A Study of the Safety and Efficacy of Prime Editing (PM359) in Participants With p47phox Autosomal Recessive Chronic Granulomatous Disease (CGD )

NCT06559176 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: Prime-0101
• Study Type: interventional
• Target: 12
• Locations: 3 countries
• Sites: 5

Brief Summary

This is an open-label, single-arm, multicenter Phase 1/2 study evaluating the safety and efficacy of gene therapy by transplantation of Prime Edited autologous CD34+ stem cells modified ex vivo (PM359) in participants with autosomal recessive Chronic Granulomatous Disease (CGD) caused by mutations in the NCF1 (Neutrophil Cytosolic Factor 1) gene.

Conditions

Chronic Granulomatous Disease; Granulomatous Disease, Chronic

Keywords

Granulomatous Disease, Chronic; Chronic Granulomatous Disease; Autosomal Recessive Chronic Granulomatous Disease; Genetic Therapy; Gene Therapy; Gene Editing; Genome Editing; Stem Cell Transplantation; Transplantation, Stem Cell; Hematopoietic Stem Cell Transplantation; Transplantation, Hematopoietic Stem Cell

Outcome Measures

Primary Outcomes (2)

• Safety of administration of PM359, as quantified by frequency of adverse events (AEs) after drug product infusion

  PM359 infusion through Month 12 after PM359 infusion

• Percentage of participants with sustained reconstitution of NADPH oxidase activity in neutrophils

  At Month 6 and Month 12 after PM359 infusion, as compared to baseline

Secondary Outcomes (16)

• Frequency of all drug product-related AEs, ≥ Grade 3 AEs, and serious adverse events (SAEs)

  Signing of ICF through Month 36 following PM359 infusion

• Time to neutrophil engraftment

  From PM359 infusion through engraftment, typically within 2-3 weeks but assessed up to 36 months

• Transplant related mortality

  From PM359 infusion, assessed at 100 Days and 1 Year post-PM359 infusion

• Overall survival

  From PM359 infusion, assessed at 1 Year and 3 Years post-PM359 infusion

• Incidence of acute graft-versus-host disease (GvHD)

  From PM359 infusion through Month 36

Study Arms (1)

PM359

EXPERIMENTAL

PM359 is an autologous CD34+ hematopoietic stem cell (HSC) suspension that is Prime Edited at the NCF1 locus resulting in expression of the p47phox protein.

Biological: PM359

Interventions

PM359 BIOLOGICAL

Single dose of PM359 administered autologously by intravenous (I.V.) infusion following myeloablative conditioning with busulfan

PM359

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Autosomal recessive Chronic Granulomatous Disease due to the delGT mutation in NCF1 causing dysfunction of p47phox
• Treated and followed for at least the past 2 years in a specialized center
• Willingness to participate in this study as well as a long-term follow-up study with the understanding that the total participation is 15 years
• At least 1 prior severe CGD-related infection OR an ongoing severe CGD-related infection requiring therapy or that is refractory to standard therapy; OR an autoimmune or inflammatory condition related to CGD that is active or requiring therapy to maintain remission.

You may not qualify if:

• For participants younger than 16 years of age: known, willing, and available 10/10 (A,B,C,DR,DQ) HLA-matched related donor (10/10 MRD)
• Active bacteremia or fungemia
• Ongoing inflammatory condition that is ≥ CTCAE v5.0 Grade 3 despite high-dose steroids (≥ 0.5 mg/kg/day of prednisone and/or equivalent).
• Any contraindication which in the opinion of the transplant physician would make the participant ineligible to undergo autologous HSCT, including, but not limited to:
• Contraindication to mobilization and apheresis, including severe allergic reaction to receipt of any medication or other drug substance required for mobilization and apheresis (e.g., G-CSF, plerixafor) or PM359 manufacture (e.g., DMSO).
• Contraindication to receipt of the conditioning agent, busulfan.
• Positive for presence of human immunodeficiency virus (HIV)-1 or HIV-2, or active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV).
• Inadequate organ function, including known chronic advanced end-organ damage which in the opinion of the investigator would put the participant at risk for undergoing HSCT
• Prior or current malignancy or myeloproliferative disorder (excluding Stage 1 or lower, fully treated/excised malignant and pre-malignant disease of the skin, cervix or colon).
• Any other condition that, in the opinion of the Investigator, may compromise the safety or compliance of the participant or would preclude the participant from successful study completion, including Participant/Parent/Guardian unable or unwilling to comply with the protocol requirements.
• Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile participants. Females of childbearing potential and non-sterile male participants who are or may become sexually active with female partners of childbearing potential are required to use highly effective contraception from Screening through at least 12 months after drug product infusion.
• Participation in another clinical study with an investigational drug within 30 days of Screening or at least 5 times the half-life of the investigational drug (whichever is longer), or any prior receipt of gene therapy or hematopoietic stem cell transplant.

Sponsors & Collaborators

• Prime Medicine, Inc.: lead

Study Sites (5)

University of California Los Angeles Medical Center

Los Angeles, California, 90027, United States

Location

NIH Clinical Center

Bethesda, Maryland, 20892, United States

Location

The Children's Hospital at Tristar Medical Group/Sarah Cannon Center for Blood Cancers

Nashville, Tennessee, 37203, United States

Location

CHU - Sainte Justine Hospital

Montreal, Quebec, H3T 1C5, Canada

Location

University College of London Hospital

London, England, NW1 2PG, United Kingdom

Location

Related Publications (2)

• Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, Chen PJ, Wilson C, Newby GA, Raguram A, Liu DR. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019 Dec;576(7785):149-157. doi: 10.1038/s41586-019-1711-4. Epub 2019 Oct 21.

  PMID: 31634902 BACKGROUND

• Gori JL, Haddad E, Frangoul H, Kohn DB, Morris EC, Martin BN, Deary BA, Nickerson M, Scholz RL, Fernandez I, Leveille K, De Ravin SS, Kang EM, Pierzynski M, Estwick T, Littel P, Kuhns DB, Long Priel DA, Teira P, Turvey S, Arnold J, Evans MD, McManus M, Carpenter B, Waterman DP, Anzalone AV, Petrusich A, Osuna CE, O'Malley TT, Stewart-Ornstein J, Heath JM, Nehilla BJ, Asmal M, Malech HL. Prime Editing for p47phox-Deficient Chronic Granulomatous Disease. N Engl J Med. 2025 Dec 7. doi: 10.1056/NEJMoa2509807. Online ahead of print.

  PMID: 41358590 DERIVED

MeSH Terms

Conditions

Granulomatous Disease, Chronic

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2024
• First Posted: August 19, 2024
• Study Start: October 17, 2024
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): February 1, 2030
• Last Updated: May 25, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3); GB (1); CA (1)