See new edits in green toward end of program Sahil Khanna (00:07): Good afternoon, everybody here in San Diego. Good morning, good evening to all of our virtual attendees, depending on your time zones. Welcome to this Medscape Live Event on Case Discussions in recurrent C difficile infection, a very, very common problem in healthcare, and talking about New Horizons in Microbiome-based therapies. This symposium is sponsored by an independent educational grant from Serious Therapeutics and Immune Therapeutics. My name is Sahil Khanna. I'm a professor of medicine at the Mayo Clinic in Rochester, Minnesota, and I practice gastroenterology and C. difficile in my free time. (00:47): Along with me today is Alpesh Amin, who's a Professor of Medicine and holds several leadership positions at University of California, Irvine. He's here with me in person. Virtually today, we are joined by Dr. Yoav Golan, who is an Associate Professor of Medicine at Tufts University and an infectious disease specialist who just returned from Antarctica as his claim to fame. We also have a virtual chair for our CME program, Dr. Scott Curry, who is an Assistant Professor of Medicine and Infectious Diseases at Medical University of South Carolina, who'll be available to answer questions for our virtual attendees. Here's our agenda. We're going to talk about the role of the microbiome in C. difficile infection, talk a little bit about testing, that's going to be with Dr. Golan. Dr. Amin's going to talk about C. difficile and FMT, and I'll have the third presentation talking about the role of live biotherapeutics for recurrent C. difficile infection, and we'll have some time for Q&A at the end. Without further ado, Dr. Golan all yours. Yoav Golan (01:53): Well, thank you, Sahil, and welcome, everybody. As you heard, I am just back from Antarctica where the microbiome is really important, but not in the gut of humans, I guess in the gut of seals and other creatures. Anyways, I'm going to discuss the microbiome and C. difficile infection. I'll try to convince you that C difficile issue, we'll talk a little bit about the burden of disease and I'll have a couple of slides with questions to you as well. As you heard, at the very end of the session, we'll have an opportunity for a Q&A as well. Starting with the polling question and you have a barcode that you can scan and answer this question, how would you rate your familiarity with microbiome-directed therapeutics for the treatment of recurrent C. difficile infection? Is it one, not at all familiar? Is it two, slightly familiar? Somewhat familiar, or four, very familiar? I'll give you a few seconds to answer the polling question. (03:01): Interesting. We almost have a split between the four options. It seems like maybe not that many are very familiar and a few people are not at all familiar. Well, I hope after my discussion and at the end of the session, you'll be much more familiar with those type of treatments. I'm sure you all know that C. diff is a disease that stems from a depleted biome and some of the ways to treat the disease may be the restoration of the biome as well. A few terminology actions. One is microbiota. We tend to use that all the time. We typically use microbiota as defined as microorganisms, and this could be bacteria, fungi, protozoa, archaea, but also viruses that are not typically defined as microorganisms that inhabit the defined environment. When you talk about the microbiome generally or the microbiota, it's genes, gene products and activities in niches within a habitat. (04:07): Now, the metabolome is a large array of small molecules, so we're moving from microbes to molecules, molecule metabolites that are produced by microbiota into the inhabited environment during the metabolism of food and xenobiotics. Obviously, we are talking about the gastrointestinal environment. In the case of the gut metabolome, metabolites from both microbiota and host should be included. Then a little slightly harder to define dysbiosis, there is really no consensus on the definition despite the fact that it's very often being used in microbiome studies, it is often described as a state in which alterations to the microbiota and its functional components may be correlated with undetermined host immunity and increasing susceptibility to disease, for example, C difficile vulnerability. Dysbiosis could be, in general, just the depletion of the microbiome. (05:13): With that in mind, when you look at the universe of microbiome or gut microbiome in humans, first, it's important to note that the human body contains 10 to a hundred trillion organisms, which, in general, is about 10 microbes for each human cell. If you ever thought about yourself as being anything but a big bacterial colony, then you should change the way you think about yourself, where 90% composed of bacteria. Obviously, the highest density of organisms is in the gastrointestinal tract. The biome or the microbiome has an important function. As you know, some vitamins are broken by those microbiome members and only then can be absorbed, so metabolism, regulation of gut barrier function, as well as a lot of functions in immunity. (06:10): In addition to that, microbes that are in the gastrointestinal tract create what we call colonization resistance that interferes and limits the ability of pathogens of colonizing the gastrointestinal tract. For example, you know that for C difficile it will be almost impossible to colonize someone whose microbiome is completely intact. If you look at a composition of gut bacteria here in the center, you'll see that about 5% of the gut bacteria are undefined or many different types of bacteria, about 30% are bacteroidetes and about 65%, which is about two thirds, and the vast majority are firmicutes. (06:52): There are more than 9 million unique genes in the human gut and many of the bacteria in the gastrointestinal tract are not culturable. We can't really culture them and therefore, we can't really, identify them very well. If you look at the diversity of the microbiome in its relationship to antibiotics, I think you understand the pathophysiology in general of C difficile, and remember that C difficile is a disease of the microbiome. Before you receive