VTX002 versus Placebo for the Treatment of Moderately to Severely Active Ulcerative Colitis

Prior treatment

• Severe extensive colitis as evidenced by: a. Physician judgment that the participant is likely to require surgery (surgical intervention of any kind for UC [eg, colectomy]) within 12 weeks of baseline b. Current evidence of fulminant colitis or toxic megacolon, or recent history (within last 6 months) of toxic megacolon or bowel perforation c. Previous total colectomy
• History of alcohol or drug abuse within 1 year prior to randomization
• Active or latent tuberculosis (TB) infection at Screening. History of untreated or inadequately treated latent TB infection. The following are EXCEPTIONS to this exclusion criterion: a. Participants with latent TB, who have been ruled out for active TB, have completed an appropriate course of TB prophylaxis treatment per national/local medical guidelines or WHO guidelines, have a chest radiograph without changes suggestive of active TB infection, and have not had recent close contact with a person with active TB are eligible to enroll in the study. It is the responsibility of the Investigator to verify the adequacy of previous TB treatment and provide appropriate documentation of treatment compliance. b. Participants diagnosed with latent TB at Screening, ruled out for active TB and have received at least 4 weeks of an appropriate TB prophylaxis regimen may be rescreened for enrollment. Participant will complete their prophylactic regimen during the trial.
• Known active bacterial, viral, fungal, mycobacterial, or other infection (including TB or atypical mycobacterial disease) or any major episode of infection that required hospitalization or treatment with intravenous (IV) antibiotics within 30 days of Screening or oral antibiotics within 14 days prior to Screening. Fungal infection of nail beds is allowed.

Other illness

• Acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at Screening (positive for hepatitis B surface antigen [HBsAg], or negative for HBsAg and positive for anti-hepatitis B core antibody in conjunction with detectable HBV deoxyribonucleic acid [DNA])
• Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a fistula consistent with Crohn’s disease
• Clinically relevant hematologic, hepatic, neurological, pulmonary, ophthalmological, endocrine, metabolic (including, but not limited to, hypo- and hyperkalemia), psychiatric, or other major systemic disease that will make implementation of the protocol or interpretation of the study difficult or will put the participant at risk
• Current hepatitis C infection or test positive for hepatitis C virus (HCV) at Screening, as defined by positive hepatitis C antibody and detectable HCV ribonucleic acid.
• History of an opportunistic infection (eg, Pneumocystis jirovecii, cryptococcal meningitis), progressive multifocal leukoencephalopathy (PML), or history of disseminated herpes zoster or disseminated herpes simplex.
  • 21.History of currently active primary or secondary immunodeficiency.
• History of cancer within the last 5 years, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved) or precancerous conditions such as colonic mucosal dysplasia, cervical dysplasia, and cervical intraepithelial neoplasia
• History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma
• Human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) or positive test for HIV antibodies at Screening

Lab values

• Pregnancy, lactation, or a positive serum β-hCG measured during Screening
• Have any of the following conditions or receiving treatments that may affect cardiovascular function: a. Myocardial infarction, unstable angina, stroke/transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure within ≤ 6 months prior to or during the Screening Period b. Screening or prerandomization vital signs (taken in the sitting position) with a heart rate (HR) < 50 bpm OR systolic blood pressure (BP) < 90 mmHg OR diastolic BP < 55 mmHg. Vital signs may be repeated up to 3 times during a visit to confirm abnormal readings. c. Screening or prerandomization electrocardiogram (ECG) with PR interval > 200 msec or Fridericia’s corrected QT interval (QTcF) ≥ 450 msec in men or ≥ 470 msec in women. d. For study sites in Germany and Italy: Uncontrolled arterial hypertension. e. History of any of the following unless treated with an implanted pacemaker or an implanted cardioverter-defibrillator with pacing: i. History or presence of recurrent symptomatic bradycardia ii. Second- or third-degree atrioventricular block iii. Periods of asystole > 3 seconds iv. History of sick sinus syndrome or recurrent cardiogenic syncope (For study sites in Germany and Italy: History of cardiac arrhythmia requiring treatment or any of the following unless treated with an implanted pacemaker or an implanted cardioverter defibrillator with pacing): i. History or presence of recurrent symptomatic bradycardia ii. Second- or third-degree AV block iii. Periods of asystole > 3 seconds iv. History of sick sinus syndrome or recurrent cardiogenic syncope. f. Start, stop, or change in dosage of any Class I-IV anti-arrhythmic drugs ≤ 1 week prior to dose titration starting at randomization and up to 1 week after titration to the assigned dose. This criterion also applies to the OLE Treatment Period titration: 1 week prior to and 1 week after the dose titration period. (For study sites in Germany and Italy: this criterion is not applicable).
• Uncontrolled diabetes as determined by hemoglobin A1c (HbA1c) > 9%, or participants with diabetes with significant comorbid conditions, such as retinopathy
• Any of the following laboratory abnormalities during the Screening Period: a. Absolute white blood cell (WBC) count < 3500/μL b. Neutrophils < 1500/μL c. Absolute lymphocyte count < 800/μL d. Platelet count < 100,000/μL e. Hemoglobin < 8 g/dL

Other

• Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis
• Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) or positive test for Clostridium difficile at Screening. Note: If C. difficile or pathogen test is positive, the participant may be treated and retested ≥ 4 weeks after completing treatment.
• Forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) < 70% of predicted values and FEV1/FVC ratio < 0.70 at Screening
• History or presence of macular edema or retinopathy

