A Study to Assess the Safety and Pharmacokinetics of Multiple Ascending Subcutaneous Doses of DS-2325a in Healthy Subjects

Study Overview
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Brief Summary
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Netherton syndrome (NS) is a rare autosomal recessive disease and no systemic treatment or standard of care currently exists for patients with NS. DS-2325a, a specific and potent inhibitor of kallikrein 5, is expected to treat NS by replacing a defective gene.

Detailed Description
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This study for DS-2325a will evaluate the safety, tolerability, and pharmacokinetics of multiple ascending doses of DS-2325a in healthy participants. DS-2325a will be evaluated after subcutaneous (SC) injections.

Official Title
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A Phase 1, Subject- and Investigator-Blinded, Sponsor-Unblinded, Placebo-Controlled, Randomized, Sequential Cohort Study to Assess the Safety and Pharmacokinetics of Multiple Ascending Subcutaneous Doses of DS-2325a in Healthy Subjects

Conditions
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Netherton Syndrome

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be able to understand a written informed consent, which must be obtained prior to initiation of study procedures. Must be willing and able to comply with all study requirements. Healthy males or non-pregnant, non-lactating healthy females. Aged 18 to 50 years of age (inclusive) at the time of signing informed consent. BMI of 18.0 kg/m^2 to 30.0 kg/m^2 (inclusive) as measured at Screening. Women of childbearing potential who are sexually active with a male partner must practice effective contraception during the study treatment period and for 90 days after last IMP administration. They must agree to use 2 different means of nonhormonal contraceptive methods. Women of non-childbearing potential must be either surgically sterile or in menopausal state confirmed as follows: 1 year of spontaneous amenorrhea without an alternative medical cause and a serum follicle stimulating hormone (FSH) level ≥40 mIU/mL. Male participants who are sexually active with a female partner of childbearing potential must use, with their partner, a condom plus an approved method of highly effective contraception from the time of informed consent until 90 days after last IMP administration. Women should not donate eggs and men should not donate sperm during the study treatment period and for at least 90 days after last IMP administration. All female participants must have a negative serum pregnancy test at Screening and Admission (Day -2). Exclusion Criteria: History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, metabolic, endocrine, immunologic, infectious, dermatologic, neurologic, oncologic, psychological, psychiatric, ophthalmologic, or gastrointestinal disease (except cholecystectomy), as judged by the Investigator. History or presence of chronic lung or respiratory disease, including clinically significant asthma (as judged by the Investigator) and chronic obstructive pulmonary disease (COPD). History, or presence in the average of triplicate ECGs at Screening and Admission (Day -2). Laboratory results (serum chemistry, hematology, coagulation, and urinalysis) outside the normal range, if considered clinically significant by the Investigator at Screening or Admission (Day -2). Creatinine clearance (CrCl) <80 mL/mina t Screening. History or presence of any other clinically significant condition, including laboratory abnormality, that in the opinion of the Investigator, would jeopardize the safety of the participant, obtaining informed consent, compliance to the study procedures, or the validity of the study results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-2325a SC<br>Participants who will be randomized to receive DS-2325a as a fixed dose subcutaneous (SC) injection (starting dose 300 mg). | Drug: DS-2325a<br>* Subcutaneous injection (starting dose 300 mg)<br>|
| Experimental: Placebo SC<br>Participants who will be randomized to receive placebo as a subcutaneous (SC) injection. | Drug: Placebo<br>* Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Any Treatment-emergent Adverse Events Following Administration of DS-2325a | Treatment-emergent adverse events (TEAEs) are defined as new adverse events (AEs) that occur after the dose of study drug or as AEs that were present prior to the dose of study drug but which worsened in severity after the start of study drug. | Screening (Day -28 to -3) pre-dose up to Day 78 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameter Area Under the Concentration Curve (AUCtau) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | Day 1: pre-dose & 4, 8, 24, 72, 96, 120, 144 hours (hr) post-dose; Day 8 & 14: pre-dose; Day 22: pre-dose & 4, 8, 24, 48, 72, 96, 120, 144, 168 hr post-dose; Day 36, 43, 57, & 78 | 
| Pharmacokinetic Parameter Maximum Concentration (Cmax) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | Day 1: pre-dose & 4, 8, 24, 72, 96, 120, 144 hours (hr) post-dose; Day 8 & 14: pre-dose; Day 22: pre-dose & 4, 8, 24, 48, 72, 96, 120, 144, 168 hr post-dose; Day 36, 43, 57, & 78 | 
| Pharmacokinetic Parameter Average Concentration (Cavg) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | Day 1: pre-dose & 4, 8, 24, 72, 96, 120, 144 hours (hr) post-dose; Day 8 & 14: pre-dose; Day 22: pre-dose & 4, 8, 24, 48, 72, 96, 120, 144, 168 hr post-dose; Day 36, 43, 57, & 78 | 
| Pharmacokinetic Parameter Drug Accumulation Ratio for AUCtau and Cmax (Rac) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | Day 1: pre-dose & 4, 8, 24, 72, 96, 120, 144 hours (hr) post-dose; Day 8 & 14: pre-dose; Day 22: pre-dose & 4, 8, 24, 48, 72, 96, 120, 144, 168 hr post-dose; Day 36, 43, 57, & 78 | 
| Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | Day 1: pre-dose & 4, 8, 24, 72, 96, 120, 144 hours (hr) post-dose; Day 8 & 14: pre-dose; Day 22: pre-dose & 4, 8, 24, 48, 72, 96, 120, 144, 168 hr post-dose; Day 36, 43, 57, & 78 | 
| Pharmacokinetic Parameter Terminal Elimination Half-life (T1/2) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | Day 1: pre-dose & 4, 8, 24, 72, 96, 120, 144 hours (hr) post-dose; Day 8 & 14: pre-dose; Day 22: pre-dose & 4, 8, 24, 48, 72, 96, 120, 144, 168 hr post-dose; Day 36, 43, 57, & 78 | 
| Pharmacokinetic Parameter Elimination Rate Constant Associated With the Terminal Phase (Kel) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | Day 1: pre-dose & 4, 8, 24, 72, 96, 120, 144 hours (hr) post-dose; Day 8 & 14: pre-dose; Day 22: pre-dose & 4, 8, 24, 48, 72, 96, 120, 144, 168 hr post-dose; Day 36, 43, 57, & 78 | 
| Number of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) | Blood samples will be collected to determine ADAs. | Day 1: pre-dose and Days 15, 22, 36, 57, and 78 | 

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