antibiotic therapy and you know that the antibiotic therapy does not have to be directed at the gastrointestinal tract, almost any antibiotic that you receive systemically, whether orally, intravenously or intramuscularly, will reach in some concentration, sometimes higher, sometimes lower the gastrointestinal tract and kill or interfere with the microbiome. (07:43): Before you receive antibiotic therapy, you typically have a great diversity of microbes and your microbiome is usually healthy both in the outer mucus layer and inner mucus layer as you can see here. However, after you receive antibiotic therapy that depletes or kills many of those members of the normal microbiome, you get a decrease in both the numbers of those members as well as the size of their population, as well as a decrease in the diversity, so you don't get, some of the members will disappear. Then, if you allow sometimes after antibiotic therapy, it usually takes some time to recover your biome and sometimes you don't fully recover your biome and any time it will take a long time to recover your biome, and during this time, you are vulnerable to C difficile infection, as well as other issues related to an unhealthy or an incomplete microbiome. (08:44): If you look at the C difficult and the burden of disease, I think one does not need much to get convinced how important and how costly disinfection is. First of all, there are about half a million cases and about 30,000 deaths. Annually in the United States, typically within a month after being diagnosed with C diff, very high estimated costs. The costs are not just for the healthcare system, the costs are also for hospitals. As you know, many hospitals do not get paid now for caring for patients with recurrent C diff it happens within a month of a discharge from that hospital, and so the cost is really a big burden to all members of society, including care facilities. (09:26): It's considered to be an urgent threat by the CDC, which put it at the highest threat level, both because of how common it is, the consequences and the fact that we don't really have many ways to treat it. It's a leading cause of antibiotic and healthcare associated infective diarrhea with symptoms that range from mild diarrhea to severe debilitating disease with life-threatening complications. As you know, many people in order to stay alive require phallectomies and long admissions. (09:56): If you look at the annual incidents and some of the risk factors when it comes to age, you see that we have seen some decrease from 2012 to 2019 where we have pretty good information. There are many potential reasons for this decrease. One is our enhancing infection control measures. Two is our using more antibiotic stewardship, maybe the decrease in the hypervirulent strains during this time period. If you look at the trends by age group, you see that most of this decrease was seen in people who were 80 and older, while the other age groups were less affected and are more or less plateaued with a very slight decrease over this period of time. However, despite of the decrease, if you look at the number of cases, we still see a huge burden of disease. Remember that many of those cases actually happen in hospitals as we'll discuss in a minute. (10:52): If you look at community versus hospital or healthcare-associated disease, with healthcare-associated disease in a lighter shade of green and the darker green for community-associated C diff, you see that there has been a slow but steady increase in community associated C diff. We see more and more cases that arise in the community, which means that for a primary care physician and a general practitioner and people who practice in the community, it becomes more and more important to actually suspect C diff in patients with adequate or clinical manifestations that are consistent with C diff. If you look at the bacterium itself, C diff is a really, really interesting bacterium. It's a gram-positive bacillus. It produces spores. It's an obligatory anaerobe, which means that as it gets exposed to oxygen in its vegetative form, it dies and it's commonly found in soil, water, air, humans, and animal feces as well as hospital surfaces. (11:57): What is interesting about C diff is that people walking in the streets are very unlikely to be colonized with C diff, and typically, you need to be exposed to the reservoir C diff that's usually healthcare institutions in order to get colonized. The transmission is fecal-oral and those C diff strains that are pathogenic produce toxin A and toxin B. Toxin B has been reported globally, and these are the pathogenic toxins, and so this is a toxin-mediated disease. In fact, there isn't much known pathogenicity for the bacteria itself. It's mostly, most of the damage to the colonic mucosa and the disease itself is done by the toxins. If you look at the C diff lifecycle, it has mainly two forms as a spore and as a vegetative form. As I mentioned earlier, the vegetative form dies with oxygen exposure, and therefore, people cannot be infected with vegetative cells because as they get evacuated with stool, they die, and the transmission is through spores. (13:06): Spores, on the other hand, are very transmissible and infectious, but they cannot cause disease. Those spores have to germinate and this germination in the release of the active bacteria that produces toxin is causing disease. As I mentioned earlier, spore shedding can affect the community, can affect surfaces in hospitals and healthcare related surfaces. Many infants, very young infants are colonized with C diff, animals. C. diff is a major issue in horses, for example. Food and water can also be contaminated. What's really interesting, and I mentioned earlier that it's not just about the microbiome, which is the universe of microbes in the gastrointestinal tract, but also about their products. The metabolome, those molecules that are produced by those bacteria, and there is an emerging field that is looking at the impact of the metabolome on C diff. Without getting into too many details, as we have a lot of information to convey to you in this session, in general, those bile acids that are released by the liver that are known as primary bile acids are very