Evasayil TM: A placebo-controlled trial to evaluate the efficacy and safety of spesolimab in the treatment of patients with Netherton syndrome

The primary objective of this clinical trial is to evaluate the **treatment response** of spesolimab in patients diagnosed with Netherton syndrome. This objective is clinically relevant as it aims to determine the efficacy of spesolimab, a potential therapeutic agent, in managing the symptoms and progression of this rare genetic skin disorder, which currently has limited treatment options.

Secondary objectives include:

• Reduction in other skin severity assessments, which is important for understanding the broader impact of spesolimab on skin health.
• Improvement in quality-of-life assessments, highlighting the potential benefits of spesolimab on the overall well-being of patients.
• Improvement in sleep, itch, and scalp hair assessments, addressing specific symptoms that significantly affect patients' daily lives.
• Descriptive safety evaluation, including the incidence of adverse events (AEs), to ensure the safety profile of spesolimab is well-characterized.

The clinical trial involves a total of **16 participants** diagnosed with **Netherton syndrome (NS)**, characterized by SPINK5 causative mutations. The study population includes both male and female subjects aged 12 years and older, with a minimum weight requirement of 35 kg. Participants were selected based on a confirmed diagnosis of NS and at least moderate severity of erythema at baseline, as indicated by specific IASI and IGA scores. The trial includes individuals who have provided signed and dated written informed consent and assent in accordance with ICH-GCP and local legislation. Women of childbearing potential are required to use highly effective methods of birth control. The trial population is considered vulnerable, and the selection process ensures adherence to ethical standards. The study does not specify particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy and safety of **spesolimab** in patients with **Netherton syndrome**. This study is a randomized, double-blind, placebo-controlled trial. The trial is expected to last until August 2026, with recruitment having commenced in May 2023. Participants will be involved in the study for a maximum treatment period of 156 weeks for the subcutaneous administration and 4 weeks for the intravenous administration of spesolimab. The trial includes a placebo group for both administration routes to ensure the reliability of the results.

Study visits are structured to include an initial screening visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit involves screening participants to confirm eligibility based on criteria such as age, weight, and a confirmed diagnosis of Netherton syndrome with specific severity scores. Follow-up visits are scheduled to monitor treatment response and safety, with assessments including the Investigator's Global Assessment (IGA) and the Investigator's Assessment of Skin Involvement (IASI) scores. The primary endpoint is the IASI response, defined as a decrease of at least 50% in the IASI score from baseline. Secondary endpoints include changes in IGA scores, pain, itch, and quality of life indices.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the occurrence of serious adverse events or the participant's decision to withdraw consent. The trial is conducted in accordance with ICH-GCP guidelines, ensuring ethical and scientific integrity throughout the study. The trial's design and procedures are meticulously planned to provide robust data on the therapeutic potential of spesolimab in treating Netherton syndrome.

The clinical trial involves the administration of **Spesolimab**, a solution for injection in a pre-filled syringe. This experimental medication is of biological origin and is produced by Boehringer Ingelheim International. The active substance, spesolimab, is a humanized monoclonal antibody classified as an immunoglobulin G1-kappa, targeting the human interleukin-1 receptor-like 2 (IL1RL2). The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous. The dosing schedule allows for a maximum treatment period of 156 weeks, with specific dosing details to be determined based on the study protocol. Participant compliance will be monitored through regular assessments and documentation of administration.

Additionally, the trial includes the administration of **Spesolimab** as a solution for infusion. This formulation is also of biological origin and is administered intravenously. The maximum treatment period for this formulation is 4 weeks. The pharmaceutical form is a solution for infusion, and the active substance remains spesolimab, consistent with the subcutaneous formulation. The dosing schedule and administration details will be outlined in the study protocol, with compliance monitored through similar methods as the subcutaneous administration.

The study employs a placebo control to evaluate the efficacy and safety of spesolimab. The placebo is provided in two forms: a solution for infusion and a solution for injection, both labeled as "Placebo for BI 655130." These placebo formulations are designed to match the appearance and administration routes of the active drug formulations, ensuring blinding of the study. The placebo for infusion is administered intravenously, while the placebo for injection is administered subcutaneously. The placebo treatments are integral to maintaining the study's double-blind design, allowing for an unbiased assessment of spesolimab's therapeutic effects.

The efficacy of spesolimab in the treatment of patients with Netherton syndrome will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **IASI response**, defined as a decrease of at least 50% in the IASI score from baseline. Secondary endpoints include the IGA response, which is characterized by a decrease of at least 1-grade in the IGA score from baseline, and achieving an IGA score of 0 or 1. Additional secondary endpoints involve the IASI response, IASI-E and IASI-S subscore responses, percent change from baseline in IASI score, and absolute changes from baseline in NRS pain, NRS itch, DLQI score, and CDLQI score. The occurrence of treatment-emergent adverse events, including serious and/or opportunistic infections, will also be monitored.