider some of the foundational clinical trials that got us to this point. The first trial that I'd like to talk about was a study by [inaudible 00:15:23] and colleagues. The [inaudible 00:15:25] trial was the first prospective randomized control trial that considered patients with multiple recurrent C. difficile and randomized them into a group that received a nasoduodenal transplant, a group that received vancomycin and bowel lavage, or a group that received vancomycin alone.

(15:43):

The study was stopped at interim analysis due to futility. Yes, I said futility, due to futility of the vancomycin intervention arms. The recurrence rates or the overall sustained clinical response in the nasoduodenal transplant was 81.3% versus 23.1% in the vancomycin and bowel lavage and 30.8% in the vancomycin alone arm. The study included 16 patients in the transplant arm at 13 in each of the other arms.

(16:12):

But the study was profound and was published in the New England Journal of Medicine, partly because it showed efficacy of fecal transplant in a group with multiple recurrent C. difficile infection. But even more importantly, it looked at the microbiota, and it showed that the microbiota in the recipients post-transplant was similar to the microbiota in, the donor pre-transplant form-fit-function.

(16:34):

After that, there was a slurry of clinical trials looking at fecal transplant in a whole ton of populations, peaking largely in 2017 with a meta-analysis by Quraishi, et al. The Quraishi, et al meta-analysis included 37 studies, seven prospective, 30 retrospective, and showed an efficacy of fecal microbiota transplant in patients with a recurrent C. difficile of 92%. We essentially thought we were putting ourselves out of business.

(17:02):

They showed no statistically significant difference between known or unknown donors, no difference between fresh or frozen stools, but very importantly, as we proceeded ahead, we started to get more sophisticated with our analyses, and when we got more sophisticated with our analyses, we realized, you know what? A lot of those trials were retrospective.

(17:22):

So, a very nice meta-analysis that was published in 2019 started to fix that problem. This meta-analysis by Darrell Pardi, Raseen Tariq, and Sahil Khanna said, let's just look at patients that received fecal microbiota transplantation in clinical trials that had a control group, a basic premise from clinical trials, but was largely missing in the past. They looked at 13 studies, 610 total patients, and showed an efficacy of 76.1%, not quite that 92% that we were seeing previously, but still really good.

(17:54):

But when they drilled deeper, the results were interesting. The open-label studies, they had an efficacy of 82.7%. The randomized controlled trials, the gold standard, they had an efficacy of 67.7%. That 67.7% is probably our most accurate depiction of what we might see in clinical practice with the application of fecal microbiota transplantation after a standard of care and to microbial patients with recurrent or multiple recurrent C. Difficile.

(18:23):

Using these foundational trials, the American College of Gastroenterology guidelines, published in May of 2021, made the following recommendations for fecal microbiota transplantation. Firstly, they recommended that if patients had two or more recurrences or three or more episodes of C. difficile, we should consider standard of care antimicrobial followed by fecal microbiota transplantation.

(18:46):

They recommended that if patients recur after a transplant within eight weeks, we give a second transplant. Finally, they made a recommendation with regards to fulminant disease following Dr. Monika Fischer's protocol with patients that are ineligible to go to the OR that have fulminant disease. We give the fecal transplant again and again and again, every other day until the patient symptomatically improves and/or the pseudomembranes disappear.

(19:11):

So, what about the safety of fecal microbiota transplantation? Fecal transplant seems very safe, but there are still some signals we need to consider, including transient changes in bowel habits and abdominal cramps, possible onset of new conditions including Sjogren's disease, peripheral neuropathy, idiopathic thrombocytopenic purpura, rheumatoid arthritis, and transferal of infectious pathogens.

(19:33):

This can be thought of similarly to when we first started considering blood transfusions. We did not realize that we were transcribing patients hepatitis C and HIV until, of course, it was identified. So, there is a bit of a kind of black box concern here, but largely, fecal microbiota transplantation is safe.

(19:50):

There have been four overall FDA reports. The first one was issued in June of 2019. In that report, patients receiving fecal transplants, not for C. difficile infection, were transcribed multi-drug resistant organisms. One was receiving fecal transplants who prevent hepatic encephalopathy. The other was receiving fecal microbiota transplantation to prevent graft versus host disease after a bone marrow transplant.

(20:14):

So, these patients were largely immune-compromised, and they were transcribed extended spectrum beta-lactamase-producing E. coli. So, what has been our fix? We now, of course, screen for this, and therefore it's incredibly unlikely that this would be transcribed.

(20:29):

The second FDA report came on March 12th, 2020. I want each of you to think about what you were doing on March 12th, 2020. You probably were not thinking about the side effects or the risks associated with fecal transplant in patients with recurrent C. difficile. You were probably more focused on the fact that the world was essentially shutting down for the COVID-19 pandemic.