protective from C diff but are very, I'm sorry, are very friendly to C diff. (14:21): But in most humans that have an intact biome, those primary bile acids will very quickly be changed into a non-conjugated and secondary bile acids and these are protective from C diff. You need the gut bacteria, the gut flora to be able to cleave and biotransform primary bile acids into secondary bile acids, which is the common type of bile acids found in the gastrointestinal tract of people with intact biome. People with intact biome who have not been exposed to antibiotics typically have a hostile environment to C diff, and C diff struggles to establish colonization and germination. But once you receive antibiotics and lose many of the members of the microbiota, you lose your ability to biotransform primary bile acids, you are loaded with primary bile acids and those make it very easy for C diff to colonize, grow and produce the toxin as well, and this is also depicted in this slide, as I mentioned. (15:22): Will end the presentation with a case. This is a 63-year-old woman with diarrhea and abdominal pain. She presents with diarrhea for three weeks after finishing a course of clindamycin for dental procedure. She also has a medical history for hypertension, diabetes, chronic kidney disease, and a few additional conditions and a history of appendectomy and knee replacement. She describes five to seven bowel movements per day that are liquid. She has diffuse cramping, abdominal pain and subjective fever, and no history of inflammatory bowel disease or other GI diseases. Here we get to the second polling question for you, what test will you order for this patient? Would it be a cell culture cytotoxin neutralization? Would it be a GDH or a toxin EIA test? Would it be a PCR or would it be a stool culture? Please take your time to answer this polling question. (16:17): All right. Even here we have an almost even split. Let's go through the algorithm going in details through testing and adequate testing for C diff will take a long time, but just in a summary approach, if you have a patient who is suspected with C diff, typically most institutions will try to rule it out first. They will start with a highly sensitive test, either a GDH, a glutamate dehydrogenase, which is an antigen on the surface of C difficile or a NAAT like a PCR test. Now, if the test is negative, because it's highly sensitive, you can say that the patient does not have C diff and you ruled it out. But if the test is positive, you still have not differentiated between potential colonization and infection, and to do that, you need to do a second test. (17:11): Typically, a toxin EIA test asking the question, is it enough toxin to be detected by an enzyme immunoassay? If the answer is yes and the test is positive, then the patient is diagnosed with C diff from the lab component. Remember that the patient still requires to have the clinical manifestations at least three loose bowel movements per day in addition to positive test results. Now, if the test is negative, then the patient is not diagnosed with C diff. The patient could be diagnosed, there could be a false negative toxin EIA or the toxin levels are below the threshold of detection. But in general, this is the way people proceed. Now, there are many different variations to that and we can discuss that during the Q&A if you have a specific interest. Some of the advantages of the different tests, so the PCR is very sensitive and rapid and inexpensive, but you also probably know that PCR does not differentiate colonization from infection. (18:12): It just tells you that there are genes of C diff in the gut and may lead to overdiagnosis, overtherapy and in fact, may increase the risk of some people of developing C diff. The advantage of the GDH and enzyme immunoassay for the toxin is that it's able to detect active toxin production. It's rapid and it's very inexpensive. The problem is that the sensitivity of the test is low, which means that about 25%, 30% of those with C diff can actually be missed and may lead to missed cases and untreated cases. That's typically the reason why we start with a very sensitive test and go and proceed to a very specific test if the sensitive test is positive. This completes my part of this presentation. I'll be happy to answer questions at the very end. Then, back to Dr. Khanna. Sahil Khanna (19:06): Thanks, Dr. Golan. I'm going to take it over to Dr. Amin, who's going to talk about the role of fecal-microbe transplantation and other treatments for C difficile infection, what's available today? How do we manage patients like this? Dr. Amin. Alpesh Amin (19:18): Thank you. Thank you. I think I'm probably the closest to San Diego. I'm up at UC, Irvine, so I want to welcome everybody to San Diego, and thank you for participating in today's program. Without further ado, that 63-year-old wonderful patient, female, presented with diarrhea after receiving clindamycin for dental work. You ordered the tests based on what Dr. Golan said and you ended up at ordering a PCR and it was positive for C diff infection. Now, the question is what next? Let's have you guys answer this polling question. What would be your preferred therapy for this patient? Would it be oral fidaxomicin, 200 milligrams, twice a day for 10 days? Oral metronidazole, 500 milligrams, three times a day for 10 days. Oral vancomycin, 125 milligrams, four times a day for 10 days. Antibiotics plus IV bezlotoxumab, which is a monoclonal antibody, 10 milligrams per kilogram once a day. Would you refer it to our friends here, Sahil or Golan, GI and ID specialist for treatment? Which one would you guys do? (20:46): There's a couple of things here that I want to point out off these results. The first is, I like the fact that, I love Dr. Golan and Dr. Sahil, but you're absolutely right, we do not want to refer these patients to GI or ID off the bat. We're internist, I'm an internist, and we should be able to manage these patients, that's the first step. Sahil and Golan and I will talk about that as we continue to head forward. But the choices that were here, looks like about twice the number of you would've chosen oral vancomycin. Another quarter of you would've chosen, which is about 