First ever clinical evaluation of an in vivo HSC-directed gene insertion therapy aims to restore immune function for people living with X-linked chronic granulomatous disease
BOSTON–(BUSINESS WIRE)–Ensoma, an in vivo cellular engineering company with a mission to advance the future of medicine through one-time therapies, today announced that the first patient has been dosed in the company’s Phase 1/2 clinical trial of EN-374. EN-374 is an in vivo hematopoietic stem cell (HSC)-directed gene insertion therapy for the treatment of X-linked chronic granulomatous disease (X-CGD), a rare and severe genetic disorder.
“Dosing our first patient in this Phase 1/2 trial is a significant milestone for Ensoma and for the X-linked CGD community,” said Jim Burns, CEO of Ensoma. “It represents the first time an in vivo HSC-directed gene insertion therapy has been evaluated in a patient, opening the door to a potentially simpler approach to addressing the root cause of this life-threatening disease. EN-374 is designed as a one-time treatment to restore immune function in patients who currently face a lifelong burden of severe infections, repeated hospitalizations and limited therapeutic options. The results of this study would also provide both clinical proof of concept for our platform and readthrough to our programs in oncology and sickle cell disease, as well other potential indications. We are deeply grateful to the patients, families, clinicians, hospitals and advocacy partners supporting the study.”
The Phase 1/2 study is an open-label, multicenter clinical trial evaluating the safety, tolerability, pharmacodynamics and preliminary efficacy of EN-374, with the goal of identifying a dose for further clinical development in X-CGD. Key safety endpoints include the incidence of treatment-emergent, treatment-related and serious adverse events, while efficacy endpoints include changes in functional DHR+ neutrophils and the proportion of participants reaching predefined DHR+ neutrophil thresholds (≥10–50%). Adult participants with X-CGD will be enrolled in the dose-escalation portion of the trial. Following completion of the adult cohorts, pediatric participants would be enrolled in a dose-expansion cohort. Earlier this year, the FDA granted Ensoma rare pediatric disease and orphan drug designations for EN-374.
“People living with X-CGD are highly susceptible to recurrent, life-threatening bacterial and fungal infections, which can be severe and accompanied by lengthy hospitalizations,” said Ahmad Rayes, M.D., principal investigator and associate professor of pediatrics in the Pediatric Immunology and Hematopoietic Cell Transplantation/Cellular Therapy Program at the University of Utah and Intermountain Primary Children’s Hospital in Salt Lake City. “Current treatment options may reduce infection risk but often fall short of meaningful immune restoration, particularly for children. Evaluating an in vivo HSC-directed gene insertion therapy offers real hope to families who have been waiting for safer, more accessible and more durable solutions.”
About CGD
Chronic granulomatous disease (CGD) is a rare, severe genetic disorder that affects approximately 1 in 100,000-200,000 live births, and the median life expectancy for individuals with the condition is around 45 years. X-linked CGD (X-CGD), the most common form of the condition, comprises 60-70% of cases and is caused by mutations in the CYBB gene of the NAPDH oxidase complex in neutrophils. CGD severely compromises immune function and leaves those with the disease vulnerable to recurrent bacterial and fungal infections, often leading to chronic and life-threatening dysregulated inflammation and serious complications. Current treatments, including antibiotics, antifungals, interferon gamma and allogeneic stem cell transplantation, offer limited benefit and/or come with significant burdens.
About EN-374
EN-374 is a first-in-class in vivo hematopoietic stem cell (HSC)-directed therapy for X-CGD that employs virus-like particles (VLPs) to deliver payloads having a CYBB transgene to HSCs. Neutrophils arising from the engineered HSC then express the protein product of the CYBB transgene. In this way, EN-374 is designed to restore function of the infection-fighting NADPH oxidase enzyme complex critical for immune defense in humans having an impaired CYBB gene. In preclinical studies, EN-374 demonstrated therapeutic restoration of CYBB protein expression and NADPH oxidase activity in circulating neutrophils. EN-374 represents the first in vivo HSC-directed therapy for X-CGD, building on a mechanism that has been validated ex vivo.
About Ensoma
Ensoma is developing potentially curative medicines for genetic diseases, immune disorders and cancer through in vivo cellular engineering. Our platform combines class-leading proprietary base editing and high-efficiency gene integration systems with high-capacity virus-like particles (VLPs) to provide potentially one-time, durable genetic medicines. The VLPs preferentially bind to hematopoietic stem cells (HSCs), efficiently delivering DNA to the nucleus. With a 35-kilobase cargo capacity, these VLPs can carry a diverse range of sophisticated genomic engineering tools capable of precise changes from single base edits to large multi-gene insertions, along with control elements for HSC-lineage cell specific expression. Ensoma is supported by top-tier investors and a passionate team committed to a bold, global vision for genomic medicines. Ensoma is based in Boston. For more information, visit ensoma.com.
Contacts
Josie Butler, 1AB
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