RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY OF VE202 IN PATIENTS WITH MILD-TO-MODERATE ULCERATIVE COLITIS

K2. Background of the study (in English)
Ulcerative colitis (UC) and Crohn*s disease (CD) are the 2 major forms of
inflammatory bowel disease (IBD). The exact pathogenesis of UC is unknown, but
predisposing factors are thought to include genetics, environmental and dietary
exposures, and a disordered immune response. In addition, dysbiosis of the
intestinal microbiota has been observed in patients with CD and UC, and it is
hypothesized that the microbiota may be a trigger for inflammation and disease
development in genetically or immunologically vulnerable individuals (Manichanh
et al. 2012). It has been suggested that the primary defect in UC may be
epithelial dysfunction at the intestinal barrier, or alternatively the presence
of inflammatory mediators and cells in the colonic lamina propria, which in
turn leads to barrier disruption (Kobayashi et al. 2020).
The onset of UC can occur at any age but is most frequent in young adulthood.
Whereas CD is characterized by patchy transmural disease, the inflammation of
UC extends proximally from the rectum and is limited to the mucosal layer of
the gut. Moreover, UC is limited to the colon and CD can occur throughout the
entire gastrointestinal tract.
Ulcerative colitis incidence is generally similar in men and women. Regarding
geography, the incidence of UC seems to have plateaued over the past decade in
some Western countries; however, the prevalence in these countries continues to
increase. In contrast, UC incidence has historically been much lower in
developing countries but is now increasing (GBD 2017 Inflammatory Bowel Disease
Collaborators 2020).
Ulcerative colitis is generally characterized by periods of disease activity
interspersed with periods of remission. A number of scales are available to
categorize disease activity, including the Mayo scoring system that is being
utilized in the current study (Schroeder et al. 1987). Disease activity is
generally defined as mild, moderate, or severe, based on number of bowel
movements per day, amount of rectal bleeding, and presence or absence of
constitutional symptoms and markers of inflammatory response (eg, fecal
calprotectin). These manifestations of UC can lead to an increased risk of
anxiety, depression, and impaired social interactions (Regueiro et al. 2017).
First-line treatment of UC usually consists of a 5-aminosalicylate agent, which
leads to remission of varying duration in most patients. Corticosteroids are
often prescribed during exacerbations of disease but repeated and/or prolonged
use is discouraged due to short- and long-term adverse effects associated with
these agents. For those patients who have inadequate response, an increasingly
broad array of therapeutic agents including biologics can be used to induce and
maintain remissions. A variety of other immunomodulatory agents are also used
for disease maintenance. Over the long term, UC patients with a chronic
inflammatory response are at increased risk of dysplasia and colorectal cancer
(Kobayashi et al. 2020). Treatment of UC, therefore, has a number of goals*
symptomatic control, endoscopic healing, the potential for histologic
normalization, steroid avoidance, prevention of hospitalization and surgery,
psychosocial/quality-of-life support, and prevention of cancer.
Increasingly, the intestinal microbiota has been implicated as both a source of
nutrients to maintain gut barrier function and as a regulator of immune
function. Although dysbiosis, including both reduced relative abundance of some
common commensal species and expansion of potentially inflammatory bacteria,
has been reported in patients with UC, no single species is known to drive
onset or severity of UC. Decreases in overall microbial diversity and in
production of short-chain fatty acids (SCFA) and other beneficial
microbiota-derived metabolites have been reported in patients with UC. Given
the potential role of the microbiota in either regulating intestinal immunity
or triggering inflammation, several investigators have explored the therapeutic
potential of fecal microbiota transplantation (FMT) in IBD. In randomized,
controlled studies that have been published to date, FMT has produced clinical
and endoscopic remission in some patients with UC (Costello et al. 2019;
Moayyedi et al. 2015; Paramsothy et al. 2017; Sood et al. 2019). However, FMT
is a complex, costly process that is not standardized, and as a result, there
has been inconsistency in the reported efficacy*both across donors and across
recipients of FMT material from a given donor. In addition, although FMT is
generally well tolerated with transient gastrointestinal adverse events (AEs)
being most commonly reported, the procedure has been reported to carry risk of
transmission of undetected microbial agents, which has resulted in serious
morbidity and mortality in immunocompromised patients (DeFilipp et al. 2019).
Consequently, different approaches to restore a healthy gut microbiome,
including defined bacterial consortia such as VE202, are under investigation.


Description of VE202
VE202 is a rationally defined, live biotherapeutic product (LBP) for oral (po)
administration that consists of 16 well-characterized, clonally-derived,
nonpathogenic, nontoxigenic, commensal strains of Clostridia species. VE202
includes 12 strains from Clostridium cluster XIVa, 2 strains from cluster IV,
and 2 strains from cluster XVIII. These bacteria, which were originally derived
from the stool of a single healthy human, are obligate anaerobes that were
selected for inclusion in the LBP based on individual strain- and
consortia-specific properties that include association with healthy human gut
microbiomes, promotion of colonic regulatory T (Treg) cells, production of
beneficial and immunoregulatory metabolites, and lack of overt pathogenic or
toxigenic features. VE202 is intended to treat UC via the suppression of
IBD-associated inflammation in the gut, reduction of pathobionts associated
with IBD, induction of immunoregulatory cells in the intestine, and production
of epithelium-protective metabolites.

