Dr. Feuerstadt (00:06):
Hello, I'm Dr. Paul Feuerstadt, and I am an Assistant Clinical Professor of Medicine at the Yale University School of Medicine
and an attending gastroenterologist at the PACT Gastroenterology Center in Hamden, Connecticut. In this program, I will summarize
key information that was presented at a live symposium by my colleagues, Dr. Jessica Allegretti, Dr. Krishna Rao, and myself
at the 2022 American College of Gastroenterology annual meeting in Charlotte, North Carolina.
(00:34):
If you would like additional resources, please see the accompanying audio and slides from the full symposium. During this
session, we will discuss the epidemiology, pathophysiology, and treatment of C. difficile infection in a very focused approach
on the microbiota. C. Difficile is a major problem in the United States.
(00:54):
The Centers for Disease Control and Prevention issued a threat level of urgent for C. difficile in 2013 and then again in
2019, speaking to the gravity of the problem and the burden on our patients and the healthcare system.
(01:07):
- difficile is the most common healthcare-associated infection, accounting for approximately 15.5% of all healthcare associated
infections, and in the United States alone, there are an estimated 365,200 patients testing positive annually. The microbiota
plays an important role in our general health and a specifically important role in preventing C. difficile infection.
(01:33):
The human colonic microbiota has an estimated 100 trillion different microorganisms and between 500 and a thousand different
species. Within the colonic microbiota, there are several different microorganisms including bacteria, archaea, fungi, protozoa,
and viruses. There are several most common phyla that we see, including within the bacterial phyla, such as the Bacteroidetes,
the Firmicutes, the Actinobacteria, the Proteobacteria, the Verrucomicrobia, the Fusobacteria.
(02:04):
Under the fungi, they're the Ascomycota and Basidiomycota and viruses, Caudiovirales. When considering the microbiota and
anything within medicine, it's important to define certain terminology, and these terms include microbiota. So, what is the
microbiota?
(02:21):
The microbiota is a group of microorganisms within a defined space, and that differs from the microbiome. The microbiome is
the genetic compliment of all of those microorganisms. Now, dysbiosis is a really important term. Dysbiosis is any differentiation
of the microbiota from what is considered to be normal for that individual.
(02:44):
Finally, and probably most importantly, the metabolum. The metabolism is the metabolic output that occurs as a result of that
group of microorganisms. So, it's really important to realize that, yes, we care which microorganisms are present, but even
more importantly, we care what that group of microorganisms is producing metabolically and how that interacts with the body.
(03:06):
If that interacts with the body positively, it can prevent disease. If that interacts with the body negatively, it can actually
promote disease. Overall, the microbiota has many functions including aiding in digestion, forming a mechanical barrier between
the intestinal mucosa and the lumen of the bowel and the so-called colonization resistance.
(03:27):
Colonization resistance is a term used for the microbiota's ability to minimize foreign pathogenic agents from proliferating
and causing disease. With this basic understanding of the microbiota in mind, let's now focus on C. difficile and its pathophysiology.
(03:44):
It's important to remember that two main things have to happen for somebody to get C. difficile. One, they need to be exposed
to the bacteria and, two, they need to have a change in their microbiota, the so-called dysbiosis.
(03:57):
So, let's first focus on that bacteria itself, and I'm going to take us back to our textbook years and remind you that C.
difficile is a gram-positive spore-forming anaerobic rod. There are two main phases of C. difficile infection, the spore phase
and the vegetative phase.
(04:14):
The vegetative phase is the phase that each of you, if you're a clinician, thought about when you heard that we would be discussing
C. difficile today, because the vegetative phase is the phase of infection that releases two main toxins, toxin A and toxin
B. Those toxins act on the surface of the bowel, the epithelium of the bowel, resulting in fluid release and resulting in
the clinical syndrome we most commonly associate with C. difficile infection.