50%, quarter of you chose oral fidaxomicin. I'm happy to see that because those are probably the two best options on the table here compared to the other options that are listed there. We'll talk about this a little bit here. There are some guidelines, national society, professional society guidelines, and so we're lucky to have them. The American College of Gastroenterology recommends either vancomycin or fidaxomicin. They do give us a little bit of a leeway in low-risk patients where metronidazole could be an alternative. (22:11): The IDSA actually recommends for these days fidaxomicin over vancomycin and the European Society for Clinical Microbiology and Infectious Diseases actually follows the IDSA and recommends fidaxomicin over vancomycin. Both of those last two professional organizations say metronidazole to be used only if the above options are unavailable. The key point here is fidaxomicin, if you can get it and do it or vancomycin is the answer to somebody who's got active infection for C difficile. Now, one of the things we know is that we're not ever done with C difficile after treating the primary infection. The rate of recurrence can be as high as 30% to 60%. It's a big problem. It creates issues in healthcare delivery, cost, comorbidities to patients and so forth. There are risk factors for recurrent CDI that's similar to those of the initial infection. (23:26): Here, this nice slide by Dr. Khanna has recommended, outlines the risk factors, as you can see here. The elderly above age 65 have a higher risk for recurrence. Certain types of antibiotics and PPIs have a higher risk, but antibiotics can be modifiable. This gets into antibiotic stewardship, which is really important, and we as general intern, as primary care hospitalist, so forth, we should own this along with our ID colleagues. Immunosuppression of the patient in comorbid conditions such as IBD or chemotherapy use kidney disease malignancy put patients at risk for recurrence. Being in contact with active carriers, care delivery folks is also a risk factor. Prolonged length of stay in the hospital is also, or in skilled nursing facilities or long-term facilities is also a risk. Then having prior or recurrent C diff infections is also a risk. It's important to understand this because risk assessment is really key and should be a driver in how you think about managing these patients. (24:46): Now, when we think about C diff, we should think about it in two broad categories, the treatment and then the prevention side. In terms of treatment, we talked about fidaxomicin or vancomycin as your initial approach to it. If patients have had a primary infection already and you're seeing them as, and you need to treat them for their first recurrence, you might also think about pulse or tapered regimen of vancomycin fidaxomicin. These treatment strategies center around a first recurrence. If you've used vanco, then go to either fidaxomicin. If you've used fidaxomicin for the primary infection, then go to vanco or consider this pulse-tapered regimen of either vanco or fidaxomicin. Then there's a so-called post vancomycin chaser with rifaximin that one can also consider. That's on the treatment side. (25:52): On the prevention side, there's two approaches that can be done. One is C. diff toxin B neutralizing monoclonal antibody. Remember, there's two types of toxins that can be produced with C diff, toxin A and toxin B. Bezlotoxumab actually works against toxin B. There's another monoclonal antibody that actually is against toxin A. Microbiota restoration or FMT or fecal transplant is another approach to prevention of recurrence, and we'll talk a little bit more about that. Let's talk about bezlotoxumab. It's really exciting that this is now available to us. You all may be a little bit more familiar now with the concept of monoclonal antibodies. Post-COVID, we tended to use the monoclonal antibodies quite a bit in covid management. You may have spent some time referring patients, you certainly use monoclonal antibodies in other immunosuppressed areas. (26:56): Well, in this case, patients with one or two key episodes of CDI. This study that was called modify one and modify two, and then the pooled analysis of modify one and two, which was published in New England Journal of Medicine by Wilcox and colleagues looked at comparing bezlotoxumab against placebo. It also had another arm which was bezlotoxumab and actoxumab against placebo. Here, the results will show you that bezlotoxumab versus placebo, both in Modify I, Modify II, and the pooled analysis, I tend to just remember about a 10% reduction in each one of these. When you broke it down by those risk factors, for recurrence, you could see that bezlotoxumab actually performed better than placebo in the elderly population, people with history of C diff infections, low immune systems, severe C diff infections and this ribo type. (28:05): It was really a really nice study. Then, if you actually go and look at the study even further, the combination of bezlotoxumab and actoxumab did not fare any better than bezlotoxumab alone. All right. The recommendation really is to think about bezlotoxumab as a preventive measure here. You can see the percentage of recurrence again in the slide below also that look at the number of risk factors as it grows from zero to greater than three. The spread actually starts getting a little bit bigger and when you get to more than three risk factors, you almost have a 25% reduction, as you can see in this study. (28:53): I wanted to briefly mention and give Dr. Khanna, Sahil to my right here, a lot of credit because I was talking to him before this and he published this very beautiful article that I will refer to you a couple years ago where he talks about the microbiota restoration. One of his impetus is for publishing this nice little graphic is, he draws this when he talks to his patients. The whole concept is that we all have a diverse microbiota. Then, when patients have risk factors for C difficile and all those risk factors that we talked about, the diversity starts to reduce. Then, if there's an attack by C difficile spores because there's a reduction in diversity, now you got spores and you got a lower diversity, and this can