Evaluation of TEV-48574 (Duvakitug) in Adults with Moderate to Severe Ulcerative Colitis or Crohn's Disease: A Randomized, Double-Blind, Dose-Ranging Study

The primary objective of this study is to characterize the **efficacy** of TEV-48574, administered subcutaneously every two weeks, in adult patients with moderate to severe **ulcerative colitis** (UC) or **Crohn's disease** (CD). This will be assessed by the induction of clinical remission in UC and endoscopic response in CD at week 14. The clinical relevance of this objective lies in its potential to provide a new therapeutic option for patients with these chronic inflammatory bowel diseases, which can significantly impact quality of life.

Secondary objectives include:

• Evaluating the efficacy of two different doses of TEV-48574, as assessed by multiple standard measures at week 14.
• Assessing the safety and tolerability of these doses in the same patient population.
• Evaluating the immunogenicity of the two different doses of TEV-48574.

The clinical trial involves a total of **83 participants** diagnosed with **Crohn's disease** or **ulcerative colitis**, focusing on individuals with moderate to severe forms of these conditions. The study population comprises adults of both male and female genders, aged between 18 and 75 years. Participants were selected based on their ability to communicate effectively with the investigator and comply with study requirements. The trial does not include any vulnerable populations. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. Key inclusion criteria include adults who can understand the study's nature and potential hazards, with specific considerations for women of non-childbearing potential and male participants with partners of childbearing potential. The trial aims to assess the efficacy of TEV-48574 administered subcutaneously every two weeks, with the primary objective of achieving clinical remission in ulcerative colitis and an endoscopic response in Crohn's disease by week 14.

The clinical trial is a **randomized**, **double-blind**, dose-ranging study designed to evaluate the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with moderate to severe **ulcerative colitis** or **Crohn's disease**. The trial is set to last for 14 weeks, with the primary objective being the induction of clinical remission in ulcerative colitis and endoscopic response in Crohn's disease by week 14. Participants will be randomly assigned to receive either the investigational product, TEV-48574, or a placebo, both administered via **subcutaneous injection** every two weeks.

The study will commence with an inclusion (screening) visit to assess eligibility based on criteria such as age, ability to communicate with the investigator, and understanding of the study's nature. Following successful screening, participants will undergo a series of study visits at weeks 2, 4, 8, and 14, during which efficacy and safety assessments will be conducted. These assessments include clinical laboratory tests, vital signs measurements, and 12-lead electrocardiograms. The end-of-study visit will occur at week 14, where final evaluations will be made to determine the primary and secondary endpoints, including clinical remission and response rates.

Participant involvement is expected to last for the entire 14-week duration of the trial. However, conditions such as adverse events or non-compliance with study requirements may lead to early termination from the study. The trial will also include a follow-up visit to monitor any treatment-emergent anti-drug antibodies and assess the presence of neutralizing antibodies in patients who tested positive for anti-drug antibodies. The study aims to provide comprehensive data on the safety and efficacy of TEV-48574, contributing to the understanding of its potential as a treatment for inflammatory bowel diseases.

The clinical trial involves the administration of **TEV-48574**, an investigational medication formulated as a **solution for injection**. The active substance in TEV-48574 is **duvakitug**, a protein-based compound. The medication is administered via **subcutaneous use**. The dosing regimen for TEV-48574 involves a maximum daily dose of 900 mg, with a total maximum dose of 2250 mg over a treatment period of 14 weeks. The administration frequency is every two weeks (Q2W), aligning with the study's objective to evaluate the pharmacokinetics, efficacy, safety, and tolerability of TEV-48574 in adult patients with moderate to severe **ulcerative colitis** or **Crohn's disease**.

The study also includes a **placebo** comparator, which is provided as a liquid solution identical in formulation to TEV-48574, except for the absence of the active protein, duvakitug. The placebo is used to ensure the integrity of the double-blind study design, allowing for an unbiased assessment of TEV-48574's efficacy and safety. The placebo is administered following the same route and frequency as the experimental medication, ensuring consistency in the treatment protocol across all study participants.

The efficacy of TEV-48574 in the treatment of moderate to severe **Ulcerative Colitis** (UC) and **Crohn's Disease** (CD) will be assessed through a series of primary and secondary endpoints. The primary endpoints include the induction of clinical remission in UC, defined by a modified Mayo score of ≤2 points, and an endoscopic response in CD, characterized by a reduction in the Simple Endoscopic Score for Crohn's Disease (SES-CD) of at least 50% from baseline, both evaluated at week 14.

Secondary endpoints for UC patients involve clinical response at week 14, which is a decrease from baseline in the modified Mayo score by at least 2 points and a 30% reduction from baseline, with specific criteria for rectal bleeding subscores. Endoscopic improvement and remission are also assessed using the Mayo endoscopic subscore. For CD patients, clinical response is defined by a ≥100-point decrease in the Crohn's Disease Activity Index (CDAI) score from baseline at weeks 4, 8, 12, and 14, with clinical remission indicated by a CDAI score of <150 at week 14. Additional assessments include changes in patient-reported outcomes (PRO2) and endoscopic response using the modified multiplier SES-CD.

Safety and tolerability will be monitored through adverse events, changes in clinical laboratory test results, vital signs, ECG findings, and local tolerability at the injection site. Immunogenicity endpoints will be evaluated by changes in treatment-emergent anti-drug antibody (ADA) levels at specified timepoints, including weeks 2, 4, 8, 14, and a follow-up visit, along with the presence of neutralizing ADA in ADA-positive patients.