Evaluation of Safety, Efficacy, and Pharmacokinetics of PRA023 Induction Therapy in Moderate to Severe Ulcerative Colitis: A Phase 2, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-509741-12-00
Protocol: PR200-102
Sponsor: Prometheus Biosciences Inc.

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Diseases & Conditions

Colitis ulcerative

Objectives

The primary objective of this study is to assess the **safety** and tolerability of PRA023 following 12 weeks of induction therapy in subjects with moderately to severely active **ulcerative colitis**. This is clinically relevant as it evaluates the potential of PRA023 to be a safe treatment option for patients suffering from this chronic inflammatory bowel disease, which can significantly impact quality of life.

Secondary objectives include:

Comparing the efficacy of PRA023 versus placebo for induction of endoscopic improvement, clinical response, clinical remission, symptomatic remission, histologic remission, histologic-endoscopic mucosal improvement, and mucosal healing at Week 12.
Evaluating the efficacy of PRA023 in CDx positive (CDx+) subjects for the same endpoints as above, and comparing it to CDx negative (CDx-) subjects for clinical remission.
Assessing changes in the Inflammatory Bowel Disease Questionnaire (IBDQ) scores at Week 12.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic potential of PRA023 in improving various clinical and histological outcomes in ulcerative colitis, thereby informing its efficacy profile in different patient subgroups.

Participants

The clinical trial involves a total of **23 participants** diagnosed with **Ulcerative Colitis**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their diagnosis of moderately to severely active Ulcerative Colitis, confirmed by endoscopy and histology, and their previous treatment history. The trial includes individuals who have had an inadequate response or intolerance to certain treatments, such as corticosteroids, immunosuppressants, or biologic therapies, or those currently receiving specific treatments. Participants are required to meet drug stabilization requirements and adhere to contraception guidelines if applicable. The trial population is composed of individuals who are able to provide informed consent and comply with study requirements. The study also includes a vulnerable population, ensuring a comprehensive assessment of the investigational treatment's safety and efficacy.

Plans and Procedures

The clinical trial is designed as a **Phase 2**, multi-center, double-blind, placebo-controlled study to evaluate the safety, efficacy, and pharmacokinetics of induction therapy with the investigational drug **tulisokibart** in subjects with moderately to severely active **ulcerative colitis**. The trial aims to assess the safety and tolerability of the drug following 12 weeks of induction therapy and to compare its efficacy against a placebo for inducing clinical remission at Week 12. The study is expected to run from October 2021 to January 2027, with participant involvement lasting up to 12 weeks.

Participants will be randomly assigned to receive either tulisokibart or a placebo, administered via **intravenous infusion**. The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, diagnosis of ulcerative colitis, and previous treatment history. Eligible participants will then proceed to the baseline visit, where they will be randomized and receive their first dose of the study drug. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will take place at Week 12, where final assessments will be conducted to evaluate the primary and secondary endpoints, including clinical remission and endoscopic improvement.

Participants are expected to remain in the study for the full 12-week duration unless they experience adverse events that necessitate early termination, fail to comply with study procedures, or withdraw consent. The primary endpoints include the proportion of subjects reporting adverse events and achieving clinical remission as defined by the 3-component Modified Mayo Score. Secondary endpoints focus on endoscopic improvement, symptomatic remission, and histologic remission, among others. The study will ensure that a balanced proportion of subjects with prior biologic therapy experience is maintained, with specific criteria for inclusion and exclusion to optimize the study's scientific validity.

Treatment

The clinical trial involves the administration of the experimental medication **tulisokibart**, which is a **concentrate for solution for infusion**. This investigational product is developed by Merck & Co. Inc. and is identified by the sponsor product code MK-7240. The active substance, **tulisokibart**, is of biological/biotechnological origin, specifically classified as a protein of other origin. The pharmaceutical form of tulisokibart is designed for intravenous infusion, ensuring direct delivery into the bloodstream. The dosing regimen for tulisokibart includes a maximum daily dose of 1000 mg and a maximum total dose of 2500 mg over a treatment period not exceeding 170 days. The administration schedule is tailored to achieve optimal therapeutic outcomes while maintaining participant safety.