lead to vegetative forms of C diff being in that microbiota space, if you like, that ultimately produce toxins and then lead to diarrhea. That's what happens. (30:04): Then, when you try to deal with microbiota restoration, the whole idea of the restoration is to improve on that vegetative form, but it doesn't tend to resolve the spores. The microbiota restoration is actually a really important part of affecting the vegetative forms. As you can see here, antibiotics actually that are active against C difficile can help with the vegetative forms, but they actually don't do much in terms of the spore activity and vancomycin and fidaxomicin more than fidaxomicin. Looking at our patient two months later, she again has her second episode of C difficile recurrence. The patient had two courses of oral vancomycin with good response after each for approximately five days, but her diarrhea or abdominal pain or subjective fevers continue within seven days of completion of the vanco. The question now is raised, "Well, what else can we do?" (31:14): This is where the question of fecal microbiota transplantation comes in. You will see here that FMT, the American College of Gastroenterology in 2021 published some guidelines around the indications for FMT. The indications are patients experiencing their second or further recurrence of CDI to prevent further recurrences. There's strong recommendation with moderate quality of evidence for that. (31:45): Another indication would be repeat FMT for patients experiencing a recurrence of CDI within eight weeks of the initial FMT. This is a conditional recommendation with very low quality of evidence. Thirdly, FMT can be considered for patients with severe or fulminant CDI refractory antimicrobial therapy, particularly when the patients are deemed spore surgical candidates. There is strong recommendation, but unfortunately, lower quality of evidence for that. When you look at pooled analysis, meta-analysis of 37 studies around FMT for recurrent CDI. These 37 studies, seven of them were randomized control trials, 30 of them were case studies or case series. It shows effectiveness. There's an overall effectiveness of somewhere on the order of 92%. That is good. But then, you have to ask yourself the question, and it also looks like that FMT may actually be more effective than vancomycin or taper or recurrent if a recurrent refractory CDI. (32:57): But there are some challenges that we've had to deal with F M T despite its effective nature. Administration of FMT is not the easiest thing. We've also learned that there's no difference between fresh and frozen FMT from an administration standpoint. But there are some adverse events that occur with FMT that you should be familiar with that's starting to come up in the literature as we continue to learn more and more about this. There's transient constipation, diarrhea and discomfort. There could even be post-infectious irritable bowel syndrome. There's single case reports around peripheral neuropathy, Sjogren's ITP, rheumatoid arthritis, obesity and microscopic colitis. Then there's also infectious transmissions that can occur with FMT. Both the ESBL E. Coli, as well as Shiga toxin producing e coli. (33:59): Where do we stand in 2023 with FMT? Well, we know that the efficacy is really strong. It's above 85%, 90% to prevent recurrence. It's superior to oral vancomycin, so both are good things and that there is not really, from an administration standpoint despite some of the challenges, there's no difference between fresh and freeze [inaudible 00:34:20] tro and they have similar efficacy. There's no effect on the donor in terms of efficacy, and so screening and recruitment standardization is needed there. There's more adverse events there being reported than we just described. FDA still considers FMT investigational and the donor stool is now becoming more scarce and costly, so those are concerns that we actually have. With that, I'm going to hand it back to Dr. Khanna, sorry and he'll talk about recurrent CDI. Sahil Khanna (34:59): Thank you, Yoav. Thank you Alpesh. The most exciting part of medicine is the future. Today, I'm going to share with you the future of C difficile therapeutics is not in the future, it's actually in the present, and it's here now and it's here today. Believe it or not, your patients are going to ask you about live biotherapeutics the next time you see a recurrent C difficile patient, and I'm going to empower all of you with all the tools and answers to answer those difficult patient questions, but also to think about using these treatments in your own clinical practice, then you don't have to refer those patients to a gastroenterologist like me. (35:45): Let's talk about our patient. This is our 63-year-old, who now has a fourth episode, and this happens in clinical practice. We've tried vancomycin, we've tried fidaxomicin, she does well on the antibiotics, but about a week after she stops them, the symptoms come back. She's heard Dr. Amin talk about the risks of infection transmission for FMT. She's a little scared about it. What do you do now? Can you give her one of these antibiotics and bezlotoxumab? We talked about that. Can you use one of those live biotherapeutics that I'm going to talk about in the future slides? Should you do FMT or should you repeat one of those vancomycin taper pulse regimens. Scan the QR code, put one of these answers in and we'll talk about which one's correct. Wonderful. Completely agree. We should not be repeating treatments that didn't work in the past, so probably not a good idea to repeat the vanco taper pulse. (36:42): Everybody who was listening paying attention, yes, bezlotoxumab could have been an option. Slight caveat, if you are a good test taker, you remembered this patient had congestive heart failure and that's one of the black box warnings. We do not use bezlotoxumab in a heart failure patient, which is not an uncommon comorbidity in our patients who have recurrent C difficile infection. That's the reason bezlotoxumab was not going to be the correct answer. Then, yes, you could consider FMT with the right risk benefit discussion, but also think about one of these live biotherapeutic products. I've been seeing a lot live