A Study to Explore Safety, Pharmacokinetics, and Early Clinical Signal of Efficacy of DS-2325a in Patients With Netherton Syndrome

Study Overview
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Brief Summary
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Netherton Syndrome (NS) is a severe rare disease characterized by generalized scaling, erythema, and epidermal barrier defects. This study assessed the safety, pharmacokinetics (PK), and efficacy of DS-2325a in patients with NS.

Detailed Description
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This study will explore the safety, pharmacokinetics (PK), and early clinical signal efficacy of DS-2325a in adult patients with NS. The primary objective of the study will be to explore the safety and tolerability of DS-2325a in patients with NS by administering DS-2325a every week for 12 consecutive weeks (Main Phase, which will be double-blind and during which some participants will receive placebo as a control) and to confirm by administering for an additional 24 weeks (Extension Phase, which will be open-label and during which all participants will receive DS-2325a). Secondary objectives of the study will include exploring the PK properties, efficacy, and immunogenicity of DS-2325a in patients with NS by administering DS-2325a every week for 12 consecutive weeks (Main Phase) and to confirm by administering for an additional 24 weeks (Extension Phase).

Official Title
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A Phase 1b/2, Double-Blind, Placebo-Controlled, Randomized, Parallel-Arm Study to Explore Safety, Pharmacokinetics, and Early Clinical Signal of Efficacy of DS-2325a in Patients With Netherton Syndrome

Conditions
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Netherton Syndrome