Supportive Nonclinical Data
-Pharmacology
The 16 strains in VE202 are a subset of a 17-strain bacterial consortium that
was isolated from healthy human stool and selected based on the ability to
induce Treg accumulation in the colon of germ-free mice. The 17-strain
consortium was demonstrated to significantly reduce disease severity in several
murine models of colitis. Disease amelioration was associated with accumulation
of colonic lamina propria Treg cells, which are critical for suppression of
pathogenic inflammation. Bacteria in this consortium were shown to produce
several beneficial metabolites including SCFAs, bile acids, and indole.
Colonization of the mouse gut with this consortium significantly increased the
microbial diversity of the gut microbiome and suppressed colitis-associated
expansion of gut mucosal Enterobacteriaceae, a family of bacteria linked to
IBD. Further analysis of the 17-strain consortium identified 1 strain that
exhibited certain attributes of clinical concern (potential for beta-lactamase
activity). That strain was subsequently removed to develop the 16-strain
consortium, VE202.
An LBP that includes 11 of the 16 strains in VE202 also significantly reduced
disease severity in a murine model of colitis; however, the 17-strain
consortium was associated with the production of key beneficial metabolites
that were not produced with the 11-strain consortium (known as VE818). Taken
together, these data suggest that VE202 can promote intestinal immune and
microbial homeostasis.
VE202 strains belong to groups of bacteria that normally colonize the human
intestine in high abundance. They are not known to have any propensity for
clinically relevant drug interactions or cytochrome P450-mediated drug
interactions.

-Toxicology
The Clostridia species in VE202 are co

This study has been transitioned to CTIS with ID 2024-512558-40-00 check the CTIS register for the current data.

Primary
• Evaluate the efficacy of 8 weeks of treatment with VE202 in terms of
endoscopic response at Day 56
• Evaluate the safety of VE202 in Part 1 and Part 2 of the study


Secondary objective
Secondary objective
1. Evaluate the safety of VE202 in Parts 1, 2, and 3 of the study
2. Evaluate the efficacy of 2 weeks of treatment with VE202 in terms of
endoscopic response at Day 56
3. Evaluate the efficacy of 2- and 8 week courses of VE202 in terms of response
as measured by Mayo score at Day 56, compared with baseline
4. Evaluate the efficacy of 2- and 8 week courses of VE202 in terms of
histologic improvement
5. Evaluate the efficacy of 2- and 8 week courses of VE202 in terms of effect
on fecal calprotectin levels
6.• Characterize VE202 colonization in patients treated with 2- and 8-week
courses of VE202
7. • Determine microbiome and metabolite composition in patients treated with
2- and 8-week courses of VE202
8. Evaluate the impact of 2- and 8-week courses of VE202 on IBD-specific
healthcare resource utilization
9. Evaluate the impact of 2- and 8 week courses of VE202 on IBD-specific
health-related quality of life
Exploratory Objective
Summarize changes from baseline in exploratory markers with 2- and 8-week
courses of VE202

Unless a change is medically necessary, study Investigators should attempt to
keep all patients* UC
medications and dosages, including corticosteroids, stable through the end of
Part 2. Should UC rescue
therapy be needed at any time during the study because of an exacerbation of
UC, the choice of therapy
will be at the discretion of the study Investigator; anti-diarrheal agents
should not be administered
unless necessary.
Prior to initiation of any UC rescue therapy, Investigators should perform a
flexible sigmoidoscopy to
corroborate the symptomatic flare, unless specific circumstances preclude this.
The findings of this
additional sigmoidoscopy or the reason for not doing one, must be documented on
the appropriate electronic case report form. If an
exacerbation of UC is confirmed and rescue therapy is initiated, then the study
drug should be
permanently discontinued. However, every effort should be made to retain the
patient in the study for
clinic or remote/virtual safety follow-up visits at the protocol-specified
times.
Part 1:
Eligible randomized patients (100 in total) will receive 5 days of pretreatment
with oral (po)
vancomycin at a dose of 125 mg 4 times daily (QID). After completing vancomycin
pretreatment,
patients in Group A will receive VE202 and patients in Group B will receive
VE202 placebo at a dose
of 10 capsules po once daily (QD) for 14 days, followed by 1 capsule po QD from
Day 15 to 56. The interval between the last dose of vancomycin and the first
dose of VE202 or VE202 placebo should be as short as possible, and no more than
24 hours. The first dose of VE202 or VE202 placebo will be administered under
supervision of study personnel at the Day 1
visit. At the completion of Part 1, all patients will undergo flexible
sigmoidoscopy.

