Study of EXE-346 Live Biotherapeutic to Reduce High Bowel Movement Frequency in Subjects with an IPAA (PROF)

The aim of this study is to assess the safety and preliminary efficacy of treatment with EXE-346, a live biotherapeutic, which may reduce bowel movement frequency in patients with an ileal pouch-anal anastomosis (IPAA) and lead to a higher quality of life.

The aim of this study is to assess the safety and preliminary efficacy of treatment with EXE-346 which may reduce bowel movement frequency in patients with an IPAA and lead to a higher quality of life. EXE-346 is a live biotherapeutic product containing a fixed proportion mixture of 8 individual bacterial strains.

The Phase 1b part of the study is an open label (OL), single-arm study to assess the safety of EXE-346 administered orally for up to 4 weeks.

The Phase 2 part of the study is a randomized, double-blinded study to assess the safety and efficacy of the same dose of EXE-346 administered orally for up to 8 weeks, compared with placebo. Subjects who complete the Phase 2 double-blinded part of the study will be eligible to participate in an optional open label extension phase to receive EXE-346 for up to 8 weeks.

Eligibility Criteria:
Inclusion Criteria - Phase 1b Only

1. Subject is a male or female and is between the age of 18 to 70 years, inclusive, at screening.
2. Subject has had a documented pouchoscopy within 12 months prior to screening.
3. Subject or the subject's legally authorized representative is willing and able to provide written informed consent prior to the initiation of any study-related procedures.
4. Subject has an average daily bowel movement frequency of at least 10 bowel movements recorded during screening and has correctly completed at least 7 days of eDiary entries during the screening period (Days -13 to 0).

Inclusion Criteria - Phase 2 Double-Blinded Part Only

1. Subject is a male or female and is aged 18 years or older at screening.
2. Subject is willing and able to provide written informed consent prior to the initiation of any study-related procedures.
3. Subject has an average daily bowel movement frequency of at least 10 bowel movements recorded during screening and has correctly completed at least 7 days of eDiary entries during the screening period (Days -21 to 0).

Inclusion Criteria - Both Phase 1b and Phase 2 Double-Blinded Parts

1. Subject has had an IPAA for at least 6 months prior to screening.
2. Female subjects of childbearing potential must have a negative serum pregnancy test result at screening and must not be lactating and/or breastfeeding.
3. Subjects (female subjects of childbearing potential and male subjects with partners of childbearing potential) must agree to use proper contraceptive methods (see Section 13.2 for contraceptive guidance) to avoid pregnancy during the study. Nonchildbearing potential is defined as at least 6 weeks after a hysterectomy with or without surgical bilateral oophorectomy or postmenopausal (at least 12 months since natural amenorrhea).

Inclusion Criteria - Optional Open-Label Extension Phase Only

1. Subjects must have completed the Phase 2 double-blinded part of the study and are willing to participate in the optional open-label extension phase.

   Note: Subjects who discontinued study treatment in the Phase 2 double-blinded part but who have remained in the study for safety monitoring are eligible for continued safety monitoring in the optional open-label extension phase; however, study treatment will not be re-started in such subjects.
2. Subjects must understand the study procedures, the risks involved, and are willing to continue to adhere to the study visit/protocol schedule.

Exclusion Criteria Subjects meeting any of the criteria specified below for the study phase in which they are enrolling will be excluded from the study.

Exclusion Criteria - Phase 1b Only

1. Subject has Crohn's-like disease of the pouch, as indicated by their most recent pouchoscopy during the 12 months prior to screening.
2. Subject has a stricture of the IPAA or afferent limb stricture, as indicated by their most recent pouchoscopy during the 12 months prior to screening.
3. Subject has taken biologics, azathioprine, or methotrexate within the 12 weeks prior to screening or systemic steroids within 4 weeks of screening.
4. Subject has a positive reverse transcriptase-PCR diagnostic test for SARS-CoV-2 within the 14 days prior to screening.
5. Subject has uncontrolled hypertension (systolic pressure \>160 mm Hg or diastolic pressure \>95 mm Hg on at least 2 measures performed at least 10 minutes apart) at screening.