(04:39):
The vegetative phase is susceptible to gastric acid and susceptible to alcohol-based hand sanitizers. So, when it comes in
contact with these things, it gets wiped out. Alternatively, the spore phase is much more resistant. The spore phase is resistant
to gastric acid and resistant to alcohol-based hands sanitizers. In fact, the spore phase can last on dry surfaces on the
order of six to eight months and remain viable.
(05:10):
The spore phase largely explains the spread of C. Difficile, and the spore phase also explains recurrence of C. difficile
because it's the spore phase that remains within our systems after a standard of care antimicrobial. If our microbiota is
unable to eradicate that spore phase, we potentially could get a recurrence.
(05:29):
So, how do we actually get C. difficile? Classically, what happens is, we swallow the spore phase. It's resistant to our gastric
acid, gets through our gastric acid into our small bowel where there's a rapid conversion or germination to the vegetative
phase. The vegetative phase multiplies and divides and multiplies some more as it builds an army of sorts heading towards
the colon.
(05:50):
In my introduction, I said I'm a gastroenterologist and, as a gastroenterologist, I think the colon is a brilliant organ because
the colon has its own defense system independent of that bloodborne defense system that protects it. What is that defense
system? The microbiota. What classically weakens the microbiota in patients with C. Difficile? Amoxicillin, ampicillin, clarithromycin,
fluoroquinolones, cephalosporins, and piperacillin/tazobactam.
(06:17):
You weaken the colonization resistance. You deplete the diversity of the microbiota and make an environment that's more welcoming
for the C. difficile and the vegetative phase to proliferate, release its toxins, and wreak havoc.
(06:30):
So now we know a little bit about the bug. Let's now talk about the dysbiosis, and probably the best test and the best study
that looked into dysbiosis was a study that was conducted and published by Chang, et al in 2008. Within that analysis, they
looked at 10 total patients. Three were controls. They didn't have C. Difficile. Four had initial infection and three had
recurrent C. difficile.
(06:55):
When they compared no infection with initial infection, there were no statistically significant differences with regards to
the diversity of the microbiota or the constituency. However, when they compared initial infection with recurrent infection,
there was a statistically significant depletion of the diversity with a decrease of the Bacteroidetes and the Firmicutes.
(07:18):
So, a couple of important points with regards to this study. Firstly, we know that, in individuals who get C. difficile who
are treated initially even with standard of care antimicrobials, 25 to 35% of them will recur. Of those that recur, 40 to
50% will go on to recur after that, and greater than 60% thereafter as individuals get caught in that cycle of recurrence
after recurrence after recurrence. Well, this study somewhat explains that.
(07:43):
We know that when they compared no infection with initial infection, there were no statistically significant differences in
the diversity. The diversity was depleted, but it wasn't devastated. However, once we got to recurrence, the diversity was
devastated, there was a statistically significant decrease, and there was a depletion of the Bacteroidetes and the Firmicutes.
(08:02):
So, we know now that the Bacteroidetes and the Firmicutes play a key role in minimizing future recurrence if they're able
to regrow naturally without further intervention. So, now that we know about C. difficile, the bacteria and the changes in
the microbiota, what is happening with the metabolic interaction of the microbiota and these patients leaving them prone?
This is essentially the metabolum that we discussed before.
(08:26):
With C. Difficile, we believe that the metabolic changes largely emanate from the bile salt milieu. So, where does the bile
salt milieu start? The bile salt milieu starts within the liver. It starts with cholesterol, and in the liver there are synthesis
to two primary bile salts, cholate and chenodeoxycholate. Those get released into the bowel.
(08:47):
Within the bowel, they interact with an enzyme, 7-hydroxylase. The 7-hydroxylase is released by a bacteria [inaudible 00:08:54].
That 7-hydroxylase converts cholate to deoxycholate, chenodeoxycholate to lithocholate. Those secondary bile acids, deoxycholate
and lithocholate, they inhibit the vegetative phase. We want those. Those are good.
(09:11):
The primary bile acids, those enhance germination. So, those enhance the onset of infection or the onset of recurrence. So,
primary bile salts are bad, secondary bile salts are good. That's a really important concept as we move forward.