In addition to the experimental treatment, the study employs a placebo-controlled design to evaluate the efficacy and safety of tulisokibart. The placebo is administered in a manner identical to the experimental drug, serving as a comparator to assess the true effects of tulisokibart. The placebo is also delivered via intravenous infusion, ensuring blinding and maintaining the integrity of the study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the treatment's impact on moderately to severely active **ulcerative colitis**.

Efficacy

Efficacy in this clinical trial will be assessed using the **3-component Modified Mayo Score**, which evaluates clinical remission in subjects with moderately to severely active ulcerative colitis. The primary endpoint is the proportion of subjects achieving clinical remission at Week 12, defined by an endoscopic subscore of 0 or 1, a rectal bleeding subscore of 0, and a stool frequency subscore of 0 or 1, with scores not exceeding Baseline. Secondary endpoints include the proportion of subjects with endoscopic improvement, clinical response, symptomatic remission, histologic remission, histologic-endoscopic mucosal improvement, and mucosal healing, all evaluated at Week 12. The Modified Mayo Score ranges from 0 to 9 and includes domains for rectal bleeding, stool frequency, and endoscopic assessment. Additionally, the proportion of subjects with an Inflammatory Bowel Disease Questionnaire (IBDQ) response, defined by a ≥16-point increase from Baseline, will be measured. These efficacy parameters will be collected and analyzed at the specified timepoint of Week 12 to determine the effectiveness of the investigational product, PRA023, compared to placebo. The trial will employ validated scales and assessments to ensure the accuracy and reliability of the efficacy data collected.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female ≥ 18 years of age.
Subjects must have had a diagnosis of UC at least 3 months before Screening (confirmed by endoscopy + histology) to be eligible for study participation. For subjects with no documented confirmation of UC diagnosis or if previous diagnosis is not deemed conclusive, UC diagnosis must be confirmed at time of screening colonoscopy. Note that mention of “chronic inflammation” or “ulcerative colitis” or equivalent on histology report is acceptable.
Moderately to severely active UC as defined by 3-component Modified Mayo score (3 components of rectal bleeding, stool frequency, and endoscopy) of 4 to 9, inclusive, with Modified Mayo endoscopic subscore ≥ 2 and rectal bleeding subscore ≥ 1.
Subjects must satisfy at least one of the following criteria: a) In the past, had an inadequate response to one or more of the following treatments: • Oral prednisone ≥ 40 mg/day (or equivalent) or budesonide ≥ 9 mg/day or equivalent or beclomethasone ≥ 5 mg/day for at least 2 weeks • Corticosteroid dependence as defined by failed to successfully taper to < 10 mg/day of prednisone or equivalent (i.e., had a flare of disease) within 3 months of starting therapy, or if relapse occurs within 3 months of stopping corticosteroids • Immunosuppressants (azathioprine ≥ 2 mg/kg/day or 6 mercaptopurine ≥ 1.0 mg/kg/day [or documentation of a therapeutic concentration of 6-thioguanine nucleotide]) for at least 8 weeks. Note: a lower dosage of 6-MP or AZA is acceptable if local guidelines specify a different