Evaluation of Safety, Efficacy, and Pharmacokinetics of Tulisokibart in Patients with Moderately to Severely Active Crohn's Disease: A Phase 2a, Open-Label Study

Trial ID: 2023-509742-35-00
Protocol: PR200-103
Sponsor: Prometheus Biosciences Inc.

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Diseases & Conditions

Crohn's disease

Objectives

The primary objective of this study is to evaluate the **safety** and tolerability of PRA023 following 12 weeks of induction therapy in subjects with moderately to severely active **Crohn's disease**. Additionally, the study aims to assess the proportion of subjects achieving endoscopic improvement, defined as a decrease in the simple endoscopy score for Crohn's disease (SES-CD) by at least 50% from baseline at Week 12. These objectives are clinically relevant as they address both the safety profile of the investigational product and its potential efficacy in reducing disease activity, which are critical factors in the management of Crohn's disease.

Secondary objectives include:

Assessing the proportion of subjects with clinical remission, defined as a Crohn's disease activity index (CDAI) score of less than 150 at Week 12.
Evaluating the proportion of subjects with endoscopic and clinical improvement, indicated by a decrease in SES-CD by at least 50% and a reduction in CDAI by at least 100 points from baseline at Week 12.
Determining the proportion of subjects with biomarker and clinical improvement, characterized by a decrease in high sensitivity C-reactive protein (hsCRP) or fecal calprotectin by at least 50% from baseline, among those with elevated biomarkers at baseline, and a reduction in CDAI by at least 100 points from baseline at Week 12.
Assessing the normalization of C-reactive protein (hsCRP) and fecal calprotectin levels among subjects with elevated concentrations at baseline at Week 12.
Evaluating the proportion of subjects with clinical improvement, defined as a reduction in CDAI by at least 100 points from baseline at Week 12.
Assessing the proportion of subjects achieving two-component patient-reported outcome (PRO-2) remission, defined as an average daily abdominal pain score of 1 point or less and an average daily stool frequency of 3 points or less, with no worsening from baseline at Week 12.
Evaluating the change in SES-CD score from baseline to Week 12.
Assessing the pharmacokinetics and immunogenicity of PRA023.

These secondary objectives provide a comprehensive evaluation of the therapeutic potential of PRA023, encompassing clinical, endoscopic, and biomarker outcomes, which are essential for understanding the overall impact of the treatment on disease management.

Participants

The clinical trial involves a total of **10 participants** diagnosed with **Crohn's disease**, a chronic inflammatory condition of the gastrointestinal tract. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on a confirmed diagnosis of Crohn's disease, with a requirement for moderately to severely active disease as defined by a Crohn's Disease Activity Index (CDAI) score between 220 and 450. The trial includes individuals who have either had an inadequate response or intolerance to previous treatments, or are currently receiving specific therapies. Participants must adhere to drug stabilization requirements and, if applicable, use two highly effective methods of contraception. The trial population is characterized by a mix of biologic-experienced and biologic-naïve subjects, with a focus on ensuring a balanced representation. The study does not provide specific details on lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** and efficacy of the investigational product, tulisokibart, in individuals with moderately to severely active **Crohn's disease**. This is a Phase 2a, multi-center, open-label study. The trial will assess the safety and tolerability of tulisokibart following a 12-week induction therapy, with a primary focus on the proportion of subjects achieving endoscopic improvement, defined as a decrease in the simple endoscopy score for Crohn's disease (SES-CD) by at least 50% from baseline at Week 12. The study is expected to conclude by June 2027, with recruitment having commenced in May 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and disease activity. The trial will include follow-up visits at regular intervals to monitor safety, efficacy, and pharmacokinetics. The end-of-study visit will occur at the conclusion of the 12-week treatment period. The expected duration of participant involvement is approximately 12 weeks, with conditions for early termination including the occurrence of serious adverse events or failure to adhere to study protocols.

Key elements of the research methodology include the administration of tulisokibart via intravenous infusion, with a maximum daily dose of 1000 mg and a total dose not exceeding 2500 mg over the treatment period. The study will include both biologic-experienced and biologic-naïve subjects, with specific inclusion criteria ensuring a balanced representation. The trial will not include subjects who have failed more than four approved biologic therapies. The primary endpoints focus on safety and endoscopic improvement, while secondary endpoints include clinical remission, biomarker improvement, and pharmacokinetic assessments.

Treatment

The clinical trial involves the administration of **tulisokibart**, an experimental medication formulated as 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. Tulisokibart is a protein-based substance of biological or biotechnological origin. The pharmaceutical form is specifically designed for intravenous infusion, ensuring direct delivery into the bloodstream. The maximum daily dose of tulisokibart is set at 1000 mg, with a total maximum dose of 2500 mg over the course of the treatment period. The treatment duration is capped at 170 days, with dosing schedules and participant compliance closely monitored to ensure adherence to the protocol.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus remains solely on evaluating the safety, efficacy, and pharmacokinetics of tulisokibart in subjects with moderately to severely active Crohn's disease. The trial is designed to assess the therapeutic potential of tulisokibart, with particular attention to its safety profile and the degree of endoscopic improvement in participants. Compliance with the dosing regimen is critical, and measures are in place to monitor and document participant adherence throughout the study period.