Exclusion Criteria - Phase 2 Double Blinded Part Only

1. Subject has Crohn's-like disease of the pouch, as indicated by the pouchoscopy conducted during study screening.
2. Subject has isolated severe cuffitis without pouch inflammation (endoscopic mPDAI score of 2 or lower), as indicated by the pouchoscopy conducted during study screening.
3. Subject has a clinically significant stricture of the IPAA or afferent limb stricture which requires surgery or recurrent dilations more than every 3 months, as indicated by the pouchoscopy conducted during study screening. Subjects who have a planned dilation during the active study period are excluded (dilation during the screening pouchoscopy is allowed).
4. Subject has taken biologics, azathioprine, methotrexate or small molecules (e.g., JAK inhibitors, S1P receptor modulators) within the 12 weeks prior to screening or systemic steroids within 4 weeks prior to screening.
5. Subject has a positive reverse transcriptase-PCR diagnostic test for SARS-CoV-2 within the 7 days prior to screening, per subject self report.
6. Subject has an average daily bowel movement frequency of \>25 bowel movements recorded during the screening period (Days -21 to 0).
7. Subject is taking opioid therapy as a long-term treatment or has taken opioids within 2 weeks prior to screening.
8. Subject has taken probiotics within 2 weeks prior to screening.
9. Subject has previously received EXE-346 for any duration. Subjects who participated in Phase 1b are excluded from Phase 2.
10. Subject has a concurrent, clinically significant, serious, unstable or uncontrolled medical or psychiatric condition that, in the opinion of the investigator, might confound study results, pose additional risk to the subject, or interfere with the subject's ability to participate fully in the study.

Exclusion Criteria - Both Phase 1b and Phase 2 Double-Blinded Part

1. Subject has enterocutaneous or recto- or pouch-vaginal fistula.
2. Subject has active Clostridium difficile infection.
3. Subject has known or suspected active CMV infection.
4. Subject initiated a new treatment with antibiotics or antimotility therapies within the 2 weeks prior to screening or plans to start a new or change doses of a current treatment during the study period (screening visit through the safety follow-up visit \[Day 57 in the Phase 1b part or Day 71 in the Phase 2 part\]). Subjects taking antibiotics to treat antibiotic-dependent pouchitis or antidiarrheal medication are eligible for the study provided they have been on the therapy at a stable dose for at least 2 weeks prior to screening.
5. Subject is taking NSAIDs as a long-term treatment (ie, consistent use for at least 4 days/week each month). Acute use of NSAIDs is allowed.
6. Subject has a known history or positive test during screening for HIV, HIV-1, HIV-2, or active HBV or HCV. Active HCV infection is defined as a subject with a positive hepatitis C antibody and detectable hepatitis C viral load RNA.
7. Subject has a history of malignancy within the 5 years prior to screening, with the exception of nonmelanoma skin cancer that has been treated with no evidence of recurrence, treated cervical dysplasia, or treated in situ grade 1 cervical cancer.
8. Subject has estimated glomerular filtration rate \<30 mL/min/1.73 m2 at screening.
9. Subject has known hypersensitivity to EXE-346 or any product components.
10. Female subject is pregnant or lactating and/or breastfeeding.
11. Subject has participated in any clinical study of an approved or nonapproved investigational medicinal product within the 30 days prior to screening.
12. Subject has any disorder that, in the investigator's opinion, might jeopardize the subject's safety or compliance with the protocol, including but not limited to:

    1. Decompensated liver disease
    2. Elevation of AST, ALT, or bilirubin \>2 × ULN
    3. Primary sclerosing cholangitis with elevated transaminases

Exclusion Criteria - Optional Open-Label Extension Phase Only

1. Subjects who have developed any medical or psychologic condition, which was excluded in the Phase 2 double-blinded part of the study or in the opinion of the investigator and/or medical monitor might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.