Evaluation of APG777 Efficacy and Safety in Moderate-to-Severe Atopic Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

The primary objective of this study is to evaluate the **effectiveness** of APG777 compared to placebo in patients with moderate-to-severe **Atopic Dermatitis** (AD) after 16 weeks of treatment. This is clinically relevant as it aims to determine the potential of APG777 as a therapeutic option for managing symptoms in patients with this chronic inflammatory skin condition, which can significantly impact quality of life.

Secondary objectives include:

• Part A: Evaluating the safety and tolerability of APG777.
• Part A: Assessing the effectiveness of APG777 compared to placebo in patients with moderate-to-severe AD after 52 weeks of treatment.
• Part A: Evaluating the effectiveness of APG777 compared to placebo in reducing itching, skin pain, and the effect of eczema on sleep.
• Part A: Measuring the amount of study drug in the blood at different times.
• Part B: Evaluating the safety and tolerability of three different doses of APG777.
• Part B: Assessing the effectiveness of three different doses of APG777 compared to placebo in patients with moderate-to-severe AD after 52 weeks of treatment.
• Part B: Evaluating the effectiveness of APG777 compared to placebo in reducing itching, skin pain, and the effect of eczema on sleep.
• Part B: Measuring the amount of study drug in the blood at different times for three different doses of APG777.

The clinical trial involves a total of **237 participants** diagnosed with **Atopic Dermatitis** (AD), specifically targeting individuals with moderate-to-severe conditions. The study population includes both male and female subjects, with an age range encompassing children and adults. Participants were selected based on their diagnosis of AD for at least one year prior to the screening visit, and a history of inadequate response to topical treatments or a medical determination that such therapies are inadvisable. All participants have been using a stable dose of non-medicated over-the-counter emollients or moisturizers for at least 14 days before the baseline visit and have agreed to continue this regimen throughout the study, except on the day of study visits. Additionally, they have completed itch questionnaires in an electronic diary for at least four out of seven days prior to the baseline visit. The trial does not include a vulnerable population, ensuring a focus on general health status without significant lifestyle restrictions beyond the use of moisturizers.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the safety and efficacy of **APG777** in patients with moderate-to-severe **atopic dermatitis**. The trial is divided into two parts, with Part A focusing on the effectiveness of APG777 compared to placebo after 16 weeks of treatment, and Part B evaluating three different doses of APG777 against placebo over the same duration. The study is expected to commence recruitment on September 1, 2024, and conclude by October 15, 2028, with a total estimated duration of 48 months for the entire trial.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of atopic dermatitis for at least one year, moderate-to-severe disease at screening and baseline, and a history of inadequate response to topical treatments. Following the screening, eligible participants will be randomized to receive either APG777 or placebo via **subcutaneous injection**. The primary endpoint is the percent change from baseline in the Eczema Area and Severity Index (EASI) at Week 16. Secondary endpoints include the number of participants with treatment-emergent adverse events, changes in EASI scores, and various pharmacokinetic measures over a period of up to 106 weeks.

Study visits will include baseline assessments, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to evaluate final outcomes. Participants are expected to be involved in the study for a period of up to 52 weeks, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that necessitate discontinuation. The trial aims to provide comprehensive data on the safety and efficacy of APG777, contributing to the understanding of its potential as a treatment for atopic dermatitis.

The clinical trial involves the administration of **APG777**, an experimental medication developed by Apogee Therapeutics, Inc. **APG777** is formulated as a **solution for injection** and is administered via **subcutaneous injection**. The active substance, also named **APG777**, is classified as a protein of other origin. The trial is designed to evaluate the safety and efficacy of **APG777** in patients with moderate-to-severe atopic dermatitis. The dosing schedule for **APG777** involves administration over a maximum treatment period of 48 weeks. The specific dosage and frequency of administration are determined based on the study protocol, with compliance monitored throughout the trial to ensure adherence to the dosing regimen.

The study also includes a **placebo** group to serve as a comparator for evaluating the effectiveness of **APG777**. The **placebo** is used in a double-blind manner, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The **placebo** is designed to mimic the pharmaceutical form of **APG777** to maintain the integrity of the study's blinding process. The inclusion of a **placebo** group is critical for assessing the true therapeutic effect of **APG777** by providing a baseline for comparison. Participants' adherence to the treatment protocol, including the administration of the **placebo**, is closely monitored to ensure the reliability of the study outcomes.

The efficacy of APG777 in patients with moderate-to-severe **Atopic Dermatitis** will be assessed through a series of primary and secondary endpoints. The primary endpoint for both Part A and Part B of the study is the percent change from baseline in the Eczema Area and Severity Index (EASI) at Week 16. Secondary endpoints include the number of participants with treatment-emergent adverse events (TEAEs) up to 106 weeks, change from baseline in EASI through Week 16 and at Week 52, and the proportion of participants achieving EASI 50, 75, 90, and 100 scores over the same period.

Additional secondary endpoints involve the proportion of participants achieving a validated Investigator Global Assessment (vIGA-AD) score of 0 (clear) or 1 (almost clear) with a ≥2-point reduction, change from baseline in body surface area (BSA) involvement, and the proportion of participants achieving a ≥4-point improvement in the weekly mean of the daily Itch Numeric Rating Scale (I-NRS). The percent change from baseline in the weekly mean of the daily I-NRS will also be evaluated. Pharmacokinetic parameters such as serum concentrations of APG777, predose serum concentrations (Ctrough), maximum concentration (Cmax), time to reach Cmax (tmax), and area under the concentration-time curve (AUC) will be measured up to 106 weeks.