Evaluation of Low-Dose Aldesleukin in Chronic Inflammatory Barrier Diseases: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

The primary objective of this exploratory, indication-finding basket trial is to evaluate and compare the **safety** and the relationship between the magnitude of Treg responses and clinical responses elicited by low-dose interleukin-2 (IL-2) therapy in participants with active Pemphigus vulgaris/foliaceus, Mucous Membrane Pemphigoid, Polymyositis/Dermatomyositis, and Primary Sclerosing Cholangitis. This is clinically relevant as it aims to determine the therapeutic potential and safety profile of low-dose IL-2 in managing these chronic inflammatory barrier diseases, which could lead to improved treatment strategies.

Secondary objectives are to estimate the clinical efficacy of low-dose IL-2 therapy assessed by changes in disease-specific measures of disease activity compared to placebo-treated participants. This will provide insights into the potential benefits of IL-2 therapy in reducing disease activity and improving patient outcomes.

The clinical trial involves participants diagnosed with **Primary Sclerosing Cholangitis (PSC)**, Mucous Membrane Pemphigoid, Polymyositis/Dermatomyositis, and Pemphigus vulgaris/foliaceus. The study population includes both male and female subjects, aged between 18 and 80 years, with a focus on individuals exhibiting mild to moderate disease activity. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on specific disease activity criteria, such as PDAI and MMPDAI scores for Pemphigus vulgaris/foliaceus and Mucous Membrane Pemphigoid, respectively, and elevated plasma concentrations of creatine kinase or alkaline phosphatase for Polymyositis/Dermatomyositis and Primary Sclerosing Cholangitis. The trial includes a vulnerable population, and both genders are represented. Lifestyle factors such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and **placebo-controlled** phase 2 exploratory study. The primary objective is to evaluate the safety and efficacy of low-dose **interleukin-2** (IL-2) therapy in participants with active **Pemphigus vulgaris**, **Mucous Membrane Pemphigoid**, **Polymyositis/Dermatomyositis**, and **Primary Sclerosing Cholangitis**. The trial will assess the relationship between the magnitude of Treg responses and clinical responses elicited by the therapy. The study is expected to commence recruitment on April 1, 2024, and conclude by April 1, 2027.

Participants will be involved in the study for a maximum treatment period of 8 weeks. The trial will include several key visits: an initial screening visit to confirm eligibility based on specific inclusion criteria, such as age between 18 and 80 years and defined disease activity levels. Following the screening, participants will undergo a series of study visits, including baseline assessments on day 1, followed by regular follow-up visits to monitor safety and efficacy, with the primary endpoint being assessed on day 57. The end-of-study visit will occur at the conclusion of the treatment period to evaluate the final outcomes and any long-term effects.

Participants will receive either the investigational product, **aldesleukin**, or a placebo, administered subcutaneously. The maximum daily dose for aldesleukin is 1,500,000 IU, with a total maximum dose of 18,000,000 IU over the treatment period. The placebo will consist of a glucose solution for injection. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The primary endpoints include the IL-2 induced Treg response and clinical response at day 57, with secondary endpoints focusing on changes in disease-specific measures compared to placebo.

The clinical trial involves the administration of **Aldesleukin**, marketed under the name PROLEUKIN® S 18 x 10⁶ IE, which is a **solution for injection/infusion**. The active substance, Aldesleukin, is a protein-based therapeutic agent. The pharmaceutical form is a powder intended for the preparation of an injection or infusion solution. The administration route is **subcutaneous**, with a maximum daily dose of 1,500,000 IU and a total maximum dose of 18,000,000 IU over the treatment period. The dosing schedule involves administering 12 times lower single doses than those authorized for subcutaneous injections, specifically single doses of 1.5 million IU, diluted as described in the Investigator's Brochure. The treatment period is set for a maximum of 8 weeks. Compliance with the dosing regimen will be monitored throughout the trial.

In addition to the experimental treatment, the trial includes the use of **Glucose** as a comparator treatment. Glucose is provided as a **solution for injection** and serves as a placebo in this double-blind study. The administration route is also subcutaneous, with a maximum daily dose of 10 ml and a total maximum dose of 1,000 ml over the treatment period. The glucose solution is used to maintain the blinding of the study and ensure that participants and investigators remain unaware of the treatment assignments. The treatment period for glucose administration is also set for a maximum of 8 weeks. Participant compliance with the administration of glucose will be monitored to ensure adherence to the study protocol.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints include the **IL-2 induced Treg response**, which is defined as the increase in absolute numbers of CD3+CD4+FoxP3+CD127loCD25hi Treg, measured by the area under the curve (AUC) from day 1 to day 57. Additionally, the clinical response at day 57 will be evaluated by assessing absolute changes in disease-specific and z-standardized disease activity measures from day 1 to day 57. These measures include the Pemphigus Disease Area Index (PDAI), Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), and plasma levels of Creatine-Kinase (CK) or Alkaline Phosphatase (AP).

The secondary endpoint involves assessing the clinical response at day 57 by comparing absolute and relative changes in disease-specific measures (PDAI, MMPDAI, CK, AP) between day 1 and day 57 against a placebo. These efficacy parameters will be collected and analyzed at specified timepoints, with the primary focus on day 57. The trial is designed to evaluate the relationship between the magnitude of Treg responses and clinical responses elicited by low-dose IL-2 therapy in participants with active Pemphigus vulgaris/foliaceus, Mucous Membrane Pemphigoid, Polymyositis/Dermatomyositis, and Primary Sclerosing Cholangitis.