biotherapeutics, let's talk about what are those live biotherapeutics. (37:20): In today's world, there are not one, not two, but three live biotherapeutic products or microbiome-based therapies that are in different stages of clinical development or even available. There are two of them that are on the left side of the slide that are derived from human stool or are donor-derived. First one here is SER-109, which is an oral capsule of donor stool treatable ethanol and has purified Firmicutes spores. As Dr. Golan mentioned earlier, Firmicutes is important to maintain the homeostasis of the gut and it's currently under FDA review. (37:57): Believe it or not, you can't time it better. We're hoping to hear from the FDA today. Haven't heard as yet, but I'm waiting for that email to see what it's going to show, what's they're going to approve it. The other one is RBX2660, also known as FMBL or fecal microbiota live, which is a rectal administration on enema-based therapy. It's a broader consortium. It's also derived from donor stool and it has been FDA approved since November 2022 and may be available in your center or probably your center is considering that. These are donor-derived. Then, do you really have to get this, all of this from donors? Maybe, maybe not, but there is a defined consortium meaning bacteria that we exactly grow in a lab, every capsule is similar to the one before, and it's currently in clinical trials. It has eight different clostridia, which have been shown to perhaps be beneficial in a smaller clinical trial, and I'll show the results of all of those. (38:53): These are the three things your patients are going to ask you about and I think we should all know about them and we should think about prescribing them to our patients. Let's talk about this. Let's talk about the data behind all of this because a deeper understanding of the data is going to let us to think about using these products. FMBL JSLM or fecal microbiota live JSLM, that's the generic name of RRX2660. This was studied in a large clinical development program. This is the design of the phase three clinical trial. You give people the antibiotics to treat C diff, and then this prevents the next episode from coming back. (39:30): Antibiotics stopped for 24 to 72 hours and then these were patients who had two or more episodes diagnosed with one of the diagnostic tests available, either got treatment or placebo and were followed for eight weeks. If C difficile resolved, they were followed for six months. If they didn't resolve, they had the option of being in a second treatment. It's one or two treatment options that are available for patients. These are data from the phase three clinical trial that had a Bayesian analysis, 70.6% cure rates with RBX266o or FMBL live compared to 57.5% with placebo, but a 13% difference. When we see this posterior probability of superiority 0.9991, that means I'm 99.1% certain, this difference is truly statistically different. Statistically significant difference between RBX2660 and placebo. There were some treatment emergent adverse events, but there are similar in the placebo arm and the active arm, so no infection transmission was noted and the GI adverse events were more common and they were similar across the two arms. (40:34): What about sustained, because patients come and ask me, "Oh, you're showing me eight weeks of data. You're showing me two months of data. I'm going to live a life longer. What's going to happen longer term?" This graph here demonstrates on the Y-axis patients who had a recurrence compared to not, and here, you can see patients who treated placebo had a higher risk of recurrence compared to RBX2660, but the difference was sustained and once you get a response and you don't have a recurrence at two months, that sustains over several months. It is a sustained clinical response, not just a short-term clinical response. (41:09): Patients come and ask me, "Doc, I've been feeling miserable. What's going to happen to my quality of life after this?" This gets asked to me several times a week because these patients suffer from horrible, horrible quality of life when they have recurrent C difficile. Their life's tied to a bathroom. Formal studies have been done based on a C diff 32 quality of life survey designed by Kevin Gary from Texas. These data show that people who got RBX2660 in blue ended up having a higher quality of life, and again, that was sustained over eight weeks compared to placebo, so you do improve quality of life in addition to clinical improvement, which is very important for our patient population. (41:51): This was also studied in open label study because trials are trials. But what happens in the real world when you remove all the exclusion criteria, and here, you see success rates from 300 patients of 74.6% at eight weeks, and people who responded, again, looking at the sustained response over six months of those who responded, there was an 84% sustained response over six months. Sick patient population, they go to the hospital frequently, they get more antibiotics frequently, but you can still continue to have their C difficile suppressed the majority of the times. (42:26): Moving on from the first product to the second product, that was a rectal administration. This is an oral microbiota restoration therapy called SER-109. This was also studied in a large clinical development program, and these are data from a large phase three clinical trial published in the New England Journal of Medicine last year. 280 patients were screened, 182 were actually enrolled, they were all diagnosed based on that toxin assay, antibiotics, magnesium citrate to wash out the residual antibiotics and they got SER-109 or placebo and then reference was evaluated for eight weeks. Now, look at this therapy. It's four capsules once a day for three days. Patients can take the therapy at home also. (43:10): These are exciting data, 88% lack of recurrence, meaning 88% success rate. When you look at historical data, oh my god, these patients keep getting reference over and over again. Compare that to placebo, 60% with placebo, you flip it around 12% recurrence rates from SER-109, 40% from placebo. Statistically significant, clinically meaningful difference