Efficacy

The efficacy of the investigational product, **tulisokibart**, in the treatment of moderately to severely active Crohn's Disease will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the proportion of subjects achieving endoscopic improvement, defined as a decrease in the Simple Endoscopic Score for Crohn's Disease (SES-CD) by at least 50% from baseline at Week 12. Secondary efficacy endpoints include the proportion of subjects in clinical remission, indicated by a Crohn's Disease Activity Index (CDAI) score of less than 150 at Week 12, and the proportion of subjects with both endoscopic and clinical improvement, defined by a decrease in SES-CD by at least 50% and a reduction in CDAI by at least 100 points from baseline at Week 12.

Additional secondary endpoints involve the assessment of biomarker and clinical improvement, with a focus on the reduction of high-sensitivity C-reactive protein (hsCRP) or fecal calprotectin levels by at least 50% from baseline, alongside a CDAI reduction of at least 100 points at Week 12. The normalization of hsCRP and fecal calprotectin levels, defined as concentrations below the upper limit of normal (ULN), will also be evaluated among subjects with elevated baseline levels. Furthermore, the study will assess the proportion of subjects achieving clinical response, defined by a CDAI reduction of at least 100 points from baseline, and PRO-2 remission, characterized by an average daily abdominal pain score of 1 point or less and an average daily stool frequency of 3 points or less, with no worsening from baseline, at Week 12.

Changes in SES-CD scores from baseline to Week 12 will be documented, and descriptive summaries of pharmacokinetics (PK) and immunogenicity of PRA023 will be provided. The development of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) will also be monitored. These efficacy assessments will be conducted at specified timepoints, primarily at Week 12, using validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female ≥ 18 years of age.
Subjects must have had a diagnosis of CD (confirmed by endoscopy + histology) at least 3 months prior to screening to be eligible for study participation. For subjects with no documented confirmation of CD diagnosis or if previous diagnosis is not deemed conclusive, CD diagnosis must be confirmed at time of screening colonoscopy. Note that mention of “chronic inflammation” or “Crohn’s disease” or equivalent on histology report is acceptable.
Moderately to severely active CD as defined by CDAI of ≥ 220 and ≤ 450.
SES-CD score (per central reading) ≥ 6 if ileocolonic or colonic disease; or ≥ 4 if isolated ileal disease only.
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 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] or methotrexate ≥ 15 mg/week) 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 • An approved anti-integrin (e.g., vedolizumab) at an approved labeled dose for at least 8 weeks • An approved anti-IL-12/23 (e.g., ustekinumab) at an approved labeled dose for at least 8 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) or budesonide ≥ 3 mg/day or beclomethasone ≥ 5 mg/day 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 approved biologic therapy(ies) (e.g., anti-TNF, anti-integrin, and/or anti-IL-12/23): • The study will include a maximum of 70% and a minimum of approximately 50% subjects who have had prior approved biologic therapy(ies) experience. Upon reaching the maximum number of allowed biologic experienced subjects (70%), subjects who have had prior biologic experience will no longer be allowed to enter the study. Upon reaching the maximum number of allowed biologic-naïve subjects (approximately 50%), subjects who have never been exposed to a prior biologic will no longer be allowed to enter the study. • Subjects cannot have had failed (no response, insufficient response, loss of response, and/or intolerance) > 4 approved biologic therapies, whether of same or different mechanism of action • Subjects previously on clinical trials only (i.e., did not receive commercial available therapy post-approval) are not considered to have received the approved therapy for purpose of this inclusion criteria.
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.
Subjects 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 Day 1 b) Oral aminosalicylates should be at a stable dose for at least 2 weeks prior to Day 1 c) Azathioprine, 6-mercaptopurine, and methotrexate should be at a stable dose for at least 4 weeks prior to Day 1
Able to provide written informed consent and understand and comply with the requirements of the study.

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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 Day 1.
Diagnosis of ulcerative colitis or indeterminate colitis.
CD isolated to the stomach, duodenum, jejunum, or perianal region, without colonic and/or ileal involvement.
Suspected or diagnosed intra-abdominal or perianal abscess at Screening.
Known symptomatic stricture or stenosis not passable in endoscopy (including pediatric colonoscope).
Current stoma or need for colostomy or ileostomy.
Previous small bowel resection with combined resected length of > 100 cm or previous colonic resection of > 2 segments.
Currently receiving total parenteral nutrition.
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 Day 1, 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 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 Polymerase Chain Reaction (PCR) if Investigator deems this positivity reflects infection rather than colonization or positive culture for enteric pathogens.
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) d) Serum creatinine > 2 times ULN e) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times ULN f) 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) > 4 approved biologic therapies (anti-TNF, anti-integrin, anti-IL12/23), whether of same or different mechanism of action.
Any marketed biologic within 8 weeks for anti-TNF agents and 12 weeks for anti-integrin agents (e.g., vedolizumab) and ustekinumab prior to Day 1 or if drug level per therapeutic dose monitoring is greater than lower limit of detection.
Any biologic immunomodulators used for CD or other conditions within 8 weeks or 5 half-lives, whichever is longer, prior to Day 1 or if drug level per therapeutic dose monitoring is greater than lower limit of detection.
Rituximab within 1 year prior to Day 1.
Parenteral corticosteroids within 4 weeks or rectal administration of corticosteroids within 2 weeks prior to Day 1.
Rectal administration of 5-ASA within 2 weeks prior to Day 1.
Tacrolimus, cyclosporine, mycophenolate mofetil (CellCept®), immunoadsorption columns (such as Prosorba columns), D Penicillamine, Leflunomide, Thalidomide, chronic use of non-steroidal anti-inflammatory agents (NSAIDs), and aspirin > 81 mg/day within 2 weeks prior to Day 1.
Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 5 half-lives (whichever is longer) of entry into the IP.
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.
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.