(09:29):
So, as we start to contextualize this basic science information, it is important to realize that antimicrobials such as vancomycin
and fidaxomicin control the vegetative phase of infection, but the spore phase remains and is associated with the spread of
infection and recurrence, as I just alluded to.
(09:46):
This is a really important point because antimicrobials largely control that vegetative phase, which is why when patients
are on antimicrobials, as a clinician would attest to, they usually will have complete control of their symptoms. But after
that antimicrobial's removed, it is up to the microbiota to eradicate that spore phase. A deficient microbiota or a microbiota
that has a hard time replenishing itself leaves patients prone to recurrence.
(10:11):
So, before we focus on the microbiota, an intervention to heal a damaged microbiota, it is important that we discuss the recommendations
for antimicrobial and non-microbiota-based treatments.
(10:23):
So what are the American College of Gastroenterology guidelines published in 2021 recommend for the treatment of C. difficile
infection, and what they recommend is for a initial infection, we triage patients based on severity. If patients have a white
cell count less than 15,000 and a creatinine less than 1.5 milligrams per deciliter, they have non-severe infection.
(10:45):
With non-severe infection, the ACG guidelines recommend that we use either vancomycin 125 milligrams four times daily for
10 days, fidaxomicin 200 milligrams twice daily for 10 days or metronidazole 500 milligrams three times daily for 10 days,
metronidazole all largely being reserved for a patient cohort that is at very low risk for occurrence.
(11:08):
Once we get to that severe form of C. difficile where the white cell count's greater than 15,000 or the creatinine is greater
than 1.5 milligrams per deciliter, we pull off that metronidazole, only 10 day treatments of vancomycin or fidaxomicin.
(11:22):
Now for the recurrent cohort, they made some recommendations with regards to what the patients failed the first time. If patients
failed vancomycin, metronidazole, or fidaxomicin initially, it was recommended that we consider a taper/pulse course of vancomycin.
If patients failed vancomycin or metronidazole initially, it was recommended that we consider a 10-day treatment course with
fidaxomicin.
(11:45):
Now, before we move on to the microbiota-based therapies, let's briefly discuss a product called bezlotoxumab. So, what is
bezlotoxumab? Bezlotoxumab is a fully humanized monoclonal antibody designed to bind toxin B in a very specific manner. It
is given as a onetime infusion in addition to a standard of care antimicrobial.
(12:07):
So, what's the data for bezlotoxumab? Bezlotoxumab ran through two prospective multi-centered randomized controlled trials
where patients with C. difficile infection all received the standard of care in a microbial and then were randomized to either
receive an infusion of placebo, an infusion of bezlotoxumab, an infusion of bezlotoxumab and a product called actoxumab or
an infusion of actoxumab alone.
(12:31):
The short is that actoxumab was not productive. It didn't help patients, so it didn't come to market. So, when we look at
the results of these MODIFY I and MODIFY II trials, we really largely need to look at the 90-day recurrence rates in the placebo
arm versus bezlotoxumab. Recurrence rates in modify one and the placebo arm were 28% versus 17% in the bezlotoxumab arm.
(12:53):
In the MODIFY II, 26% placebo, 16% bezlotoxumab. The number needed to treat to reduce one recurrence with bezlotoxumab was
10. However, in an Apriori set analysis looking at risk factors for recurrence in the age over 65 cohort, the number needed
to treat was six. So, really a profound difference in something that we should think about in our patients with recurrent
C. difficile infection to break that cycle. So the ACG guidelines recommend that we use this in patients at high risk for
recurrence.
(13:25):
So what defines that? I think there's another study that looked at that, a subgroup analysis of the Apriori set risk factors
for occurrence from the MODIFY I, MODIFY II trials. Those include age over 65, any history of C. difficile over the previous
six months, any form of immune compromise, the hypervirulent strain, as well as severe infection. If patients had three or
more of those risk factors, the recurrence rates in the placebo group was 46.1% versus 21.2% in the bezlotoxumab arm.