between a capsule-based therapy. Looking at adverse events, they're similar between SER-109 and placebo, and most were GI. People get transient abdominal pain, constipation, diarrhea, no infection transmission was noted. This was also studied through week 24. And looking at the efficacy at 4 weeks, 8 weeks, 12 weeks and 24 weeks, you can see that the difference between SER-109 and placebo is maintained. The delta is maintained up to 24 weeks, so again, a longer term efficacy that we see a sustained clinical response. (44:10): Moving on, patients worry about how they're going to feel. Quality of life again was studied in this clinical development program also. Here, you're seeing in the dark blue bars, percentage of patients in quality of life improved, unchanged or in whom who felt that their quality of life worsened. The first bar graph is overall quality of life. You're seeing a higher percentage in SER-109 compared to placebo. The different domains that were studied were physical quality of life, mental quality of life, or their social quality of life, and all of them, we see that with the microbiome-based therapeutics, you are improving people's quality of life, which is very, very important. (44:51): This also was studied in an open label phase three clinical trial that was recently published in JAMA Network Open. This was 263 patients that were in northern US and Canada. A little bit more expanded study, had fewer exclusion criteria, had more inclusion criteria. This now moved from three episodes to two episodes in this clinical development program and could have been diagnosed by PCR or EIA. Look at the success rates here. The blue bars, the dark blue bars are some patients who are enrolled in this study from the clinical trial that was the randomized control trial. The purple bars are this cohort, which is the larger one, 234, and then the overall is in the light blue bars. The Y-axis is the recurrence rates, and I'll just point towards the very last bar here, 13.7 for 13.7% recurrence rates at 24 weeks. Even the real world where you're including almost everybody who could be eligible to get these therapies, you are seeing very low recurrence rates in this, otherwise, very difficult to treat patient population. (45:56): Those were the two products that were available, which were donor-derived. The science is also moving somewhat quickly into donor-independent products. Not probiotics, but live biotherapeutics where we know and understand the mechanisms of those bacteria, we understand viability. V303 is a live biotherapeutic product, which has eight commensal clostridial stains. This has now been studied in a phase two clinical trial and a phase three is being planned. These were patients, some had one episode, some had two, some had three episodes and about 79 patients were enrolled. They got a high dose treatment, low dose treatment and placebo. This was a dose finding studied in addition to efficacy. When we look at the rates of recurrence for the high dose, 13.8%, 37% for low dose, so the low dose didn't really work as well as we hope it would be, and 45% for placebo. Again, looking at the graph here, look at the very bottom bar, that's the recurrence rates in your high dose. It's very different from placebo, statistically significant difference, and a product that's in clinical development right now. Please remove the pause here (47:10): Those are all the live biotherapeutic products. The question that arises Dr. Amin, Dr. Golan, we've got a group of highly intelligent primary care providers who understand and know medicine way more than a petty gastroenterologist like me. How do we empower our primary care providers to incorporate these microbiome based therapies into their practices? Remember we've got rectal administration that's FDA approved. We've got an oral therapeutic that hopefully will be FDA approved, today hopefully will be FDA approved today. I'm like at the edge of my chair waiting for that. Then we've got others that are in clinical development. Dr. Amin, what do you think? Alpesh Amin (47:52): It's a great question. I'm a big believer that there's several steps in the process as we start. I look at this as redesigning healthcare. We already know that C difficile has a high rate of recurrence as an infectious source despite primary antibiotic therapy, whatever you choose to use. We also know that when patients, so there's two things, we're used to talking about C difficile occurring in the hospital, so there's a hospital component here. But we're also realizing that C difficile is occurring in the community more and more also. I think we got to think about this from a strategic standpoint. In the hospital, this should be part of our thought process in terms of discharge planning, which takes the issues around multidisciplinary care. Setting up a system to think about how do you set up a patient for long-term follow up. (49:00): We know in other disease states that if you actually start therapy in the hospital, there's a good chance that patients will actually continue that therapy long term. In the aspect of starting therapy, you'll start the antibiotics in the hospital, but having a follow-up that encourages patients to get one of these new therapeutics that will prevent recurrence as an outpatient is the process of care that we need to establish. Educating our frontline workers, thinking about the continuum of care, establishing that continuum of care in the discharge notes and discharge orders that are put into place becomes a really important process that I think we need to think about. For the primary care doctors, it's receiving these patients and then being well-educated and knowing that, "Hey, once I finish the therapy of either vanco or fidaxomicin, what should I do next in order to help prevent recurrence from occurring?" (50:06): The lucky part of what we have today is we actually have therapeutics that are shown to actually help prevent recurrence. We should be proactive in initiating that, and that includes making sure that you can get access to the medications, making sure that they're on formularies that exist and ensuring that the patients are following up and are well-educated to continue the next phase of therapy. Those are a