Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HM15912 in Adults with Short Bowel Syndrome-associated Intestinal Failure

The primary objective of this study is to evaluate the **safety** and **tolerability** of HM15912 following multiple subcutaneous doses over a 24-week period in adult subjects with Short Bowel Syndrome-associated Intestinal Failure (SBS-IF). This is clinically relevant as it aims to ensure that the treatment is safe for patients and can be tolerated over an extended period, which is crucial for managing a chronic condition like SBS-IF. Additionally, the study seeks to assess the **pharmacokinetic** profile of HM15912, which involves understanding how the drug is absorbed, distributed, metabolized, and excreted in the body, providing essential information for optimizing dosing regimens.

The secondary objective is to assess the **pharmacodynamic** profile of HM15912. This involves evaluating the drug's biological effects and its mechanism of action, which is important for understanding its therapeutic potential and efficacy in treating SBS-IF.

The clinical trial involves a total of **5 participants** diagnosed with **Short Bowel Syndrome-associated Intestinal Failure (SBS-IF)**. The study population includes both male and female subjects aged 18 years or older. Participants were selected based on specific criteria, including having undergone their most recent bowel surgery at least 6 months prior to the study and having a stoma. The trial population is characterized by individuals who have either no growth of cancer cells in their large intestine or have had any growths removed within 6 months before joining the study. The participants are considered a vulnerable population due to their medical condition. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM15912 in adult subjects with **Short Bowel Syndrome-associated Intestinal Failure (SBS-IF)**. The trial is a Phase II study, with an estimated duration from October 2021 to August 2026. Participants will be involved for a maximum of 52 weeks, receiving multiple subcutaneous doses of the investigational product, HM15912, which is a **human glucagon-like peptide-2 analogue linked to a human immunoglobulin FC fragment**. The primary endpoints include the assessment of safety and tolerability, as well as the pharmacokinetic profile of HM15912, with specific measures such as incidence of adverse events, injection site reactions, and changes in vital signs and ECG parameters.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, diagnosis of SBS, and recent medical history. Following successful screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, tolerability, and pharmacokinetic parameters. These visits will assess primary endpoints, including maximum serum concentration and elimination half-life, and secondary endpoints, such as changes in weekly parenteral nutrition/IV fluid volume. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participants may be subject to early termination from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The study is conducted under strict ethical guidelines, ensuring participant safety and data integrity throughout the trial duration.

The clinical trial involves the administration of an **experimental medication** identified as HM15912, which is a **human glucagon-like peptide-2 analogue** linked to a human immunoglobulin FC fragment. This medication is provided in the form of a solution for injection in a pre-filled syringe. The pharmaceutical form is specifically designed for **subcutaneous use**. The dosing regimen for HM15912 is set at a maximum daily dose of 1.5 mg/kg, with a total maximum dose of 19.5 mg/kg over the course of the treatment period, which extends up to 52 weeks. The administration frequency is determined by the study protocol, ensuring consistent and accurate dosing throughout the trial duration. Participant compliance with the dosing schedule is monitored to ensure adherence to the treatment plan.

In addition to the experimental treatment, the study includes a **placebo** group to serve as a comparator. The placebo is also administered as a solution for injection in a pre-filled syringe, matching the form and route of administration of the experimental medication. This design allows for a controlled comparison of the safety, tolerability, and pharmacokinetic profile of HM15912 against the placebo. The placebo administration follows the same dosing schedule and monitoring procedures as the experimental treatment to maintain consistency across the study groups.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints focus on the safety and tolerability of HM15912 after multiple subcutaneous doses over a 24-week period. These include the incidence of adverse events, injection site reactions, clinical laboratory abnormalities, clinically significant findings on physical examination, and changes from baseline in vital signs and 12-lead electrocardiogram (ECG) parameters. Additionally, the pharmacokinetic profile of HM15912 will be evaluated by measuring parameters such as maximum serum concentration (**Cmax**), time to maximum serum concentration (**tmax**), elimination half-life (**t1/2**), volume of distribution (**Vd/F**), clearance (**CL/F**), and area under the concentration-time curve (AUC) at specified dosing intervals.

The secondary endpoint involves assessing the change in weekly parenteral nutrition/intravenous fluid (PN/IV) volume from baseline to Week 25. The baseline PN/IV volume is determined as the average volume received during the last two weeks of the stabilization period. These efficacy parameters will be collected and analyzed at designated timepoints throughout the trial to ensure comprehensive evaluation of the treatment's impact on subjects with Short Bowel Syndrome-associated Intestinal Failure (SBS-IF).