(13:55):
If they had two risk factors, 41.1% recurrence rate in the placebo arm, 26.9% in the bezlotoxumab arm. Even one single risk
factor, 31.3% in the placebo arm, 17.1% in the bezlotoxumab arm. So, if patients have at least one risk factor, and I would
argue that one risk factor be age over 65, this should be strongly considered. So, those are the recommendations for antimicrobials
and for bezlotoxumab.
(14:23):
But even with the best treatments that we have available with regards to antimicrobials, about 25 to 35% of patients with
initial infection will recur, 40 to 50% of those with a single recurrence will recur, and up to 60% thereafter will get caught
in this vicious cycle of recurrence after recurrence after recurrence. This is where microbiota-based therapeutics can come
into play.
(14:49):
We identify deficiencies in the microbiota that were seen in the Chang, et al study from 2008, specifically the bacteroidetes
and Firmicutes. If we replace those deficiencies and not simply allow the microbiota to naturally repair itself as we do with
only antimicrobial therapy, we can likely decrease rates of future recurrence. That is the theory behind fecal microbiota
transplant, and that is what we see in clinical practice.
(15:14):
So, let's consider some of the foundational clinical trials that got us to this point. The first trial that I'd like to talk
about was a study by [inaudible 00:15:23] and colleagues. The [inaudible 00:15:25] trial was the first prospective randomized
control trial that considered patients with multiple recurrent C. difficile and randomized them into a group that received
a nasoduodenal transplant, a group that received vancomycin and bowel lavage, or a group that received vancomycin alone.
(15:43):
The study was stopped at interim analysis due to futility. Yes, I said futility, due to futility of the vancomycin intervention
arms. The recurrence rates or the overall sustained clinical response in the nasoduodenal transplant was 81.3% versus 23.1%
in the vancomycin and bowel lavage and 30.8% in the vancomycin alone arm. The study included 16 patients in the transplant
arm at 13 in each of the other arms.
(16:12):
But the study was profound and was published in the New England Journal of Medicine, partly because it showed efficacy of
fecal transplant in a group with multiple recurrent C. difficile infection. But even more importantly, it looked at the microbiota,
and it showed that the microbiota in the recipients post-transplant was similar to the microbiota in, the donor pre-transplant
form-fit-function.
(16:34):
After that, there was a slurry of clinical trials looking at fecal transplant in a whole ton of populations, peaking largely
in 2017 with a meta-analysis by Quraishi, et al. The Quraishi, et al meta-analysis included 37 studies, seven prospective,
30 retrospective, and showed an efficacy of fecal microbiota transplant in patients with a recurrent C. difficile of 92%.
We essentially thought we were putting ourselves out of business.
(17:02):
They showed no statistically significant difference between known or unknown donors, no difference between fresh or frozen
stools, but very importantly, as we proceeded ahead, we started to get more sophisticated with our analyses, and when we got
more sophisticated with our analyses, we realized, you know what? A lot of those trials were retrospective.
(17:22):
So, a very nice meta-analysis that was published in 2019 started to fix that problem. This meta-analysis by Darrell Pardi,
Raseen Tariq, and Sahil Khanna said, let's just look at patients that received fecal microbiota transplantation in clinical
trials that had a control group, a basic premise from clinical trials, but was largely missing in the past. They looked at
13 studies, 610 total patients, and showed an efficacy of 76.1%, not quite that 92% that we were seeing previously, but still
really good.
(17:54):
But when they drilled deeper, the results were interesting. The open-label studies, they had an efficacy of 82.7%. The randomized
controlled trials, the gold standard, they had an efficacy of 67.7%. That 67.7% is probably our most accurate depiction of
what we might see in clinical practice with the application of fecal microbiota transplantation after a standard of care and
to microbial patients with recurrent or multiple recurrent C. Difficile.
