A PHASE 1/1B STUDY TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND IMMUNOGENICITY OF SINGLE AND MULTIPLE ASCENDING DOSES OF BCX17725 IN HEALTHY PARTICIPANTS AND MULTIPLE DOSES OF BCX17725 IN PARTICIPANTS WITH NETHERTON SYNDROME

Trial ID: 2025-521973-16-00
Protocol: BCX17725-101
Sponsor: Biocryst Pharmaceuticals Inc.

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Diseases & Conditions

Netherton's syndrome

Objectives

The primary objective of this study is to evaluate the therapeutic potential of BCX17725 in adult and adolescent participants with Netherton syndrome. Additionally, the study aims to assess the safety and tolerability of BCX17725 when administered for 12 weeks in this patient population. The pharmacokinetic profile will be characterized by measuring BCX17725 concentrations in serum of adult and adolescent participants with Netherton syndrome. These objectives are clinically relevant as Netherton syndrome is a rare genetic disorder requiring novel therapeutic approaches, and understanding the efficacy, safety profile, and pharmacokinetic behavior of this anti-KLK5 Fc fusion protein is essential for determining its potential clinical utility in managing this condition.

Participants

This clinical trial enrolled a total of **6 participants** diagnosed with **Netherton Syndrome**. The study population included both **male and female** individuals aged **12 to 65 years**, encompassing **adolescents** and **adults**. Participants were required to have a confirmed diagnosis of Netherton Syndrome, with those lacking pre-existing documentation of **SPINK5 gene variant(s)** required to undergo genetic testing at screening. The selection criteria specified that participants must have an **Investigator's Global Assessment (IGA) score** of 3 or higher and an **IASI score** of 16 or higher at both screening and baseline. **Females of childbearing potential** and males with female partners of childbearing potential were required to adhere to specified contraception requirements from screening until 90 days after the last dose of the investigational product. Participants or their parent/legal guardian needed to demonstrate willingness and ability to comply with all study requirements, including availability to complete the entire study duration, ability to understand study procedures and complete self-assessment questionnaires, and willingness to have skin strip samples collected. The trial included a **vulnerable population** as defined by regulatory standards.

Plans and Procedures

This is a Phase 1/1b clinical trial designed to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of BCX17725, an anti-KLK5 Fc fusion protein administered as a solution for injection via intravenous, subcutaneous, or intramuscular routes. The trial investigates both single and multiple ascending doses in healthy participants and multiple doses in participants diagnosed with Netherton Syndrome. The investigational medicinal product contains the active substance BCX17725, classified as a protein-based therapeutic agent.

The primary objective of the trial is to evaluate the therapeutic potential of BCX17725 in adult and adolescent participants with Netherton Syndrome, assess the safety and tolerability of the investigational product when administered for 12 weeks, and characterize BCX17725 concentrations in serum. The trial is categorized as a combined Phase 1/1b study in healthy participants and patients with exploratory assessment of effectiveness. This is not classified as a low-intervention clinical trial.

The trial employs a structured design to assess effectiveness, safety, and pharmacokinetic parameters. The primary effectiveness endpoint is the change from baseline in Ichthyosis Area and Severity Index (IASI) score at Week 12. Safety assessment focuses on the incidence of treatment-emergent adverse events (TEAEs) through end-of-study. Pharmacokinetic evaluation measures the concentration of BCX17725 in serum through end-of-study. Key secondary effectiveness endpoints include change from baseline in Investigator Global Assessment (IGA) score at Week 12 and change from baseline in the Worst Itch Numerical Rating Scale (NRS) score at Week 12.

Eligible participants include male or non-pregnant, non-lactating female individuals aged 12 to 65 years with a confirmed diagnosis of Netherton Syndrome. Participants must have an IGA score of 3 or higher and an IASI score of 16 or higher at both screening and Day 1 baseline. Participants without pre-existing documentation of SPINK5 gene variants confirming Netherton Syndrome diagnosis are required to provide a blood sample for genetic testing at screening. Adolescent participants must provide assent with parent or legal guardian consent. Females of childbearing potential and males with female partners of childbearing potential must agree to follow contraception requirements from screening until 90 days after the last dose of BCX17725. Participants or their parent/legal guardian must be willing and able to complete the entire study duration, understand study procedures including completion of self-assessment questionnaires or instruments, and be willing to have skin strip samples collected.

The estimated recruitment start date is January 2, 2026, with an estimated end date of December 3, 2026. Participant involvement includes a screening visit to confirm eligibility, baseline assessments on Day 1, and follow-up visits during the 12-week treatment period. The end-of-study visit occurs after completion of the treatment phase and follow-up period. Throughout the trial, participants undergo regular monitoring for safety, effectiveness, and pharmacokinetic assessments. Skin strip samples are collected at designated time points for evaluation of treatment effects. The total duration of participant involvement extends beyond the 12-week treatment period to include a 90-day follow-up for safety monitoring after the last dose of BCX17725.