Part 2: After the flexible sigmoidoscopy at Day 56, patients in Group A will
receive vancomycin
placebo po QID for 5 days, followed by placebo for VE202 at a dose of 10
capsules po QD for 14 days.
Patients in Group B will receive vancomycin 125 mg po QID for 5 days, followed
by VE202 at a dose
of 10 capsules po QD for 14 days. The interval between the last dose of
vancomycin (or vancomycin placebo) and the first dose of VE202 or VE202 placebo
should be as short as possible, and no more than 24 hours. Patients will remain
at the study site for direct monitoring of potential AEs for at least 30
minutes following the administration of the first dose of VE202 or VE202
placebo.
There is no study drug administration from Day 15 to Day 56 of Part 2. Another
flexible sigmoidoscopy will be performed 56 days after the start of this second
course of VE202 or VE202 placebo.


Part 3: After completing Part 2, patients will then enter Part 3 long-term
follow-up, which there will be no administration of study drugs. lasting until
approximately365 days (52 weeks) after the first dose of VE202 or VE202 placebo
in Part 1. During ilPart 3 of the study, certain safety parameters (SAEs),
medically attended adverse events [MAAEs], and adverse events of special
interest [AESIs]), safety
clinical disease activity, and colonization dynamics will continue to be
monitored.
Sponsor*s study team and study site personnel will remain blinded throughout
the study period. An
independent Data Monitoring Committee (DMC) will oversee the study and will
have access to
unblinded study data as outlined in the DMC Charter

Investigational product, dosage and mode of administration:
Study patients will be randomized in a 1:1 ratio to Group A or Group B after
all screening criteria are
met. Upon successful completion of pretreatment with vancomycin (125 mg po QID
for 5 days), study
patients in Part 1 will receive VE202 or VE202 placebo as follows:
• Group A: VE202 at a dose of 10 capsules po QD for 14 days, followed by VE202
at a dose of
1 capsule po QD for 42 days
• Group B: VE202 placebo at a dose of 10 capsules po QD for 14 days, followed
by VE202
placebo at a dose of 1 capsule po QD for 42 days
After undergoing flexible sigmoidoscopy at Day 56, patients will begin Part 2
of the study and
receive:
• Group A: Pretreatment with vancomycin placebo po QID for 5 days, followed by
VE202
placebo 10 capsules po QD for 14 days
• Group B: Pretreatment with vancomycin 125 mg po QID for 5 days, followed by
VE202
10 capsules po QD for 14 days
Duration of treatment: 11.5 weeks
• Part 1: 5 days vancomycin plus 56 days VE202/ or VE202 placebo
• Part 2: 5 days vancomycin/placebo plus 14 days VE202/ or VE202 placebo
• Part 3: long term-follow-up (Day 183 to Day 365)
On study (including screening and follow-up): Approximately 56 weeks

VE202 Risks
VE202 has been given to 21 healthy volunteers and has not yet been studied in
patients with ulcerative colitis. The side effects reported in
>1 subject who received VE202 were headache, abdominal discomfort, diarrhea,
weight loss, upper respiratory infection, fatigue, and joint pain. The side
effects were generally mild or moderate, went away without the need for
treatment, and did not last for a long time.

Vancomycin Risks
The most commonly reported risks with the antibiotic vancomycin are:
• Nausea and stomach/abdominal discomfort or pain (very common)
• Muscle or bone pain
• Fever (common)
• Diarrhea
• Swelling in the hands or feet
• Fatigue
• Headache
• Vomiting
• Urinary tract infection

Placebo capsules in this study do not have vancomycin or VE202 in them but they
do have other ingredients that are found in the medication capsules. Rarely, a
person can have an allergic reaction to one of the materials in the placebo
capsule.

Study staff will use a needle to draw blood from the arm. The subject may have
a bruise (black and blue mark) or pain where the blood samples are taken. There
is also a very small risk of infection, lightheadedness, and/or fainting with
blood draws.

See E4

In the days before your flexible sigmoidoscopy, the study doctors may ask the
subject to follow special recommendations about diet and to take certain
preparatory (*prep*) medications. These medications may cause stomach
discomfort, diarrhea, or other unpleasant effects. Right before the exam, the
subject may be given medication to relax/sedate. There is a risk that the
subject may develop an allergic reaction or side effect to that medication.

Complications of flexible sigmoidoscopy are uncommon, occurring in about 1 out
of 1000 procedures. The known complications include bleeding, infection, and
puncturing the intestine. Although very rare, should this occur, surgery may be
necessary to repair the puncture. Heart attacks and strokes are also reported
rarely after sigmoidoscopy.

Some other risks are related to a loss of confidentiality, especially when
using electronic devices to send, store and access information.

See E4, E1a