(18:23):
Using these foundational trials, the American College of Gastroenterology guidelines, published in May of 2021, made the following
recommendations for fecal microbiota transplantation. Firstly, they recommended that if patients had two or more recurrences
or three or more episodes of C. difficile, we should consider standard of care antimicrobial followed by fecal microbiota
transplantation.
(18:46):
They recommended that if patients recur after a transplant within eight weeks, we give a second transplant. Finally, they
made a recommendation with regards to fulminant disease following Dr. Monika Fischer's protocol with patients that are ineligible
to go to the OR that have fulminant disease. We give the fecal transplant again and again and again, every other day until
the patient symptomatically improves and/or the pseudomembranes disappear.
(19:11):
So, what about the safety of fecal microbiota transplantation? Fecal transplant seems very safe, but there are still some
signals we need to consider, including transient changes in bowel habits and abdominal cramps, possible onset of new conditions
including Sjogren's disease, peripheral neuropathy, idiopathic thrombocytopenic purpura, rheumatoid arthritis, and transferal
of infectious pathogens.
(19:33):
This can be thought of similarly to when we first started considering blood transfusions. We did not realize that we were
transcribing patients hepatitis C and HIV until, of course, it was identified. So, there is a bit of a kind of black box concern
here, but largely, fecal microbiota transplantation is safe.
(19:50):
There have been four overall FDA reports. The first one was issued in June of 2019. In that report, patients receiving fecal
transplants, not for C. difficile infection, were transcribed multi-drug resistant organisms. One was receiving fecal transplants
who prevent hepatic encephalopathy. The other was receiving fecal microbiota transplantation to prevent graft versus host
disease after a bone marrow transplant.
(20:14):
So, these patients were largely immune-compromised, and they were transcribed extended spectrum beta-lactamase-producing E.
coli. So, what has been our fix? We now, of course, screen for this, and therefore it's incredibly unlikely that this would
be transcribed.
(20:29):
The second FDA report came on March 12th, 2020. I want each of you to think about what you were doing on March 12th, 2020.
You probably were not thinking about the side effects or the risks associated with fecal transplant in patients with recurrent
C. difficile. You were probably more focused on the fact that the world was essentially shutting down for the COVID-19 pandemic.
(20:49):
But there was a very important advisory by the FDA. From a major stool bank in the northeast, a stool bank that was providing
stool and fecal transplant material to many sites across the country, they reported six individuals that got various forms
of E. coli. Two got enteropathogenic E. coli, four got Shiga toxin-producing E. coli, and of those four, two subsequently
died. We do not believe as a result of the Shiga toxin E. Coli. We believe it was a result of their medical comorbidities.
(21:18):
But it's important that we acknowledge that we're evolving with this, and we're learning what we need to screen for as we
go. Now, the other two recommendations from the FDA were not specific risks, but they were recommendations for screening.
One, of course, was for SARS-CoV-2 or COVID-19 infection, and the other came in August of 2022, warning that we need to also
be cognizant of monkeypox infections.
(21:41):
Now, given these concerns and the variability seen with the rudimentary methods of fecal microbiota transplantation, as clinicians,
we are striving toward products with predictable safety and efficacy profiles. These products are called microbiota-based
live biotherapeutic products and the FDA overseen forms of microbiota replacement therapy.
(22:02):
There are four products currently in the pipeline, with two having completed Phase 3 trials, SER-109 and RBX2660 and, two,
having completed Phase 2 trials, CP101 and VE303. As we approach the clinical trials, it is important to realize that there
were some similarities between these trials, including that they were all prospective, multi-center, randomized, placebo-controlled,
with all patients having recurrent C. difficile infection, all patients receiving a standard of care antimicrobial, having
an eight-week efficacy assessment, and all having a 24-week safety assessment.
(22:37):
However, there are significant differences among the trials and the products, as well, including differences in the actual
treatment. SER-109, for example, is a narrow spectrum. This product essentially states that there is a deficiency in the Formicidae
spores, so let's replace those Formicidae spores solely and not include anything else, targeted therapy to the problem.