Intervention / Treatment
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* Drug: DS-2325a
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants aged 18 to 65 years with clinical diagnosis of NS including at least 3 out of the 4 following clinical criteria: Neonatal erythroderma Bamboo hair and/or alopecia Chronic atopy specified as food allergy and/or asthma and/or rhino-conjunctivitis and/or eczema for at least 2 years Ichthyosis linearis circumflexa or scaling erythroderma or equivalent Immunohistochemistry documentation of absence of LEKTI in the skin or confirmed SPINK5 gene mutations NS involvement of ≥20% of Body Surface Area (BSA) Patients must give written informed consent to participation in the study prior to Screening Participants must be willing and able to understand and comply with study requirements Participants must be willing to have skin tape harvests collected from lesional and nonlesional skin areas Exclusion Criteria: Any skin disease that may interfere with the diagnosis or evaluation of NS Cutaneous infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, or antifungals within 2 weeks before Screening visit Concomitant systemic disease not controlled by treatment. Stability for 3 months prior to Screening is required Kidney or liver disease with significant impairment of organ function (creatinine clearance <30 mL/min, calculated using the Cockcroft-Gault Equation, and Child-Pugh Class C) Concomitant disease or condition that may interfere with, or treatment of which may interfere with, the conduct of the study or that would, in the opinion of the Investigator, pose an unacceptable risk to the patient in this study Any significant condition (eg, medical, psychiatric, or social) that according to Investigator's judgment would prevent compliance with study protocol and full study participation Known hypersensitivity to any ingredient of the study drug product Anticipation of the need for surgery or hospitalization during the study History of suicide attempt or suicidal ideation within 1 year prior to Screening History of substance abuse within 6 months prior to Screening or a positive urine drug test at Screening. Medical marijuana may be used per discretion of the Investigator History or positive test result for human immunodeficiency virus (HIV) at Screening Active hepatitis B virus (HBV) infection, determined by positive test result for hepatitis B surface antigen, at Screening Active hepatitis C virus (HCV) infection, determined as HCV ribonucleic acid (RNA) above the limit of detection in patients with positive HCV antibody titer, at Screening Use of topical drugs that may alter the course of NS (eg, topical corticosteroids and topical calcineurin inhibitors) within 2 weeks before Screening or anticipation of need to use these drugs during study drug Systemic treatment with corticosteroids, immunosuppressants, targeted therapeutics, biologics, and IV Ig within 8 weeks before Screening Participation in any other clinical study or expanded access program with an investigational drug or device within 4 weeks before Screening Suspected or confirmed COVID-19 within 4 weeks before or ongoing at Screening and planned vaccination against COVID-19 during study drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-2325a<br>Participants will be randomized to receive a single initial (loading) intravenous (IV) dose of DS-2325a 1000 mg (Week 1) followed by weekly (maintenance) subcutaneous (SC) doses of 600 mg (Weeks 2-12) for a total of 12 weeks (Main Phase). Participants will receive weekly DS-2325 SC doses of 600 mg for a total of 24 weeks (Extension Phase). | Drug: DS-2325a<br>* Main Phase: Loading IV infusion of 1000 mg followed by weekly SC doses of 600 mg Extension Phase: Weekly SC doses of 600 mg<br>|
| Placebo Comparator: Placebo<br>Participants will be randomized to receive a single initial (loading) IV dose of placebo followed by weekly (maintenance) SC doses of placebo for a total of 12 weeks (Main Phase). | Other: Placebo<br>* Main Phase: IV infusion followed by weekly SC doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events |  | Screening up to Week 45 (end of study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameter Trough Concentration (Ctrough) |  | Main Phase: Baseline and predose of Weeks 3, 5, 7, 9, and 11; Extension Phase: Predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 45 | 
| Pharmacokinetic Parameter Area Under the Concentration-Time Curve Over a Dosing Interval at Steady State (AUCtau,ss) |  | Main Phase: Baseline and predose of Weeks 3, 5, 7, 9, and 11; Extension Phase: Predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 45 | 
| Pharmacokinetic Parameter Total Body Clearance (CL) |  | Main Phase: Baseline and predose of Weeks 3, 5, 7, 9, and 11; Extension Phase: Predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 45 | 
| Pharmacokinetic Parameter Apparent Total Body Clearance (CL/F) |  | Main Phase: Baseline and predose of Weeks 3, 5, 7, 9, and 11; Extension Phase: Predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 45 | 
| Pharmacokinetic Parameter Skin-to-Plasma DS2325a Concentration Ratio at Steady State (Ksp,ss) |  | Main Phase: Baseline and predose of Weeks 3, 5, 7, 9, and 11; Extension Phase: Predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 45 | 
| Mean Ichthyosis Area Severity Index (IASI) Scores | The IASI measures the severity of the erythema (IASI-Erythema) and scaling (IASI-Scaling) based on a 4-point Likert scale where 0 (none) and 4 (very severe). The total IASI is determined by adding IASI-Erythema and IASI-Scaling scores. Higher scores indicate worse clinical outcome. | Screening; Observational: Predose of Weeks 1, 5, and 9; Main Phase: Baseline, predose of Weeks 3, 5, 7, 9, and 11; Extension Phase, predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, and 37 | 
| Mean Investigator Global Assessment (IGA) Scores | The IGA measures, using a 5-point scale (0, clear; 1, almost clear; 2, mild; 3, moderate; 4, severe) erythema, scaling, inflammatory papules or plaques, oozing, and lichenification. Higher scores indicate worse clinical outcome. | Screening; Observational: Predose of Weeks 1, 5, and 9; Main Phase: Baseline, predose of Weeks 3, 5, 7, 9, and 11; Extension Phase, predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, and 37 | 
| Mean Itch Numerical Rating Scale (NRS) Scores | The Itch NRS is a self-rated single item scale designed for assessing worst pruritus in the past 7 days. The scale utilizes an 11-point NRS, scored from 0 (no itch) to 10 (worst imaginable itch. Higher scores indicate worse clinical outcome. | Screening; Observational: Predose of Weeks 1, 5, and 9; Main Phase: Baseline, predose of Weeks 3, 5, 7, 9, and 11; Extension Phase, predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, and 37 | 
| Skindex-29 Responses | The Skindex-29 is a self-reported measure of skin-related symptoms, functioning, and emotional well-being, designed for use across dermatologic conditions. | Screening; Observational: Predose of Weeks 1, 5, and 9; Main Phase: Baseline, predose of Weeks 3, 5, 7, 9, and 11; Extension Phase, predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, and 37 | 
| Dermatology Life Quality Index (DLQI) Questionnaire | The DLQI is a self-reported measure of patients' perception of the impact of skin diseases on different aspects of their quality-of-life over the last week. | Screening; Observational: Predose of Weeks 1, 5, and 9; Main Phase: Baseline, predose of Weeks 3, 5, 7, 9, and 11; Extension Phase, predose of Weeks 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, and 37 | 
| Number of Participants With Anti-Drug Antibodies Against DS-2325a |  | Main Phase: Baseline and predose of Weeks 5 and 9; Extension Phase: Predose of Weeks 13, 17, 21, 25, 29, 33, 37, and 45 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Netherton Syndrome, DS-2325a