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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.