Study of EN-374 Gene Therapy in Participants With X-Linked Chronic Granulomatous Disease

Phase 1

Recruiting

• Conditions: X-Linked Chronic Granulomatous Disease

• Registration Number: NCT06876363
• Lead Sponsor: Ensoma

Brief Summary

The goal of this clinical trial is to evaluate the safety and potential efficacy of the EN-374 treatment regimen and identify a dose level for further evaluation in participants with x-linked chronic granulomatous disease.

The main questions it aims to answer are:

* safety of the EN-374 treatment regimen

* effect of the EN-374 treatment regimen on the production of functional neutrophils with NADPH oxidase activity

Detailed Description

Chronic granulomatous disease (CGD) is a rare primary immune deficiency disorder characterized by recurrent bacterial or fungal infections starting in infancy. The x-linked form of CGD (X-CGD) is caused by mutations in the CYBB gene.

EN-374 is a helper-dependent adenoviral (HDAd)-based gene therapy in development for the treatment of X-CGD using an in vivo approach, which is administered by IV infusion, to genetically modify hematopoietic stem cells (HSCs) to express a wild-type CYBB gene. The EN-374 treatment regimen includes HSC mobilization, immune prophylaxis, EN-374 administration, and enrichment of genetically modified HSCs.

Adult participants with X-CGD will be enrolled into the dose-escalation part of the study. Following completion of the adult cohorts, then pediatric participants will be enrolled into the dose-expansion part of the study in decreasing age cohorts from ≥ 12 and \< 18 years of age, to ≥ 2 and \< 12 years of age, and finally to ≥ 3 months and \< 2 years of age.

Study Timeline

• Study First Submitted: 2025-03-10
• Study First Submitted QC: 2025-03-10
• Study First Posted: 2025-03-14
• Study Start: 2025-08-05
• Status Verified: 2025-10
• Last Update Submitted: 2025-10-17
• Last Update Posted: 2025-10-21
• Primary Completion: 2027-12
• Study Completion: 2027-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 15

Inclusion Criteria

• Male
• ≥ 18 years of age during dose escalation, then ≥ 3 months of age during dose expansion
• Diagnosis of X-CGD with DHR+ cells ≤ 5% and a pathogenic mutation in the CYBB gene
• History of at least 1 severe infection requiring medical intervention or chronic inflammatory disorder
• Does not have a suitable, available, and willing human leukocyte antigens (HLA)-matched (10/10) related donor
• Non-sterile male participants who are or may become sexually active with female partners of childbearing potential are required to use highly effective contraception
• Informed consent, with informed assent from capable participants
• Adequate organ function

Exclusion Criteria

• Active bacteremia or fungemia
• History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
• History or clinical evidence of any medical or social issues likely to put the participant at additional risk or to interfere with study conduct
• History of HSCT or granulocyte transfusions
• Known hypersensitivity to elements in the treatment regimen
• Undergone investigational gene therapy
• Treated with another investigational drug product within 30 days before screening
• Unable to comply with the visits and requirements of the protocol as determined by the Investigator

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Safety of EN-374	From start of mobilization until Month 12	Incidence rate across all age groups of: * treatment-emergent adverse events (TEAEs); * treatment-related TEAEs (TRAEs); * serious adverse events (SAEs)

Secondary Outcome Measures

Name	Time	Method
Effect of the EN-374 treatment regimen on the production of functional neutrophils with NADPH oxidase activity	From infusion of EN-374 until Month 12	* Change from baseline in the percentage of dihydrorhodamine (DHR)+ neutrophils; * Change from baseline in the percentage of participants with ≥ 10%, 20%, 30%, 40%, or 50% DHR+ neutrophils

Trial Locations

Locations (3)

Columbia University Irving Medical Center, Morgan Stanley Children's Hospital; 🇺🇸 New York, New York, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

University of Utah, Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States