Study to Evaluate the Clinical Activity and Safety of Oral NX-13 in Participants with Moderate to Severe Ulcerative Colitis

Prior treatment

• Severe extensive colitis as evidenced by: • Physician judgment that the participant is likely to require hospitalization for medical care or surgical intervention of any kind for UC (e.g., colectomy) within the 12 weeks after randomization • Current evidence of fulminant colitis, toxic megacolon or recent history (within 6 months prior to screening) of toxic megacolon, or bowel perforation
• Hospitalization for exacerbation of UC requiring IV steroids (i.e., UC flare) within 12 weeks prior to screening (a single dose of IV steroids is acceptable)
• Treatment with cyclosporine, tacrolimus, sirolimus, methotrexate, or mycophenolate mofetil within 4 weeks prior to screening.
• Thiopurine washout is required to be completed within 6 weeks prior to screening.
• Treatment with a biologic agent (e.g., infliximab, vedolizumab) within 6 weeks or 5 elimination half-lives (whichever is less) prior to screening. For anti-IL-12/23 (p19 or p40 subunits) (e.g., ustekinumab) a total of 12 weeks (6 weeks prior to screening and 6 weeks of screening) or 5 elimination half-lives (whichever is less) of washout.
• Treatment with an advanced oral UC therapy (e.g., JAK inhibitor, S1P modulator) within 4 weeks prior to screening
• Treatment with IV glucocorticosteroids/glucocorticoids, rectal glucocorticosteroids/ glucocorticoids, rectal or topical 5-ASA, or enema within 2 weeks prior to screening
• Treatment with oral prednisone at a daily dose of > 20 mg (or equivalent) or active oral glucocorticosteroids/ glucocorticoids , e.g., budesonide at a daily dose of > 9 mg or equivalent, within 30 days prior to screening. If receiving systemically active oral glucocorticosteroids/ glucocorticoids , must be on a stable dose for at least 14 days prior to screening.
• Live virus vaccination within 4 weeks prior to randomization (Note: no currently available vaccine for SARS-CoV-2 is a live virus vaccine)
• Fecal microbial transplantation within 30 days prior to screening
• Previously received stem cell transplantation
• Has been a previous recipient of an organ transplant, which requires continued immunosuppression
• Any surgical procedure requiring general anesthesia within 4 weeks prior to randomization, or planned elective surgery during the study
• Requirement for regular dosing of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) or inducers (e.g., rifampin, phenytoin, carbamazepine) or CYP2C19 inhibitors (e.g., fluconazole, fluoxetine, fluvoxamine, ticlopidine) or inducers (e.g., rifampin).
• Any concurrent clinically significant medical condition that, in the judgment of the investigator, may pose an unacceptable risk to the participant, including any known hypersensitivity to the drug product or any of its excipients
• Participants with evidence of active or latent infection with Mycobacterium tuberculosis (TB) or participants with this history who have not completed a generally accepted full course of treatment (with completion of this treatment at least 6 months prior to start of screening) are excluded. All other participants must have either the Mantoux (purified protein derivative [PPD]) tuberculin skin test or interferon gamma release assay (IGRA) performed. See Section 12.7 for details.
• Concurrent participation in any other investigational study, or individuals who have received any investigational therapy within 4 weeks or 5 elimination half-lives (whichever is longer) prior to screening
• Women who are pregnant, breastfeeding, or contemplating pregnancy, from the time of informed consent until at least 30 days after the last dose of investigational product.
• Diagnosis of microscopic colitis, ischemic colitis, or radiation colitis
• History of active bacterial, viral, fungal, or mycobacterial infectious colitis requiring oral antibiotic/anti-infective treatment within 4 weeks prior to screening.
• Infection requiring hospitalization or intravenous (IV) antimicrobial therapy within 8 weeks prior to screening

Other illness

• Confirmed or suspected infection of the intestinal tract, including positive Clostridioides difficile stool test at screening
• Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at screening
• Have current hepatitis C infection or test positive for hepatitis C virus (HCV) at screening
• Diagnosis of Crohn’s disease (CD) or indeterminate colitis, or the presence or history of a fistula consistent with CD
• Have known infection with human immunodeficiency virus as confirmed by medical history
• History of malignant neoplasms or carcinoma within 5 years prior to screening (except basal cell and in situ squamous cell carcinomas of the skin that have been fully excised and resolved)
• Current or recent history of alcohol dependence or recreational drug use that, in the opinion of the investigator, may interfere with the individual’s ability to comply with the study procedures
• Mental or legal incapacitation at the time of screening or a history of clinically significant psychiatric disorders that would impact the individual’s ability to participate in the study, according to the investigator
• Presence of indefinite dysplasia or UC-associated dysplasia on colonoscopy or FS, or a history of UC-associated dysplasia
• History of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy; or is planning bowel surgery
• History of spontaneous gastrointestinal (GI) perforation (other than appendicitis or mechanical injury), diverticulitis, or at significantly increased risk of GI perforation per the investigator’s judgment