treatment regimen (which would need be documented in the source document) • An approved anti-TNF agent at an approved labeled dose for at least 8 weeks • Vedolizumab at the approved labelled dose for at least 8 weeks • An approved JAK inhibitor (e.g., tofacitinib, upadacitinib, or filgotinib) at an approved labelled dose for at least 8 weeks • An approved anti-IL-12/23 (e.g., ustekinumab) at an approved labelled dose for at least 8 weeks • An approved sphingosine 1-phosphate receptor (S1PR) modulator (e.g., ozanimod) at an approved labelled dose for least 12 weeks OR b) Had been intolerant to one or more of the above-mentioned treatments (e.g., unable to achieve doses or treatment durations because of dose limiting side effects [e.g., leukopenia, psychosis, uncontrolled diabetes, elevated liver enzymes]). OR c) Currently receiving one or more of the following treatments: • Oral Prednisone ≥ 10 mg/day (or equivalent) for at least 3 months • Immunosuppressants [azathioprine ≥ 2 mg/kg/day or 6 mercaptopurine ≥ 1.0 mg/kg/day (or documentation of a therapeutic concentration of 6 thioguanine nucleotide)] for at least 8 weeks. Note: a lower dosage of 6-MP or AZA is acceptable if local guidelines specify a different treatment regimen (which would need be documented in the source document) Notes on subjects who have had prior biologic/biologic-like therapy(ies) (anti-TNF, JAK inhibitor, S1PR modulator, anti-IL-12/23, and/or anti-integrin): • The study will include a maximum of 70% and a minimum of approximately 50% subjects who have had prior biologic/biologic-like therapy(ies) experience. Upon reaching the maximum number of allowed biologic/biologic-like experienced subjects (70%), subjects who have had prior biologic/biologic-like experience will no longer be allowed to enter the study. Upon reaching the maximum number of allowed biologic/biologic-like naïve subjects (approximately 50%), subjects who have never been exposed to a prior biologic/biologic-like will no longer be allowed to enter the study. • Subject cannot have failed (no response, insufficient response, loss of response, and/or intolerance) > 3 classes or > 4 individual biologic/biologic-like therapies (refer to exclusion criterion #26).
For subjects who are women of childbearing potential (WOCBP) involved in any sexual intercourse that could lead to pregnancy, the subject has used two highly effective methods of contraception for at least 4 weeks prior to Day 1 and agrees to continue to use two highly effective methods of contraception until at least 12 weeks after the last dose of study drug.
Male subjects must use, with their female partner of childbearing potential, two highly effective methods of contraception and refrain from sperm donation from screening to 12 weeks after the last dose of study drug.
Subject must meet drug stabilization requirements, as applicable: a) Oral corticosteroid treatment must be equivalent of ≤ 20 mg prednisone or ≤ 9 mg budesonide or beclomethasone ≤ 5 mg daily at a stable dose for at least 2 weeks prior to randomization b) Oral aminosalicylates should be at a stable dose for at least 2 weeks prior to randomization c) Azathioprine and 6-mercaptopurine should be at a stable dose for at least 4 weeks prior to randomization
Able to provide written informed consent and understand and comply with the requirements of the study.
For Cohort 2 only: Subjects must be CDx+.

