Efficacy and Safety Evaluation of Debio 4126, a 12-Week Octreotide Formulation, in Acromegaly Patients Previously Treated with Somatostatin Analogs

The primary objective of this study is to assess the maintenance of **Insulin-like growth factor 1 (IGF-1)** levels at or below 1x the upper limit of normal (ULN) during the double-blind period (Period 1) with Debio 4126 (Arm A) compared to placebo (Arm B) at week 36 in patients with **acromegaly**. This is clinically relevant as maintaining IGF-1 levels within the normal range is crucial for managing acromegaly, a condition characterized by excessive growth hormone production, which can lead to significant morbidity if not controlled.

Secondary objectives include:

• Assessing the maintenance of IGF-1 ≤1x ULN in Arm C at week 36.
• Evaluating IGF-1 and **Growth hormone (GH)** levels over time in Arms A, B, and C.
• Comparing the safety profile of Debio 4126 (Arm A) with placebo (Arm B) up to week 36, and evaluating the long-term safety and local tolerability profiles of Debio 4126 in all arms.
• Assessing the use of rescue medication in Arm A compared to Arm B.
• Evaluating the pharmacokinetics of Debio 4126.

The clinical trial involves a total of **19 participants** diagnosed with **acromegaly**. The study population includes both male and female subjects, aged 18 years and older. Participants were selected based on their current treatment with octreotide or lanreotide monotherapy for acromegaly, which they have been receiving for at least six months at a stable dose for the last 12 weeks. All participants have an Insulin-like growth factor 1 (IGF-1) level at or below the upper limit of normal at screening. The trial includes individuals with adequate bone marrow, hepatic, and renal function. The study population is considered vulnerable, and the selection process adhered to specific protocol-defined criteria. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is a **Phase 3** randomized, three-arm study designed to evaluate the efficacy and safety of Debio 4126, a 12-week formulation of **octreotide**, in patients with **acromegaly** who have been previously treated with somatostatin analogs. The trial employs a double-blind design for the Debio 4126 and placebo control arms, while the third arm is open-label. The primary objective is to assess the maintenance of **Insulin-like growth factor 1 (IGF-1)** levels at or below the upper limit of normal (ULN) during the double-blind period. The trial is expected to conclude by March 2029, with recruitment starting in June 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), stable treatment with **octreotide** or **lanreotide** for at least six months, and adequate organ function. The primary endpoint is the percentage of participants with IGF-1 levels at or below 1x ULN at week 36, based on the average of two samples taken at weeks 34 and 36. Secondary endpoints include changes in IGF-1 and **growth hormone (GH)** levels, the incidence of treatment-emergent adverse events, and local tolerability assessments.

The trial duration for each participant is approximately 96 weeks, with the possibility of early termination if specific conditions arise, such as significant adverse events or failure to meet protocol-defined criteria. Follow-up visits will be conducted to monitor safety and efficacy, with the end-of-study visit marking the completion of the participant's involvement. The trial's design ensures rigorous assessment of Debio 4126's therapeutic potential in managing acromegaly, with a focus on maintaining IGF-1 levels within the desired range.

The clinical trial involves the administration of **Debio 4126**, a suspension for injection containing the active substance **octreotide**. This investigational product is administered via **intramuscular injection**. The maximum daily dose is 30 mg, with a total maximum dose of 240 mg over a treatment period of 96 weeks. The formulation is not pediatric and is classified as a peptide. The product is provided by DEBIOPHARM and is used in the trial as a test treatment.

Another investigational product used in the trial is **octreotide**, provided in the form of a powder and solvent for suspension for injection. This product is also administered via **intramuscular injection**. The maximum daily dose is 20 mg, with a total maximum dose of 220 mg over a treatment period of 44 weeks. This formulation is not pediatric and is classified as a peptide. The product may be centrally sourced by the sponsor and relabeled to comply with language requirements.

The trial also includes the use of **lanreotide**, a solution for injection in a pre-filled syringe. This product is administered via **subcutaneous injection**. The maximum daily dose is 60 mg, with a total maximum dose of 660 mg over a treatment period of 44 weeks. This formulation is not pediatric and is classified as a peptide. Similar to octreotide, lanreotide may be centrally sourced by the sponsor and relabeled to comply with language requirements.

A placebo resembling the Debio 4126 doses is also utilized in the trial. This ready-to-use suspension is designed to mimic the 30, 60, or 90 mg doses of Debio 4126. The placebo is used to maintain the double-blind nature of the trial, ensuring unbiased assessment of the investigational product's efficacy and safety.

The efficacy of Debio 4126 in the treatment of **acromegaly** will be assessed through a Phase 3 randomized 3-arm trial. The primary endpoint for evaluating efficacy is the percentage of participants with Insulin-like growth factor 1 (IGF-1) levels ≤1x Upper Limit of Normal (ULN) at Week 36. This will be determined based on the average of two IGF-1 samples acquired at Weeks 34 and 36. Participants with an average IGF-1 ≤1x ULN will be classified as responders.

Secondary endpoints include various measures related to IGF-1 and Growth Hormone (GH) levels. These include the percentage of participants with IGF-1 ≤1x ULN in Arm C, changes from baseline in IGF-1 values, percent change from baseline in IGF-1 values, and the percentage of participants with GH levels <1 ng/mL. Additional secondary endpoints involve changes from baseline in GH values, mean logarithm with base 10 (Log10) change from baseline in GH values, and the percentage of participants with GH values categorized as <1, ≥1 and <2.5, and ≥2.5 ng/mL.

Other secondary endpoints focus on safety and tolerability, including the number of participants with at least one treatment-emergent adverse event (TEAE), clinically significant abnormalities in laboratory parameters, vital signs, electrocardiogram (ECG), and pituitary tumor size. Local tolerability of Debio 4126 will be assessed by erythema, swelling, and induration at the injection site using investigator assessment, as well as pain at the injection site based on a Pain Visual Analog Scale (VAS) score. The percentage of participants taking rescue medication and pharmacokinetic parameters of Debio 4126, including octreotide concentration at the end of the 12-week treatment interval (Ctrough), will also be evaluated.