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

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.

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 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 for 12 consecutive weeks (Main Phase) and to confirm by administering for an additional 24 weeks (Extension Phase).

Eligibility Criteria:
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
* Any 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; ALT and AST \>2 × ULN range; total bilirubin \>1 × ULN).
* 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