(20:49):

But there was a very important advisory by the FDA. From a major stool bank in the northeast, a stool bank that was providing stool and fecal transplant material to many sites across the country, they reported six individuals that got various forms of E. coli. Two got enteropathogenic E. coli, four got Shiga toxin-producing E. coli, and of those four, two subsequently died. We do not believe as a result of the Shiga toxin E. Coli. We believe it was a result of their medical comorbidities.

(21:18):

But it's important that we acknowledge that we're evolving with this, and we're learning what we need to screen for as we go. Now, the other two recommendations from the FDA were not specific risks, but they were recommendations for screening. One, of course, was for SARS-CoV-2 or COVID-19 infection, and the other came in August of 2022, warning that we need to also be cognizant of monkeypox infections.

(21:41):

Now, given these concerns and the variability seen with the rudimentary methods of fecal microbiota transplantation, as clinicians, we are striving toward products with predictable safety and efficacy profiles. These products are called microbiota-based live biotherapeutic products and the FDA overseen forms of microbiota replacement therapy.

(22:02):

There are four products currently in the pipeline, with two having completed Phase 3 trials, SER-109 and RBX2660 and, two, having completed Phase 2 trials, CP101 and VE303. As we approach the clinical trials, it is important to realize that there were some similarities between these trials, including that they were all prospective, multi-center, randomized, placebo-controlled, with all patients having recurrent C. difficile infection, all patients receiving a standard of care antimicrobial, having an eight-week efficacy assessment, and all having a 24-week safety assessment.

(22:37):

However, there are significant differences among the trials and the products, as well, including differences in the actual treatment. SER-109, for example, is a narrow spectrum. This product essentially states that there is a deficiency in the Formicidae spores, so let's replace those Formicidae spores solely and not include anything else, targeted therapy to the problem.

(23:01):

This differs from something like RBX-2660 and CP101, which are broader treatments more akin to more sophisticated treatments, fecal microbial transplant based, but with much greater screening procedures for the donors and their stool samples.

(23:16):

Let's start with the data for SER-109. So as I just mentioned, SER-109 is a narrow consortium. It is donor stool-derived. It is brought through an ethanol purification process, and it's made in an encapsulated form. It's given as four capsules daily for three days following a standard of care antimicrobial. Within its pivotal Phase 3 trial, the ECOSPOR III trial, 182 individuals with at least two recurrences of C. difficile infection all received 10 to 21 days of either fidaxomicin or vancomycin.

(23:54):

They then had a washout period, and then after that washout period, they received magnesium citrate and were randomized to SER-109 or placebo, followed for eight weeks for recurrence, 24 weeks for safety. Overall efficacy in the SER-109 arm, 88% at eight weeks versus 60% in the placebo arm, a statistically significant difference.

(24:15):

But the bigger question is, did form-fit-function, and the answer is yes. When they looked at the microbiota analysis and looked at baseline comparing placebo and SER-109, there statistically significant increases at weeks one, two, and eight of the Firmicutes groups, specifically increases in ruminococci and Lachnospiraceae and decreases in the pro-inflammatory Enterobacteriaceae. But once again, I mentioned earlier, we care about the metabolum and we care about those bile salts, primary bile salts bad, secondary biosalts are good.

(24:46):

What they showed compared with baseline, comparing placebo with SER-109s, SER-109 at weeks one, two and eight had statistically significantly higher rates of secondary bile acids. So once again, the lock and key fit, form-fit-function for why recurrence rates were, in fact, decreased.

(25:06):

Recently in October of 2022, there was a publication looking at the 24-week data from the ECOSPOR III trial, and the results were consistent with the already reported Phase 3 data showing recurrence rates in the SER-109 group of 21.3% versus 47.3% in the placebo arm.

(25:25):

Just presented at the American College of Gastroenterology meeting was open-label study data, broader inclusion criteria, more realistic to the real world. Within the open-label study, 263 individuals were included. 29 rolled over from ECOSPOR III. The remainder directly entered the open-label study, and at eight weeks, the efficacy of SER-109 was 91.3%.

(25:50):

Importantly, they looked at a group with first recurrence, and recurrence rates in that group at eight weeks was 6.5%, so further reinforcing the efficacy, as well as the safety, of SER-109.

(26:03):

Let's now talk about RBX2660. So, what is RBX2660? RBX2660 is a microbiota-based live biotherapeutic product that is a broad consortium. It includes both spore and non spore-forming bacteria. It is administered as a single rectal installation following a standard of care antimicrobial. It includes 10 to the seventh microorganisms per cc. It's 150 ccs, so it includes 15 times 10 to the eighth microorganisms in total.