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Exclusion Criteria

WOCBP and men with female partners of childbearing potential who are unwilling or unable to use two highly effective methods of contraception to avoid pregnancy for the entire study period and for up to 12 weeks after the last dose of study drug.
Women who are pregnant or breastfeeding.
Women with a positive pregnancy test on enrollment or prior to randomization.
Diagnosis of Crohn’s disease or indeterminate colitis.
UC limited to the rectum (< 15 cm from anal verge).
Current evidence of fulminant colitis, toxic megacolon, or bowel perforation.
Current or impending need for colostomy or ileostomy.
Previous total proctocolectomy or partial colectomy.
Surgical bowel resection within 3 months before screening.
Concomitant primary sclerosing cholangitis (PSC)
Past or current evidence of definite low-grade or high-grade colonic dysplasia that has not been completely removed.
Subjects who are scheduled or anticipate the need for surgery, aside from dermatologic procedures
Subjects who have a history of clinically significant drug or alcohol abuse.
Concomitant illness that in the opinion of the Investigator, is likely to require systemic glucocorticosteroid therapy during the study (e.g., moderate to severe asthma).
Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, pulmonary, cardiac, neurological, ophthalmologic or cerebral disease. Concomitant medical conditions that in the opinion of the Investigator might place the subject at unacceptable risk for participation in this study
Subjects with a history of cancer within the last 5 years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to enrollment. Subjects with carcinoma in situ or localized cervical cancer, treated with definitive surgical intervention, are allowed.
Subjects at risk for tuberculosis (TB). Specifically, subjects with: a) A history of active TB b) Current clinical, radiographic or laboratory evidence of active TB c) Latent TB which was not successfully treated. Subjects with a positive TB screening test indicative of latent TB will not be eligible for the study unless active TB infection has been ruled out, and an appropriate course of intervention for latent TB has been initiated at least 2 weeks prior to randomization, and no evidence of active TB on chest x-ray during Screening.
Subjects with any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection (such as chronic pyelonephritis, osteomyelitis and bronchiectasis).
Female subjects who have had a breast cancer screening that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations.
Subjects with any active infections (excluding fungal infections of nail beds) including, but not limited to, those that require intravenous (IV) antimicrobial treatment 4 weeks or oral antimicrobial treatment 2 weeks prior to randomization. Subjects with evidence of Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C infection detected during screening are also excluded, but subjects with successfully treated Hepatitis C with no recurrence for ≥ 1 year are allowed. Subjects with active documented or suspected COVID-19 infection within 4 weeks of randomization or asymptomatic SARS-CoV-2 test positivity within 2 weeks of randomization are excluded
Subjects with herpes zoster reactivation or cytomegalovirus (CMV) that resolved less than 2 months prior to signing informed consent.
Subjects who have received any live vaccines within 3 months of the anticipated first dose of study medication or who will have need of a live vaccine at any time during the study.
Positive stool studies [e.g., by Polymerase Chain Reaction (PCR), bacterial culture, toxin, etc.] if Investigator deems this positivity reflects infection rather than colonization. Subjects who have an infection can be retested after the completion of a full course of treatment, if treatment is deemed medically indicated.
Stool positive for Clostridium difficile (C. difficile) toxin. Subjects who are positive can be retested after the completion of a full course of treatment for C. difficile infection.
Any of the following lab values: a) Hemoglobin (Hgb) < 8.0 g/dL (80 g/L) b) White blood cell (WBC) < 2,500/mm^3 (2.5 x 10^9/L) c) Neutrophils < 1,000/mm^3 (1 x 10^9/L) d) Platelets < 100,000/mm^3 (100 x 10^9/L) e) Serum creatinine > 2 times upper limit of normal (ULN) f) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times ULN g) Any other laboratory test results that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study
Failed (no response, insufficient response, loss of response, and/or intolerance) > 3 classes (anti-TNF, anti-integrin, anti-IL12/23, JAK inhibitor, S1PR modulator) or > 4 individual biologic/biologic-like therapies.
Any marketed biologic or biologic-like within 2 weeks for JAK inhibitors (e.g., tofacitinib, upadacitinib, or filgotinib, 8 weeks for anti-TNF agents, 10 weeks for S1PR modulators (e.g., ozanimod), and 12 weeks for vedolizumab and anti-IL-12/23 (e.g., ustekinumab) prior to randomization or if drug level per therapeutic dose monitoring is greater than lower limit of detection
Any biologic immunomodulators not covered in exclusion criterion 27, used for UC or other conditions within 8 weeks or 5 half-lives, whichever is longer, prior to randomization or if drug level per therapeutic dose monitoring is greater than lower limit of detection.
Rituximab within 1 year prior to randomization.
Parenteral corticosteroids within 4 weeks or rectal administration of corticosteroids within 2 weeks prior to randomization.
Rectal administration of 5-ASA within 2 weeks prior to randomization.
Tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil (CellCept®), immunoadsorption columns (such as Prosorba columns), d-penicillamine, leflunomide, thalidomide, fish-oil preparations, probiotics, fecal transplantation, non-steroidal anti-inflammatory agents (NSAIDs), aspirin > 81 mg/day within 2 weeks prior to randomization.
Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 5 half-lives (whichever is longer) of randomization.
Prior exposure to PRA023.
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
Legal or mental incapacitation, or inability to understand and comply with the requirements of the study.
Known allergies, hypersensitivity, or intolerance to PRA023 or its excipients.