A Study of the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of BCX17725

Parts 1 and 2 are randomized, placebo-controlled, single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study parts, respectively, in healthy participants. Part 3 will evaluate multiple dose administrations in participants with Netherton syndrome in an open-label design. Part 4 will evaluate multiple administrations of BCX17725 in participants with Netherton syndrome in an open-label study design over 12 weeks, with an 8-week post-treatment follow-up period.

• BCX17725 (Drug): BCX17725 for injection
• Placebo (Drug): Placebo for injection

Primary outcomes

• Incidence of treatment-emergent adverse events (TEAEs) [From screening through EOS (ie, through Day 78 in Parts 1 and 3, and Day 106 in Part 2)]: Incidence of TEAEs as assessed by Common Terminology Criteria for Adverse Events (CTCAE) from screening through end-of-study (EOS) in each study part
• Change from baseline in Ichthyosis Area and Severity Index (IASI) score at Week 12 (Part 4) [From baseline to Week 12]: IASI measures the severity of erythema (IASI-E) and scaling (IASI-S); the maximum sub-scores for the IASI-E and IASI-S being 24, and the maximum total IASI score being 48. Higher scores indicate worse clinical outcome.

Secondary outcomes

• Maximum observed serum concentration (Cmax) [Up to Day 64 (Part 1), Day 92 (Part 2), and Day 78 (Part 3)]: Cmax of BCX17725
• Time to maximum observed serum concentration (Tmax) [Up to Day 64 (Part 1), Day 92 (Part 2), and Day 78 (Part 3)]: Time to Cmax of BCX17725
• Area under the serum concentration-time curve (AUC) from time 0 to the time of last measurable concentration (AUC0-t) [Up to Day 64 (Part 1), Day 92 (Part 2), and Day 78 (Part 3)]: AUC0-t of BCX17725
• Terminal elimination half-life (t1/2) [Up to Day 64 (Part 1), Day 92 (Part 2), and Day 78 (Part 3)]: Terminal elimination half-life (t1/2) of BCX17725
• Number of participants who are anti-drug antibody (ADA)-positive (baseline and post-baseline) and number of participants who have treatment-emergent ADAs [Day 1 pre-dose and up to Day 64 (Part 1), Day 92 (Part 2), and Day 78 (Part 3)]: Incidence of ADAs to BCX17725
• Change from baseline in Investigator Global Assessment (IGA) score at Week 12 (Part 4) [From baseline to Week 12]: IGA assesses the overall severity of a participant's NS skin disease based on a 5-point scale (0, clear; 1, almost clear; 2, mild; 3, moderate; and 4, severe). Higher scores indicate worse clinical outcome.
• Change from baseline in Worst Itch Numerical Rating Score (NRS) at Week 12 (Part 4) [From baseline to Week 12]: Worst Itch Numerical Rating Scale (NRS) is a self-rated, single-item scale designed for assessing the worst itch in the past 7 days. The scale uses an 11-point NRS, scored from 0 (no itch) to 10 (worst possible itch). Higher scores indicate worse clinical outcome.
• Incidence of TEAEs (Part 4) [From baseline through Week 20]: Incidence of TEAEs as assessed by CTCAE
• Serum concentrations of BCX17725 (Part 4) [From baseline through Week 20]: Serum concentrations of BCX17725

Sex: All, ages: 12 Years to 65 Years, accepts healthy volunteers

Key Inclusion Criteria:

* Male or non-pregnant, non-lactating female aged 18 to 55 years, inclusive (Parts 1 and 2), 18 to 65 years, inclusive (Part 3), or 12 to 65 years, inclusive (Part 4)
* Confirmed diagnosis of Netherton syndrome (Parts 3 and 4)
* IGA score of ≥ 3 (Parts 3 and 4) and IASI score of ≥ 16 (Part 4)
* BMI between 18 and 30 kg/m\^2, inclusive (Parts 1 and 2)
* Estimated glomerular filtration rate (eGFR) of ≥ 90 mL/min/1.73 m\^2 (Parts 1 and 2) or ≥ 60 mL/min/1.73 m\^2 (Part 3)
* Agree to follow the protocol contraception requirements from screening until 90 days after the last dose of study drug
* In the opinion of the investigator, expected to adequately comply with all required study procedures and restrictions for the duration of the study

NIH grants: 2025