(26:34):

With its study, the Phase 3 trial, the PUNCH CD3 trial, 262 individuals with at least one recurrence of C. difficile infection all received at least 10 days of standard of care antimicrobial. They then had a washout period and then were randomized to either receive RBX2660 or placebo, followed for eight weeks for recurrence, 24 weeks for safety. Overall efficacy within this analysis with 70.4% for RBX2660 versus 58.1% in the placebo arm.

(27:06):

Important to note that a Bayesian analysis was performed to assess this data. So, what is a Bayesian analysis? A Bayesian analysis is an analysis that leverages another study with the primary study to increase the size of the study and the hardiness of the statistical analysis. In this case, the Phase 2 study data was used to be leveraged. Why? They had the same diagnostics, the same efficacy endpoint, the same safety endpoint, and the same product.

(27:34):

If the signals of efficacy in the placebo arm and the RBX2660 arm are consistent, you can leverage the data, and that's where the 70.4% for RBX2660 versus 58.1% in the placebo arm largely came from. The posterior probability superiority was 0.986 a statistically significant difference.

(27:54):

But once again, we care about the microbiota analysis and, within this analysis, comparing baseline with weeks one, four, eight, three months and six months, there were increases in Clostridia and Bacteroidia and decreases in bacilli and Gammaproteobacteria. Again, we care about the metabolic effect and, again, form-fit-function.

(28:16):

When we look at the baseline where there were more primary bile salts, disproportionately more primary bile salts at weeks one, four and eight, there were much more secondary bile acids, so we see form-fit-function. Now, RBX2660 has been taken through three Phase 2 trials and two Phase 3 trials, over a thousand patients included. Lindy [inaudible 00:28:37] presented interesting data about a year ago at IDWeek in 2021.

(28:41):

At that study, they showed across those five trials, consistent efficacy and consistent safety. At the American College of Gastroenterology meeting in 2022, open-label study data was presented for RBX2660, as well. An interim analysis of 300 patients showed an eight-week efficacy of 74.6%, and of that 74.6%, 84% had a sustained effect at 24 weeks, so consistent safety, as well as efficacy, for RBX2660.

(29:12):

What about CP101? What differentiates CP101 from the other products? CP101 is a broad consortium, and being a broad consortium, it includes a wide array of microorganisms. CP101 finished its Phase 2 trial, the PRISM3 trial.

(29:28):

With this, what they found through their prospective randomized control trials that all patients receive standard of care antimicrobial, a washout period, and then they were given CP101 as 10 capsules on a single day following a standard of care antimicrobial, 60 times 10 to the 10th microorganisms versus placebo, followed for eight weeks for occurrence, 24 weeks for safety. Overall efficacy of CP101 was 74.5% versus 61.5% in the placebo arm, a statistically significant difference.

(30:00):

But very importantly, they looked at the alpha diversity and, again, form-fit-function, comparing the placebo arm with the CP101 arm as you would expect with a broad consortium, a wide array of microorganisms, the diversity increased more in the CP101 group. At the American College of Gastroenterology meeting in 2022, CP101 also presented open-label study data of 132 patients. Efficacy in that group was overall 80.3% versus 78.8% in follow up. So, 80.3% responded at eight weeks. 78.8% had a sustained effect.

(30:38):

Finally, VE303. VE303 says, look, maybe we don't need to give the whole kitchen sink. Maybe we don't need to give just a narrow consortium. Maybe we should just give eight bacterial strains, and that's what they did, and they reported their results of a dose-ranging study, their Phase 2 data at the Digestive Disease Week in San Diego, California in May of 2022.

(31:01):

Within that study, they showed that the high dose arm, 10 capsules daily for 14 days, had a statistically significantly higher response rate at eight weeks than the placebo arm, 86.2% for VE303, 54.5% in the placebo arm. So, now it's important that we talk about this data, but it's also important to acknowledge that there are some differences amongst these trials that make them challenging to compare.

(31:29):

These differences include the length of treatment, the number of episodes, the diagnostic tools, the washout period, whether or not there's a bowel purge and dosing. So, it remains important to realize that with these differences among the trials, we need to contextualize the study itself to best understand the results seen within the respective trials.

(31:47):

This learning session has covered a lot of information. C. difficile is a major problem for our patients and our healthcare system, with recurrence being one key piece of the problem. By understanding the pathophysiology of the infection, we can optimize therapy, following the ACG guidelines for antimicrobial usage and add-on therapy such as bezlotoxumab and fecal microbiota transplantation to prevent recurrence.

(32:10):

As we have seen, the microbiota plays such an important role in preventing recurrence when healthy. As we move forward, there are several products with exciting data that have completed Phase 3 and Phase 2 studies. We hope that in the future, there will be an FDA-approved treatment that offers safe and effective microbiota therapies, offering wider availability to our patient population.

(32:31):

The future is so bright in this space. Thank you so much for participating in this activity. Please continue on to the answer the questions, the follow, and complete the evaluation.