A Phase 2b Study to Evaluate Rezpegaldesleukin (Rezpeg) in the Treatment of Adult Patients With Moderate-to-Severe Atopic Dermatitis (REZOLVE-AD)

Prior treatment

• Full exclusion criteria are provided in Protocol Section 4.2. Skin conditions • Are currently experiencing or have a history of concomitant skin conditions other than AD (e.g., psoriasis or cutaneous lupus), that, in the opinion of the Investigator, would interfere with assessments or interpretation of the effect of study intervention on AD. • Are currently experiencing a skin infection in the area affected by the patient’s AD that requires treatment with, or is currently being treated with, topical antimicrobial therapy. Note: Patients who are not eligible (screen fail) due to this criterion should not be rescreened until at least 4 weeks after screen failure and at least 2 weeks after resolution of the infection. • History of chronic idiopathic urticaria at any time or urticaria from other causes within 4 weeks prior to randomization Previous or current therapies • Have a history of TCS use suggestive of a high risk for TCS withdrawal (e.g., a history of prolonged or frequent use of moderate- to high-potency TCS, especially on the face [Hajar, 2015]), such that, in the opinion of the Investigator, the patient will be unable to withdraw and abstain from TCS for several weeks during the study.

Lab values

• Have received any of the following treatments at any time before Visit 1: a) aldesleukin b) investigational IL-2 analog c) oral Janus kinase (JAK) inhibitor for any indication, including, but not limited to, baricitinib, upadacitinib, abrocitinib, tofacitinib, and ruxolitinib, whether marketed or investigational d) systemic immune-modulating biologic therapy (including, but not limited to, dupilumab, tralokinumab, lebrikizumab, nemolizumab, rocatinlimab, etc.) whether marketed or investigational • Have received any of the following therapies during the specified time period (“washout”) or are anticipated to require any of these therapies during the study: Table is provided in Protocol Section 4.2 • Are unstable with respect to use of chronic treatments (prescription or over the counter) to improve sleep: a) Have started or restarted using a sleep medication during the 2 weeks before the day of the first dose of study intervention b) Have changed the dose of a sleep medication during the 2 weeks before the day of the first dose of study intervention, or c) Are likely to need to start or change the dose of sleep medication during this study, in the opinion of the Investigator. Note: Individuals on a stable dose of sleep medication at screening may be eligible to be enrolled if other study entry criteria are met, but such individuals should remain on the stable dose throughout the study unless, in the Investigator’s opinion, the dose should be changed or stopped to address a safety concern.
  • Previous or current infections • Have a current or recent acute, active infection. For at least 30 days prior to screening (Visit 1) and up to the Randomization Visit (Visit 2), patients must have no symptoms or signs of confirmed or suspected infection, and must have completed any appropriate anti-infective treatment. Note: Patients who have an oral, upper respiratory, or vaginal candida infection and who are being treated only symptomatically and not requiring systemic anti infectives may be considered for enrollment if other study eligibility criteria are met. Enrollment of patients with other uncomplicated local infections should be discussed with the Sponsor’s designated Medical Monitor. • Have had any of the following types of infection within 12 weeks prior to the Screening Visit (Visit 1) or develops any of these infections before the Randomization Visit (Visit 2): a) serious (requiring hospitalization, or intravenous or equivalent oral antibiotic treatment, or both) b) opportunistic (as defined in Winthrop, 2015) Note: Herpes zoster is considered active and ongoing until all vesicles are dry and crusted over. c) Chronic (duration of symptoms, signs, and/or treatment of 6 weeks or longer) d) Recurring (including, but not limited to, herpes simplex, herpes zoster, recurring cellulitis, chronic osteomyelitis). Note: Patients with only recurrent mild and uncomplicated oral herpes, or genital herpes, or both may be discussed with the Sponsor’s designated Medical Monitor and considered for enrollment if other study eligibility criteria are met.
  • Diagnostic assessments • Have any of the following specific abnormalities on screening laboratory tests: a) serum creatinine, alanine transaminase (ALT), or aspartate transaminase (AST) > 2 × upper limit of normal (ULN) b) alkaline phosphatase (ALP) ≥ 2 × ULN c) total bilirubin level (TBL) ≥ 1.5 × ULN d) hemoglobin < 10.0 g/dL e) eosinophilia (absolute eosinophil count) > 1000 cells/μL f) estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] Creatinine Equation) (FDA 2020; NKF 2021). Note: For repeat testing of screening laboratory tests, see Section 4.4.1.
• Have other laboratory test results at screening (Visit 1) which are outside the normal reference range for the population or study site and, in the opinion of the Investigator, indicate unacceptable risk for the patient’s safety in the study. Other previous or current medical conditions • Any malignancies or history of malignancies within 5 years prior to randomization (except for basal cell or squamous epithelial carcinomas of the skin that have been sucessfully treated with no evidence of metastatic disease for 3 years or cervical carcinoma in situ that has been sucessfully treated, with no evidence of recurrence within the 3 years prior to randomization). • Have a history of any of the following within 12 months before the Screening Visit (Visit 1): a) myocardial infarction b) unstable ischemic heart disease c) cerebrovascular accident d) stroke, or e) New York Heart Association Stage III or IV heart failure.

• Full inclusion criteria are provided in Protocol Section 4.1. Informed consent and contraception requirements • Provide written, informed consent to participate in the study and follow the study procedures, including compliance with the use of highly effective contraceptives. Patient characteristics • Male or female patients, at least 18 years of age, inclusive, on the day of signing the informed consent form. Note: In some jurisdictions, the legal age of consent for study participation is greater than 18 years. For sites in such jurisdictions, the legal age of consent will be used as the lower limit of the age range for this criterion. Disease-specific characteristics • Present with a diagnosis of AD at least 12 months prior to screening (Visit 1), as defined by the American Academy of Dermatology “Guidelines of care for the management of atopic dermatitis: Section 1. Diagnosis and assessment of atopic dermatitis” (Eichenfield, 2014) • Patients must meet the following AD severity criteria: a) EASI ≥ 16.0 at screening (Visit 1) and randomization (Visit 2). b) vIGA-AD score ≥ 3 at screening (Visit 1) and randomization (Visit 2). c) ≥ 10% of BSA involvement at screening (Visit 1) and randomization (Visit 2).
• Are candidates for systemic therapy and have history, documented by a physician and/or the Investigator, of inadequate response to existing topical medications within 6 months preceding screening (Visit 1), or history of intolerance to topical therapy as defined by at least 1 of the following: a) Inability to achieve good disease control defined as mild disease or better (eg, vIGA-AD ≤ 2) after use of at least a medium potency TCS for at least 4 weeks, or for the maximum duration recommended by the product prescribing information, eg, 14 days for super potent TCS, whichever is shorter. Note: For the purpose of this criterion, a TCS may be used with or without TCI to address areas of disease. Note: Failing a nonbiologic systemic therapy intended to treat AD,eg, cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, or other small molecules, within 6 months before screening (Visit 1) will be considered a surrogate for inadequate response to existing topical medications. b) A history of clinically significant adverse reactions with the use of TCS, eg, skin atrophy, allergic reaction, or systemic effects that, in the opinion of the Investigator, outweigh the benefits of retreatment.