• Men or women, 18 to 80 years of age, inclusive, at the time of consent (For study sites in Germany and Italy: Men or women, 18 to 75 years of age, inclusive, at the time of consent.)
• Participants are permitted to receive the following concomitant medications: a. Oral 5-ASA compounds at a stable dose or discontinued for ≥ 2 weeks prior to Screening endoscopy (For study sites in Germany and Italy: Oral 5-ASA compounds at a stable dose or discontinued for ≥ 4 weeks prior to Screening endoscopy.) b. Oral corticosteroid therapy at a stable dose or discontinued for ≥ 2 weeks prior to Screening endoscopy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a stable dose ≤ 9 mg/day) c. Probiotics, provided the dose has been stable for ≥ 2 weeks prior to Screening endoscopy
• Women must meet either a or b of the following criteria and men must meet criterion c to qualify for the study: a. A woman who is not of childbearing potential must meet 1 of the following: i.Postmenopausal, defined as no menses for 12 months without an alternative medical cause ii.Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or bilateral oophorectomy b. A nonpregnant woman of childbearing potential must agree to use a highly effective contraception method that can achieve a failure rate of less than 1% per year when used consistently and correctly. The highly effective contraception must be used through the duration of the study and for 30 days )for study sites in Germany and Italy: 35 days) after the last dose of study treatment. The following are considered highly effective birth control methods: i. Combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, which may be oral, intravaginal, or transdermal. ii. Progesterone-only hormonal contraception associated with inhibition of ovulation, which may be oral, injected, or implanted iii. Intrauterine device iv. Intrauterine hormone-releasing system v. Bilateral tubal occlusion vi. Vasectomized partner, provided that the partner is the sole sexual partner of the woman of childbearing potential study participant and the vasectomized partner has received medical assessment of the surgical success vii. Sexual abstinence (complete sexual abstinence, defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatments). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (calendar, symptothermal, postovulation methods) is not acceptable. c. A man with a pregnant or nonpregnant partner who is a woman of childbearing potential must agree to use condoms through the duration of the study and for 30 days (for study sites in Germany and Italy: 90 days) after the last dose of study treatment
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form
• 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 the source documents; however, if not available, the Screening endoscopy and histology may serve as such.
• Active UC confirmed by endoscopy with ≥ 10 cm rectal involvement. Participants with proctitis only at baseline who meet the other eligibility criteria for inclusion, including the endoscopic and rectal bleeding criteria for moderate to severe disease, will be capped at 10% of the total participants enrolled.
• Moderately to severely active UC, defined as an MMS of 5 to 9, including an endoscopic subscore (ES) ≥ 2 and a rectal bleeding (RB) subscore ≥ 1
• Surveillance colonoscopy (performed according to local standard) within 12 months before baseline to rule out dysplasia in participants with pancolitis > 8 years duration or participants with left-sided colitis > 12 years duration. Participants without a surveillance colonoscopy within the prior 12 months will have a colonoscopy at Screening (ie, in place of Screening proctosigmoidoscopy). Any adenomatous polyps must be removed per local standard of care prior to the first dose of study drug.
• Demonstrated inadequate response to, loss of response to, or intolerance to at least 1 of the following therapies: a. Conventional therapy: i. Oral 5-aminosalicylic acid (5-ASA) compounds (For study sites in Germany and Italy: This conventional therapy is not applicable) ii. Corticosteroids (For study sites in Germany and Italy: • Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen at doses per institutional standard of care OR • 2 failed attempts to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily OR • History of intolerance of corticosteroids (including, but not limited to Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection.) iii. Thiopurines (eg, azathioprine or 6-mercaptopurine) (For study sites in Germany and Italy: • Signs and symptoms of persistently active disease despite a history of at least one 8-week regimen of oral azathioprine or 6-mercaptopurine at doses per institutional standard of care OR • History of intolerance of at least one of these immunosuppressives (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities, lymphopenia, TPMT genetic mutation, infection.) b. Biologic therapy or JAK inhibitor therapy: i. Anti-tumor necrosis factor alpha (TNFα) antibodies (eg, infliximab, adalimumab, or golimumab) (For study sites in Germany and Italy: • Signs and symptoms of persistently active disease despite a history of completing an induction regimen with at least one of the following: infliximab, adalimumab, or golimumab at doses per the current labeling and/or institutional standard of care OR • Recurrence of symptoms during maintenance dosing with infliximab, adalimumab, or golimumab following prior clinical benefit (discontinuation despite clinical benefit does not qualify) OR • History of intolerance to infliximab, adalimumab, or golimumab (including, but not limited to infusion- or injection-related reaction, demyelination, congestive heart failure, infection) ii. Anti-interleukin (anti-IL)12/23 (eg, ustekinumab)(For study sites in Germany and Italy: • Recurrence of symptoms during maintenance dosing with ustekinumab following prior clinical benefit (discontinuation despite clinical benefit does qualify) per the current labeling and/or institutional standard of care OR • History of intolerance to ustekinumab (including, but not limited to infusion- or injection-related reaction) iii. Anti-integrin antibodies (eg, vedolizumab) (For study sites in Germany and Italy: • Recurrence of symptoms during maintenance dosing with vedolizumab following prior clinical benefit (discontinuation despite clinical benefit does qualify) per the current labeling and/or institutional standard of care OR • History of intolerance to vedolizumab (including, but not limited to infusion related reaction) iv. JAK inhibitors (eg, tofacitinib, upadacitinib) (For study sites in Germany and Italy: • Recurrence of symptoms during maintenance dosing with a JAK inhibitor following prior clinical benefit (discontinuation despite clinical benefit does qualify) per the current labeling and/or institutional standard of care OR • History of intolerance to a JAK inhibitor.)
• Adequate hepatic function, defined as a total bilirubin level of ≤ 1.5 × upper limit of normal (ULN) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of ≤ 2.0 × ULN. Participants with Gilbert’s syndrome who have an isolated total bilirubin and normal AST and ALT levels may participate.
• Adequate renal function, defined as an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration equation at Screening