Treatment

The experimental medicinal product under investigation is **BCX17725**, an **anti-KLK5 Fc fusion protein**. This investigational agent is formulated as a **solution for injection** and is manufactured by BioCryst Pharmaceuticals, Inc. The active substance, BCX17725, is classified as a protein of non-recombinant origin. The pharmaceutical form allows for flexible administration through multiple **routes of administration**, including **intravenous**, **subcutaneous**, or **intramuscular** delivery. The study employs a **single and multiple ascending dose** design to evaluate the safety, tolerability, **pharmacokinetics**, and **immunogenicity** of BCX17725. In the Phase 1b portion of the trial, multiple doses of BCX17725 are administered over a **12-week treatment period** to adult and adolescent participants with **Netherton syndrome**. The dosing regimen follows an escalation protocol to characterize BCX17725 serum concentrations and assess therapeutic potential in the target population. This is not a paediatric formulation, and the product has been assigned the sponsor product code BCX17725 with the manufacturer's investigational medicinal product number IMP11566/00001.

Efficacy

Efficacy will be assessed through multiple parameters designed to evaluate the therapeutic potential of BCX17725 in participants with Netherton syndrome. The primary efficacy endpoint is the change from baseline in Ichthyosis Area and Severity Index (IASI) score at Week 12. Key secondary efficacy endpoints include the change from baseline in Investigator Global Assessment (IGA) score at Week 12 and the change from baseline in the Worst Itch Numerical Rating Scale (NRS) score at Week 12. Baseline assessments will be conducted on Day 1, with participants required to have an IGA score of 3 or greater and an IASI score of 16 or greater at both screening and baseline to be eligible for enrollment. Efficacy parameters will be measured and collected through the end of the study, with specific evaluation timepoints at Week 12 for the primary and key secondary endpoints. Skin strip samples will be collected as part of the assessment procedures. The study will administer BCX17725 for a period of 12 weeks in adult and adolescent participants with Netherton syndrome to evaluate its therapeutic potential.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Able to provide written informed consent. Adolescent participants should provide assent (age determined by applicable institutional policy) with parent/legal guardian consent.
Male or non-pregnant, non-lactating female, aged 12 to 65 years, inclusive, with a confirmed diagnosis of NS. Note: Participants without pre-existing documentation of SPINK5 gene variant(s) confirming NS diagnosis will be required to provide a blood sample for genetic testing at screening.
IGA score ≥ 3 and an IASI score of ≥ 16 at screening and Day 1 (baseline).
Females of childbearing potential and males with female partners of childbearing potential, must agree to follow the contraception requirements outlined in Section 5.3 of the protocol from screening until 90 days after the last dose of BCX17725.
Participant (or, where applicable, parent/legal guardian) is willing and able to understand and comply with all applicable study requirements, including:a.a. Available to complete the entire study duration; b: Able to understand the study procedures including the ability to complete any self assessment questionnaires or instruments; c: Willing to have skin strip samples collected

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Exclusion Criteria

Apart from a diagnosis of NS, any clinically significant disease or condition (eg, medical, psychiatric, or social) that, in the opinion of the investigator, would interfere with the participant’s ability to participate in the study or increase the risk of participation for that participant.
Any other skin disease that may interfere with planned NS skin evaluations.
Any infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, or antifungals within 2 weeks prior to Day 1.
History of malignancy within 5 years prior to screening, with exception of adequately treated non-melanoma skin or superficial bladder cancer, curatively treated carcinoma in situ of the cervix, or other curatively treated solid tumor deemed by the investigator and medical monitor to be at low risk for recurrence.
Any clinically significant history of a cardiovascular abnormality, including but not limited to angina, known coronary artery disease, myocardial infarction, clinically significant cardiac arrhythmias, left ventricular hypertrophy, cardiomyopathy, or aortic stenosis.
History of significant drug or alcohol abuse in the 6 months prior to screening or a positive drugs of abuse screen (not supported by a legitimate prescription) at screening.
Positive test result for HIV at screening.
Active hepatitis B virus infection, determined by positive test result for hepatitis B surface antigen, at screening.
Active hepatitis C infection, determined as HCV RNA above the limit of detection in participants with positive HCV antibody titer, at screening.
Any abnormal laboratory parameter at screening or Day 1 that, in the opinion of the investigator, is clinically significant and relevant for this study, including but not limited to those listed below. Enrollment of a participant with a laboratory value outside of the reference range may be permissible if the abnormality is documented by the investigator not to be of clinical significance. a. AST, ALT, or total bilirubin value > 1.5 × ULN b. Platelet count < 150,000/µL
History of anaphylaxis or other severe reaction to any biologic or protein therapeutic agent, which, in the opinion of the investigator or sponsor medical monitor, should contraindicate their participation in this study.
History of sensitivity to any component of the IMP.
Receipt of any investigational drug, systemic biologic, or systemic immunoglobulin within 8 weeks prior to Day 1 or anticipated receipt during the study (excluding potential receipt of BCX17725 during the study). Note: Individuals who participate in Part 3 may additionally participate in Part 4, providing they meet all applicable eligibility criteria for Part 4 and experienced no significant safety concerns related to BCX17725 administration in Part 3. Part 3 participants qualifying for Part 4 enrollment will be subject to the washout period as described above
Use of systemic retinoids, other systemic immunosuppressants, systemic corticosteroids, or phototherapy within 4 weeks prior to Day 1 or anticipated use during the study.
Use of ultra-high to medium potency topical corticosteroids (WHO Classes 1 to 5 or equivalent; see Appendix 3) within 2 weeks prior to Day 1 or anticipated use during the study.
Participant is pregnant, planning to become pregnant, or having been pregnant within 90 days before Day 1, or lactating.