few ideas. Sahil Khanna (50:35): Yoav, what do you think? Yoav Golan (50:36): Well, I agree. My best advice to primary care clinicians is to not wait until their patients have multiple episodes of C diff. Once you had multiple episodes of C diff, it's really hard to break this chain of events. Try to be proactive, try to consider microbiome targeted therapies in any of your patients who had an episode of C diff. Evaluate them for risk factors for severe C diff. Evaluate them for risk factors for recurrent C diff and target those people at the highest risk for microbiome therapies before they had multiple episodes of C diff. Sahil Khanna (51:11): Thanks, Yoav. I've been, thankfully been in the microbiome therapeutic space for about a decade or so. I'm a firm believer of that these do not need to be in their hands of gastroenterologists or ID doctors. I also feel that there is a very simple pathway. You got to get them on your [inaudible 00:51:28]. These are out going to be outpatient therapies, not inpatient for the most part. Once your patient has had two or more episodes, talk to them about it. The majority of patients who come to my practice, they come and see me for FMT because their primary care doctor hasn't mentioned it to them. Patients believe what you all say more than what I say, tell them I promise that. (51:49): The majority of them are probably going to need some form of insurance approval or prior authorizations. We all have template letters. If anybody needs them, reach out to me, we can share that information with you. Then give them enough antibiotic, get their prior ath done and feel empowered to prescribe the capsule-based therapy if that's available to you or the rectal administration if you've got a setup to do that. Those can be done very easily. The rectal administration does not have to be done in a gastroenterologist office, can be done in a primary care's office. Alpesh Amin (52:20): Can I just make one comment about depending on where you practice and so forth, doing a referral to the specialist just adds time to the process. What we're trying to encourage here, like Dr. Khanna is saying, is that feel empowered, be proactive and go ahead and initiate the therapy because the therapies will have been shown to actually help. Time is of essence. Otherwise, especially in elderly patients that are fragile, if you don't initiate early, wait for a referral and let the referral happen, that can be several days to weeks before that happens and that's not good. Sahil Khanna (53:05): Thank you. Alpesh, you already answered part of this. Do you have anything else to talk about? How is the interprofessional care team at your institution? Who all are involved in managing patients with C diff? Alpesh Amin (53:17): Okay. All right, I'll start and then hand it over to Dr. Golan. In our institution, the physicians play a very key role, as you can imagine, but our care managers play a key role. Pharmacists are extremely important. APPs are very important in the process, and even the OTH coordinators and the social workers are all very important. One of the things that you don't see here, part of the interprofessional care team is actually the patient themselves. The patient and the family are centered to this process. I tend to look at the hospital setting as an opportunity to educate patients. I have a unique opportunity in the hospital to spend 3, 4, 5, 6 days with the patient to reinforce education in the outpatient setting. This multidisciplinary team is a bit more complicated to achieve, but it is really important that you engage the family and the patients. I'll hand it over to Dr. Golan. Yoav Golan (54:24): Yeah, and I agree. I would say even further, when you have a disease where the recurrence rate varies, but on average about a quarter of patients will have a recurrent infection, and once they have a recurrent infection, they're even more likely to have additional episodes of this disease while other people will have low risk. It's really important to risk stratify your patient. It's really important to identify those patients who are at higher risk of recurrence, higher risk of severe disease, and as we know, very often those patients are not being risk stratified. It may be because physicians are very busy and they have many other things to do, and when you don't re-stratify your patients, you're never going to identify those patients who need a more proactive approach, who need to be treated with those interventions that decrease their future risk of developing C diff. (55:19): Therefore, I actually think that nurses, physician assistants, as well as pharmacists, particularly pharmacists and particularly ID pharmacists where they're available are extremely important in stratifying patients according to risk. If they identify patient with risk factors for severe disease or recurrent disease such as advanced stage, such as people with history of C diff, such as people who take PPIs, people with chronic kidney disease and so forth, they should alert the physicians and they should alert the caring team so that those patients could be treated more proactively. Sahil Khanna (55:52): It takes a village to manage patients with recurrent C difficile infection and starts with their primary care providers. Delete this. C difficile infection incidence is high, higher in the community nowadays, perhaps in the hospital. For initial C difficile, for initial recurrent C difficile, you could use antibiotics. Think about using the gut microbiome restoration therapy arm or restoring the gut microbiota after two or more episodes going forward, based on the data that we are seeing from live Biotherapeutics. For FMT, at this time, FMT is investigational or remains investigational. It's effective, but it's limited. This lack of standardization really limits it. Donor stool is limited. There is that infection risk because of lack of standardization. The future is here. The future is here today. The future is here now. We have one already approved FMBL live JSLM or fecal microbiota live therapeutic, which is rectal administration. The other one, SER-109, as you can see in the slide, the PDUFA date for the FDA approval hopefully is today. Thank you everyone for your attention.