A Study to Assess the Safety and Pharmacokinetics of Single Ascending Subcutaneous and Intravenous 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 first-in-human study for DS-2325a will evaluate the safety, tolerability, and pharmacokinetics of single ascending doses of DS-2325a in healthy participants. DS-2325a will be evaluated after both subcutaneous (SC) injections and intravenous (IV) infusions, as it may have to be given intravenously to young patients and as loading dose.

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

Conditions
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Netherton Syndrome

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must give written informed consent to participation in the study prior to Screening Healthy men and women 18 to 45 years of age (inclusive), with a BMI of 18 kg/m2 to 30 kg/m^2 (inclusive) at Screening All women must have a negative serum pregnancy test at Screening and all women of childbearing potential must have a negative urine pregnancy test on Day -1 Women must not be lactating during the study treatment period and for 3 months after the last dose of study treatment Women of childbearing potential must practice effective contraception during the study treatment period and for 3 months after the last dose of study treatment. They must agree to use 2 different means of nonhormonal contraceptive methods Women of non-childbearing potential must be either surgically sterile (ie, bilateral tubal ligation at least 3 months prior to dosing) or in menopausal state confirmed as follows: 1 year of spontaneous amenorrhea without an alternative medical cause and a serum FSH level ≥40 mIU/mL Men must agree to use contraception (condom with spermicide) during the study treatment period and for at least 3 months after the last dose of study treatment or be surgically sterile (vasectomy at least 3 months prior to dosing) Women should not donate eggs and men should not donate sperm during the study treatment period and for at least 3 months after the last dose of study treatment Participants must be in good health as determined by Screening medical history, physical examination, vital signs, ECGs, serum chemistry, hematology, virology, and urinalysis performed at Screening and on Day -1 Exclusion Criteria: History or current chronic lung disease including asthma, chronic obstructive pulmonary disease (COPD), or heavy smoking of >10 pack years Previous or current treatment with systemic corticosteroids or any immunosuppressive agents Participants who have received a transfusion or any blood products within the last year prior to dosing Participants who have made any blood donation or have had a loss of blood of ≥500 mL within 56 days prior to the dose of study drug Participants who consume more than 21 units of alcohol per week (1 unit of alcohol equals 1/2 pint of beer, 4 ounces of wine, or 1 ounce of spirits) or those participants who have a significant history of alcoholism or drug/chemical abuse within the last 2 years. Participants with positive results on tests for drugs of abuse, cotinine, or alcohol at Screening and/or Day -1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Double


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 30 mg). | Drug: DS-2325a<br>* Subcutaneous injection (starting dose 30 mg)<br>|
| Placebo Comparator: Placebo SC<br>Participants who will be randomized to receive placebo as a subcutaneous (SC) injection. | Drug: Placebo<br>* Subcutaneous injection<br>|
| Experimental: DS-2325a IV<br>Participants who will be randomized to receive DS-2325a as a fixed dose intravenous (IV) infusion (starting dose 100 mg). | Drug: DS-2325a<br>* Intravenous infusion (starting dose 100 mg)<br>|
| Placebo Comparator: Placebo IV<br>Participants who will be randomized to receive placebo as an intravenous infusion. | Drug: Placebo<br>* Intravenous infusion<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 57 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Parameter Area Under the Concentration Curve (AUC) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | SC and IV cohorts: Day 1 pre-dose and 1, 2, 4, 8 hours (hr) post-dose; 24, 48, 96, 120, 144, 168, 192, 240, 288, 336, 384, 432, 480, 552, 624, 696, 768, 840, 1008, 1176, 1344 hr post-dose | 
| Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | SC and IV cohorts: Day 1 pre-dose and 1, 2, 4, 8 hours (hr) post-dose; 24, 48, 96, 120, 144, 168, 192, 240, 288, 336, 384, 432, 480, 552, 624, 696, 768, 840, 1008, 1176, 1344 hr post-dose | 
| Pharmacokinetic Parameter Maximum Concentration (Cmax) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | SC and IV cohorts: Day 1 pre-dose and 1, 2, 4, 8 hours (hr) post-dose; 24, 48, 96, 120, 144, 168, 192, 240, 288, 336, 384, 432, 480, 552, 624, 696, 768, 840, 1008, 1176, 1344 hr post-dose | 
| Pharmacokinetic Parameter Last Measurable Time (Tlast) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | SC and IV cohorts: Day 1 pre-dose and 1, 2, 4, 8 hours (hr) post-dose; 24, 48, 96, 120, 144, 168, 192, 240, 288, 336, 384, 432, 480, 552, 624, 696, 768, 840, 1008, 1176, 1344 hr post-dose | 
| Pharmacokinetic Parameter Elimination Rate Constant Associated With the Terminal Phase (Kel) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | SC and IV cohorts: Day 1 pre-dose and 1, 2, 4, 8 hours (hr) post-dose; 24, 48, 96, 120, 144, 168, 192, 240, 288, 336, 384, 432, 480, 552, 624, 696, 768, 840, 1008, 1176, 1344 hr post-dose | 
| Pharmacokinetic Parameter Elimination Half-life (T1/2) | Pharmacokinetic parameters will be calculated for DS-2325a by noncompartmental methods. | SC and IV cohorts: Day 1 pre-dose and 1, 2, 4, 8 hours (hr) post-dose; 24, 48, 96, 120, 144, 168, 192, 240, 288, 336, 384, 432, 480, 552, 624, 696, 768, 840, 1008, 1176, 1344 hr post-dose | 
| Number of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) and Number of Participants Who Have Treatment-emergent ADA | Blood samples will be collected to determine ADAs. | Day 1 pre-dose and 336 hours (hr), 552 hrs, 696 hrs, and 1344 hrs post-dose | 

 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