Lab values

• Liver transaminases (ALT, AST) > 1.5× ULN at screening
• Total bilirubin > 1.5× ULN at screening, or > 2.0× ULN for individuals with Gilbert’s syndrome
• Hemoglobin < 9g/dL (< 5.6 mmol/L) at screening

Other

• Known primary or secondary immunodeficiency
• Inadequate response to an induction course of more than 2 classes of biologics (e.g. TNF alpha, integrin or IL-12/23) approved for UC
• Unable to comply with study activities (e.g., swallow 3 whole tablets per day without crushing, breaking, or chewing)
• Estimated absolute glomerular filtration rate of < 30 mL/minute
• Individuals who are investigational site staff members or relatives of those site staff members or are Sponsor or CRO employees directly involved in the conduct of the study

• 18 to 75 years of age at time of informed consent
• Women of childbearing potential (WOCBP) must: • Agree to use birth control methods that are considered highly effective: o Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal o Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable o Intrauterine device (IUD) o Intrauterine hormone-releasing system (IUS) o Bilateral tubal occlusion o Vasectomized partner o Sexual abstinence Note: Contraceptive measures such as Plan B (used after unprotected sex) are not considered highly effective methods of contraception for this study • Agree not to participate in a conception process (i.e., active attempt to become pregnant, egg donation, in vitro fertilization) for at least 30 days after the last dose of investigational product
• Able to give informed consent, attend, and comply with study visits and e-diaries
• Diagnosed with UC ≥ 3 months prior to screening. The diagnosis of UC must be confirmed by endoscopic and histologic evidence. The endoscopy and histology report should be present in source documents; however, if not available, the screening endoscopy and histology report may serve as such.
• Received a surveillance colonoscopy (performed according to local standard) within 12 months prior to the planned randomization date to rule out dysplasia in individuals with pancolitis > 8 years duration or individuals with left sided colitis > 12 years duration. Individuals without a surveillance colonoscopy within the prior 12 months will have a colonoscopy at screening (i.e., in place of the screening proctosigmoidoscopy). Any adenomatous polyps must be removed according to routine practice prior to the study participant’s first dose of investigational product.
• Moderate to severe disease activity, characterized by all of the following (see Section 7.3.1 for details): • MMS ≥ 5 defined as follows: • ES ≥ 2 within 14 days prior to randomization • RBS ≥ 1
• An inadequate response to, loss of response to, or intolerance of at least 1 of the following therapies, as defined below (see Section 12.9 for details): Conventional therapy classes: • Oral 5-ASA compounds plus systemic glucocorticosteroids/glucocorticoids • Systemic glucocorticosteroids/glucocorticoids • Thiopurines Biologic therapy classes: • Anti-TNF monoclonal antibodies or biosimilars • Anti-integrin monoclonal antibodies • Anti-IL-12/23 monoclonal antibodies Advanced therapy classes: • JAK inhibitors • S1P receptor modulators
• Eligible male participants must either: • Be surgically sterile (i.e., vasectomy) for ≥ 3 months (≥ 90 days) before screening; or • Agree to the following, from the time of randomization until at least 30 days after last dose of investigational product: o Agree to use a condom with spermicide when sexually active with a female partner who was not using a highly effective method of birth control o Agree not to participate in a conception process (i.e., active attempt to impregnate, sperm donation, or in vitro fertilization)
• Eligible female participants must be: • Nonpregnant, evidenced by a urine dipstick pregnancy test within 24 hours prior to randomization, and • Nonlactating
• Eligible female participants of non-childbearing potential must be surgically sterile or postmenopausal (defined as ≥ 1 year without menses). • Women must be surgically sterile for at least 6 months before screening as confirmed by medical history. Surgical procedures are tubal ligation performed laparoscopically, hysterectomy, and/or bilateral oophorectomy; or other procedures if sponsor agrees. • A postmenopausal state is defined as no menses for ≥ 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.