(23:01):
This differs from something like RBX-2660 and CP101, which are broader treatments more akin to more sophisticated treatments,
fecal microbial transplant based, but with much greater screening procedures for the donors and their stool samples.
(23:16):
Let's start with the data for SER-109. So as I just mentioned, SER-109 is a narrow consortium. It is donor stool-derived.
It is brought through an ethanol purification process, and it's made in an encapsulated form. It's given as four capsules
daily for three days following a standard of care antimicrobial. Within its pivotal Phase 3 trial, the ECOSPOR III trial,
182 individuals with at least two recurrences of C. difficile infection all received 10 to 21 days of either fidaxomicin or
vancomycin.
(23:54):
They then had a washout period, and then after that washout period, they received magnesium citrate and were randomized to
SER-109 or placebo, followed for eight weeks for recurrence, 24 weeks for safety. Overall efficacy in the SER-109 arm, 88%
at eight weeks versus 60% in the placebo arm, a statistically significant difference.
(24:15):
But the bigger question is, did form-fit-function, and the answer is yes. When they looked at the microbiota analysis and
looked at baseline comparing placebo and SER-109, there statistically significant increases at weeks one, two, and eight of
the Firmicutes groups, specifically increases in ruminococci and Lachnospiraceae and decreases in the pro-inflammatory Enterobacteriaceae.
But once again, I mentioned earlier, we care about the metabolum and we care about those bile salts, primary bile salts bad,
secondary biosalts are good.
(24:46):
What they showed compared with baseline, comparing placebo with SER-109s, SER-109 at weeks one, two and eight had statistically
significantly higher rates of secondary bile acids. So once again, the lock and key fit, form-fit-function for why recurrence
rates were, in fact, decreased.
(25:06):
Recently in October of 2022, there was a publication looking at the 24-week data from the ECOSPOR III trial, and the results
were consistent with the already reported Phase 3 data showing recurrence rates in the SER-109 group of 21.3% versus 47.3%
in the placebo arm.
(25:25):
Just presented at the American College of Gastroenterology meeting was open-label study data, broader inclusion criteria,
more realistic to the real world. Within the open-label study, 263 individuals were included. 29 rolled over from ECOSPOR
III. The remainder directly entered the open-label study, and at eight weeks, the efficacy of SER-109 was 91.3%.
(25:50):
Importantly, they looked at a group with first recurrence, and recurrence rates in that group at eight weeks was 6.5%, so
further reinforcing the efficacy, as well as the safety, of SER-109.
(26:03):
Let's now talk about RBX2660. So, what is RBX2660? RBX2660 is a microbiota-based live biotherapeutic product that is a broad
consortium. It includes both spore and non spore-forming bacteria. It is administered as a single rectal installation following
a standard of care antimicrobial. It includes 10 to the seventh microorganisms per cc. It's 150 ccs, so it includes 15 times
10 to the eighth microorganisms in total.
(26:34):
With its study, the Phase 3 trial, the PUNCH CD3 trial, 262 individuals with at least one recurrence of C. difficile infection
all received at least 10 days of standard of care antimicrobial. They then had a washout period and then were randomized to
either receive RBX2660 or placebo, followed for eight weeks for recurrence, 24 weeks for safety. Overall efficacy within this
analysis with 70.4% for RBX2660 versus 58.1% in the placebo arm.
(27:06):
Important to note that a Bayesian analysis was performed to assess this data. So, what is a Bayesian analysis? A Bayesian
analysis is an analysis that leverages another study with the primary study to increase the size of the study and the hardiness
of the statistical analysis. In this case, the Phase 2 study data was used to be leveraged. Why? They had the same diagnostics,
the same efficacy endpoint, the same safety endpoint, and the same product.
(27:34):
If the signals of efficacy in the placebo arm and the RBX2660 arm are consistent, you can leverage the data, and that's where
the 70.4% for RBX2660 versus 58.1% in the placebo arm largely came from. The posterior probability superiority was 0.986 a
statistically significant difference.
