FDA clears EN-374 therapy application for X-linked chronic granulomatous disease

FDA clears EN-374 therapy application for X-linked chronic granulomatous disease } Image credit: Contemporary Pediatrics

On May 12, 2025, the FDA cleared an investigational new drug application for Ensoma's lead program EN-374 in X-linked chronic granulomatous disease (X-CGD), according to a press release from genomic medicines company.¹

CGD is a rare and severe genetic disorder that impacts approximately 1 in 100,00 to 200,000 live births, with the median life expectancy for those with the condition being 45 years. The most common form of the condition, X-CGD, comprises 60% to 70% of cases, caused by CYBB gene mutations that prevent white blood cells called neutrophils from fighting infection. According to Ensoma, those with CGD are vulnerable to recurrent, severe bacterial and fungal infections, which can lead to chronic and life-threatening dysregulated inflammation in addition to serious complications.

The investigational therapy is a first-in-class in vivo hematopoietic stem cell (HSC)-directed therapy for X-CGD. EN-374 employs virus-like particles that deliver payloads that engineer HSCs for sustained expression of a CYBB transgene in neutrophils, thereby restoring the function of the infection-fighting NADPH oxidase enzyme complex critical for immune defense, according to Ensoma.

EN-374 demonstrated therapeutic restoration of CYBB protein expression and NADPH oxidase activity in circulating neutrophils in preclinical studies.

"The FDA’s clearance of our EN-374 IND is a pivotal moment for Ensoma that further establishes our unique in vivo HSC engineering platform and brings us one step closer to meaningfully improving outcomes for people living with X-CGD and other chronic diseases,” said Jim Burns, CEO of Ensoma, in the press release. "We have completed all manufacturing activities for EN-374, through which we have successfully demonstrated reproducibility and scalability, and anticipate initiating our Phase 1/2 clinical trial in Q4 2025. We are excited to explore the potential of EN-374 to offer a simpler, more accessible approach to restoring immune function in X-CGD than HSC transplantation or ex vivo therapies.”

The trial aims to evaluate the safety and potential efficacy of the therapy while identifying a dose for further clinical development. Adults will first be enrolled in a dose-escalation portion of the trial. After completion of adult cohorts, pediatric patients will be enrolled in a dose-expansion cohort. EN-374 was granted both rare pediatric disease and orphan drug designations by the FDA in February 2025.²

“One of the strengths of our platform is its modular nature – we can evaluate multiple products for a family of diseases in a single clinical trial by inserting different genes to address the various genetic forms of CGD, for example. This exciting approach should enable greater efficiency in the clinic and facilitate the regulatory process,” said Robert Peters, PhD, chief scientific officer of Ensoma, in a statement. “Our EN-374 program will support a greater understanding of our technology’s broad applicability and also validate its potential to develop future HSC-directed, one-time medicines for other genetic diseases, cancer, and immunologic conditions.”¹

References:

1. Ensoma Announces FDA Clearance of IND Application for First In Vivo HSC-Directed Gene Insertion Therapy. Ensoma. Press release. May 12, 2025. Accessed May 12, 2025. https://www.businesswire.com/news/home/20250512555261/en/Ensoma-Announces-FDA-Clearance-of-IND-Application-for-First-In-Vivo-HSC-Directed-Gene-Insertion-Therapy

2. Ensoma Receives Rare Pediatric Disease and Orphan Drug Designations for EN-374 for Treatment of Chronic Granulomatous Disease. Ensoma. Press release. February 13, 2025. Accessed May 12, 2025. https://www.businesswire.com/news/home/20250213170131/en/Ensoma-Receives-Rare-Pediatric-Disease-and-Orphan-Drug-Designations-for-EN-374-for-Treatment-of-Chronic-Granulomatous-Disease