(27:54):
But once again, we care about the microbiota analysis and, within this analysis, comparing baseline with weeks one, four,
eight, three months and six months, there were increases in Clostridia and Bacteroidia and decreases in bacilli and Gammaproteobacteria.
Again, we care about the metabolic effect and, again, form-fit-function.
(28:16):
When we look at the baseline where there were more primary bile salts, disproportionately more primary bile salts at weeks
one, four and eight, there were much more secondary bile acids, so we see form-fit-function. Now, RBX2660 has been taken through
three Phase 2 trials and two Phase 3 trials, over a thousand patients included. Lindy [inaudible 00:28:37] presented interesting
data about a year ago at IDWeek in 2021.
(28:41):
At that study, they showed across those five trials, consistent efficacy and consistent safety. At the American College of
Gastroenterology meeting in 2022, open-label study data was presented for RBX2660, as well. An interim analysis of 300 patients
showed an eight-week efficacy of 74.6%, and of that 74.6%, 84% had a sustained effect at 24 weeks, so consistent safety, as
well as efficacy, for RBX2660.
(29:12):
What about CP101? What differentiates CP101 from the other products? CP101 is a broad consortium, and being a broad consortium,
it includes a wide array of microorganisms. CP101 finished its Phase 2 trial, the PRISM3 trial.
(29:28):
With this, what they found through their prospective randomized control trials that all patients receive standard of care
antimicrobial, a washout period, and then they were given CP101 as 10 capsules on a single day following a standard of care
antimicrobial, 60 times 10 to the 10th microorganisms versus placebo, followed for eight weeks for occurrence, 24 weeks for
safety. Overall efficacy of CP101 was 74.5% versus 61.5% in the placebo arm, a statistically significant difference.
(30:00):
But very importantly, they looked at the alpha diversity and, again, form-fit-function, comparing the placebo arm with the
CP101 arm as you would expect with a broad consortium, a wide array of microorganisms, the diversity increased more in the
CP101 group. At the American College of Gastroenterology meeting in 2022, CP101 also presented open-label study data of 132
patients. Efficacy in that group was overall 80.3% versus 78.8% in follow up. So, 80.3% responded at eight weeks. 78.8% had
a sustained effect.
(30:38):
Finally, VE303. VE303 says, look, maybe we don't need to give the whole kitchen sink. Maybe we don't need to give just a narrow
consortium. Maybe we should just give eight bacterial strains, and that's what they did, and they reported their results of
a dose-ranging study, their Phase 2 data at the Digestive Disease Week in San Diego, California in May of 2022.
(31:01):
Within that study, they showed that the high dose arm, 10 capsules daily for 14 days, had a statistically significantly higher
response rate at eight weeks than the placebo arm, 86.2% for VE303, 54.5% in the placebo arm. So, now it's important that
we talk about this data, but it's also important to acknowledge that there are some differences amongst these trials that
make them challenging to compare.
(31:29):
These differences include the length of treatment, the number of episodes, the diagnostic tools, the washout period, whether
or not there's a bowel purge and dosing. So, it remains important to realize that with these differences among the trials,
we need to contextualize the study itself to best understand the results seen within the respective trials.
(31:47):
This learning session has covered a lot of information. C. difficile is a major problem for our patients and our healthcare
system, with recurrence being one key piece of the problem. By understanding the pathophysiology of the infection, we can
optimize therapy, following the ACG guidelines for antimicrobial usage and add-on therapy such as bezlotoxumab and fecal microbiota
transplantation to prevent recurrence.
(32:10):
As we have seen, the microbiota plays such an important role in preventing recurrence when healthy. As we move forward, there
are several products with exciting data that have completed Phase 3 and Phase 2 studies. We hope that in the future, there
will be an FDA-approved treatment that offers safe and effective microbiota therapies, offering wider availability to our
patient population.
(32:31):
The future is so bright in this space. Thank you so much for participating in this activity. Please continue on to the answer
the questions, the follow, and complete the evaluation.